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.
Monomethyl Auristatin E (MMAE)，作为海兔毒素 10 的合成衍生物，海兔毒素 10 是一种线性五肽，最初是从海兔 Dolabella auriculari 的提取物中分离出来的。 Monomethyl Auristatin E，作为海兔毒素 10 的合成衍生物，海兔毒素 10 是一种线性五肽，最初是从海兔 Dolabella auriculari 的提取物中分离出来的。单甲基 Auristatin E 可以抑制微管蛋白聚合，从而阻断有丝分裂。[1]
在体外，Monomethyl Auristatin E 和 Monomethyl Auristatin E-phosphate 在 PC-3 和 C4-2B 细胞系中的 IC50 分别为 2 和 48 nM。[1]体外实验表明，5 nM MMAE 导致 50% 的 HCT-116 细胞在 G2/M 期受阻，2 nM 在 PANC-1 细胞中受阻。[2] MMAE 显示出抑制细胞生长的 IC50在 HCT-116 中为 1.7 nM，在 PANC-1 中为 0.6 nM，在 779E 细胞中为 5.6 nM。[2] 此外，MMAE 在 MDCK-WT 和 MDCK 中也表现出明显的极化转运-ER 分别为 13.6 和 44.5 的 MDR1 细胞，所得比率为 3.3。 MMAE 在 HepG2、Hep3B2、H226、N87 或 OVCAR3 细胞中表现出剂量依赖性细胞毒性。[3]
在体内，用 30 mg/kg cAC10-vcMMAE 处理小鼠没有毒性迹象。[4] 体内药效试验表明，用 6.5 mg/kg DD1-MMAE 处理（二价 DARPin 二聚体）或 DFc-MMAE（一种 DARPin-Fc）每周两次在小鼠体内未引起任何后遗症。[5] 此外，裸鼠静脉注射 2.5、5 和 10 mg/ kg hertuzumab-vcMMAE 在第 0 天产生明显和持续的抗肿瘤作用。 [6]