Mechanism of Action of Eculizumab (Soliris)

Introduction

Eculizumab is a humanized monoclonal antibody that selectively binds to complement protein C5, inhibiting its cleavage and preventing terminal complement complex formation. It is approved for paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome (aHUS), generalized myasthenia gravis (gMG), and neuromyelitis optica spectrum disorder (NMOSD).

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Step-by-Step Mechanism of Action

1. Binding to complement C5
   Eculizumab attaches with high affinity to C5, blocking its activation by C5 convertase.
2. Prevents formation of C5a and C5b
   This inhibition stops generation of the potent anaphylatoxin C5a and C5b.
3. Blocks membrane attack complex
   By preventing C5b formation, it stops assembly of the membrane attack complex (C5b–C9), thus avoiding cell lysis.
4. Reduces hemolysis and inflammation
   In PNH and aHUS, this reduces intravascular hemolysis, endothelial damage, and inflammatory tissue injury.
5. Modulates immune response
   Lower levels of C5a decrease neutrophil and macrophage activation, reducing inflammation and tissue damage in autoimmunity.

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Pharmacokinetic Parameters

Parameter	Value
Route	Intravenous infusion (every 2 weeks)
Distribution	Extracellular fluid, limited tissue penetration
Half-life	~11 days
Metabolism	Proteolytic degradation
Excretion	None—cleaved by proteolysis into amino acids

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Clinical Uses

• Paroxysmal nocturnal hemoglobinuria (PNH)
• Atypical hemolytic uremic syndrome (aHUS)
• Generalized myasthenia gravis with anti-AChR antibodies
• Neuromyelitis optica spectrum disorder (NMOSD)

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Adverse Effects

• Increased risk of meningococcal infections (vaccination required)
• Upper respiratory tract infections
• Headache, nausea, diarrhea
• Rare infusion reactions

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Comparative Analysis

Drug	Target	Dosing Frequency	Main Indications
Eculizumab	C5	Every 2 weeks IV	PNH, aHUS, gMG, NMOSD
Ravulizumab	C5	Every 8 weeks IV	Similar indications, longer dosing
C3 inhibitors	C3	Under investigation	PNH, C3 glomerulopathy

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MCQs

1. Eculizumab binds to which complement protein?
   a) C3 b) C5 c) C7 d) C9
   Answer: b) C5
2. It prevents formation of which complex?
   a) C3 convertase b) MAC (C5b–C9) c) Anaphylatoxin C3a d) C4b2a
   Answer: b) MAC (C5b–C9)
3. Which potent inflammatory mediator is reduced?
   a) C3a b) C5a c) IL‑6 d) TNF‑α
   Answer: b) C5a
4. Main risk with eculizumab therapy is:
   a) Hepatitis b) Meningococcal infection c) Pancreatitis d) Cardiomyopathy
   Answer: b) Meningococcal infection
5. Primary route of clearance is:
   a) Renal b) Hepatic CYP c) Proteolysis d) Biliary
   Answer: c) Proteolysis
6. Typical dosing interval is:
   a) Weekly b) Every 2 weeks c) Monthly d) Daily
   Answer: b) Every 2 weeks
7. Which enzyme activates C5?
   a) C3 convertase b) C5 convertase c) Factor D d) Thrombin
   Answer: b) C5 convertase
8. Eculizumab reduces which symptom in PNH?
   a) Thrombocytopenia b) Hemolysis c) Hypertension d) Diabetes
   Answer: b) Hemolysis
9. Complement activation blocked stops:
   a) TNF production b) MAC formation c) IgG binding d) T-cell activation
   Answer: b) MAC formation
10. Vaccination required before initiation is directed against:
    a) Pneumococcus b) Meningococcus c) Influenza d) Varicella
    Answer: b) Meningococcus

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FAQs

1. Why is meningococcal vaccination necessary?
Blocking C5 impairs complement-mediated bacterial defense; vaccination reduces meningococcal risk.

2. How is eculizumab administered?
Given as an intravenous infusion every two weeks.

3. Can therapy be paused if infection occurs?
Clinical judgment needed—treatment may be paused or continued with antibiotic coverage.

4. Are there alternatives with longer dosing intervals?
Yes—ravulizumab targets C5 with 8-week dosing intervals.

5. Is renal function affected?
No—excretion is proteolytic; no dose adjustment in renal impairment.

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References

• Eculizumab prescribing information (FDA)
• DrugBank: Eculizumab properties and mechanism
• StatPearls: Eculizumab in PNH and aHUS
• PubMed review: complement inhibition in aHUS and PNH