Auristatin | ADC Cytotoxin

Auristatins

As a depsipeptide derivative of dolastoxin, auristatin could inhibit tumor growth through acting on tubulin. The activity of auristatin is higher than that of traditional chemotherapeutic drugs by 1000 times. As a linear depsipeptide natural toxic protein isolated from dolabella auricularia, dolastoxin shows strong antitumor activity by acting on tubulin. In addition to containing abundant hydroxy acids, thiophenols, D-amino acids and α-amino acids, the structure of dolastoxin also contains ethylenic and acetylenic bonds. All these groups improve the biological activity and stability of these kind of compounds.

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Chemical Structural Characteristics of Auristatins

Auristatins are a series of derivatives developed by modifying the C- and N-terminal of dolastoxin-10. All structural modifications of dolastoxin-10 are designed to maintain its anticancer activity while reducing its cytotoxicity. Especially for the compounds MMAE and MMAF modified by the N-terminal and C-terminal of dolastoxin-10, they not only have good inhibitory ability for multiple tumor cells, but also show less toxicity in vivo and good pharmacokinetic characteristics. As an effective anticancer microtubule targeting agent (MTA), monomethyl auristatin E (MMAE) is a synthetic pentapeptide derived from dolastoxin-10. It introduces a 2-amino-1-phenylpropane-1-alcohol at the C-terminal and converts the N-terminal tertiary amino in the structure into secondary amino group, which can be coupled with a linker. The MMAE keep its original biological activity whose IC₅₀ as high as 10^-9-10^-11 mol/L in various human cancer cell lines. Except for secondary amino coupling site, MMAF also contains a carboxyl group with larger polarity at the C- terminal, which can act as the coupling site. The introduction of carboxyl group significantly improves the ionization effect of cytotoxin part and the metabolic rate of off-target cytotoxin. It is significance to reduce the toxic and side effects of drugs by reducing the membrane permeability of off-target MMAF conjugate as well as accelerating its metabolic rate.

Mechanism of Action of Auristatins

As a tubulin inhibitor, the anti-cancer mechanism of auristatin is to inhibit and prevent the formation of tubulin and the hydrolysis of GTP by binding to the amino acid residues of tubulin. Meanwhile, auristatin can prevent the mitosis of cancer cells, make them stagnate in the intercellular phase. Further studies indicated that auristatin could bind to the active site of genmycin/medenin exchange GTP on tubulin, resulting in cell arrest in M phase.

Application of Auristatins

Auristatin not only has strong growth inhibitory activities on many kinds of human hematological malignancies and solid tumor cells (eg, colon cancer, pancreatic cancer, melanoma, ovarian cancer, gastric cancer, breast cancer, lung cancer, prostate cancer and renal cell carcinoma), but also almost no drug-resistance in these cell lines. It should be noted, auristatin also show good pharmacokinetic properties in vivo studies. The Food and Drug Administration (FDA) approved auristatin-based antibody drug conjugates (ADCs), followed by Adcetris®, recently Polivy® became 2nd approved ADC in 2019. Adcetris®, is an anti-CD30 ADC comprising a cleavable linker by proteases, such as cathepsin B and monomethyl auristatin (MMAE) as a payload with an average drug-to-antibody ratio (DAR) of 4. Polivy® is an anti-CD79b ADC comprising the same linker and payload as Adcetris® with DAR of 3.5. In addition, including our ADCs, enfortumab vedotin, over 10 ADCs with auristatins such as MMAE or monomethyl auristatin F (MMAF) as payload are currently in clinical trials, which account for half of all ADCs in clinical trials at present.

References

Best, R.L.; et al. Microtubule and tubulin binding and regulation of microtubule dynamics by the antibody drug conjugate (ADC) payload, monomethyl auristatin E (MMAE): Mechanistic insights into MMAE ADC peripheral neuropathy. Toxicology and Applied Pharmacology, 2021, 421: 115534.
Mendelsohn, B.A.; et al. Investigation of hydrophilic auristatin derivatives for use in antibody drug conjugates. Bioconjugate Chem., 2017, 28: 371−381.