Department Regulatory Toxicology and Safety Assessment, H. Lundbeck A/S, Valby, Denmark.
Department Exploratory Toxicology, H. Lundbeck A/S, Valby, Denmark.
MAbs. 2021 Jan-Dec;13(1):1994690. doi: 10.1080/19420862.2021.1994690.
Alpha-synuclein is a 15 kDa protein associated with neurodegenerative diseases such as Parkinson disease and multiple-system atrophy where pathological forms of alpha-synuclein aggregate and become neurotoxic. Here we describe the nonclinical program to support a first-in-human (FIH) single ascending dose (SAD) study for Lu AF82422, a human recombinant, anti-alpha-synuclein monoclonal antibody (mAb) in development for treatment of synucleinopathies. Alpha-synuclein is primarily expressed in brain, peripheral nerves and in blood cells. A tissue cross-reactivity assessment showed that Lu AF82422 binding was generally restricted to nervous tissues. Flow cytometry analysis did not show extracellular surface binding of Lu AF82422 to human platelets, erythrocytes, granulocytes, or lymphocytes, but to a low fraction of monocytes, without any functional consequences on activation or phagocytic capacity. A single dose pharmacokinetic (PK) study in cynomolgus monkeys with dose levels of 1-30 mg/kg confirmed PK properties in the expected range for a mAb with a soluble target, and target engagement was shown as a decrease in free alpha-synuclein in plasma. Four-week repeat-dose toxicity studies were conducted in rats and cynomolgus monkeys at doses up to 600 mg/kg administered intravenously every 10 days. Results showed no treatment-related adverse findings and the no-observed-adverse-effect-level was the highest dose tested. Target engagement was shown in plasma and cerebrospinal fluid. Taken together, the nonclinical data indicated no safety signal of concern and provided adequate safety margins between observed safe doses in animals and the planned dose levels in the FIH SAD study.
α-突触核蛋白是一种 15 kDa 的蛋白质，与神经退行性疾病有关，如帕金森病和多系统萎缩，其中病理性的 α-突触核蛋白聚集并变得神经毒性。在这里，我们描述了支持 Lu AF82422 首次人体（FIH）单次递增剂量（SAD）研究的非临床计划，Lu AF82422 是一种人源重组抗 α-突触核蛋白单克隆抗体（mAb），用于治疗突触核蛋白病。α-突触核蛋白主要在大脑、周围神经和血细胞中表达。组织交叉反应性评估显示，Lu AF82422 的结合通常仅限于神经组织。流式细胞术分析显示，Lu AF82422 并未与人类血小板、红细胞、粒细胞或淋巴细胞的细胞外表面结合，但与单核细胞的一小部分结合，对其激活或吞噬能力没有任何功能影响。在食蟹猴中进行的单次剂量药代动力学（PK）研究，剂量水平为 1-30mg/kg，证实了与可溶性靶标结合的 mAb 的 PK 特性，并且通过检测到游离的α-突触核蛋白在血浆中的减少，表明了靶标结合。在大鼠和食蟹猴中进行了为期 4 周的重复剂量毒性研究，剂量高达 600mg/kg，每 10 天静脉注射一次。结果显示，无治疗相关的不良发现，最高剂量组未观察到不良反应。在血浆和脑脊液中均观察到了靶标结合。综上所述，非临床数据表明没有值得关注的安全性信号，并在动物中观察到的安全剂量与 FIH SAD 研究中计划的剂量水平之间提供了足够的安全裕度。
