Antibody
RCSB PDB 6OGE
Payload
PubChem CID 118305111
Fam-trastuzumab deruxtecan
Enhertu
- Mechanism of action
- HER2-targeted antibody-drug conjugate
- In plain language
- A HER2-targeting antibody carrying a potent DNA-damaging chemotherapy payload that's released once the antibody enters a cancer cell, with enough payload leaking out to also reach neighboring tumor cells that carry little or no HER2 themselves.
- How it works
- Fam-trastuzumab deruxtecan-nxki is a HER2-directed antibody-drug conjugate in which a humanized anti-HER2 IgG1 monoclonal antibody — the same antibody as trastuzumab — is linked to an average of eight molecules of a topoisomerase I inhibitor payload, deruxtecan, via a protease-cleavable tetrapeptide linker. Binding to HER2 on the tumor cell surface triggers internalization of the conjugate; lysosomal enzymes then cleave the linker and release the membrane-permeable payload, DXd, an exatecan derivative that inhibits topoisomerase I and causes DNA damage and apoptotic cell death. Because DXd can diffuse across cell membranes once released, preclinical studies have documented a 'bystander effect' in which it also damages neighboring tumor cells with low or no HER2 expression — a mechanism not spelled out in the FDA label's own Clinical Pharmacology section, but consistent with the drug's approved use in HER2-low and HER2-ultralow disease, not just HER2-positive tumors.
- Therapeutic applications
- FDA-approved indications include: neoadjuvant and adjuvant treatment of HER2-positive (IHC 3+ or ISH+) early breast cancer; first-line treatment (in combination with pertuzumab) and later-line monotherapy for HER2-positive unresectable or metastatic breast cancer following a prior anti-HER2-based regimen; monotherapy for HR-positive, HER2-low or HER2-ultralow metastatic breast cancer after progression on endocrine therapy, and for HER2-low metastatic breast cancer after prior chemotherapy; monotherapy for unresectable or metastatic non-small cell lung cancer with activating HER2 (ERBB2) mutations following prior systemic therapy; monotherapy for locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma following a prior trastuzumab-based regimen; and monotherapy for unresectable or metastatic HER2-positive solid tumors following prior systemic treatment.
- Class
- Antibody-drug conjugate
- Therapeutic area
- Oncology
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