Jeffrey Stavenhagen, PhD, Therini Bio, Inc, Sacramento, CA, USA, Email:
J Prev Alzheimers Dis. 2023;10(4):647-660. doi: 10.14283/jpad.2023.105.
Blood-brain barrier (BBB) disruption is an early event in the development of Alzheimer's disease. It precedes extracellular deposition of amyloid-β in senile plaques and blood vessel walls, the intracellular accumulation of neurofibrillary tangles containing phosphorylated tau protein, microglial activation, and neuronal cell death. BBB disruption allows the coagulation protein fibrinogen to leak from the blood into the brain, where it is converted by thrombin cleavage into fibrin and deposits in the parenchyma and CNS vessels. Fibrinogen cleavage by thrombin exposes a cryptic epitope termed P2 which can bind CD11b and CD11c on microglia, macrophages and dendritic cells and trigger an inflammatory response toxic to neurons. Indeed, genetic and pharmacological evidence demonstrates a causal role for fibrin in innate immune cell activation and the development of neurodegenerative diseases. The P2 inflammatory epitope is spatially and compositionally distinct from the coagulation epitope on fibrin. Mouse monoclonal antibody 5B8, which targets the P2 epitope without interfering with the clotting process, has been shown to reduce neurodegeneration and neuroinflammation in animal models of Alzheimer's disease and multiple sclerosis. The selectivity and efficacy of this anti-human fibrin-P2 antibody in animal models supports the development of a monoclonal antibody drug targeting fibrin P2 for the treatment of neurodegenerative diseases. THN391 is a humanized, affinity-matured antibody which has a 100-fold greater affinity for fibrin P2 and improved development properties compared to the parental 5B8 antibody. It is currently in a Phase 1 clinical trial.
血脑屏障（BBB）破坏是阿尔茨海默病发展过程中的早期事件。它先于淀粉样蛋白-β在老年斑和血管壁中的细胞外沉积、含有磷酸化 tau 蛋白的神经原纤维缠结的细胞内积累、小胶质细胞激活和神经元细胞死亡。BBB 破坏允许凝血蛋白纤维蛋白原从血液漏入大脑，在那里它被凝血酶切割成纤维蛋白并沉积在实质和中枢神经系统血管中。纤维蛋白原被凝血酶切割会暴露出一个称为 P2 的隐匿表位，它可以与小胶质细胞、巨噬细胞和树突状细胞上的 CD11b 和 CD11c 结合，并引发对神经元有毒的炎症反应。事实上，遗传和药理学证据表明纤维蛋白在先天免疫细胞激活和神经退行性疾病的发展中起着因果作用。P2 炎症表位在空间和组成上与纤维蛋白上的凝血表位不同。靶向 P2 表位而不干扰凝血过程的小鼠单克隆抗体 5B8 已被证明可减少阿尔茨海默病和多发性硬化症动物模型中的神经退行性变和神经炎症。这种抗人纤维蛋白-P2 抗体在动物模型中的选择性和疗效支持开发一种针对纤维蛋白 P2 的单克隆抗体药物，用于治疗神经退行性疾病。THN391 是一种人源化、亲和力成熟的抗体，与亲本 5B8 抗体相比，它对纤维蛋白 P2 的亲和力提高了 100 倍，并且具有更好的开发特性。它目前正在进行 I 期临床试验。
