Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate for HER2-positive breast cancer. Its mechanism of killing HER2-low expressing cells beyond the target cell ('bystander killing') is unique to its payload. What property of the payload enables this?

• A The deruxtecan topoisomerase I inhibitor payload is membrane-permeable after intracellular cleavage and diffuses to adjacent HER2-negative cells ✓
• B T-DXd induces immunogenic cell death that activates NK cells to kill surrounding cells
• C Fc-mediated ADCC of trastuzumab kills neighbouring HER2-positive cells that have escaped ADC internalisation
• D Exosomal packaging of the DXd payload by dying cells transfers cytotoxicity to bystanders

Explanation

T-DXd contains a topoisomerase I inhibitor payload (deruxtecan, DXd — an exatecan derivative) connected via a tetrapeptide cleavable linker. After HER2-targeted internalisation and lysosomal cleavage, the freed DXd has high membrane permeability (being a relatively small, lipophilic molecule), allowing it to diffuse across the cell membrane into the tumour microenvironment and enter neighbouring HER2-low or HER2-negative cancer cells, killing them. This 'bystander effect' explains why T-DXd works even in HER2-low tumours (1+ or 2+ IHC). This contrasts with trastuzumab emtansine (T-DM1) whose DM1 maytansinoid payload has poor membrane permeability and lacks significant bystander activity.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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Written and medically reviewed by the StethoPrep medical team.