Genentech Inc., South San Francisco, California, United States.
Ra Pharmaceuticals, Cambridge, Massachusetts, United States.
Invest Ophthalmol Vis Sci. 2019 Oct 1;60(13):4097-4108. doi: 10.1167/iovs.18-26349.
Investigate a significant, dose-related increase in IOP, leading to glaucomatous damage to the neuroretina and optic nerve following intravitreal (ITV) administration of a bispecific F(ab')2 [anti-VEGF/Angiopoietins [ANGPT]F(ab')2] molecule in adult monkeys.
ITV ocular tolerability and investigation of anti-VEGF/ANGPT F(ab')2 (blocking both ANGPT1 and ANGPT2) was done in monkeys; mechanistic studies were done in neonatal mice.
Following the second ITV dose of anti-VEGF/ANGPT F(ab')2, all 1.5- and 4-mg/eye treated monkeys developed elevated IOP, which eventually was associated with optic disc cupping and thinning of the neuroretinal rim. Histopathologic examination showed nonreversible axonal degeneration in the optic nerves of animals administered 1.5 mg/eye and higher that was considered secondary to high IOP. Anti-ANGPT Fab also caused elevated IOP in monkeys, but anti-VEGF Fab did not contribute to the IOP increase. In addition, an anti-ANGPT2-selective antibody did not change IOP. In mice simultaneous blockade of ANGPT1 and ANGPT2 impaired the expansion and formation of Schlemm's canal (SC) vessels, similar to genetic ablation of Angpt1/Angpt2 and their receptor TIE2. As previously reported, blocking ANGPT2 alone did not affect SC formation in mice.
Dual inhibition of ANGPT1/ANGPT2, but not ANGPT2 alone, leads to increased IOP and glaucomatous damage in monkeys. This confirms a role for TIE2/ANGPT signaling in the control of IOP in adults, a finding initially identified in transgenic mice. Dual pharmacologic inhibition of ANGPT1/ANGPT2 may affect aqueous drainage and homeostasis in adult monkeys and may be useful in developing novel models of glaucoma.
研究玻璃体腔内（ITV）给予双特异性 F(ab')2 [抗 VEGF/血管生成素（ANGPT）F(ab')2]分子后，眼压（IOP）显著升高，导致神经视网膜和视神经发生青光眼损伤。
在猴子中进行 ITV 眼部耐受性和抗 VEGF/ANGPT F(ab')2（阻断 ANGPT1 和 ANGPT2）的研究；在新生小鼠中进行机制研究。
在第二次 ITV 剂量抗 VEGF/ANGPT F(ab')2 后，所有 1.5 和 4mg/眼治疗的猴子均出现眼压升高，最终与视盘凹陷和神经视网膜边缘变薄相关。组织病理学检查显示，眼压升高的动物视神经出现不可逆转的轴突变性，认为这是眼压升高的继发效应。抗 ANGPT Fab 也会引起猴子眼压升高，但抗 VEGF Fab 不会导致眼压升高增加。此外，抗 ANGPT2 选择性抗体不会改变眼压。在小鼠中，同时阻断 ANGPT1 和 ANGPT2 会损害小梁网（SC）血管的扩张和形成，类似于 Angpt1/Angpt2 及其受体 TIE2 的基因缺失。如前所述，单独阻断 ANGPT2 不会影响小鼠 SC 的形成。
双重抑制 ANGPT1/ANGPT2，但不是 ANGPT2 单独抑制，会导致猴子眼压升高和青光眼损伤。这证实了 TIE2/ANGPT 信号在成人眼压控制中的作用，这一发现最初是在转基因小鼠中确定的。双重药理学抑制 ANGPT1/ANGPT2 可能会影响成年猴子房水排出和内稳态，并可能有助于开发新的青光眼模型。
