Preclinical and first-in-human evaluation of AL002, a novel TREM2 agonistic antibody for Alzheimer's disease.

IF 7.9 1区医学 Q1 CLINICAL NEUROLOGY Alzheimer's Research & Therapy Pub Date : 2024-10-23 DOI:10.1186/s13195-024-01599-1

Hua Long, Adam Simmons, Arthur Mayorga, Brady Burgess, Tuan Nguyen, Balasubrahmanyam Budda, Anna Rychkova, Herve Rhinn, Ilaria Tassi, Michael Ward, Felix Yeh, Tina Schwabe, Robert Paul, Sara Kenkare-Mitra, Arnon Rosenthal

{"title":"Preclinical and first-in-human evaluation of AL002, a novel TREM2 agonistic antibody for Alzheimer's disease.","authors":"Hua Long, Adam Simmons, Arthur Mayorga, Brady Burgess, Tuan Nguyen, Balasubrahmanyam Budda, Anna Rychkova, Herve Rhinn, Ilaria Tassi, Michael Ward, Felix Yeh, Tina Schwabe, Robert Paul, Sara Kenkare-Mitra, Arnon Rosenthal","doi":"10.1186/s13195-024-01599-1","DOIUrl":null,"url":null,"abstract":"Background: Variants of the gene triggering receptor expressed on myeloid cells-2 (TREM2) increase the risk of Alzheimer's disease (AD) and other neurodegenerative disorders. Signaling by TREM2, an innate immune receptor expressed by microglia, is thought to enhance phagocytosis of amyloid beta (Aβ) and other damaged proteins, promote microglial proliferation, migration, and survival, and regulate inflammatory signaling. Thus, TREM2 activation has potential to alter the progression of AD. AL002 is an investigational, engineered, humanized monoclonal immunoglobulin G1 (IgG1) antibody designed to target TREM2. In AD mouse models, an AL002 murine variant has been previously shown to induce microglial proliferation and reduce filamentous Aβ plaques and neurite dystrophy.Methods: Preclinical studies assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of AL002 in cynomolgus monkeys. INVOKE-1 (NCT03635047) was a first-in-human phase 1, randomized, placebo-controlled, double-blind study assessing the safety, tolerability, PK, and PD of AL002 administered as single ascending doses (SAD) in healthy volunteers.Results: In cynomolgus monkeys, weekly intravenous injections of AL002 for 4 weeks were well tolerated, dose-dependently decreased soluble TREM2 (sTREM2) in cerebrospinal fluid (CSF) and total TREM2 in hippocampus and frontal cortex, and increased biomarkers of TREM2 signaling in CSF and brain. In the phase 1 study of 64 healthy volunteers, a single intravenous infusion of AL002 demonstrated brain target engagement based on a dose-dependent reduction of sTREM2 in CSF and parallel increases in biomarkers of TREM2 signaling and microglia recruitment. Single-dose AL002 showed central nervous system penetrance and was well tolerated, with no treatment-related serious adverse events over 12 weeks.Conclusions: These findings support the continued clinical development of AL002 for AD and other neurodegenerative diseases in which TREM2 activation may be beneficial. AL002 is currently being tested in a phase 2, randomized, double-blind, placebo-controlled study in early AD.Trial registration: Clinicaltrials.gov, NCT03635047. Registered on August 15, 2018, https://www.Clinicaltrials: gov/study/NCT03635047 .","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"16 1","pages":"235"},"PeriodicalIF":7.9000,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11515656/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Alzheimer's Research & Therapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s13195-024-01599-1","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Background: Variants of the gene triggering receptor expressed on myeloid cells-2 (TREM2) increase the risk of Alzheimer's disease (AD) and other neurodegenerative disorders. Signaling by TREM2, an innate immune receptor expressed by microglia, is thought to enhance phagocytosis of amyloid beta (Aβ) and other damaged proteins, promote microglial proliferation, migration, and survival, and regulate inflammatory signaling. Thus, TREM2 activation has potential to alter the progression of AD. AL002 is an investigational, engineered, humanized monoclonal immunoglobulin G1 (IgG1) antibody designed to target TREM2. In AD mouse models, an AL002 murine variant has been previously shown to induce microglial proliferation and reduce filamentous Aβ plaques and neurite dystrophy.

Methods: Preclinical studies assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of AL002 in cynomolgus monkeys. INVOKE-1 (NCT03635047) was a first-in-human phase 1, randomized, placebo-controlled, double-blind study assessing the safety, tolerability, PK, and PD of AL002 administered as single ascending doses (SAD) in healthy volunteers.

Results: In cynomolgus monkeys, weekly intravenous injections of AL002 for 4 weeks were well tolerated, dose-dependently decreased soluble TREM2 (sTREM2) in cerebrospinal fluid (CSF) and total TREM2 in hippocampus and frontal cortex, and increased biomarkers of TREM2 signaling in CSF and brain. In the phase 1 study of 64 healthy volunteers, a single intravenous infusion of AL002 demonstrated brain target engagement based on a dose-dependent reduction of sTREM2 in CSF and parallel increases in biomarkers of TREM2 signaling and microglia recruitment. Single-dose AL002 showed central nervous system penetrance and was well tolerated, with no treatment-related serious adverse events over 12 weeks.

Conclusions: These findings support the continued clinical development of AL002 for AD and other neurodegenerative diseases in which TREM2 activation may be beneficial. AL002 is currently being tested in a phase 2, randomized, double-blind, placebo-controlled study in early AD.

Trial registration: Clinicaltrials.gov, NCT03635047. Registered on August 15, 2018, https://www.

Clinicaltrials: gov/study/NCT03635047 .

查看原文

微信好友朋友圈 QQ好友复制链接

本刊更多论文

对治疗阿尔茨海默病的新型 TREM2 激动剂抗体 AL002 进行临床前和首次人体试验评估。

背景：髓系细胞上表达的触发受体-2（TREM2）基因变异会增加阿尔茨海默病（AD）和其他神经退行性疾病的患病风险。TREM2是一种由小胶质细胞表达的先天性免疫受体，其信号被认为可增强对淀粉样蛋白β（Aβ）和其他受损蛋白质的吞噬作用，促进小胶质细胞的增殖、迁移和存活，并调节炎症信号传导。因此，TREM2 的激活有可能改变注意力缺失症的进展。AL002 是一种正在研究的工程化人源化单克隆免疫球蛋白 G1 (IgG1) 抗体，旨在靶向 TREM2。在AD小鼠模型中，AL002小鼠变体曾被证明能诱导小胶质细胞增殖，减少丝状Aβ斑块和神经元萎缩：临床前研究评估了AL002在猴体内的安全性、耐受性、药代动力学和药效学。INVOKE-1（NCT03635047）是一项首次进行的人体1期随机、安慰剂对照、双盲研究，评估了AL002在健康志愿者体内以单次递增剂量（SAD）给药的安全性、耐受性、PK和PD：在绒猴中，每周静脉注射 AL002 4 周的耐受性良好，脑脊液（CSF）中的可溶性 TREM2（sTREM2）和海马及额叶皮层中的总 TREM2 呈剂量依赖性下降，CSF 和大脑中的 TREM2 信号传导生物标志物增加。在对64名健康志愿者进行的1期研究中，AL002的单次静脉输注显示了脑靶点参与，其依据是脑脊液中sTREM2的剂量依赖性减少以及TREM2信号传导生物标志物和小胶质细胞招募的平行增加。单剂量AL002具有中枢神经系统穿透性，耐受性良好，12周内未发生与治疗相关的严重不良事件：这些研究结果支持继续开发AL002用于治疗AD和其他神经退行性疾病（TREM2激活可能对这些疾病有益）的临床研究。AL002目前正在进行一项针对早期AD的2期随机、双盲、安慰剂对照研究：试验注册：Clinicaltrials.gov，NCT03635047。注册日期为 2018 年 8 月 15 日，https://www.Clinicaltrials：gov/study/NCT03635047 。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文去求助

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.