monomethyl-auristatin-e

Overview

Monomethyl auristatin E (MMAE; vedotin) is a synthetic antimitotic agent derived from the natural product dolastatin 10. It inhibits tubulin polymerization, causing G2/M cell-cycle arrest and apoptosis. MMAE is used as the cytotoxic warhead in multiple approved ADCs including brentuximab-vedotin (via MC-VC-PABC linker). Free MMAE is not a standalone clinical agent; its potency and bystander-killing properties are leveraged via targeted antibody conjugation.

Evidence in the corpus

  • Free MMAE at 2 nM radiosensitized both EGFR+ (CAL-27) and EGFR-low (LN229) cells indiscriminately (increased comet-tail length after 6 Gy), demonstrating that the payload alone lacks tumour selectivity PMID:27698471.
  • Conjugation of MMAE to cetuximab (C-MMAE, MC-VC linker, DAR ~3.7) restricted radiosensitization to EGFR+ cells only; conjugation to trastuzumab (T-MMAE, DAR ~3.2) restricted activity to HER2+ cells — establishing that the antibody carrier, not the payload, governs tumour selectivity PMID:27698471.
  • In HER2+ OE19 (esophageal) and EGFR+ CAL-27 (HNSCC) xenografts, MMAE-bearing ADCs (T-MMAE and C-MMAE respectively) accumulated in target-positive tumours and produced superior tumour-growth delay combined with radiotherapy compared with antibody-only or free-MMAE arms PMID:27698471.
  • The MC-VC-PABC linker used in these experimental ADCs (and clinically in brentuximab-vedotin) undergoes slow retro-Michael reaction in circulation, potentially releasing free MMAE; the authors acknowledge this as a limitation and note that improved linkers exist PMID:27698471.
  • At 2–5 nM overnight, MMAE-conjugated ADCs arrested cognate-receptor-positive cells in G2/M (by propidium-iodide flow cytometry); antibody-only controls and non-cognate ADCs had no cell-cycle effect PMID:27698471.

Resistance mechanisms

  • Cells lacking the target receptor (EGFR or HER2) do not accumulate the ADC and therefore do not enter G2/M or become radiosensitized — receptor expression is the essential determinant of MMAE-ADC activity PMID:27698471.

Cancer types (linked)

Sources

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