A patient with wet AMD is being treated with intravitreal ranibizumab. After 3 monthly loading doses, the ophthalmologist switches to a treat-and-extend (T&E) protocol. What is the primary pharmacological advantage of aflibercept over ranibizumab that may allow less frequent dosing?

• A Aflibercept binds VEGF-A only, whereas ranibizumab binds all VEGF isoforms
• B Aflibercept has a longer half-life due to its larger molecular size preventing vitreous clearance
• C Aflibercept has a higher binding affinity (picomolar vs. sub-nanomolar) and also binds VEGF-B and PlGF ✓
• D Aflibercept directly inhibits VEGFR-2 signalling without requiring VEGF binding

Explanation

Aflibercept (VEGF Trap) is a recombinant fusion protein containing extracellular domains of VEGFR-1 and VEGFR-2 fused to the Fc portion of IgG1. It binds VEGF-A with approximately 100-fold higher affinity than ranibizumab (picomolar vs. sub-nanomolar), and additionally binds VEGF-B and placental growth factor (PlGF) — both of which contribute to neovascular drive. This broader binding profile and higher affinity theoretically allow longer durability of effect, supporting 8-weekly dosing after the loading phase (VIEW trials). Ranibizumab is a Fab fragment binding VEGF-A only. The higher molecular weight of aflibercept does increase vitreous half-life somewhat, but the primary advantage is binding affinity and spectrum. Aflibercept does not inhibit VEGFR-2 directly; it acts as a soluble decoy receptor.

Reference: Khurana Comprehensive Ophthalmology, 7th ed.

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Written and medically reviewed by the StethoPrep medical team.