How does Pembrolizumab (pembrolizumab) work?

How Pembrolizumab Works

Pembrolizumab is a monoclonal antibody that binds to the PD-1 receptor on T cells and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response. 1

Mechanism of Action

Pembrolizumab functions through a specific immune checkpoint inhibition pathway:

1. PD-1 Receptor Blockade:

   • Pembrolizumab is a humanized IgG4 monoclonal antibody that binds with high affinity to the programmed death-1 (PD-1) receptor found on T cells 2, 1
   • By binding to PD-1, it prevents the receptor from interacting with its ligands PD-L1 and PD-L2

2. Reversal of T-cell Suppression:

   • In normal conditions, the PD-1 pathway serves as an immune checkpoint that protects the host from an unchecked immune response 2
   • Many tumors upregulate PD-L1 to evade immune surveillance 2
   • When pembrolizumab blocks this interaction, it releases the inhibition of T-cell activation, essentially "releasing the brake" on the immune response 2

3. Enhanced Anti-tumor Activity:

   • Blocking PD-1 activity reinvigorates exhausted T cells and restores their ability to recognize and attack tumor cells 2, 1
   • In syngeneic mouse tumor models, blocking PD-1 activity resulted in decreased tumor growth 1

Clinical Applications

Pembrolizumab has shown particular efficacy in certain tumor types:

• MSI-H/dMMR Tumors: Particularly effective in tumors with high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR), which contain thousands of mutations that can encode mutant proteins recognizable by the immune system 2

• TMB-High Tumors: Tumors with high tumor mutational burden (TMB) show higher response rates to pembrolizumab (29% vs. 6% in non-TMB high tumors) 2

Pharmacokinetic Properties

• Half-life: Approximately 22 days 1
• Steady-state: Reached by 16 weeks of repeated dosing with an every 3-week regimen 1
• Clearance: Approximately 23% lower at steady state compared to first dose 1
• Distribution: Geometric mean value for volume of distribution at steady state is 6.0 L 1

Potential Adverse Effects

Pembrolizumab's mechanism of action can lead to immune-related adverse events (irAEs) due to the enhanced immune response:

• The reinvigorated T cells can attack not only tumor cells but also normal tissues, leading to inflammatory conditions in various organ systems 2, 3
• Common irAEs include skin rashes, colitis, hepatitis, pneumonitis, and endocrinopathies 2
• Severe irAEs (grade 3-4) occur in up to 20% of patients taking PD-1/PD-L1 agents 2

Clinical Considerations

When using pembrolizumab, it's important to note:

• Response to pembrolizumab does not appear to be significantly affected by dose level (2 mg/kg vs. 10 mg/kg) or frequency (every 2 weeks or every 3 weeks) 2
• The drug's efficacy has been demonstrated across multiple tumor types, with particularly strong responses in dMMR/MSI-H tumors 2
• Immune-related adverse events can have a delayed onset and prolonged duration compared to adverse events from chemotherapy 2

Pembrolizumab represents a significant advancement in cancer immunotherapy by harnessing the body's own immune system to fight cancer through a specific mechanism of checkpoint inhibition.