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

IF 5.6 2区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
mAbs 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
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引用次数: 0

Abstract

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.

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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。
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。
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来源期刊
mAbs
mAbs 工程技术-仪器仪表
CiteScore
10.70
自引率
11.30%
发文量
77
审稿时长
6-12 weeks
期刊介绍: mAbs is a multi-disciplinary journal dedicated to the art and science of antibody research and development. The journal has a strong scientific and medical focus, but also strives to serve a broader readership. The articles are thus of interest to scientists, clinical researchers, and physicians, as well as the wider mAb community, including our readers involved in technology transfer, legal issues, investment, strategic planning and the regulation of therapeutics.
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