What is Dupilumab (dupilumab)?

What is Dupilumab?

Dupilumab is a fully human IgG4 monoclonal antibody that blocks interleukin-4 and interleukin-13 signaling by binding to the IL-4 receptor alpha (IL-4Rα) subunit, thereby inhibiting type 2 inflammatory responses across multiple diseases. 1

Molecular Structure and Production

• Dupilumab is a human monoclonal antibody of the IgG4 subclass with an approximate molecular weight of 147 kDa 1
• It is produced by recombinant DNA technology in Chinese Hamster Ovary cell suspension culture 1
• The drug is supplied as a sterile, preservative-free, clear to slightly opalescent, colorless to pale yellow solution for subcutaneous injection 1

Mechanism of Action

Dupilumab works by binding to IL-4Rα, which forms heterodimers with either the common γ chain (Type I receptor) or with IL-13Rα1 (Type II receptor), thereby blocking signaling from both IL-4 and IL-13 cytokines. 2, 1

Downstream Effects on Inflammation

• By blocking IL-4Rα, dupilumab inhibits IL-4 signaling via the Type I receptor and both IL-4 and IL-13 signaling through the Type II receptor 2, 1
• This blockade prevents multiple inflammatory processes:
  • Inhibits IgE synthesis by blocking IL-4 and IL-13 signaling responsible for B cell isotype class switching 2
  • Prevents eosinophil activation, chemotaxis, and tissue infiltration 2
  • Blocks mucus secretion from goblet cells driven by IL-4 and IL-13 2
  • Prevents airway remodeling by blocking proliferation of fibroblasts and smooth muscle cells 2
  • Restores epidermal barrier function by reversing IL-4/IL-13-induced downregulation of filaggrin expression in keratinocytes 2

Effects on Inflammatory Mediators

• Dupilumab reduces the release of proinflammatory substances, including type 2-associated cytokines and chemokines such as IL-5, IL-9, IL-13, TARC, and eotaxin 2
• Treatment decreases biomarkers of inflammation including fractional exhaled nitric oxide (FeNO), eotaxin-3, total IgE, allergen-specific IgE, TARC, and periostin 1
• The median percent reduction in total IgE concentrations reaches 52% at Week 24 and 70% at Week 52 1

Approved Indications

Dupilumab is approved for multiple type 2 inflammatory diseases where IL-4 and IL-13 drive pathogenesis. 1

The FDA has approved dupilumab for treatment of:

• Asthma 1
• Atopic dermatitis (AD) 1
• Chronic rhinosinusitis with nasal polyps (CRSwNP) 3, 1
• Eosinophilic esophagitis (EoE) 1
• Prurigo nodularis (PN) 1
• Chronic obstructive pulmonary disease (COPD) 1
• Chronic spontaneous urticaria (CSU) 1
• Bullous pemphigoid (BP) 1

Specific Indication Details

For CRSwNP, dupilumab is the only monoclonal antibody currently approved for treatment, and European guidelines specifically recommend its use in patients fulfilling criteria for monoclonal antibody therapy. 3

• In CRSwNP trials, dupilumab 300 mg every 2 weeks added to standard-of-care showed clinically relevant improvements:
  • SNOT-22 score decreased by mean difference -19.61 (95% CI -22.53 to -16.69) 3
  • Rhinosinusitis disease severity (VAS) decreased by -2.54 (95% CI -2.84 to -2.23) 3
  • Nasal congestion/obstruction score decreased by -0.86 (95% CI -0.98 to -0.75) 3
  • Smell (UPSIT score) improved by 10.83 points (95% CI 9.59 to 12.08) 3
  • Nasal polyp score decreased by -1.79 (95% CI -2.01 to -1.56) 3
  • FEV1 improved by 0.21 L (95% CI 0.20 to 0.22) in patients with comorbid asthma 3

Safety Profile

• Dupilumab has demonstrated an excellent safety profile over more than 10 years of follow-up 3
• The most prevalent adverse effects are ocular surface adverse events, occurring in 6-15% of adults in clinical trials versus 0.9-10.9% with placebo 3
• In real-world data, 26.1% of patients with atopic dermatitis developed conjunctivitis (95% CI 17.8-35.4), and 4.2% discontinued dupilumab due to ocular complications 3
• In CRSwNP trials, the most common adverse events (nasopharyngitis, worsening nasal polyps and asthma, headache, epistaxis, injection-site erythema) were actually more frequent with placebo 3
• Dupilumab induces conjunctivitis in trials of patients with atopic dermatitis but not in trials with asthma and CRSwNP 3

Important Caveat on Ocular Effects

The ocular complications represent a heterogeneous group of established ocular surface disorders rather than a novel disease entity, termed "dupilumab-related ocular surface disorders" (DROSD), which can include exacerbations of pre-existing atopic eye disease or de novo development of recognized ocular surface conditions 3

Administration and Formulation

• Dupilumab is administered subcutaneously 1
• Available as single-dose pre-filled syringe or pre-filled pen in 300 mg (2 mL) or 200 mg (1.14 mL) formulations 1
• The needle cap is not made with natural rubber latex 1
• Steady-state concentrations are achieved by Week 16 following appropriate loading and maintenance dosing 1