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当代阿耳茨海默病研究

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ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

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Research Article

阿尔茨海默病中可溶性A分子动力学和脑内抗A羟丙基单克隆抗体作用的机制建模

卷 17, 期 4, 2020

页: [393 - 406] 页: 14

弟呕挨: 10.2174/1567205017666200302122307

价格: $65

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摘要

背景:抗淀粉样蛋白-羟色胺(A羟色胺)单克隆抗体(mAbs)目前正在开发中，用于治疗阿尔茨海默病。 目的:解决羟甲基苯丙氨酸靶向药物参与情况的复杂性，提高对crenezumab在大脑中的药代动力学(PK)和药代动力学(PD)的理解，并促进具有不同结合特性的抗A羟甲基苯丙氨酸靶向药物治疗的比较。 方法:建立了一个机械数学模型来描述抗A单克隆抗体和单聚体(单聚体和寡聚体形式的双甲基单抗和双甲基单甲基单抗)在脑、脑脊液(CSF)和血浆中的分布、消除和结合动力学。根据之前的数据，将有生理意义的值分配给模型参数，剩下的参数与临床测量的脑脊液和血浆中的浓度和接受抗A疗法的患者的PK/PD数据相吻合。利用蒙特卡罗方法模拟了一种寡糖目标的接触情况，以探讨模型参数中生物不确定性的影响。 结果:基于模型的抗体对单分子A的体内亲和力的估计与之前的数据定性一致。模拟了一个目标与临床PK/PD数据的均值和方差。 结论:该模型可用于比较不同抗a药物的靶向作用，并证明60 mg/kg crenezumab与低剂量的solanezumab相比，显著提高了抗a药物的靶向作用，支持在3期研究中选择60 mg/kg crenezumab。该模型还提供了证据，证明运送足够数量的单克隆抗体到脑组织间液是一个限制步骤，相对于可溶性a低聚物中和的大小。

关键词: 阿尔兹海默症

« Previous
[1]
Alzheimer’s Association. 2017 Alzheimer’s disease facts and figures. Alzheimers Dement 2017; 13(4): 325-73.
[http://dx.doi.org/10.1016/j.jalz.2017.02.001]
[2]
El-Desouki RAKM. New insights on Alzheimer’s disease. J Microsc Ultrastruct 2014; 2(2): 57-66.
[http://dx.doi.org/10.1016/j.jmau.2014.01.002]
[3]
GBD 2015 Mortality and Causes of Death Collaborators. Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet 2016; 388(10053): 1459-544.
[http://dx.doi.org/10.1016/S0140-6736(16)31012-1] [PMID: 27733281]
[4]
Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: Progress and problems on the road to therapeutics. Science 2002; 297(5580): 353-6.
[http://dx.doi.org/10.1126/science.1072994] [PMID: 12130773]
[5]
Haass C, Selkoe DJ. Soluble protein oligomers in neurodegeneration: Lessons from the Alzheimer’s amyloid beta-peptide. Nat Rev Mol Cell Biol 2007; 8(2): 101-12.
[http://dx.doi.org/10.1038/nrm2101] [PMID: 17245412]
[6]
Benilova I, Karran E, De Strooper B. The toxic Aβ oligomer and Alzheimer’s disease: An emperor in need of clothes. Nat Neurosci 2012; 15(3): 349-57.
[http://dx.doi.org/10.1038/nn.3028] [PMID: 22286176]
[7]
Wang S, Mims PN, Roman RJ, Fan F. Is beta-amyloid accumulation a cause or consequence of Alzheimer’s disease? J Alzheimers Parkinsonism Dement 2016;; 1(2): 007.
[PMID: 28815226]
[8]
Counts SE, Ray B, Mufson EJ, Perez SE, He B, Lahiri DK. Intravenous immunoglobulin (IVIG) treatment exerts antioxidant and neuropreservatory effects in preclinical models of Alzheimer’s disease. J Clin Immunol 2014; 34(Suppl. 1): S80-5.
[http://dx.doi.org/10.1007/s10875-014-0020-9] [PMID: 24760109]
[9]
Relkin NR, Thomas RG, Rissman RA, et al. Alzheimer’s Disease Cooperative Study. A phase 3 trial of IV immunoglobulin for Alzheimer disease. Neurology 2017; 88(18): 1768-75.
[http://dx.doi.org/10.1212/WNL.0000000000003904] [PMID: 28381506]
[10]
Panza F, Lozupone M, Logroscino G, Imbimbo BP. A critical appraisal of amyloid-β-targeting therapies for Alzheimer disease. Nat Rev Neurol 2019; 15(2): 73-88.
[http://dx.doi.org/10.1038/s41582-018-0116-6] [PMID: 30610216]
[11]
Adolfsson O, Pihlgren M, Toni N, et al. An effector-reduced anti-β-amyloid (Aβ) antibody with unique aβ binding properties promotes neuroprotection and glial engulfment of Aβ. J Neurosci 2012; 32(28): 9677-89.
[http://dx.doi.org/10.1523/JNEUROSCI.4742-11.2012] [PMID: 22787053]
[12]
Ultsch M, Li B, Maurer T, et al. Structure of crenezumab complex with Aβ shows loss of β-hairpin. Sci Rep 2016; 6: 39374.
[http://dx.doi.org/10.1038/srep39374] [PMID: 27996029]
[13]
Meilandt WJ, Maloney J, Imperio J, Bainbridge TW, Reichelt M, Mandikian D, et al. Characterization of the selective in vivo and in vitro binding properties of crenezumab: insights into crenezumab’s unique mechanism of action. Neurology 2018;; 90(15 suppl): P6.174.
[14]
Salloway S, Sperling R, Gilman S, et al. Bapineuzumab 201 Clinical Trial Investigators. A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology 2009; 73(24): 2061-70.
[http://dx.doi.org/10.1212/WNL.0b013e3181c67808] [PMID: 19923550]
[15]
Ostrowitzki S, Deptula D, Thurfjell L, et al. Mechanism of amyloid removal in patients with Alzheimer disease treated with gantenerumab. Arch Neurol 2012; 69(2): 198-207.
[http://dx.doi.org/10.1001/archneurol.2011.1538] [PMID: 21987394]
[16]
Fuller JP, Stavenhagen JB, Teeling JL. New roles for Fc receptors in neurodegeneration-the impact on Immunotherapy for Alzheimer’s Disease. Front Neurosci 2014; 8: 235.
[http://dx.doi.org/10.3389/fnins.2014.00235] [PMID: 25191216]
[17]
Sevigny J, Chiao P, Bussière T, et al. The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature 2016; 537(7618): 50-6.
[http://dx.doi.org/10.1038/nature19323] [PMID: 27582220]
[18]
Humpel C, Hochstrasser T. Cerebrospinal fluid and blood biomarkers in Alzheimer’s disease. World J Psychiatry 2011; 1(1): 8-18.
[http://dx.doi.org/10.5498/wjp.v1.i1.8] [PMID: 24175162]
[19]
Karelina T, Demin O, Nicholas T, Lu Y, Duvvuri S, Barton HA. A translational systems pharmacology model for Aβ kinetics in mouse, monkey, and human. CPT Pharmacometrics Syst Pharmacol 2017; 6(10): 666-75.
[http://dx.doi.org/10.1002/psp4.12211] [PMID: 28571112]
[20]
Karelina T, Demin O Jr, Demin O, Duvvuri S, Nicholas T. Studying the progression of amyloid pathology and its therapy using translational longitudinal model of accumulation and distribution amyloid beta. CPT Pharmacometrics Syst Pharmacol 2017; 6(10): 676-85.
[http://dx.doi.org/10.1002/psp4.12249] [PMID: 28913897]
[21]
Lu Y, Zhang L, Nolan CE, et al. Quantitative pharmacokinetic/pharmacodynamic analyses suggest that the 129/SVE mouse is a suitable preclinical pharmacology model for identifying small-molecule γ-secretase inhibitors. J Pharmacol Exp Ther 2011; 339(3): 922-34.
[http://dx.doi.org/10.1124/jpet.111.186791] [PMID: 21930801]
[22]
Lu Y, Riddell D, Hajos-Korcsok E, et al. Cerebrospinal fluid amyloid-β (Aβ) as an effect biomarker for brain Aβ lowering verified by quantitative preclinical analyses. J Pharmacol Exp Ther 2012; 342(2): 366-75.
[http://dx.doi.org/10.1124/jpet.112.192625] [PMID: 22562771]
[23]
Lu Y, Barton HA, Leung L, et al. Cerebrospinal fluid β-Amyloid turnover in the mouse, dog, monkey and human evaluated by systematic quantitative analyses. Neurodegener Dis 2013; 12(1): 36-50.
[http://dx.doi.org/10.1159/000341217] [PMID: 22922480]
[24]
Lu Y. Integrating experimentation and quantitative modeling to enhance discovery of Beta amyloid lowering therapeutics for Alzheimer’s disease. Front Pharmacol 2012; 3: 177.
[http://dx.doi.org/10.3389/fphar.2012.00177] [PMID: 23060797]
[25]
Elbert DL, Patterson BW, Bateman RJ. Analysis of a compartmental model of amyloid beta production, irreversible loss and exchange in humans. Math Biosci 2015; 261: 48-61.
[http://dx.doi.org/10.1016/j.mbs.2014.11.004] [PMID: 25497960]
[26]
Potter R, Patterson BW, Elbert DL, et al. Increased in vivo amyloid-β42 production, exchange, and loss in presenilin mutation carriers. Sci Transl Med 2013; 5(189)189ra77
[http://dx.doi.org/10.1126/scitranslmed.3005615] [PMID: 23761040]
[27]
Haug KG, Staab A, Dansirikul C, Lehr T. A semi-physiological model of amyloid-β biosynthesis and clearance in human cerebrospinal fluid: a tool for alzheimer’s disease research and drug development. J Clin Pharmacol 2013; 53(7): 691-8.
[http://dx.doi.org/10.1002/jcph.91] [PMID: 23712554]
[28]
Craft DL, Wein LM, Selkoe DJ. A mathematical model of the impact of novel treatments on the A beta burden in the Alzheimer’s brain, CSF and plasma. Bull Math Biol 2002; 64(5): 1011-31.
[http://dx.doi.org/10.1006/bulm.2002.0304] [PMID: 12391865]
[29]
van Maanen EM, van Steeg TJ, Michener MS, et al. Systems pharmacology analysis of the amyloid cascade after β-secretase inhibition enables the identification of an Aβ42 oligomer pool. J Pharmacol Exp Ther 2016; 357(1): 205-16.
[http://dx.doi.org/10.1124/jpet.115.230565] [PMID: 26826190]
[30]
Uenaka K, Nakano M, Willis BA, et al. Comparison of pharmacokinetics, pharmacodynamics, safety, and tolerability of the amyloid β monoclonal antibody solanezumab in Japanese and white patients with mild to moderate alzheimer disease. Clin Neuropharmacol 2012; 35(1): 25-9.
[http://dx.doi.org/10.1097/WNF.0b013e31823a13d3] [PMID: 22134132]
[31]
Boxer AL, Mortensen DL, Li J, Pham K, Friesenhahn M, Ho C, et al. A phase I study with MABT5102A, an anti-abeta antibody, in patients with mild to moderate Alzheimer’s disease. Alzheimers Dement 2010; 6(4)e46
[http://dx.doi.org/10.1016/j.jalz.2010.08.142]
[32]
Honigberg L, Clayton D, Cho W, Rabe C, Friesenhahn M, Ward M, et al. Biomarker results from the crenezumab anti-Aβ phase 2 biomarker trial. J Prev Alzheimers Dis 2014; 1: 247.
[33]
Quartino A, Huledal G, Sparve E, et al. Population pharmacokinetic and pharmacodynamic analysis of plasma Aβ40 and Aβ42 following single oral doses of the BACE1 inhibitor AZD3839 to healthy volunteers. Clin Pharmacol Drug Dev 2014; 3(5): 396-405.
[http://dx.doi.org/10.1002/cpdd.130] [PMID: 27129013]
[34]
Cummings JL, Cohen S, van Dyck CH, et al. ABBY: A phase 2 randomized trial of crenezumab in mild to moderate Alzheimer disease. Neurology 2018; 90(21): e1889-97.
[PMID: 29695589]
[35]
Salloway S, Honigberg LA, Cho W, et al. Amyloid positron emission tomography and cerebrospinal fluid results from a crenezumab anti-amyloid-beta antibody double-blind, placebo-controlled, randomized phase II study in mild-to-moderate Alzheimer’s disease (BLAZE). Alzheimers Res Ther 2018; 10(1): 96.
[http://dx.doi.org/10.1186/s13195-018-0424-5] [PMID: 30231896]
[36]
CREAD study: a study of crenezumab versus placebo to evaluate the efficacy and safety in participants with prodromal to mild Alzheimer's disease (AD) ClinicalTrialsgov identifier: NCT02670083 Available at: https://clinicaltrials.gov/ct2/ show/NCT02670083. [Accessed June 19, 2018]..
[37]
A study of crenezumab versus placebo to evaluate the efficacy and safety in participants with prodromal to mild Alzheimer's disease (AD) (CREAD 2) ClinicalTrialsgov identifier: NCT03114657 Available at: https://clinicaltrials.gov/ct2/show/NCT03114657[Accessed June 19, 2018]..
[38]
Stone JA, Parker E, Kleijn HJ, Forman M, Egan M, Rowland M, et al. Is the peripheral sink hypothesis physiologically feasible? Evidence from model-based assessment of the amyloid pathway. Alzheimers Dement 2016; 12(7): 443.
[http://dx.doi.org/10.1016/j.jalz.2016.06.855]
[39]
Ostrowitzki S, Lasser RA, Dorflinger E, et al. SCarlet RoAD Investigators. A phase III randomized trial of gantenerumab in prodromal Alzheimer’s disease. Alzheimers Res Ther 2017; 9(1): 95.
[PMID: 29221491]

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