title: Tau passive immunotherapy in mutant P301L mice: antibody affinity versus specificity.
abstract: The use of antibodies to treat neurodegenerative diseases has undergone rapid development in the past decade. To date, immunotherapeutic approaches to Alzheimer's disease have mostly targeted amyloid beta as it is a secreted protein that can be found in plasma and CSF and is consequently accessible to circulating antibodies. Few recent publications have suggested the utility of treatment of tau pathology with monoclonal antibodies to tau. Our laboratory has begun a systematic study of different classes of tau monoclonal antibodies using mutant P301L mice. Three or seven months old mutant tau mice were inoculated weekly with tau monoclonal antibodies at a dose of 10 mg/Kg, until seven or ten months of age were reached respectively. Our data strongly support the notion that in P301L animals treated with MC1, a conformational monoclonal antibody specific for PHF-tau, the rate of development of tau pathology is effectively reduced, while injecting DA31, a high affinity tau sequence antibody, does not exert such benefit. MC1 appears superior to DA31 in overall effects, suggesting that specificity is more important than affinity in therapeutic applications. Unfortunately the survival rate of the P301L treated mice was not improved when immunizing either with MC1 or PHF1, a high affinity phospho-tau antibody previously reported to be efficacious in reducing pathological tau. These data demonstrate that passive immunotherapy in mutant tau models may be efficacious in reducing the development of tau pathology, but a great deal of work remains to be done to carefully select the tau epitopes to target.
authors: Litwin-Zucker Center for Research in Alzheimer's Disease, Feinstein Institute for Medical Research, North Shore LIJ Health System, Manhasset, New York, United States of America.
authors: Cristina
authors: C
authors: d'Abramo
authors: Christopher M
authors: CM
authors: Acker
authors: Heidy T
authors: HT
authors: Jimenez
authors: Peter
authors: P
authors: Davies
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use; D000915:Antibody Affinity; D000918:Antibody Specificity; D056547:CA1 Region, Hippocampal / Q000378:metabolism; D005260:Female; D007116:Immunization, Passive / Q000379:methods*; D051379:Mice; D009154:Mutation; D010766:Phosphorylation / Q000276:immunology; D016548:Prosencephalon / Q000378:metabolism; D024801:Tauopathies / Q000276:immunology / Q000628:therapy; D013997:Time Factors; D016875:tau Proteins / Q000235:genetics / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D016875:tau Proteins
references: Neuron. 2003 May 22;38(4):555-65
references: 12765608
references: Neurobiol Aging. 2000 Sep-Oct;21(5):719-27
references: 11016541
references: PLoS One. 2012;7(2):e31302
references: 22312444
references: Nat Cell Biol. 2009 Jul;11(7):909-13
references: 19503072
references: Neurobiol Aging. 2009 Nov;30(11):1728-36
references: 18294736
references: J Neurosci Res. 1997 Apr 15;48(2):128-32
references: 9130141
references: Neurobiol Aging. 2013 Jan;34(1):137-45
references: 22608241
references: J Clin Invest. 2006 Jan;116(1):193-201
references: 16341263
references: J Neurosci. 2007 Aug 22;27(34):9115-29
references: 17715348
references: Neurodegener Dis. 2010;7(1-3):28-31
references: 20160454
references: J Clin Invest. 2005 Feb;115(2):428-33
references: 15668737
references: Prion. 2012 Jul 1;6(3):223-33
references: 22561167
references: J Neurochem. 2003 Aug;86(3):582-90
references: 12859672
references: J Neurochem. 2011 Aug;118(4):658-67
references: 21644996
references: Methods Mol Med. 2000;32:361-73
references: 21318532
references: J Neurosci. 2007 Mar 14;27(11):2969-78
references: 17360920
references: J Biol Chem. 2009 May 8;284(19):12845-52
references: 19282288
references: J Alzheimers Dis. 2008 Oct;15(2):157-68
references: 18953105
references: J Alzheimers Dis. 2013;33(2):463-71
references: 22976073
references: Neurobiol Dis. 2012 Dec;48(3):356-66
references: 22668776
references: Neurobiol Aging. 2013 Jan;34(1):338-50
references: 22727277
references: PLoS One. 2012;7(5):e36873
references: 22615831
references: J Neurosci. 2005 Jun 1;25(22):5446-54
references: 15930395
references: Hum Vaccin. 2010 Nov;6(11):931-5
references: 20980799
references: Expert Opin Biol Ther. 2010 Jul;10(7):1121-30
references: 20497044
references: J Biol Chem. 2011 Sep 30;286(39):34457-67
references: 21841002
references: J Neurosci. 2003 May 1;23(9):3745-51
references: 12736345
references: J Neurosci. 2009 Aug 26;29(34):10741-9
references: 19710325
references: Neuron. 2012 Feb 23;73(4):685-97
references: 22365544
references: J Biol Chem. 2009 Feb 6;284(6):3546-51
references: 19010781