Mechanism of Action of Mepolizumab
Mepolizumab is a humanized monoclonal antibody (IgG1/κ) that blocks interleukin-5 (IL-5) from binding to the α-chain of the IL-5 receptor complex on eosinophil cell surfaces, thereby inhibiting IL-5 signaling and preventing eosinophil maturation, activation, proliferation, and survival. 1, 2
Core Molecular Mechanism
IL-5 is the key cytokine responsible for eosinophil maturation, differentiation, and survival, making it a strategic molecular target for anti-eosinophilic treatments 1, 3
Mepolizumab functions as a high-affinity humanized monoclonal antibody that specifically targets human IL-5, preventing it from binding to its receptor on eosinophil surfaces 2, 4
By blocking IL-5 signaling, mepolizumab inhibits the biological actions that drive eosinophil production, activation, and tissue infiltration 3
Pharmacodynamic Effects
Treatment with mepolizumab causes sustained reduction in circulating eosinophil numbers, with an estimated maximal decrease of approximately 85% from baseline 2
The half-maximal inhibitory concentration (IC50) is approximately 0.45 μg/mL, meaning relatively low drug concentrations achieve substantial eosinophil suppression 2
Reductions in eosinophil counts occur not only in peripheral blood but also in tissue compartments including esophagus, sputum, skin, bone marrow, nasal lavage fluid, and bronchial mucosa 2
Pharmacokinetic Properties
Mepolizumab is eliminated slowly with a mean terminal phase half-life of approximately 20 days, allowing for monthly dosing schedules 2
The absolute bioavailability is 64-75% following subcutaneous injection and 81% following intramuscular injection 2
Pharmacokinetics are dose proportional and time independent, with plasma clearance ranging from 0.064 to 0.163 mL/h/kg 2
Clinical Implications of the Mechanism
The mechanism translates to clinical efficacy in severe eosinophilic asthma by reducing exacerbations, improving lung function, and enabling glucocorticoid sparing 1
In eosinophilic granulomatosis with polyangiitis (EGPA), mepolizumab's anti-IL-5 action is effective for inducing and maintaining remission, particularly for respiratory manifestations 1
Despite reducing tissue eosinophilia in eosinophilic esophagitis, mepolizumab has not demonstrated consistent symptomatic improvement, highlighting that eosinophil reduction alone may not be sufficient for all eosinophilic conditions 1
Important Mechanistic Considerations
The drug-bound IL-5 complex can persist in circulation and potentially interfere with immunogenicity assays, though this is primarily a laboratory concern rather than a clinical issue 5
While mepolizumab effectively depletes circulating eosinophils, the clinical response depends on whether eosinophils are the primary pathogenic driver in the specific disease being treated 1
The mechanism is highly selective for IL-5, distinguishing it from broader immunosuppressive agents and contributing to its favorable safety profile 6