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Current Drug Metabolism


ISSN (Print): 1389-2002
ISSN (Online): 1875-5453

General Research Article

Preclinical Study of the Pharmacokinetics of p75ECD-Fc, a Novel Human Recombinant Protein for Treatment of Alzheimer’s Disease, in Sprague Dawley Rats

Author(s): Sally Kelliny, Ho Yin Lam, Ankit Parikh, Yan-Jiang Wang, Larisa Bobrovskaya, Richard Upton and Xin-Fu Zhou*

Volume 21, Issue 3, 2020

Page: [235 - 244] Pages: 10

DOI: 10.2174/1389200221666200502015203

Price: $65


Background: p75ECD-Fc is a recombinant human protein that has recently been developed as a novel therapy for Alzheimer’s disease. Current studies showed that it is able to alleviate Alzheimer’s disease pathologies in animal models of dementia. Thus, knowledge about the pharmacokinetic behavior and tissue distribution of this novel protein is crucial in order to better understand its pharmacodynamics and more importantly for its clinical development.

Methods: The aim of this study is to characterize the pharmacokinetics of p75ECD-Fc after single intravenous and subcutaneous injection of 3mg/kg in Sprague Dawley rats. We calculated the bioavailability of the SC route and studied the distribution of that protein in different tissues, cerebrospinal fluid and urine using ELISA and immunofluorescence techniques. In-vitro stability of the drug was also assessed. Data obtained were analyzed with Non-compartmental pharmacokinetic method using R.

Results: Results showed that the bioavailability of SC route was 66.15%. Half-life time was 7.5 ± 1.7 and 6.2 ± 2.4 days for IV and SC injection, respectively. Tissue distribution of p75ECD-Fc was modest with the ability to penetrate the blood brain barrier. It showed high in vitro stability in human plasma.

Conclusion: These acceptable pharmacokinetic properties of p75ECD-Fc present it as a potential candidate for clinical development for the treatment of Alzheimer’s disease.

Keywords: Alzheimer's disease, pharmacokinetics, p75ECD-Fc, amyloid-β, p75 neurotrophin receptor, non-compartmental analysis.

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Graphical Abstract
Alzheimer’s Disease International. World Alzheimer Report. The state of the art of dementia research. Alzheimer’s Disease International; ADI: London, 2018.
Hardy, J.A.; Higgins, G.A. Alzheimer’s disease: the amyloid cascade hypothesis. Science, 1992, 256(5054), 184-185.
[] [PMID: 1566067]
Mawuenyega, K.G.; Sigurdson, W.; Ovod, V.; Munsell, L.; Kasten, T.; Morris, J.C.; Yarasheski, K.E.; Bateman, R.J. Decreased clearance of CNS beta-amyloid in Alzheimer’s disease. Science, 2010, 330(6012), 1774-1774.
[] [PMID: 21148344]
Zuroff, L.; Daley, D.; Black, K.L.; Koronyo-Hamaoui, M. Clearance of cerebral Aβ in Alzheimer’s disease: reassessing the role of microglia and monocytes. Cell. Mol. Life Sci., 2017, 74(12), 2167-2201.
[] [PMID: 28197669]
Carlson, C.; Estergard, W.; Oh, J.; Suhy, J.; Jack, C.R., Jr; Siemers, E.; Barakos, J. Prevalence of asymptomatic vasogenic edema in pretreatment Alzheimer’s disease study cohorts from phase 3 trials of semagacestat and solanezumab. Alzheimers Dement., 2011, 7(4), 396-401.
[] [PMID: 21784350]
Sperling, R.; Salloway, S.; Brooks, D.J.; Tampieri, D.; Barakos, J.; Fox, N.C.; Raskind, M.; Sabbagh, M.; Honig, L.S.; Porsteinsson, A.P.; Lieberburg, I.; Arrighi, H.M.; Morris, K.A.; Lu, Y.; Liu, E.; Gregg, K.M.; Brashear, H.R.; Kinney, G.G.; Black, R.; Grundman, M. Amyloid-related imaging abnormalities in patients with Alzheimer’s disease treated with bapineuzumab: a retrospective analysis. Lancet Neurol., 2012, 11(3), 241-249.
[] [PMID: 22305802]
Morgan, D. Immunotherapy for Alzheimer’s disease. J. Intern. Med., 2011, 269(1), 54-63.
[] [PMID: 21158978]
Hu, X-Y.; Zhang, H-Y.; Qin, S.; Xu, H.; Swaab, D.F.; Zhou, J-N. Increased p75(NTR) expression in hippocampal neurons containing hyperphosphorylated τ in Alzheimer patients. Exp. Neurol., 2002, 178(1), 104-111.
[] [PMID: 12460612]
Friedman, W.J. Neurotrophins induce death of hippocampal neurons via the p75 receptor. J. Neurosci., 2000, 20(17), 6340-6346.
[] [PMID: 10964939]
Reichardt, L.F. Neurotrophin-regulated signalling pathways. Philos. Trans. R. Soc. Lond. B Biol. Sci., 2006, 361(1473), 1545-1564.
[] [PMID: 16939974]
Yaar, M.; Zhai, S.; Pilch, P.F.; Doyle, S.M.; Eisenhauer, P.B.; Fine, R.E.; Gilchrest, B.A. Binding of beta-amyloid to the p75 neurotrophin receptor induces apoptosis. A possible mechanism for Alzheimer’s disease. J. Clin. Invest., 1997, 100(9), 2333-2340.
[] [PMID: 9410912]
Wang, Y.J.; Wang, X.; Lu, J.J.; Li, Q.X.; Gao, C.Y.; Liu, X.H.; Sun, Y.; Yang, M.; Lim, Y.; Evin, G.; Zhong, J.H.; Masters, C.; Zhou, X.F. p75NTR regulates Abeta deposition by increasing Abeta production but inhibiting Abeta aggregation with its extracellular domain. J. Neurosci., 2011, 31(6), 2292-2304.
[] [PMID: 21307265]
Zeng, F.; Lu, J.J.; Zhou, X.F.; Wang, Y.J. Roles of p75NTR in the pathogenesis of Alzheimer’s disease: a novel therapeutic target. Biochem. Pharmacol., 2011, 82(10), 1500-1509.
[] [PMID: 21762680]
Zhou, X.F.; Wang, Y.J. The p75NTR extracellular domain: a potential molecule regulating the solubility and removal of amyloid-β. Prion, 2011, 5(3), 161-163.
[] [PMID: 21814043]
Yaar, M.; Zhai, S.; Fine, R.E.; Eisenhauer, P.B.; Arble, B.L.; Stewart, K.B.; Gilchrest, B.A. Amyloid β binds trimers as well as monomers of the 75-kDa neurotrophin receptor and activates receptor signaling. J. Biol. Chem., 2002, 277(10), 7720-7725.
[] [PMID: 11756426]
Knowles, J.K.; Rajadas, J.; Nguyen, T-V.V.; Yang, T.; LeMieux, M.C.; Vander Griend, L.; Ishikawa, C.; Massa, S.M.; Wyss-Coray, T.; Longo, F.M. The p75 neurotrophin receptor promotes amyloid-beta(1-42)-induced neuritic dystrophy in vitro and in vivo. J. Neurosci., 2009, 29(34), 10627-10637.
[] [PMID: 19710315]
Costantini, C.; Rossi, F.; Formaggio, E.; Bernardoni, R.; Cecconi, D.; Della-Bianca, V. Characterization of the signaling pathway downstream p75 neurotrophin receptor involved in β-amyloid peptide-dependent cell death. J. Mol. Neurosci., 2005, 25(2), 141-156.
[] [PMID: 15784962]
Pietri, M.; Dakowski, C.; Hannaoui, S.; Alleaume-Butaux, A.; Hernandez-Rapp, J.; Ragagnin, A.; Mouillet-Richard, S.; Haik, S.; Bailly, Y.; Peyrin, J.M.; Launay, J.M.; Kellermann, O.; Schneider, B. PDK1 decreases TACE-mediated α-secretase activity and promotes disease progression in prion and Alzheimer’s diseases. Nat. Med., 2013, 19, 1124.
[] [PMID: 23955714]
Yao, X.Q.; Jiao, S.S.; Saadipour, K.; Zeng, F.; Wang, Q.H.; Zhu, C.; Shen, L.L.; Zeng, G.H.; Liang, C.R.; Wang, J.; Liu, Y.H.; Hou, H.Y.; Xu, X.; Su, Y.P.; Fan, X.T.; Xiao, H.L.; Lue, L.F.; Zeng, Y.Q.; Giunta, B.; Zhong, J.H.; Walker, D.G.; Zhou, H.D.; Tan, J.; Zhou, X.F.; Wang, Y.J. p75NTR ectodomain is a physiological neuroprotective molecule against amyloid-beta toxicity in the brain of Alzheimer’s disease. Mol. Psychiatry, 2015, 20(11), 1301-1310.
[] [PMID: 25917367]
Amgen Wyeth Pharmaceuticals. Amgen Inc. and Wyeth- Ayerst, Thousand Oaks, ; 2004.Available at : .
Liu, Y-H.; Wang, Y-R.; Xiang, Y.; Zhou, H-D.; Giunta, B.; Manucat, N.; Tan, J.; Zhou, X-F.; Wang, Y-J. Clearance of amyloid-beta in Alzheimer’s disease: shifting the action site from center to periphery. Mol. Neurobiol., 2014, 51.
[PMID: 24733588]
Nalivaeva, N.N.; Turner, A.J. Targeting amyloid clearance in Alzheimer’s disease as a therapeutic strategy. Br. J. Pharmacol., 2019, 176(18), 3447-3463.
[] [PMID: 30710367]
Wang, J.; Gu, B.J.; Masters, C.L.; Wang, Y.J. A systemic view of Alzheimer disease - insights from amyloid-β metabolism beyond the brain. Nat. Rev. Neurol., 2017, 13(10), 612-623.
[] [PMID: 28960209]
R Core Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. Available at.
Denney, W.; Duvvuri, S.; Buckeridge, C. Simple, automatic noncompartmental analysis: the PKNCA R package. J. Pharmacokinet. Pharmacodyn., 2015, 42, S65-S65.
Kamath, A.V. Translational pharmacokinetics and pharmacodynamics of monoclonal antibodies. Drug Discov. Today. Technol., 2016, 21-22, 75-83.
[] [PMID: 27978991]
Wang, W.; Wang, E.Q.; Balthasar, J.P. Monoclonal antibody pharmacokinetics and pharmacodynamics. Clin. Pharmacol. Ther., 2008, 84(5), 548-558.
[] [PMID: 18784655]
Deng, R.; Jin, F.; Prabhu, S.; Iyer, S. Monoclonal antibodies: what are the pharmacokinetic and pharmacodynamic considerations for drug development? Expert Opin. Drug Metab. Toxicol., 2012, 8(2), 141-160.
[] [PMID: 22248267]
Cao, Y.; Balthasar, J.P.; Jusko, W.J. Second-generation minimal physiologically-based pharmacokinetic model for monoclonal antibodies. J. Pharmacokinet. Pharmacodyn., 2013, 40(5), 597-607.
[] [PMID: 23996115]
Shepheard, S.R.; Wuu, J.; Cardoso, M.; Wiklendt, L.; Dinning, P.G.; Chataway, T.; Schultz, D.; Benatar, M.; Rogers, M.L. Urinary p75ECD: A prognostic, disease progression, and pharmacodynamic biomarker in ALS. Neurology, 2017, 88(12), 1137-1143.
[] [PMID: 28228570]
Iliff, J.J.; Nedergaard, M. Is there a cerebral lymphatic system? Stroke, 2013, 44(6)(Suppl. 1), S93-S95.
[] [PMID: 23709744]
Gilman, S.; Koller, M.; Black, R.S.; Jenkins, L.; Griffith, S.G.; Fox, N.C.; Eisner, L.; Kirby, L.; Rovira, M.B.; Forette, F.; Orgogozo, J-M. AN1792(QS-21)-201 Study Team. Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology, 2005, 64(9), 1553-1562.
[] [PMID: 15883316]
Pan, X-D.; Zhu, Y-G.; Lin, N.; Zhang, J.; Ye, Q-Y.; Huang, H-P.; Chen, X-C. Microglial phagocytosis induced by fibrillar β-amyloid is attenuated by oligomeric β-amyloid: implications for Alzheimer’s disease. Mol. Neurodegener., 2011, 6, 45-45.
[] [PMID: 21718498]
Hellwig, S.; Masuch, A.; Nestel, S.; Katzmarski, N.; Meyer-Luehmann, M.; Biber, K. Forebrain microglia from wild-type but not adult 5xFAD mice prevent amyloid-β plaque formation in organotypic hippocampal slice cultures. Sci. Rep., 2015, 5, 14624-14624.
[] [PMID: 26416689]
Krabbe, G.; Halle, A.; Matyash, V.; Rinnenthal, J.L.; Eom, G.D.; Bernhardt, U.; Miller, K.R.; Prokop, S.; Kettenmann, H.; Heppner, F.L. Functional impairment of microglia coincides with Beta-amyloid deposition in mice with Alzheimer-like pathology. PLoS One, 2013, 8(4), e60921-e60921.
[] [PMID: 23577177]
Xiang, Y.; Bu, X.L.; Liu, Y.H.; Zhu, C.; Shen, L.L.; Jiao, S.S.; Zhu, X.Y.; Giunta, B.; Tan, J.; Song, W.H.; Zhou, H.D.; Zhou, X.F.; Wang, Y.J. Physiological amyloid-beta clearance in the periphery and its therapeutic potential for Alzheimer’s disease. Acta Neuropathol., 2015, 130(4), 487-499.
[] [PMID: 26363791]

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