Annexon Biosciences Inc., Brisbane, California, United States.
ACELYRIN, Inc., Agoura Hills, California, United States.
Invest Ophthalmol Vis Sci. 2023 Feb 1;64(2):3. doi: 10.1167/iovs.64.2.3.
C1q and the classical complement cascade are key regulators of synaptic pruning, and their aberrant activation has been implicated in neurodegenerative ophthalmic diseases including geographic atrophy and glaucoma. The antigen-binding fragment antibody ANX007 specifically recognizes globular head groups of C1q to block substrate binding and functionally inhibit classical complement cascade activation. ANX007 was assessed in nonclinical studies of biodistribution and C1q target engagement in the eye following intravitreal (IVT) administration in cynomolgus monkeys.
Female juvenile cynomolgus monkeys (n = 12) received a single bilateral dose of 1 or 5 mg ANX007/eye, with vitreous and non-perfused tissue samples collected approximately 4 weeks later. In a separate study, male (n = 6/5) and female (n = 6/5) animals received repeat bilateral dosing of 1, 2.5, or 5 mg ANX007/eye on days 1 and 29, with aqueous and vitreous collections on day 44 or day 59. Tissues from the 5 mg/eye repeat-dose group were perfused, and retina, choroid, and optic nerve samples were collected approximately 2 and 4 weeks post-last dose.
Following a single dose of ANX007, vitreous levels of free drug were measurable through 4 weeks at both the 1 and 5 mg dose levels, with approximately 3-day half-life. With repeat dose of 5 mg/eye, free-ANX007 was measurable 4 weeks post-last dose in perfused retina and choroid and up to approximately 2 weeks post-last dose in optic nerve. There was a strong correlation between C1q target engagement and free drug levels in aqueous and vitreous humors and retinal tissue.
Following IVT administration, ANX007 distributes to sites within the retina that are relevant to neurodegenerative ophthalmic disease with clear evidence of C1q target engagement. Based on its mechanism of action inhibiting C1q and its downstream activity, ANX007 is predicted to mitigate tissue damage driven by classical complement activation in the retina. These data support further clinical evaluation of ANX007.
C1q 和经典补体级联反应是突触修剪的关键调节因子，其异常激活与包括地图状萎缩和青光眼在内的神经退行性眼病有关。抗原结合片段抗体 ANX007 特异性识别 C1q 的球状头部基团，以阻止底物结合并在功能上抑制经典补体级联反应的激活。在食蟹猴玻璃体内（IVT）给药后，在眼内的分布和 C1q 靶标结合的非临床研究中评估了 ANX007。
接受单次双侧 1 或 5mg/眼 ANX007 剂量的雌性幼年食蟹猴（n=12），大约 4 周后收集玻璃体液和非灌注组织样本。在另一项研究中，雄性（n=6/5）和雌性（n=6/5）动物分别在第 1 天和第 29 天接受双侧重复剂量 1、2.5 或 5mg/眼 ANX007，第 44 天或第 59 天采集房水和玻璃体液。重复剂量 5mg/眼组的组织进行了灌注，大约在最后一次给药后 2 周和 4 周时收集视网膜、脉络膜和视神经样本。
单次剂量 ANX007 后，在 1 和 5mg 剂量水平下，玻璃体液中的游离药物水平可在 4 周内测量到，半衰期约为 3 天。重复剂量 5mg/眼后，可在最后一次给药后 4 周的灌注视网膜和脉络膜中以及最后一次给药后约 2 周的视神经中测量到游离的 ANX007。房水和玻璃体液以及视网膜组织中的 C1q 靶标结合与游离药物水平之间存在很强的相关性。
玻璃体内给药后，ANX007 分布在与神经退行性眼病相关的视网膜部位，并且有明确的 C1q 靶标结合证据。基于其抑制 C1q 及其下游活性的作用机制，ANX007 有望减轻视网膜中经典补体激活引起的组织损伤。这些数据支持进一步评估 ANX007 的临床研究。
