头脑风暴的传递™ 淀粉样蛋白-β抗体融合曲汀单抗对非人类灵长类动物大脑的作用,并预测了在人类中的有效剂量方案。

IF 8.3 2区 材料科学 Q1 MATERIALS SCIENCE, MULTIDISCIPLINARY
ACS Applied Materials & Interfaces Pub Date : 2023-01-01 Epub Date: 2023-10-12 DOI:10.1080/19420862.2023.2261509
Hans Peter Grimm, Vanessa Schumacher, Martin Schäfer, Sabine Imhof-Jung, Per-Ola Freskgård, Kevin Brady, Carsten Hofmann, Petra Rüger, Tilman Schlothauer, Ulrich Göpfert, Maximilian Hartl, Sylvia Rottach, Adrian Zwick, Shanon Seger, Rachel Neff, Jens Niewoehner, Niels Janssen
{"title":"头脑风暴的传递™ 淀粉样蛋白-β抗体融合曲汀单抗对非人类灵长类动物大脑的作用,并预测了在人类中的有效剂量方案。","authors":"Hans Peter Grimm, Vanessa Schumacher, Martin Schäfer, Sabine Imhof-Jung, Per-Ola Freskgård, Kevin Brady, Carsten Hofmann, Petra Rüger, Tilman Schlothauer, Ulrich Göpfert, Maximilian Hartl, Sylvia Rottach, Adrian Zwick, Shanon Seger, Rachel Neff, Jens Niewoehner, Niels Janssen","doi":"10.1080/19420862.2023.2261509","DOIUrl":null,"url":null,"abstract":"<p><p>There are few treatments that slow neurodegeneration in Alzheimer's disease (AD), and while therapeutic antibodies are being investigated in clinical trials for AD treatment, their access to the central nervous system is restricted by the blood-brain barrier. This study investigates a bispecific modular fusion protein composed of gantenerumab, a fully human monoclonal anti- amyloid-beta (Aβ) antibody under investigation for AD treatment, with a human transferrin receptor 1-directed Brainshuttle™ module (trontinemab; RG6102, INN trontinemab). <i>In vitro</i>, trontinemab showed a similar binding affinity to fibrillar Aβ<sub>40</sub> and Aβ plaques in human AD brain sections to gantenerumab. A single intravenous administration of trontinemab (10 mg/kg) or gantenerumab (20 mg/kg) to non-human primates (NHPs, <i>Macaca fascicularis</i>), was well tolerated in both groups. Immunohistochemistry indicated increased trontinemab uptake into the brain endothelial cell layer and parenchyma, and more homogeneous distribution, compared with gantenerumab. Brain and plasma pharmacokinetic (PK) parameters for trontinemab were estimated by nonlinear mixed-effects modeling with correction for tissue residual blood, indicating a 4-18-fold increase in brain exposure. A previously developed clinical PK/pharmacodynamic model of gantenerumab was adapted to include a brain compartment as a driver of plaque removal and linked to the allometrically scaled above model from NHP. The new brain exposure-based model was used to predict trontinemab dosing regimens for effective amyloid reduction. Simulations from these models were used to inform dosing of trontinemab in the first-in-human clinical trial.</p>","PeriodicalId":5,"journal":{"name":"ACS Applied Materials & Interfaces","volume":null,"pages":null},"PeriodicalIF":8.3000,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/f7/9d/KMAB_15_2261509.PMC10572082.pdf","citationCount":"0","resultStr":"{\"title\":\"Delivery of the Brainshuttle™ amyloid-beta antibody fusion trontinemab to non-human primate brain and projected efficacious dose regimens in humans.\",\"authors\":\"Hans Peter Grimm, Vanessa Schumacher, Martin Schäfer, Sabine Imhof-Jung, Per-Ola Freskgård, Kevin Brady, Carsten Hofmann, Petra Rüger, Tilman Schlothauer, Ulrich Göpfert, Maximilian Hartl, Sylvia Rottach, Adrian Zwick, Shanon Seger, Rachel Neff, Jens Niewoehner, Niels Janssen\",\"doi\":\"10.1080/19420862.2023.2261509\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>There are few treatments that slow neurodegeneration in Alzheimer's disease (AD), and while therapeutic antibodies are being investigated in clinical trials for AD treatment, their access to the central nervous system is restricted by the blood-brain barrier. This study investigates a bispecific modular fusion protein composed of gantenerumab, a fully human monoclonal anti- amyloid-beta (Aβ) antibody under investigation for AD treatment, with a human transferrin receptor 1-directed Brainshuttle™ module (trontinemab; RG6102, INN trontinemab). <i>In vitro</i>, trontinemab showed a similar binding affinity to fibrillar Aβ<sub>40</sub> and Aβ plaques in human AD brain sections to gantenerumab. A single intravenous administration of trontinemab (10 mg/kg) or gantenerumab (20 mg/kg) to non-human primates (NHPs, <i>Macaca fascicularis</i>), was well tolerated in both groups. Immunohistochemistry indicated increased trontinemab uptake into the brain endothelial cell layer and parenchyma, and more homogeneous distribution, compared with gantenerumab. Brain and plasma pharmacokinetic (PK) parameters for trontinemab were estimated by nonlinear mixed-effects modeling with correction for tissue residual blood, indicating a 4-18-fold increase in brain exposure. A previously developed clinical PK/pharmacodynamic model of gantenerumab was adapted to include a brain compartment as a driver of plaque removal and linked to the allometrically scaled above model from NHP. The new brain exposure-based model was used to predict trontinemab dosing regimens for effective amyloid reduction. Simulations from these models were used to inform dosing of trontinemab in the first-in-human clinical trial.</p>\",\"PeriodicalId\":5,\"journal\":{\"name\":\"ACS Applied Materials & Interfaces\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":8.3000,\"publicationDate\":\"2023-01-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/f7/9d/KMAB_15_2261509.PMC10572082.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"ACS Applied Materials & Interfaces\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1080/19420862.2023.2261509\",\"RegionNum\":2,\"RegionCategory\":\"材料科学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2023/10/12 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"MATERIALS SCIENCE, MULTIDISCIPLINARY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Applied Materials & Interfaces","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/19420862.2023.2261509","RegionNum":2,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2023/10/12 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"MATERIALS SCIENCE, MULTIDISCIPLINARY","Score":null,"Total":0}
引用次数: 0

摘要

很少有治疗方法能减缓阿尔茨海默病(AD)的神经退行性变,尽管治疗性抗体正在AD治疗的临床试验中进行研究,但它们进入中枢神经系统的途径受到血脑屏障的限制。本研究研究了一种双特异性模块化融合蛋白,该蛋白由甘特能单抗(一种正在研究用于AD治疗的全人类单克隆抗淀粉样蛋白β(aβ)抗体)和人转铁蛋白受体1导向脑脊髓炎组成™ 模块(曲汀单抗;RG6102,INN曲汀单抗)。在体外,曲汀单抗对原纤维aβ40和人AD脑切片中的aβ斑块显示出类似的结合亲和力。单次静脉注射曲坦单抗(10 mg/kg)或甘特能单抗(20 mg/kg)给非人类灵长类动物(NHPs,束猴)的剂量在两组中都具有良好的耐受性。免疫组织化学显示,与甘特能单抗相比,曲汀单抗在脑内皮细胞层和实质中的摄取增加,分布更加均匀。通过非线性混合效应模型估计了曲汀单抗的脑和血浆药代动力学(PK)参数,并对组织残留血液进行了校正,表明脑暴露量增加了4-18倍。先前开发的gantenerumab临床PK/药效学模型适用于包括作为斑块去除驱动因素的大脑隔室,并与来自NHP的异速缩放的上述模型相关联。新的基于脑暴露的模型用于预测曲汀单抗的给药方案,以有效减少淀粉样蛋白。在首次人体临床试验中,这些模型的模拟被用于告知曲坦单抗的剂量。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Delivery of the Brainshuttle™ amyloid-beta antibody fusion trontinemab to non-human primate brain and projected efficacious dose regimens in humans.

Delivery of the Brainshuttle™ amyloid-beta antibody fusion trontinemab to non-human primate brain and projected efficacious dose regimens in humans.

Delivery of the Brainshuttle™ amyloid-beta antibody fusion trontinemab to non-human primate brain and projected efficacious dose regimens in humans.

Delivery of the Brainshuttle™ amyloid-beta antibody fusion trontinemab to non-human primate brain and projected efficacious dose regimens in humans.

There are few treatments that slow neurodegeneration in Alzheimer's disease (AD), and while therapeutic antibodies are being investigated in clinical trials for AD treatment, their access to the central nervous system is restricted by the blood-brain barrier. This study investigates a bispecific modular fusion protein composed of gantenerumab, a fully human monoclonal anti- amyloid-beta (Aβ) antibody under investigation for AD treatment, with a human transferrin receptor 1-directed Brainshuttle™ module (trontinemab; RG6102, INN trontinemab). In vitro, trontinemab showed a similar binding affinity to fibrillar Aβ40 and Aβ plaques in human AD brain sections to gantenerumab. A single intravenous administration of trontinemab (10 mg/kg) or gantenerumab (20 mg/kg) to non-human primates (NHPs, Macaca fascicularis), was well tolerated in both groups. Immunohistochemistry indicated increased trontinemab uptake into the brain endothelial cell layer and parenchyma, and more homogeneous distribution, compared with gantenerumab. Brain and plasma pharmacokinetic (PK) parameters for trontinemab were estimated by nonlinear mixed-effects modeling with correction for tissue residual blood, indicating a 4-18-fold increase in brain exposure. A previously developed clinical PK/pharmacodynamic model of gantenerumab was adapted to include a brain compartment as a driver of plaque removal and linked to the allometrically scaled above model from NHP. The new brain exposure-based model was used to predict trontinemab dosing regimens for effective amyloid reduction. Simulations from these models were used to inform dosing of trontinemab in the first-in-human clinical trial.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
ACS Applied Materials & Interfaces
ACS Applied Materials & Interfaces 工程技术-材料科学:综合
CiteScore
16.00
自引率
6.30%
发文量
4978
审稿时长
1.8 months
期刊介绍: ACS Applied Materials & Interfaces is a leading interdisciplinary journal that brings together chemists, engineers, physicists, and biologists to explore the development and utilization of newly-discovered materials and interfacial processes for specific applications. Our journal has experienced remarkable growth since its establishment in 2009, both in terms of the number of articles published and the impact of the research showcased. We are proud to foster a truly global community, with the majority of published articles originating from outside the United States, reflecting the rapid growth of applied research worldwide.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信