Department of Ophthalmology, Jules Stein Eye Institute, University of California Los Angeles, Los Angeles, California, United States.
Department of Surgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States.
Invest Ophthalmol Vis Sci. 2019 Jan 2;60(1):245-254. doi: 10.1167/iovs.18-24345.
Pathologic corneal neovascularization is a major cause of blindness worldwide, and treatment options are currently limited. VEGF is one of the critical mediators of corneal neovascularization but current anti-VEGF therapies have produced limited results in the cornea. Thus, additional therapeutic agents are needed to enhance the antiangiogenic arsenal. Our group previously demonstrated epithelial membrane protein-2 (EMP2) involvement in pathologic angiogenesis in multiple cancer models including breast cancer and glioblastoma. In this paper, we investigate the efficacy of anti-EMP2 immunotherapy in the prevention of corneal neovascularization.
An in vivo murine cornea alkali burn model was used to study pathologic neovascularization. A unilateral corneal burn was induced using NaOH, and subconjunctival injection of either anti-EMP2 antibody, control antibody, or sterile saline was performed after corneal burn. Neovascularization was clinically scored at 7 days postalkali burn, and eyes were enucleated for histologic analysis and immunostaining including VEGF, CD31, and CD34 expression.
Anti-EMP2 antibody, compared to control antibody or vehicle, significantly reduced neovascularization as measured by clinical score and central cornea thickness, as well as by histologic reduction of neovascularization, decreased CD34 staining, and decreased CD31 staining. Incubation of corneal limbal cells in vitro with anti-EMP2 blocking antibody significantly decreased EMP2 expression, VEGF expression and secretion, and cell migration.
This work demonstrates the effectiveness of EMP2 as a novel target in pathologic corneal neovascularization in an animal model and supports additional investigation into EMP2 antibody blockade as a potential new therapeutic option.
病理性角膜新生血管是全球范围内导致失明的主要原因，目前的治疗选择有限。VEGF 是角膜新生血管的关键介质之一，但目前的抗 VEGF 疗法在角膜中的效果有限。因此，需要额外的治疗药物来增强抗血管生成的武器库。我们的研究小组之前已经证明，上皮膜蛋白 2（EMP2）参与了包括乳腺癌和神经胶质瘤在内的多种癌症模型中的病理性血管生成。在本文中，我们研究了抗 EMP2 免疫疗法在预防角膜新生血管中的疗效。
采用体内小鼠角膜碱烧伤模型研究病理性新生血管。使用 NaOH 诱导单侧角膜烧伤，在角膜烧伤后进行结膜下注射抗 EMP2 抗体、对照抗体或无菌盐水。在角膜碱烧伤后 7 天进行新生血管的临床评分，并对眼睛进行眼球摘除法进行组织学分析和免疫染色，包括 VEGF、CD31 和 CD34 的表达。
与对照抗体或载体相比，抗 EMP2 抗体显著降低了新生血管的临床评分和中央角膜厚度，以及新生血管的组织学减少、CD34 染色减少和 CD31 染色减少。体外培养角膜缘细胞时，抗 EMP2 阻断抗体显著降低了 EMP2 表达、VEGF 表达和分泌以及细胞迁移。
这项工作证明了 EMP2 作为一种新的病理性角膜新生血管动物模型中的靶点的有效性，并支持进一步研究 EMP2 抗体阻断作为一种潜在的新治疗选择。
