A 55-year-old woman with HER2-positive metastatic breast cancer is treated with trastuzumab but develops resistance after 18 months. Trastuzumab-deruxtecan (T-DXd) is started as second-line therapy. What structural feature distinguishes antibody-drug conjugates (ADCs) like T-DXd from standard monoclonal antibodies and explains their activity in trastuzumab-resistant tumors?

• A T-DXd carries a radioactive payload that delivers focused radiation; unlike naked antibody, it kills cells by radiation rather than immune-mediated mechanisms
• B T-DXd is a bispecific antibody targeting both HER2 and PD-L1, activating immune checkpoint and direct tumor killing simultaneously
• C T-DXd links the trastuzumab antibody to a topoisomerase I inhibitor (DXd, a deruxtecan payload) via a tumor-microenvironment-cleavable linker; after HER2-targeted internalization, lysosomal enzymes cleave the linker releasing the cytotoxic payload intracellularly; additionally, the lipophilic DXd payload can diffuse to neighboring HER2-low or HER2-negative cells ('bystander effect'), overcoming antigen heterogeneity-based resistance ✓
• D T-DXd engages natural killer cells via CD16 engagement and delivers a local cytokine storm specifically to HER2-positive cells

Explanation

Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate (ADC) consisting of: (1) trastuzumab antibody targeting HER2; (2) a tetrapeptide-based cleavable linker (GGFG); (3) a highly potent topoisomerase I inhibitor payload DXd (exatecan derivative). After T-DXd binds HER2, the complex is internalized into lysosomes where the GGFG linker is cleaved by lysosomal cysteine proteases (cathepsins). The released DXd kills the HER2-expressing cell. Critically, DXd is membrane-permeable and lipophilic — it diffuses from the target cell to kill adjacent HER2-low or HER2-negative tumor cells (bystander killing), overcoming tumor heterogeneity and antigen-negative subclone resistance — a key mechanism not available to naked trastuzumab. T-DXd was approved for HER2-low breast cancer based on DESTINY-Breast04, expanding eligibility beyond traditional HER2-positive criteria.

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

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Written and medically reviewed by the StethoPrep medical team.