Biomarkers as Predictive Factors of Anti-VEGF Response

Abstract

Age-related macular degeneration is the main cause of irreversible vision in developed countries, and intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections are the current gold standard treatment today. Although anti-VEGF treatment results in important improvements in the course of this disease, there is a considerable number of patients not responding to the standardized protocols. The knowledge of how a patient will respond or how frequently retreatment might be required would be vital in planning treatment schedules, saving both resource utilization and financial costs, but today, there is not an ideal biomarker to use as a predictive response to ranibizumab therapy. Whole blood and blood mononuclear cells are the samples most studied; however, few reports are available on other important biofluid samples for studying this disease, such as aqueous humor. Moreover, the great majority of studies carried out to date were focused on the search for SNPs in genes related to AMD risk factors, but miRNAs, proteomic and metabolomics studies have rarely been conducted in anti-VEGF-treated samples. Here, we propose that genomic, proteomic and/or metabolomic markers could be used not alone but in combination with other methods, such as specific clinic characteristics, to identify patients with a poor response to anti-VEGF treatment to establish patient-specific treatment plans.

Keywords: SNPs; aflibercept; age-related macular degeneration; anti-VEGF; antiangiogenic therapy; brolucizumab; metabolomic; microRNAs; proteomic; ranibizumab.

Figure 1

Schematic representation of an AMD eye (A) and the functional effects on vision capability (B) and structural retinal abnormalities associated with each subtype of AMD disease (C,D). Drusen accumulation, Bruch´s membrane alteration and RPE modifications are classical retinal changes associated with atrophic AMD (C), while neovascularization, fluid accumulation and vascular leakage are typical markers of exudative AMD (D).

Figure 2

Summary of the currently available anti-VEGF treatments for neovascular age-related macular degeneration: bevacizumab (off-label), ranibizumab, brolucizumab, faricimab and aflibercept. VEGF-A, B, C and D: Vascular endothelial growth factor A, B, C and D; VEGFR-1 and 2: Vascular endothelial growth factor receptors 1 and 2; PlGF: Placental growth factor; Ang 1 and 2: Angiopoietin 1 and 2.

Figure 3

Summary of the main predictive biomarkers of the anti-ranibizumab treatment response described in whole blood, mononuclear blood cells, plasma, saliva and aqueous humor samples. In green, SNPs that contribute to a better anti-VEGF response; in red, SNPs associated with a worse response to anti-VEGF treatment; in blue, proteins whose levels differ between good and poor responders; in purple, mRNAs and miRNAs differently expressed in responder and non-responder patients. Images adapted from SMART Servier Medical Art (smart.servier.com, accessed on 27 March 2022).