Targeting key angiogenic pathways with a bispecific CrossMAb optimized for neovascular eye diseases.
Targeting key angiogenic pathways with a bispecific CrossMAb optimized for neovascular eye diseases.
复制标题
DOI：
10.15252/emmm.201505889
复制
发表时间：
2016-11
影响因子：
11.1
通讯作者：
Hartmann G
中科院分区：
文献类型：
--
作者：
Regula JT;Lundh von Leithner P;Foxton R;Barathi VA;Cheung CM;Bo Tun SB;Wey YS;Iwata D;Dostalek M;Moelleken J;Stubenrauch KG;Nogoceke E;Widmer G;Strassburger P;Koss MJ;Klein C;Shima DT;Hartmann G
使用中和血管内皮生长因子-A（VEGF-A）的生物分子的抗血管生成疗法彻底改变了包括年龄相关性黄斑变性（AMD）在内的视网膜血管疾病的治疗。本研究报告了通过靶向VEGF-A和血管生成素-2（ANG-2）增强抗VEGF-A单药治疗疗效的策略的临床前评估，ANG-2是一种在视网膜血管疾病患者玻璃体液中强烈上调的因子，并与VEGF-A一起发挥其某些活性。在自发性脉络膜新生血管形成（CNV）模型中，发现同时抑制VEGF-A和ANG-2比单独抑制任一种药物更有效地减少血管病变数量、渗透性、视网膜水肿和神经元丢失。我们描述了能够结合、中和和消耗VEGF-A和ANG-2的双特异性结构域交换（交叉）单克隆抗体（CrossMAb; RG 7716）的产生。玻璃体内给药后，RG 7716在非人灵长类动物激光诱导的CNV模型中显示出比单独使用抗VEGF-A更大的疗效。RG 7716的FcRn和FcγR结合位点的修饰使抗体的Fc介导的效应子功能失效。这导致全身清除率增加，但不是眼部清除率。这些特性使RG 7716成为治疗眼部新生血管适应症的潜在下一代疗法。
Anti‐angiogenic therapies using biological molecules that neutralize vascular endothelial growth factor‐A (VEGF‐A) have revolutionized treatment of retinal vascular diseases including age‐related macular degeneration (AMD). This study reports preclinical assessment of a strategy to enhance anti‐VEGF‐A monotherapy efficacy by targeting both VEGF‐A and angiopoietin‐2 (ANG‐2), a factor strongly upregulated in vitreous fluids of patients with retinal vascular disease and exerting some of its activities in concert with VEGF‐A. Simultaneous VEGF‐A and ANG‐2 inhibition was found to reduce vessel lesion number, permeability, retinal edema, and neuron loss more effectively than either agent alone in a spontaneous choroidal neovascularization (CNV) model. We describe the generation of a bispecific domain‐exchanged (crossed) monoclonal antibody (CrossMAb; RG7716) capable of binding, neutralizing, and depleting VEGF‐A and ANG‐2. RG7716 showed greater efficacy than anti‐VEGF‐A alone in a non‐human primate laser‐induced CNV model after intravitreal delivery. Modification of RG7716's FcRn and FcγR binding sites disabled the antibodies' Fc‐mediated effector functions. This resulted in increased systemic, but not ocular, clearance. These properties make RG7716 a potential next‐generation therapy for neovascular indications of the eye.