Budda Balasubrahmanyam, Mitra Ananya, Park Lovingly, Long Hua, Kurnellas Michael, Bien-Ly Nga, Estacio William, Burgess Brady, Chao Grace, Schwabe Tina, Paul Robert, Kenkare-Mitra Sara, Rosenthal Arnon
Alector, Inc, 131 Oyster Point Blvd, #600, South San Francisco, CA, 94080, USA.
Neuron23, South San Francisco, CA, 94080, USA.
Alzheimers Res Ther. 2025 Jul 25;17(1):174. doi: 10.1186/s13195-025-01817-4.
Alzheimer's disease (AD) is characterized by amyloid plaques, tau tangles, and neuronal loss. Progranulin (PGRN) is a secreted immune regulator, lysosomal chaperone, and neuronal survival factor. Genetic polymorphisms that reduce PGRN levels are associated with an increased risk for AD and other neurodegenerative disorders. The receptor sortilin binds and targets PGRN for lysosomal degradation, resulting in a reduction of extracellular PGRN. AL101 (GSK4527226) is a monoclonal antibody that binds to the sortilin receptor and is being developed as a potential PGRN-elevating therapy for AD.
Cell-based in vitro studies examined the interaction of AL101 with sortilin and its effect on PGRN levels. In vivo studies evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of AL101 in rats and nonhuman primates. A phase 1 study in healthy volunteers assessed PK, safety, tolerability, and PD biomarkers after intravenous or subcutaneous dosing of AL101.
Cell-based assays showed that AL101 increased PGRN levels by decreasing cell surface sortilin levels and partially blocking the sortilin-PGRN interaction. Preclinical studies in rats and monkeys demonstrated that AL101 decreased cell surface sortilin levels on white blood cells and increased PGRN levels by up to 2-fold in cerebrospinal fluid (CSF) and up to 4-fold in blood. In the phase 1 study in healthy volunteers, both single and multiple doses of AL101 led to significant increases in plasma and CSF PGRN levels, providing additional support for its potential as a PGRN-elevating therapy.
The first-in-human dose-finding study was aimed at investigating the safety and tolerability of AL101 and was not sufficiently powered to detect changes in exploratory outcomes, such as neurodegeneration biomarkers. Clinical studies are needed to evaluate AL101 in AD patients.
AL101 was shown to bind sortilin and decrease cell surface sortilin levels, leading to consistent elevations of PGRN across in vitro, preclinical, and human studies. These results support continued development of AL101 and its investigation as a potential treatment for AD and other neurodegenerative conditions where PGRN could play a role.
Clinicaltrials.gov, NCT04111666. Registered on October 1, 2019. https://clinicaltrials.gov/ct2/show/NCT04111666 .
阿尔茨海默病（AD）的特征是淀粉样斑块、tau蛋白缠结和神经元丢失。颗粒蛋白前体（PGRN）是一种分泌型免疫调节因子、溶酶体伴侣蛋白和神经元存活因子。降低PGRN水平的基因多态性与AD及其他神经退行性疾病的风险增加有关。sortilin受体结合并靶向PGRN进行溶酶体降解，导致细胞外PGRN减少。AL101（GSK4527226）是一种与sortilin受体结合的单克隆抗体，正作为一种潜在的升高PGRN治疗AD的药物进行研发。
基于细胞的体外研究检测了AL101与sortilin的相互作用及其对PGRN水平的影响。体内研究评估了AL101在大鼠和非人灵长类动物中的安全性、药代动力学（PK）和药效学（PD）。一项针对健康志愿者的1期研究评估了静脉或皮下注射AL101后的PK、安全性、耐受性和PD生物标志物。
基于细胞的分析表明，AL101通过降低细胞表面sortilin水平并部分阻断sortilin-PGRN相互作用来提高PGRN水平。在大鼠和猴子身上进行的临床前研究表明，AL101降低了白细胞表面的sortilin水平，并使脑脊液（CSF）中的PGRN水平提高了2倍，血液中的PGRN水平提高了4倍。在针对健康志愿者的1期研究中，单剂量和多剂量的AL101均导致血浆和CSF中PGRN水平显著升高，为其作为升高PGRN治疗药物的潜力提供了额外支持。
首次人体剂量探索研究旨在调查AL101的安全性和耐受性，其样本量不足以检测探索性结果的变化，如神经退行性生物标志物。需要进行临床研究以评估AL101在AD患者中的疗效。
研究表明，AL101可结合sortilin并降低细胞表面sortilin水平，从而在体外、临床前和人体研究中持续提高PGRN水平。这些结果支持继续研发AL101，并将其作为AD及其他PGRN可能发挥作用的神经退行性疾病的潜在治疗方法进行研究。
Clinicaltrials.gov，NCT04111666。于2019年10月1日注册。https://clinicaltrials.gov/ct2/show/NCT04111666 。
