Trastuzumab (anti-HER2 antibody) is used in HER2-positive breast cancer. Its mechanism of action beyond inhibiting HER2 dimerisation includes which important immune effector function?
- A Complement-dependent cytotoxicity (CDC) via C1q binding to the Fc region
- B Direct induction of apoptosis via CD95 (Fas) cross-linking on tumour cells
- C Blockade of PD-L1 expression on HER2-positive tumour cells
- D Antibody-dependent cellular cytotoxicity (ADCC) via Fc-gamma receptor engagement on NK cells and macrophages ✓
Explanation
Trastuzumab's anti-tumour effects include: (1) blocking HER2 homodimerisation and heterodimerisation, preventing growth signalling; (2) preventing proteolytic cleavage of the HER2 extracellular domain (a resistance mechanism); (3) downregulating PI3K/Akt signalling; and critically (4) antibody-dependent cellular cytotoxicity (ADCC). The IgG1 Fc region of trastuzumab recruits NK cells (via their FcgammaRIII/CD16 receptors), macrophages, and neutrophils to the tumour site, inducing direct tumour cell killing. ADCC is considered a significant contributor to trastuzumab efficacy, supported by clinical data showing better outcomes in patients with high-affinity FcgammaRIIIa polymorphisms. CDC is less important for solid tumour antibodies.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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