Monomethyl auristatin E is a potent synthetic microtubule inhibitor derived from dolastatin 10, commonly used as the toxic payload in antibody-drug conjugates (ADCs). Monomethyl auristatin E can bind to the vincristine site on tubulin to trigger Caspase-3-dependent apoptosis. Monomethyl auristatin E can produce bystander killing effects through moderate hydrophobicity, helping to clear tumor cells with antigen heterogeneity. Monomethyl auristatin E is used in research related to lymphoma, breast cancer, and other malignancies, as well as in ADC drug development[1-4].
In vitro, Monomethyl auristatin E (0.002–4000nM) was applied to SKBR3 human breast cancer cells and HEK293 human embryonic kidney cells for 72h. Monomethyl auristatin E reduced cell viability and induced cell death in a dose-dependent manner[5]. Monomethyl auristatin E (0.078–10nM) was conjugated with anti-HER2 IgG1 to form IgG1-vc-MMAE, which was then used to treat HER2-positive NCI-N87 human gastric cancer cells for 24h. Monomethyl auristatin E inhibited N87 cell viability in a dose-dependent manner[6].
In vivo, Monomethyl auristatin E (0.12mg/kg; intraperitoneal injection every other day for 8 days) was administered to C57BL/6 mice and MDA-MB-231 tumor-bearing Balb/c nude mice. Monomethyl auristatin E induced chemotherapy-induced peripheral neuropathy and chemotherapy-induced cognitive impairment. In the tumor-bearing model, Monomethyl auristatin E reduced graft tumor volume and induced apoptosis[7]. Monomethyl auristatin E (5mg/kg; single dose) was injected intravenously into SCID mice and SD rats. After release from the antibody-drug conjugate, Monomethyl auristatin E was significantly distributed to red blood cells in mice and rats, reaching blood concentrations approximately 5-fold and 2-fold those in plasma, respectively[8].
References:
[1] Fu Z, Gao C, Wu T, et al. Peripheral neuropathy associated with monomethyl auristatin E-based antibody-drug conjugates. iScience. 2023 Aug 29;26(10):107778.
[2] Abawi A, Wang X, Bompard J, et al. Monomethyl Auristatin E Grafted-Liposomes to Target Prostate Tumor Cell Lines. Int J Mol Sci. 2021 Apr 15;22(8):4103.
[3] Mendes GMM, Munshani S, Wachtler N, et al. Monomethyl auristatin E and paclitaxel use different mechanisms to alter intracellular calcium signaling. Biochem Pharmacol. 2025 Dec;242(Pt 2):117188
[4] Cho IK, Shim MK, Um W, et al. Light-Activated Monomethyl Auristatin E Prodrug Nanoparticles for Combinational Photo-Chemotherapy of Pancreatic Cancer. Molecules. 2022 Apr 14;27(8):2529.
[5] Abdollahpour-Alitappeh M, Razavi-vakhshourpour S, Lotfinia M, et al. Monomethyl auristatin E exhibits potent cytotoxic activity against human cancer cell lines SKBR3 and HEK293. Novel Biomed. 2017;5(4):145-51.
[6] Kuo WY, Hsu HJ, Wu CY, et al. Antibody-drug conjugates with HER2-targeting antibodies from synthetic antibody libraries are highly potent against HER2-positive human gastric tumor in xenograft models. Mabs. 2019 Jan;11(1):153-165.
[7] Itaborahy MF, Feng IZLF, Vieira-Machado UF, et al. Chemotherapy-induced neuropathy in monomethyl auristatin E treatment: prevention by lithium. British Journal of Cancer. 2025;133(6):604-14.
[8] Yip V, Saad OM, Leipold D, et al. Monomethyl auristatin E(MMAE), a payload for multiple antibody drug conjugates(ADCs), demonstrates differential red blood cell partitioning across human and animal species. Xenobiotica. 2024;54(8):511-20.