Monomethyl auristatin E (Synonyms: Brentuximab vedotin, MMAE)

Monomethyl Auristatin E (MMAE), as a synthetic derivative of dolastatin 10, a linear pentapeptide originally isolated from the extracts of the sea hare Dolabella auriculari. Monomethyl Auristatin E, as a synthetic derivative of dolastatin 10, a linear pentapeptide originally isolated from the extracts of the sea hare Dolabella auriculari. Monomethyl Auristatin E can inhibit tubulin polymerization, thus blocking mitosis.^[1]

In vitro, Monomethyl Auristatin E and Monomethyl Auristatin E-phosphate shown the inhibition with IC50 of 2 and 48 nM, respectively, in PC-3 and C4-2B cell lines.^[1] In vitro experiment it shown that 5 nM MMAE resulted in 50% of HCT-116 cells blocked in G2/M and 2 nM in PANC-1 cells.^[2] MMAE shown the inhibition of cell growth with IC50 of 1.7 nM in HCT-116, 0.6 nM in PANC-1, and 5.6 nM in 779E cells, respectively.^[2] In addition, MMAE also showed markedly polarized transport in both MDCK-WT and MDCK-MDR1 cells with ERs at 13.6 and 44.5, respectively, resulting ratio of ratios of 3.3. MMAE shown dose-dependent cytotoxicity in HepG2, Hep3B2, H226, N87 or OVCAR3 cells.^[3]

In vivo, treatment with 30 mg/kg cAC10-vcMMAE in mice had no signs of toxicity.^[4] In vivo efficacy test it shown that treatment with 6.5 mg/kg DD1-MMAE (the bivalent DARPin dimer) or DFc-MMAE (a DARPin-Fc) twice weekly did not cause any sequela in mice.^[5] Moreover, nude mice were injected intravenously 2.5, 5, and 10 mg/kg hertuzumab-vcMMAE on day 0 resulted in obvious and sustained antitumor effects. ^[6]

References:
[1]Abawi A, et al. Monomethyl Auristatin E Grafted-Liposomes to Target Prostate Tumor Cell Lines. Int J Mol Sci. 2021 Apr 15;22(8):4103.
[2]Buckel L, et al. Tumor radiosensitization by monomethyl auristatin E: mechanism of action and targeted delivery. Cancer Res. 2015 Apr 1;75(7):1376-1387.
[3]Liu-Kreyche P, et al. Lysosomal P-gp-MDR1 Confers Drug Resistance of Brentuximab Vedotin and Its Cytotoxic Payload Monomethyl Auristatin E in Tumor Cells. Front Pharmacol. 2019 Jul 17;10:749.
[4]Francisco JA, et al. cAC10-vcMMAE, an anti-CD30-monomethyl auristatin E conjugate with potent and selective antitumor activity. Blood. 2003 Aug 15;102(4):1458-65.
[5]Karsten L, et al. Bivalent EGFR-Targeting DARPin-MMAE Conjugates. Int J Mol Sci. 2022 Feb 23;23(5):2468.
[6]Li H, et al. An anti-HER2 antibody conjugated with monomethyl auristatin E is highly effective in HER2-positive human gastric cancer. Cancer Biol Ther. 2016 Apr 2;17(4):346-54.