Chemical Identity

Property	Value
Molecular Weight	~152 kDa (ADC)
Peptide Payload	Monomethyl auristatin E (MMAE)
Linker	Valine-citrulline (protease-cleavable)
DAR	3.8 (drug-to-antibody ratio)
Target	Nectin-4

Structure

Enfortumab vedotin consists of a fully human anti-Nectin-4 IgG1 monoclonal antibody conjugated to the microtubule inhibitor MMAE via a protease-cleavable valine-citrulline dipeptide linker and a maleimidocaproyl spacer. After internalization, lysosomal proteases cleave the linker to release the cytotoxic payload.

Mechanism of Action

The antibody component binds Nectin-4 on urothelial cancer cells, triggering receptor-mediated endocytosis. In the lysosome, cathepsin B cleaves the Val-Cit linker, releasing MMAE. The free MMAE binds tubulin, inhibiting microtubule polymerization and causing G2/M arrest and apoptosis. Bystander killing of Nectin-4-negative neighboring cells also occurs.

Clinical Applications

• Urothelial carcinoma: Locally advanced or metastatic, after platinum and PD-1/PD-L1 therapy (Padcev)
• First-line urothelial cancer: With pembrolizumab (EV-302 trial)
• Nectin-4-expressing solid tumors: Under investigation
• Bladder preservation: Neoadjuvant trials ongoing

Pharmacokinetics

• Half-life: 3.6 days (antibody), 2.8 days (MMAE)
• Cmax (MMAE): ~5 ng/mL
• Steady state: ~3 weeks
• Metabolism: MMAE metabolized by CYP3A4
• Route: IV infusion (days 1, 8, 15 of 28-day cycle)

Safety and Side Effects

Peripheral neuropathy (50%), fatigue (51%), rash (including fatal skin reactions), hyperglycemia, ocular disorders (keratitis), neutropenia, and diarrhea. Fatal skin reactions (SJS/TEN-like) led to boxed warning.

References

• Powles, T., et al. (2021). Enfortumab vedotin for urothelial carcinoma (EV-301). New England Journal of Medicine, 384, 1125-1135.
• Rosenberg, J.E., et al. (2019). EV-201 trial. Journal of Clinical Oncology, 37, 3136-3144.