Development of AL101 (GSK4527226), a progranulin-elevating monoclonal antibody, as a potential treatment for Alzheimer's disease.

IF 7.6 1区医学 Q1 CLINICAL NEUROLOGY

Alzheimer's Research & Therapy Pub Date : 2025-07-25 DOI:10.1186/s13195-025-01817-4

Balasubrahmanyam Budda, Ananya Mitra, Lovingly Park, Hua Long, Michael Kurnellas, Nga Bien-Ly, William Estacio, Brady Burgess, Grace Chao, Tina Schwabe, Robert Paul, Sara Kenkare-Mitra, Arnon Rosenthal

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Abstract

Background: 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.

Methods: 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.

Results: 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.

Limitations: 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.

Conclusions: 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.

Trial registration: Clinicaltrials.gov, NCT04111666. Registered on October 1, 2019. https://clinicaltrials.gov/ct2/show/NCT04111666 .

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AL101 （GSK4527226）是一种前蛋白升高单克隆抗体，可作为阿尔茨海默病的潜在治疗药物。

背景：阿尔茨海默病（AD）以淀粉样斑块、tau蛋白缠结和神经元丢失为特征。前颗粒蛋白（PGRN）是一种分泌性免疫调节剂、溶酶体伴侣和神经元存活因子。降低PGRN水平的遗传多态性与AD和其他神经退行性疾病的风险增加有关。受体sortilin结合并靶向PGRN进行溶酶体降解，导致细胞外PGRN的减少。AL101 （GSK4527226）是一种结合sortilin受体的单克隆抗体，正被开发为一种潜在的pgrn升高治疗AD的药物。方法：体外细胞实验检测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体内的安全性、药代动力学（PK）和药效学（PD）。一项针对健康志愿者的i期研究评估了静脉或皮下给药AL101后的PK、安全性、耐受性和PD生物标志物。结果：基于细胞的实验表明，AL101通过降低细胞表面sortinin水平和部分阻断sortinin -PGRN相互作用来增加PGRN水平。在大鼠和猴子身上进行的临床前研究表明，AL101可降低白细胞上的细胞表面sortilin水平，并使脑脊液（CSF）中的PGRN水平提高2倍，血液中的PGRN水平提高4倍。在健康志愿者的1期研究中，单剂量和多剂量AL101均导致血浆和CSF PGRN水平显著升高，为其作为PGRN升高疗法的潜力提供了额外的支持。局限性：首次人体剂量发现研究旨在调查AL101的安全性和耐受性，并且没有足够的能力来检测探索性结果的变化，例如神经退行性生物标志物。需要临床研究来评估AL101在AD患者中的作用。结论：AL101与sortilin结合并降低细胞表面sortilin水平，导致PGRN在体外、临床前和人体研究中一致升高。这些结果支持AL101的继续发展及其作为AD和其他PGRN可能发挥作用的神经退行性疾病的潜在治疗方法的研究。试验注册：Clinicaltrials.gov, NCT04111666。2019年10月1日注册。https://clinicaltrials.gov/ct2/show/NCT04111666。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Alzheimer's Research & Therapy 医学-神经病学

CiteScore

13.10

自引率

3.30%

发文量

172

审稿时长

>12 weeks

期刊介绍： Alzheimer's Research & Therapy is an international peer-reviewed journal that focuses on translational research into Alzheimer's disease and other neurodegenerative diseases. It publishes open-access basic research, clinical trials, drug discovery and development studies, and epidemiologic studies. The journal also includes reviews, viewpoints, commentaries, debates, and reports. All articles published in Alzheimer's Research & Therapy are included in several reputable databases such as CAS, Current contents, DOAJ, Embase, Journal Citation Reports/Science Edition, MEDLINE, PubMed, PubMed Central, Science Citation Index Expanded (Web of Science) and Scopus.