Sanofi R&D Neuroscience Unit, Sanofi, 1Av P. Brossolette, 91385, Chilly-Mazarin, France.
Sanofi R&D Biotherapeutics Research, Vitry s/Seine, France.
Alzheimers Res Ther. 2018 Nov 28;10(1):117. doi: 10.1186/s13195-018-0447-y.
Anti-amyloid β (Aβ) immunotherapy represents a major area of drug development for Alzheimer's disease (AD). However, Aβ peptide adopts multiple conformations and the pathological forms to be specifically targeted have not been identified. Aβ immunotherapy-related vasogenic edema has also been severely dose limiting for antibodies with effector functions binding vascular amyloid such as bapineuzumab. These two factors might have contributed to the limited efficacy demonstrated so far in clinical studies.
To address these limitations, we have engineered SAR228810, a humanized monoclonal antibody (mAb) with limited Fc effector functions that binds specifically to soluble protofibrillar and fibrillar forms of Aβ peptide and we tested it together with its murine precursor SAR255952 in vitro and in vivo.
Unlike gantenerumab and BAN2401, SAR228810 and SAR255952 do not bind to Aβ monomers, low molecular weight Aβ oligomers or, in human brain sections, to Aβ diffuse deposits which are not specific of AD pathology. Both antibodies prevent Aβ42 oligomer neurotoxicity in primary neuronal cultures. In vivo, SAR255952, a mouse aglycosylated IgG1, dose-dependently prevented brain amyloid plaque formation and plaque-related inflammation with a minimal active dose of 3 mg/kg/week by the intraperitoneal route. No increase in plasma Aβ levels was observed with SAR255952 treatment, in line with its lack of affinity for monomeric Aβ. The effects of SAR255952 translated into synaptic functional improvement in ex-vivo hippocampal slices. Brain penetration and decoration of cerebral amyloid plaques was documented in live animals and postmortem. SAR255952 (up to 50 mg/kg/week intravenously) did not increase brain microhemorrhages and/or microscopic changes in meningeal and cerebral arteries in old APPSL mice while 3D6, the murine version of bapineuzumab, did. In immunotolerized mice, the clinical candidate SAR228810 demonstrated the same level of efficacy as the murine SAR255952.
Based on the improved efficacy/safety profile in non-clinical models of SAR228810, a first-in-man single and multiple dose administration clinical study has been initiated in AD patients.
针对淀粉样β（Aβ）的抗免疫疗法是治疗阿尔茨海默病（AD）的主要药物研发领域之一。然而，Aβ 肽具有多种构象，尚未确定要针对的病理形式。具有结合血管淀粉样物质（如 bapineuzumab）的效应子功能的 Aβ 免疫治疗相关血管源性水肿也严重限制了抗体的剂量。这两个因素可能导致迄今为止在临床试验中显示的疗效有限。
为了解决这些限制，我们设计了 SAR228810，这是一种具有有限 Fc 效应子功能的人源化单克隆抗体（mAb），可特异性结合可溶性原纤维和纤维形式的 Aβ 肽，并对其与鼠前体 SAR255952 在体外和体内进行了测试。
与 gantenerumab 和 BAN2401 不同，SAR228810 和 SAR255952 不与 Aβ 单体、低分子量 Aβ 寡聚体结合，也不与人类大脑切片中的 Aβ 弥散沉积物结合，这些沉积物不是 AD 病理学特有的。两种抗体均可防止原代神经元培养物中 Aβ42 寡聚物的神经毒性。在体内，SAR255952（一种未经糖基化的 IgG1 鼠抗体）通过腹腔途径以 3mg/kg/周的最小有效剂量，剂量依赖性地阻止了脑淀粉样斑块的形成和斑块相关的炎症。用 SAR255952 治疗未观察到血浆 Aβ 水平升高，这与它对单体 Aβ 的亲和力缺乏一致。SAR255952 的作用转化为离体海马切片中突触功能的改善。在活体动物和尸检中证明了 SAR255952 在大脑淀粉样斑块中的穿透和修饰。SAR255952（最高 50mg/kg/周静脉内）并未增加老年 APPsL 小鼠脑膜和脑动脉中的脑微出血和/或微观变化，而 bapineuzumab 的鼠版本 3D6 则会增加。在免疫耐受小鼠中，临床候选药物 SAR228810 显示出与鼠 SAR255952 相同的疗效。
基于 SAR228810 在非临床 AD 模型中改善的疗效/安全性特征，已在 AD 患者中启动了一项 SAR228810 的首次人体单剂量和多剂量给药临床研究。
