Pembrolizumab is an anti-PD-1 monoclonal antibody used in multiple cancers. Its immune-related adverse events (irAEs) are mechanistically explained by:
- A Direct binding of pembrolizumab to normal tissue antigens causing complement-mediated organ destruction
- B Pembrolizumab activates NK cells that non-specifically kill rapidly dividing normal cells
- C Blockade of PD-1 prevents self-tolerance by removing T-cell inhibitory signaling, allowing autoreactive T cells to attack normal tissues including thyroid, lung, colon, pituitary, skin, and joints ✓
- D Pembrolizumab blocks CTLA-4 in addition to PD-1, amplifying T regulatory cell depletion
Explanation
PD-1 (programmed death-1) acts as an immune checkpoint that normally downregulates T-cell responses upon binding its ligands PD-L1/PD-L2 on normal tissues, maintaining peripheral self-tolerance. Anti-PD-1 antibodies like pembrolizumab remove this brake, unleashing T-cell activity against tumors but also against self-antigens on normal tissues. Common irAEs include immune-related thyroiditis/hypothyroidism, pneumonitis, colitis, hepatitis, hypophysitis, and dermatitis. Most are managed with corticosteroids; high-grade toxicity requires drug discontinuation. Pembrolizumab does not target CTLA-4 (that is ipilimumab).
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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Written and medically reviewed by the StethoPrep medical team.