Alector, Inc., 131 Oyster Point Blvd, #600, South San Francisco, CA, 94080, USA.
Neuron23, South San Francisco, CA, 94080, USA.
J Transl Med. 2023 Jun 15;21(1):387. doi: 10.1186/s12967-023-04251-y.
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 .
颗粒体蛋白前体（PGRN）基因（GRN）的杂合功能丧失性突变导致 PGRN 减少，从而引发额颞叶痴呆（FTD-GRN）。PGRN 是一种分泌性溶酶体伴侣、免疫调节剂和神经元存活因子，通过包括分选蛋白在内的多种受体被转运到溶酶体。在这里，我们报告了 latozinemab 的特征，这是一种人源单克隆抗体，可降低分选蛋白的水平，分选蛋白在髓细胞和神经元细胞上表达，并将 PGRN 转运到溶酶体进行降解，从而阻断其与 PGRN 的相互作用。
首先进行了体外特征研究，以评估 latozinemab 的作用机制。在体外研究之后，进行了一系列体内研究，以评估鼠交叉反应性抗分选蛋白抗体的功效，以及在非人类灵长类动物和人类中 latozinemab 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选蛋白抗体 S15JG 降低了白细胞（WBC）裂解物中的总分选蛋白水平，使血浆中的 PGRN 恢复正常水平，并挽救了行为缺陷。在食蟹猴中，latozinemab 降低了 WBC 中的分选蛋白水平，同时使血浆和脑脊液（CSF）中的 PGRN 增加 2 至 3 倍。最后，在一项首次人体 I 期临床试验中，单次输注 latozinemab 可降低 WBC 分选蛋白水平，使健康志愿者的血浆 PGRN 增加三倍，CSF PGRN 增加两倍，并使无症状 GRN 突变携带者的 PGRN 恢复到生理水平。
这些发现支持了 latozinemab 用于治疗 FTD-GRN 和其他神经退行性疾病的开发，在这些疾病中 PGRN 的升高可能是有益的。
ClinicalTrials.gov，NCT03636204。于 2018 年 8 月 17 日注册，https://clinicaltrials.gov/ct2/show/NCT03636204。
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