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Monomethyl auristatin E (MMAE) – CAS: 474645-27-7 – Cytotoxic payload

Monomethyl auristatin E (MMAE) is a cytotoxic payload member of the tubulin inhibitor family. Indeed, MMAE is a potent antimitotic agent that block the polymerization of tubulin thanks to its ability to inhibit cell division and MMAE actions result in cell apoptosis. MMAE is a member of auristatin family, which are synthetic analogues of the ultrapotent cytotoxic microtubule inhibitors: Dolastatin 10. MMAE can be linked to a lot of peptides and antibodies such as the anti-CD30 monoclonal antibody which form SGN-35 antibody-drug conjugate. MMAE is used in the composition of Antiboby-Drug Conjugate (ADC) and Peptide-Drug Conjugate (PDC) for cancer therapies.


MMAE as cytotoxic payload is available for the design of your Peptide-Drug conjugate.

1-Okeley Nicole M. et al. Clin Cancer Res. 16(3):888-97 (2010)
Intracellular activation of SGN-35, a potent anti-CD30 antibody-drug conjugate

Purpose: SGN-35 is an antibody-drug conjugate (ADC) containing the potent antimitotic drug, monomethylauristatin E (MMAE), linked to the anti-CD30 monoclonal antibody, cAC10. As previously shown, SGN-35 treatment regresses and cures established Hodgkin lymphoma and anaplastic large cell lymphoma xenografts. Recently, the ADC has been shown to possess pronounced activity in clinical trials. Here, we investigate the molecular basis for the activities of SGN-35 by determining the extent of targeted intracellular drug release and retention, and bystander activities.

Experimental design: SGN-35 was prepared with (14)C-labeled MMAE. Intracellular ADC activation on CD30(+) and negative cell lines was determined using a combination of radiometric and liquid chromatograhpy/mass spectrometry-based assays. The bystander activity of SGN-35 was determined using mixed tumor cell cultures consisting of CD30(+) and CD30(-) lines.

Results: SGN-35 treatment of CD30(+) cells leads to efficient intracellular release of chemically unmodified MMAE, with intracellular concentrations of MMAE in the range of 500 nmol/L. This was due to specific ADC binding, uptake, MMAE retention, and receptor recycling or resynthesis. MMAE accounts for the total detectable released drug from CD30(+) cells, and has a half-life of retention of 15 to 20 h. Cytotoxicity studies with mixtures of CD30(+) and CD30(-) cell lines indicated that diffusible released MMAE from CD30(+) cells was able to kill cocultivated CD30(-) cells.

Conclusions: MMAE is efficiently released from SGN-35 within CD30(+) cancer cells and, due to its membrane permeability, is able to exert cytotoxic activity on bystander cells. This provides mechanistic insight into the pronounced preclinical and clinical antitumor activities observed with SGN-35.

2-Buckel Lisa et al. Cancer Res. 75(7):1376-1387 (2015)
Tumor radiosensitization by monomethyl auristatin E: mechanism of action and targeted delivery

A new and highly pathogenic coronavirus (severe acute respiratory syndrome coronavirus-2, SARS-CoV-2) caused an outbreak in Wuhan city, Hubei province, China, starting from December 2019 that quickly spread nationwide and to other countries around the world1,2,3. Here, to better understand the initial step of infection at an atomic level, we determined the crystal structure of the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 bound to the cell receptor ACE2. The overall ACE2-binding mode of the SARS-CoV-2 RBD is nearly identical to that of the SARS-CoV RBD, which also uses ACE2 as the cell receptor4. Structural analysis identified residues in the SARS-CoV-2 RBD that are essential for ACE2 binding, the majority of which either are highly conserved or share similar side chain properties with those in the SARS-CoV RBD. Such similarity in structure and sequence strongly indicate convergent evolution between the SARS-CoV-2 and SARS-CoV RBDs for improved binding to ACE2, although SARS-CoV-2 does not cluster within SARS and SARS-related coronaviruses1,2,3,5. The epitopes of two SARS-CoV antibodies that target the RBD are also analysed for binding to the SARS-CoV-2 RBD, providing insights into the future identification of cross-reactive antibodies.