Mechanism of Action of Enhertu (Trastuzumab Deruxtecan)
Enhertu is a HER2-directed antibody-drug conjugate (ADC) that combines a humanized anti-HER2 monoclonal antibody (trastuzumab) with a potent topoisomerase I inhibitor payload (DXd) via a cleavable tetrapeptide-based linker. 1
Core Mechanism Components
The drug works through a multi-step process:
Targeted Binding: The trastuzumab component specifically binds to HER2 receptors on tumor cell surfaces 1
Internalization: Following HER2 binding, the entire ADC complex undergoes receptor-mediated endocytosis into the tumor cell 1
Payload Release: Once inside the cell, lysosomal enzymes cleave the tetrapeptide-based linker, releasing the cytotoxic DXd payload 1
DNA Damage: The released DXd (a topoisomerase I inhibitor) causes DNA damage through inhibition of topoisomerase I, ultimately triggering apoptotic cell death 1
Unique Bystander Effect
A critical distinguishing feature of Enhertu is its membrane-permeable payload that enables a "bystander effect." 2 The DXd molecule can cross cell membranes and diffuse into the tumor microenvironment, allowing it to kill neighboring tumor cells regardless of their HER2 expression status 2. This mechanism explains Enhertu's efficacy even in HER2-low and HER2-ultralow tumors where traditional HER2-targeted therapies fail 3.
Extracellular Payload Release
Recent evidence demonstrates that Enhertu's efficacy in HER2-low/negative settings is independent of HER2 engagement and ADC internalization 4. Instead, extracellular proteases like cathepsin L (CTSL) within the tumor microenvironment can cleave the specialized linker, facilitating payload release and inducing cytotoxicity against HER2-low/negative tumors 4.
Immunomodulatory Effects
In HER2-positive cancers, Enhertu demonstrates additional immune-activating properties:
- The antibody backbone engages Fcγ-receptors and drives antibody-dependent cellular phagocytosis (ADCP) 4
- The DXd payload induces immunogenic cell death, activating myeloid cells via TLR4 and STING pathways 4
- This enhances tumor antigen presentation to CD8+ T cells 4
High Drug-to-Antibody Ratio
Enhertu has approximately 8 molecules of deruxtecan attached to each antibody molecule 1, which is higher than many other ADCs. This high drug-to-antibody ratio (8:1) ensures substantial DXd concentration delivery to target tumor cells 5.
Clinical Implications
The unique mechanism explains why Enhertu demonstrates activity across a spectrum of HER2 expression levels—from HER2-positive (IHC 3+) to HER2-low (IHC 1+ or 2+/ISH-negative) to even HER2-ultralow tumors 6, 3. The combination of targeted delivery, membrane-permeable payload, bystander effect, and extracellular protease-mediated release creates a broader therapeutic window than traditional HER2-targeted therapies.
Important caveat: The mechanism also underlies the risk of interstitial lung disease/pneumonitis, as the membrane-permeable payload can affect normal lung tissue 6. This requires vigilant monitoring and patient education regarding respiratory symptoms.