Latozinemab, a novel progranulin-elevating therapy for frontotemporal dementia.
Latozinemab, a novel progranulin-elevating therapy for frontotemporal dementia.
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Latozinemab，一种治疗额颞叶痴呆的新型颗粒体蛋白前体升高疗法。
DOI：
10.1186/s12967-023-04251-y
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发表时间：
2023-06-15
影响因子：
7.4
通讯作者：
Rosenthal, Arnon
中科院分区：
文献类型：
--
作者：
Kurnellas, Michael;Mitra, Ananya;Schwabe, Tina;Paul, Robert;Arrant, Andrew E.;Roberson, Erik D.;Ward, Michael;Yeh, Felix;Long, Hua;Rosenthal, Arnon
关键词：
颗粒蛋白前体（PGRN）基因（GRN）中的杂合功能丧失突变导致PGRN减少并导致额颞叶痴呆（FTD-GRN）的发展。PGRN是一种分泌的溶酶体伴侣、免疫调节剂和神经元存活因子，其通过多种受体（包括分拣蛋白）穿梭于溶酶体。在这里，我们报告了latozinemab的表征，latozinemab是一种人单克隆抗体，可降低分拣蛋白的水平，分拣蛋白在骨髓和神经元细胞上表达，并将PGRN穿梭于溶酶体进行降解，并阻断其与PGRN的相互作用。首先进行了体外表征研究，以评估拉他齐单抗的作用机制。体外研究后，进行了一系列体内研究，以评估小鼠交叉反应性抗分拣蛋白抗体的疗效以及拉唑单抗在非人灵长类动物和人体中的药代动力学、药效学和安全性。在FTD-GRN的小鼠模型中，啮齿动物交叉反应性抗分拣蛋白抗体S15 JG降低了白色血细胞（WBC）裂解物中的总分拣蛋白水平，使PGRN恢复至血浆中的正常水平，并挽救了行为缺陷。在食蟹猴中，拉唑单抗可降低WBC中分拣蛋白水平，同时使血浆和脑脊液（CSF）PGRN增加2- 3倍。最后，在一项首次人体I期临床试验中，单次输注拉唑单抗可导致健康志愿者WBC分拣蛋白降低，血浆PGRN增加3倍，CSF PGRN增加2倍，无症状GRN突变携带者PGRN恢复至生理水平。这些发现支持开发拉唑单抗用于治疗FTD-GRN和其他神经退行性疾病，其中PGRN升高可能有益。试用注册ClinicalTrials.gov，NCT 03636204。于2018年8月17日注册，https://clinicaltrials.gov/ct2/show/NCT03636204。在线版本包含补充材料，可通过10.1186/s12967-023-04251-y获得。
Heterozygous loss-of-function mutations in the progranulin (PGRN) gene (GRN) cause a reduction in PGRN and lead to the development of frontotemporal dementia (FTD-GRN). PGRN is a secreted lysosomal chaperone, immune regulator, and neuronal survival factor that is shuttled to the lysosome through multiple receptors, including sortilin. Here, we report the characterization of latozinemab, a human monoclonal antibody that decreases the levels of sortilin, which is expressed on myeloid and neuronal cells and shuttles PGRN to the lysosome for degradation, and blocks its interaction with PGRN. In vitro characterization studies were first performed to assess the mechanism of action of latozinemab. After the in vitro studies, a series of in vivo studies were performed to assess the efficacy of a mouse-cross reactive anti-sortilin antibody and the pharmacokinetics, pharmacodynamics, and safety of latozinemab in nonhuman primates and humans. In a mouse model of FTD-GRN, the rodent cross-reactive anti-sortilin antibody, S15JG, decreased total sortilin levels in white blood cell (WBC) lysates, restored PGRN to normal levels in plasma, and rescued a behavioral deficit. In cynomolgus monkeys, latozinemab decreased sortilin levels in WBCs and concomitantly increased plasma and cerebrospinal fluid (CSF) PGRN by 2- to threefold. Finally, in a first-in-human phase 1 clinical trial, a single infusion of latozinemab caused a reduction in WBC sortilin, tripled plasma PGRN and doubled CSF PGRN in healthy volunteers, and restored PGRN to physiological levels in asymptomatic GRN mutation carriers. These findings support the development of latozinemab for the treatment of FTD-GRN and other neurodegenerative diseases where elevation of PGRN may be beneficial. Trial registration ClinicalTrials.gov, NCT03636204. Registered on 17 August 2018, https://clinicaltrials.gov/ct2/show/NCT03636204. The online version contains supplementary material available at 10.1186/s12967-023-04251-y.
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影响因子：
4
作者：
Bateman, Andrew;Bennett, Hugh P. J.
通讯作者：
Bennett, Hugh P. J.
影响因子：
15.1
作者：
Beel S;Herdewyn S;Fazal R;De Decker M;Moisse M;Robberecht W;Van Den Bosch L;Van Damme P
通讯作者：
Van Damme P
影响因子：
3.5
作者：
Beel S;Moisse M;Damme M;De Muynck L;Robberecht W;Van Den Bosch L;Saftig P;Van Damme P
通讯作者：
Van Damme P
DOI：
10.1523/jneurosci.6103-11.2013
发表时间：
2013-03-20
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Filiano AJ;Martens LH;Young AH;Warmus BA;Zhou P;Diaz-Ramirez G;Jiao J;Zhang Z;Huang EJ;Gao FB;Farese RV Jr;Roberson ED
通讯作者：
Roberson ED
影响因子：
16.2
作者：
Hu, Fenghua;Padukkavidana, Thihan;Vaegter, Christian B.;Brady, Owen A.;Zheng, Yanqiu;Mackenzie, Ian R.;Feldman, Howard H.;Nykjaer, Anders;Strittmatter, Stephen M.
通讯作者：
Strittmatter, Stephen M.