Jo Dong Hyun, Kim Jin Hyoung, Yang Wonjun, Kim Hyori, Chang Shinjae, Kim Dongjo, Chang Minseok, Lee Kihwang, Chung Junho, Kim Jeong Hun
Fight Against Angiogenesis-Related Blindness (FARB) Laboratory, Clinical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea.
Department of Biomedical Sciences and Protein Metabolism, Medical Research Center, Seoul National University College of Medicine, Seoul, Republic of Korea.
Oncotarget. 2017 Jul 11;8(28):45506-45516. doi: 10.18632/oncotarget.17221.
Age-related macular degeneration (AMD) is one of the main causes of visual impairment in adults. Visual deterioration is more prominent in neovascular AMD with choroidal neovascularization (CNV). Clinical and postmortem studies suggested that complement system activation might induce CNV. In this study, we demonstrated that an anti-mouse complement component 5 (C5) antibody targeting MG4 domain of β chain effectively inhibited CNV which was induced by laser photocoagulation in mice. The targeted epitope of this anti-C5 antibody was different from that of currently utilized anti-C5 antibody (eculizumab) in the MG7 domain in which a single nucleotide polymorphism (R885H/C) results in poor response to eculizumab. Even with targeting MG4 domain, this anti-C5 antibody reduced production of C5a, monocyte chemoattractant protein-1 and vascular endothelial growth factor to prevent infiltration of F4/80-positive cells into CNV lesions and formation of CNV. Furthermore, anti-C5 antibody targeting MG4 domain induced no definite toxicity in normal retina. These results demonstrated that anti-C5 antibody targeting MG4 domain inhibited CNV in neovascular AMD.
年龄相关性黄斑变性（AMD）是成人视力损害的主要原因之一。在伴有脉络膜新生血管（CNV）的新生血管性AMD中，视力恶化更为突出。临床和尸检研究表明，补体系统激活可能诱导CNV。在本研究中，我们证明了一种靶向β链MG4结构域的抗小鼠补体成分5（C5）抗体可有效抑制小鼠激光光凝诱导的CNV。这种抗C5抗体的靶向表位与目前使用的抗C5抗体（依库珠单抗）在MG7结构域中的不同，在MG7结构域中，单核苷酸多态性（R885H/C）导致对依库珠单抗反应不佳。即使靶向MG4结构域，这种抗C5抗体也能减少C5a、单核细胞趋化蛋白-1和血管内皮生长因子的产生，以防止F4/80阳性细胞浸润到CNV病变中并形成CNV。此外，靶向MG4结构域的抗C5抗体在正常视网膜中未诱导明确的毒性。这些结果表明，靶向MG4结构域的抗C5抗体可抑制新生血管性AMD中的CNV。
