Mechanistic Modeling of Soluble Aβ Dynamics and Target Engagement in the Brain by Anti-Aβ mAbs in Alzheimer’s Disease

Author(s): Gregory Z. Ferl*, Reina N. Fuji, Jasvinder K. Atwal, Tony Sun, Saroja Ramanujan, Angelica L. Quartino

Journal Name: Current Alzheimer Research

Volume 17 , Issue 4 , 2020

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Abstract:

Background: Anti-amyloid-β (Aβ) monoclonal antibodies (mAbs) are currently in development for treating Alzheimer’s disease.

Objectives: To address the complexity of Aβ target engagement profiles, improve the understanding of crenezumab Pharmacokinetics (PK) and Aβ Pharmacodynamics (PD) in the brain, and facilitate comparison of anti-Aβ therapies with different binding characteristics.

Methods: A mechanistic mathematical model was developed describing the distribution, elimination, and binding kinetics of anti-Aβ mAbs and Aβ (monomeric and oligomeric forms of Aβ1-40 and Aβ1-42) in the brain, Cerebrospinal Fluid (CSF), and plasma. Physiologically meaningful values were assigned to the model parameters based on the previous data, with remaining parameters fitted to clinical measurements of Aβ concentrations in CSF and plasma, and PK/PD data of patients undergoing anti-Aβ therapy. Aβ target engagement profiles were simulated using a Monte Carlo approach to explore the impact of biological uncertainty in the model parameters.

Results: Model-based estimates of in vivo affinity of the antibody to monomeric Aβ were qualitatively consistent with the previous data. Simulations of Aβ target engagement profiles captured observed mean and variance of clinical PK/PD data.

Conclusion: This model is useful for comparing target engagement profiles of different anti-Aβ therapies and demonstrates that 60 mg/kg crenezumab yields a significant increase in Aβ engagement compared with lower doses of solanezumab, supporting the selection of 60 mg/kg crenezumab for phase 3 studies. The model also provides evidence that the delivery of sufficient quantities of mAb to brain interstitial fluid is a limiting step with respect to the magnitude of soluble Aβ oligomer neutralization.

Keywords: Alzheimer's disease, amyloid-β, monoclonal antibodies, mathematical, quantitative systems pharmacology, pharmacokinetics, pharmacodynamics, crenezumab.

[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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VOLUME: 17
ISSUE: 4
Year: 2020
Page: [393 - 406]
Pages: 14
DOI: 10.2174/1567205017666200302122307
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