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

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 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.

研究目的：雷珠单抗（Ranibizumab）是一种抗血管内皮生长因子-A（anti-VEGF-A, vascular endothelial cell growth factor-A）单克隆抗体片段，是治疗糖尿病性黄斑水肿患者的成熟临床方案。然而，目前对于雷珠单抗在眼内促炎与抗炎信号通路的调控作用，以及这些信号通路对血管内皮生长因子家族成员的调控效应，相关研究仍较为匮乏，本研究即以此为核心目标展开。
材料与方法：纳入10名年龄≥18岁的糖尿病患者，均确诊为中心性糖尿病黄斑水肿，最佳矫正视力（Best Corrected Visual Acuity, BCVA）＞24。
研究结果：正如预期，雷珠单抗可降低VEGF-A水平，减轻中心黄斑厚度（Central macular thickness, CMT），并改善视力（visual acuity, VA）。此外，其可显著降低房水中白细胞介素-10（IL-10）、干扰素-γ（IFNγ）、可溶性白细胞介素-1受体1（sIL-1R1）、可溶性白细胞介素-1受体2（sIL-1R2）、可溶性晚期糖基化终末产物受体（sRAGE）及VEGF-D的水平。VEGF-A与VEGF-C的水平变化，与IL-6信号通路相关的可溶性受体sgp130及可溶性白细胞介素-6受体（sIL-6R）的变化显著相关。与之相反，VEGF-D的水平变化与参与IL-1信号通路的可溶性受体sIL-1R1、sIL-1R2呈显著关联。中心黄斑厚度与视力的变化，与VEGF家族成员的水平变化无明显相关性。然而，治疗后中心黄斑厚度值与治疗后VEGF-C水平呈显著正相关。治疗后视力值与多种与炎症相关的潜在生物标志物存在关联。
研究结论：雷珠单抗治疗可显著调控与IL-1及IL-6信号通路密切相关的可溶性受体水平。因此，全面阐明雷珠单抗的作用机制，将有助于开发更多辅助治疗糖尿病性黄斑水肿的新型疗法。