Ranibizumab Alters Levels of Intraocular Soluble Cytokine Receptors in Patients with Diabetic Macular Edema

ABSTRACT

Purpose: Ranibizumab, an anti-VEGF-A (vascular endothelial cell growth factor-A) monoclonal antibody fragment, is a well-established treatment for diabetic patients with macular edema. However, very little is known about the effect of ranibizumab on intraocular regulation of pro – and anti-inflammatory signaling pathways and their regulation of VEGF family members, which was the aim of this study.

Materials and Methods: Diabetic patients (n = 10) aged ≥18 years with central diabetic macular edema, BCVA >24 and <78, and central macular thickness (CMT) greater than 250 μm were enrolled in this study. Following a full eye exam, imaging, and an aqueous tap, patients received ranibizumab (0.3 mg/0.05 mL) injections at day one and weeks four and eight. At week 12, a full eye exam, imaging, and a second aqueous tap was obtained prior to the last injection of ranibizumab. Pre – and post-treatment aqueous humor samples were then analyzed using Milliplex MAP magnetic bead assays.

Results: As expected, ranibizumab lowered levels of VEGF-A, decreased CMT, and improved VA (visual acuity). In addition, it significantly lowered aqueous levels of IL-10, IFNγ, sIL-1R1, sIL-1R2, sRAGE, and VEGF-D. Changes in levels of VEGF-A and VEGF-C strongly correlated with changes in soluble receptors, sgp130 and sIL-6R, associated with IL-6 signaling pathways. In contrast, changes in VEGF-D correlated with sIL-1R1 and sIL-1R2, soluble receptors participating in IL-1 signaling. Changes in CMT and VA did not correlate with changes in levels of VEGF family members. However, post-treatment values of CMT correlated with post-treatment levels of VEGF-C. Post-treatment VA values correlated with a wide variety of potential biomarkers linked to inflammation.

Conclusions: Ranibizumab treatment had strong effects on regulating levels of soluble receptors closely linked to IL-1 and IL-6 signaling pathways. Therefore, a complete understanding of the actions of ranibizumab will further the development of additional therapies to support treatment of diabetic macular edema.

KEYWORDS:

• Diabetic macular edema
• ranibizumab
• aqueous humor
• vascular endothelial growth factors
• cytokines

Declaration of Interest

The material presented is the result of work supported with funding from GenenTech (LCG and SM). BAC, PGN, AS, and SM have no financial disclosures that would be potential conflicts of interests with this manuscript. LCG is a clinician working with drugs provided by GenenTech.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/02713683.2019.1665187.

Additional information

Funding

The material presented is the result of work supported with funding from GenenTech (LCG and SM).