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Preclinical in vivo longitudinal assessment of KG207-M as a disease-modifying Alzheimer’s disease therapeutic
Journal of Cerebral Blood Flow & Metabolism ( IF 4.9 ) Pub Date : 2021-08-11 , DOI: 10.1177/0271678x211035625
Min Su Kang 1, 2, 3 , Monica Shin 1, 2 , Julie Ottoy 1 , Arturo Aliaga Aliaga 1, 2, 3 , Sulantha Mathotaarachchi 1, 2 , Kely Quispialaya 1 , Tharick A Pascoal 1, 2 , D Louis Collins 3 , M Mallar Chakravarty 2 , Axel Mathieu 2 , Åsa Sandelius 4 , Kaj Blennow 4, 5 , Henrik Zetterberg 4, 5, 6, 7 , Gassan Massarweh 3 , Jean-Paul Soucy 3 , A Claudio Cuello 8 , Serge Gauthier 1, 2, 3 , Michael Waterston 9 , Nathan Yoganathan 10 , Etienne Lessard 11 , Arsalan Haqqani 11 , Kerry Rennie 11 , Danica Stanimirovic 11 , Balu Chakravarthy 11 , Pedro Rosa-Neto 1, 2, 3
Affiliation  

In vivo biomarker abnormalities provide measures to monitor therapeutic interventions targeting amyloid-β pathology as well as its effects on downstream processes associated with Alzheimer’s disease pathophysiology. Here, we applied an in vivo longitudinal study design combined with imaging and cerebrospinal fluid biomarkers, mirroring those used in human clinical trials to assess the efficacy of a novel brain-penetrating anti-amyloid fusion protein treatment in the McGill-R-Thy1-APP transgenic rat model. The bi-functional fusion protein consisted of a blood-brain barrier crossing single domain antibody (FC5) fused to an amyloid-β oligomer-binding peptide (ABP) via Fc fragment of mouse IgG (FC5-mFc2a-ABP). A five-week treatment with FC5-mFc2a-ABP (loading dose of 30 mg/Kg/iv followed by 15 mg/Kg/week/iv for four weeks) substantially reduced brain amyloid-β levels as measured by positron emission tomography and increased the cerebrospinal fluid amyloid-β42/40 ratio. In addition, the 5-week treatment rectified the cerebrospinal fluid neurofilament light chain concentrations, resting-state functional connectivity, and hippocampal atrophy measured using magnetic resonance imaging. Finally, FC5-mFc2a-ABP (referred to as KG207-M) treatment did not induce amyloid-related imaging abnormalities such as microhemorrhage. Together, this study demonstrates the translational values of the designed preclinical studies for the assessment of novel therapies based on the clinical biomarkers providing tangible metrics for designing early-stage clinical trials.



中文翻译:

KG207-M 作为一种改善阿尔茨海默病的治疗药物的临床前体内纵向评估

体内生物标志物异常提供了监测针对β-淀粉样蛋白病理学的治疗干预措施及其对与阿尔茨海默病病理生理学相关的下游过程的影响的措施。在这里,我们应用了体内纵向研究设计与成像和脑脊液生物标志物相结合,反映了人类临床试验中用于评估新型脑穿透性抗淀粉样蛋白融合蛋白治疗在 McGill-R-Thy1-APP 转基因大鼠模型中的功效。双功能融合蛋白由通过小鼠 IgG (FC5-mFc2a-ABP) 的 Fc 片段与淀粉样蛋白-β 寡聚体结合肽 (ABP) 融合的血脑屏障单域抗体 (FC5) 组成。用 FC5-mFc2a-ABP 进行为期五周的治疗(负荷剂量为 30 mg/Kg/iv,然后是 15 mg/Kg/week/iv,持续 4 周)显着降低了正电子发射断层扫描测量的脑淀粉样蛋白-β 水平并增加了脑脊液淀粉样蛋白-β 42/40比率。此外,5 周的治疗纠正了使用磁共振成像测量的脑脊液神经丝轻链浓度、静息状态功能连接和海马萎缩。最后,FC5-mFc2a-ABP(简称KG207-M)治疗不会诱发淀粉样蛋白相关的影像学异常,例如微出血。总之,这项研究证明了设计的临床前研究的转化价值,用于评估基于临床生物标志物的新疗法,为设计早期临床试验提供了切实的指标。

更新日期:2021-08-11
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