ranibizumab

MECHANISM: Ranibizumab is a humanized murine-derived monoclonal antibody Fab fragment (no Fc region) that binds all active isoforms of VEGF-A (e.g., VEGF110, VEGF121, VEGF165) and prevents binding to VEGFR-1 and VEGFR-2 on endothelial cells. This decreases endothelial proliferation, neovascularization, and vascular permeability (leakage). It was engineered with affinity maturation for stronger VEGF binding than its parent antibody, bevacizumab. Lacking the Fc portion gives it a smaller size (~48 kDa) for better retinal penetration and a shorter systemic half-life, which reduces systemic exposure and avoids Fc-mediated effects (complement activation, inflammation).

PATHOPHYSIOLOGY CONTEXT: In wet (neovascular, exudative) AMD, hypoxia and inflammation upregulate VEGF-A, driving choroidal neovascularization (CNV) through Bruch's membrane into the subretinal/sub-RPE space. These fragile vessels leak fluid and blood, causing rapid central vision loss, metamorphopsia (distorted, wavy lines on Amsler grid), and central scotoma. In diabetic retinopathy, chronic hyperglycemia and retinal ischemia raise VEGF, causing macular edema (the leading cause of vision loss in diabetics) and proliferative disease.

INDICATIONS: Neovascular (wet) AMD; diabetic macular edema (DME); diabetic retinopathy; macular edema following retinal vein occlusion (branch or central); myopic choroidal neovascularization. A biosimilar (e.g., ranibizumab-nuna/Byooviz, ranibizumab-eqrn/Cimerli) is available.

ADMINISTRATION: Intravitreal injection, typically monthly initially, then extended intervals or treat-and-extend regimens. Standard sterile technique is used.

ADVERSE EFFECTS: Endophthalmitis (most feared; presents with pain, redness, decreased vision days after injection), retinal detachment or tear, traumatic cataract, increased intraocular pressure, intraocular inflammation/uveitis, conjunctival hemorrhage (common, benign). Systemic risks include a theoretical increased risk of arterial thromboembolic events (stroke, MI) from systemic VEGF inhibition, mainly with higher doses and in patients with prior stroke.

COMPARISON (high-yield): - Bevacizumab (Avastin): full-length IgG antibody; used off-label intravitreally and approved IV for cancers (colorectal, NSCLC, glioblastoma, renal cell, cervical). CATT trial showed non-inferior visual outcomes to ranibizumab for wet AMD at much lower cost. - Aflibercept (Eylea): recombinant fusion protein (VEGFR-1 and VEGFR-2 extracellular domains fused to Fc of IgG1); a "VEGF trap" that binds VEGF-A, VEGF-B, and placental growth factor (PlGF). Longer dosing intervals. - Brolucizumab (Beovu): single-chain Fv fragment; associated with retinal vasculitis/vascular occlusion. - Faricimab (Vabysmo): bispecific antibody targeting VEGF-A and angiopoietin-2. - Pegaptanib (Macugen): aptamer against VEGF165 only; largely obsolete.

CLINICAL PEARLS: Anti-VEGF therapy has replaced laser photocoagulation and photodynamic therapy (verteporfin) as first-line treatment for wet AMD. It does not treat dry (atrophic) AMD, which is managed with AREDS2 supplements (vitamin C, E, zinc, copper, lutein, zeaxanthin) for intermediate or advanced disease. Diagnosis of wet AMD relies on OCT (subretinal/intraretinal fluid), fluorescein angiography (leakage), and dilated fundus exam (hemorrhage, drusen). Ranibizumab suffix "-zumab" = humanized monoclonal antibody; "-ra-" or "-ci-" infixes denote target class (circulatory = -ci-) in older naming conventions.