Lima E Silva Raquel, Mirando Adam C, Tzeng Stephany Y, Green Jordan J, Popel Aleksander S, Pandey Niranjan B, Campochiaro Peter A
Department of Ophthalmology and The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
iScience. 2023 Jan 30;26(2):106078. doi: 10.1016/j.isci.2023.106078. eCollection 2023 Feb 17.
AXT107, a collagen-derived peptide that binds integrins αβ and αβ with high affinity, suppresses vascular endothelial growth factor (VEGF) signaling, promotes angiopoietin 2-induced Tie2 activation, and suppresses neovascularization (NV) and vascular leakage. Immunohistochemical staining for αβ and αβ was markedly increased in NV compared with normal retinal vessels. After intravitreous injection of AXT107, there was no staining with an anti-AXT107 antibody on normal vessels but robust staining of NV that co-localized with αβ and αβ. Likewise, after intravitreous injection, fluorescein amidite-labeled AXT107 co-localized with αβ and αβ on NV but not normal vessels. AXT107 also co-localized with α and α at cell-cell junctions of human umbilical vein endothelial cells (HUVECs). AXT107-integrin binding was demonstrated by cross-linking/pull-down experiments. These data support the hypothesis that AXT107 therapeutic activity is mediated through binding αβ and αβ which are markedly upregulated on endothelial cells in NV providing selective targeting of diseased vessels which has therapeutic and safety benefits.
AXT107是一种源自胶原蛋白的肽，它能以高亲和力结合整合素αβ和αβ，抑制血管内皮生长因子（VEGF）信号传导，促进血管生成素2诱导的Tie2激活，并抑制新生血管形成（NV）和血管渗漏。与正常视网膜血管相比，NV中αβ和αβ的免疫组织化学染色明显增加。玻璃体内注射AXT107后，正常血管上未出现抗AXT107抗体染色，但NV上有强烈染色，并与αβ和αβ共定位。同样，玻璃体内注射后，荧光素亚磷酰胺标记的AXT107在NV上与αβ和αβ共定位，但在正常血管上则没有。AXT107在人脐静脉内皮细胞（HUVECs）的细胞间连接处也与α和α共定位。通过交联/下拉实验证明了AXT107与整合素的结合。这些数据支持了以下假设：AXT107的治疗活性是通过结合αβ和αβ介导的，这两种整合素在NV的内皮细胞上明显上调，从而实现对病变血管的选择性靶向，具有治疗和安全益处。
