IP Library › Granted Patent US 12,234,280
Granted Patent B2
US 12,234,280 · App. 16/978,022 · Granted Feb 25, 2025

Anti-PHF-tau antibodies and uses thereof

Inventors: Kristof Van Kolen (Haacht, BE); Marc Mercken (Turnhout, BE); Linda Barone (Exton, PA); Eilyn R. Lacy (Lansdowne, PA); Rupesh Nanjunda (Hatfield, PA); John Wheeler (Downington, PA); Jinquan Luo (Malvern, PA); Marianne Borgers (Balen, BE)
Assignee: Janssen Pharmaceutica NV
C07K16/18A61P25/16A61P25/28C12N15/62C12N15/85G01N33/563G01N33/6896A61K2039/505C07K2317/565G01N2800/2821G01N2800/2835
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 12,234,280
App. No.
16/978,022
Granted
Feb 25, 2025
Kind
B2
Abstract

Monoclonal anti-tau antibodies and antigen-binding fragments thereof are described. Also described are nucleic acids encoding the antibodies, compositions comprising the antibodies, methods of producing the antibodies and using the antibodies for treating or preventing conditions such as tauopathies. The antibodies of the invention may also be used to quantify tau in biological samples.

Claims (16)

1. An isolated antibody or antigen-binding fragment thereof that binds to paired helical filament-tau (PHF-tau), comprising:

(a) a heavy chain variable region consisting of the amino acid sequence of SEQ ID NO: 15, and a light chain variable region consisting of the amino acid sequence of SEQ ID NO: 16;

(b) a heavy chain variable region consisting of the amino acid sequence of SEQ ID NO: 17, and a light chain variable region consisting of the amino acid sequence of SEQ ID NO: 18;

(c) a heavy chain variable region consisting of the amino acid sequence of SEQ ID NO: 19, and a light chain variable region consisting of the amino acid sequence of SEQ ID NO: 20;

(d) a heavy chain variable region consisting of the amino acid sequence of SEQ ID NO: 21, and a light chain variable region consisting of the amino acid sequence of SEQ ID NO: 22;

(e) a heavy chain variable region consisting of the amino acid sequence of SEQ ID NO: 23, and a light chain variable region consisting of the amino acid sequence of SEQ ID NO: 20; or

(f) a heavy chain variable region consisting of the amino acid sequence of SEQ ID NO: 24, and a light chain variable region consisting of the amino acid sequence of SEQ ID NO: 25.

2. The isolated antibody or antigen-binding fragment thereof of claim 1 , wherein the heavy chain variable region consists of the amino acid sequence of SEQ ID NO: 15, and the light chain variable region consists of the amino acid sequence of SEQ ID NO: 16.

3. The isolated antibody or antigen-binding fragment thereof of claim 1 , wherein the heavy chain variable region consists of the amino acid sequence of SEQ ID NO: 17, and the light chain variable region consists of the amino acid sequence of SEQ ID NO: 18.

4. The isolated antibody or antigen-binding fragment thereof of claim 1 , wherein the heavy chain variable region consists of the amino acid sequence of SEQ ID NO: 19, and the light chain variable region consists of the amino acid sequence of SEQ ID NO: 20.

5. The isolated antibody or antigen-binding fragment thereof of claim 1 , wherein the heavy chain variable region consists of the amino acid sequence of SEQ ID NO: 21 and the light chain variable region consists of the amino acid sequence of SEQ ID NO: 22.

6. The isolated antibody or antigen-binding fragment thereof of claim 1 , wherein the heavy chain variable region consists of the amino acid sequence of SEQ ID NO: 23 and the light chain variable region consists of the amino acid sequence of SEQ ID NO: 20.

7. The isolated antibody or antigen-binding fragment thereof of claim 1 , wherein the heavy chain variable region consists of the amino acid sequence of SEQ ID NO: 24 and the light chain variable region consists of the amino acid sequence of SEQ ID NO: 25.

8. The isolated antibody or antigen-binding fragment thereof of claim 1 that is humanized.

9. A pharmaceutical composition comprising the isolated antibody or antigen-binding fragment thereof of claim 1 and a pharmaceutically acceptable carrier.

10. A pharmaceutical composition comprising the isolated antibody or antigen-binding fragment thereof of claim 8 and a pharmaceutically acceptable carrier.

Continuity (2)
Provisional Application 62638535 · Mar 5, 2018
Related Publication 20210002358A1 · Jan 7, 2021
References Cited (267)
US 4816567A · Cabilly et al. · 1989 [cited by applicant]
US 5225539A · Winter · 1993 [cited by applicant]
US 5492812A · Vooheis · 1996 [cited by applicant]
US 5530101A · Queen et al. · 1996 [cited by applicant]
US 5585089A · Queen et al. · 1996 [cited by applicant]
US 5693761A · Queen et al. · 1997 [cited by applicant]
US 5693762A · Queen et al. · 1997 [cited by applicant]
US 6008024A · Vandermeeren · 1999 [cited by applicant]
US 6121003A · Vanmechelen · 2000 [cited by applicant]
US 6670137B2 · Vanmechelen · 2003 [cited by applicant]
US 7442516B2 · Ohno · 2008 [cited by applicant]
US 7657380B2 · Lazar et al. · 2010 [cited by applicant]
US 7888050B2 · Reagan · 2011 [cited by applicant]
US 8114617B2 · Reagan · 2012 [cited by applicant]
US 8748386B2 · Sigurdsson · 2014 [cited by applicant]
US 8778343B2 · Kayed · 2014 [cited by applicant]
US 9051367B2 · Griswold-prenner et al. · 2015 [cited by applicant]
US 9221902B2 · Smider · 2015 [cited by applicant]
US 9226961B2 · Gokarn et al. · 2016 [cited by applicant]
US 9371376B2 · Alderfer et al. · 2016 [cited by applicant]
US 9733260B2 · Michaelsen · 2017 [cited by applicant]
US 9745371B2 · Alderfer et al. · 2017 [cited by applicant]
US 10000559B2 · Alderfer et al. · 2018 [cited by applicant]
US 10196440B2 · Alderfer et al. · 2019 [cited by applicant]
US 10591492B2 · Kolb et al. · 2020 [cited by applicant]
US 10766953B2 · Mercken et al. · 2020 [cited by applicant]
US 10836817B2 · Adolfsson et al. · 2020 [cited by applicant]
US 10976325B2 · Kolb et al. · 2021 [cited by applicant]
US 11365244B2 · Mercken et al. · 2022 [cited by applicant]
US 20030138972A1 · Vandermeeren et al. · 2003 [cited by applicant]
US 20050288491A1 · Wilson et al. · 2005 [cited by applicant]
US 20060140932A1 · Dickinson et al. · 2006 [cited by applicant]
US 20070048785A1 · Lin et al. · 2007 [cited by applicant]
US 20070065430A1 · Ellis et al. · 2007 [cited by applicant]
US 20070280935A1 · Bohrmann et al. · 2007 [cited by applicant]
US 20090142261A1 · Hsu et al. · 2009 [cited by applicant]
US 20090169547A1 · Sahin et al. · 2009 [cited by applicant]
US 20100021477A1 · Tsui et al. · 2010 [cited by applicant]
US 20100261620A1 · Almagro et al. · 2010 [cited by applicant]
US 20110059093A1 · Bohrmann et al. · 2011 [cited by applicant]
US 20110077224A1 · Pandey et al. · 2011 [cited by applicant]
US 20110092372A1 · Almagro et al. · 2011 [cited by applicant]
US 20110118299A1 · Lovell et al. · 2011 [cited by applicant]
US 20110143443A9 · Mercken et al. · 2011 [cited by applicant]
US 20110256154A1 · Vincent et al. · 2011 [cited by applicant]
US 20110318339A1 · Smider et al. · 2011 [cited by applicant]
US 20120058906A1 · Smider et al. · 2012 [cited by applicant]
US 20120087861A1 · Nitsch et al. · 2012 [cited by applicant]
US 20120108795A1 · Kehoe · 2012 [cited by applicant]
US 20120276009A1 · Pfeifer et al. · 2012 [cited by applicant]
US 20130100152A1 · Feng · 2013 [cited by applicant]
US 20140017242A1 · Williams · 2014 [cited by applicant]
US 20140161875A1 · Winderickx · 2014 [cited by applicant]
US 20140302046A1 · Sigurdsson · 2014 [cited by applicant]
US 20160304593A1 · Alderfer et al. · 2016 [cited by applicant]
US 20160324770A1 · Dolcetta et al. · 2016 [cited by applicant]
US 20160376351A1 · Adolfsson · 2016 [cited by applicant]
US 20170152307A1 · Wadia · 2017 [cited by applicant]
US 20170298119A1 · Wollacott · 2017 [cited by applicant]
US 20180016330A1 · Pedersen et al. · 2018 [cited by applicant]
US 20180019832A1 · Okuda · 2018 [cited by applicant]
US 20180186855A1 · Rosenthal · 2018 [cited by applicant]
US 20180333493A1 · Shenoy · 2018 [cited by applicant]
US 20190234966A1 · Steen et al. · 2019 [cited by applicant]
US 20200182888A1 · Kolb et al. · 2020 [cited by applicant]
US 20200408781A1 · Kolb et al. · 2020 [cited by applicant]
US 20220018857A1 · Kolb et al. · 2022 [cited by applicant]
US 20220127345A1 · Galpern et al. · 2022 [cited by applicant]
US 20220127346A1 · Henley et al. · 2022 [cited by applicant]
US 20230047413A1 · Mercken et al. · 2023 [cited by applicant]
US 20230075314A1 · Hou et al. · 2023 [cited by applicant]
US 20230151083A1 · Van Kolen et al. · 2023 [cited by applicant]
WO 9007861A1 · 1990 [cited by applicant]
WO 199201047A1 · 1992 [cited by applicant]
WO 9222653A1 · 1992 [cited by applicant]
WO 9308302A1 · 1993 [cited by applicant]
WO 9517429A1 · 1995 [cited by applicant]
WO 9604309A1 · 1996 [cited by applicant]
WO 0155725A2 · 2001 [cited by applicant]
WO 2002098897A2 · 2002 [cited by applicant]
WO 2002098897A3 · 2002 [cited by applicant]
WO 02098897A2 · 2002 [cited by applicant]
WO 2004006955A1 · 2004 [cited by applicant]
WO 2004100898A2 · 2004 [cited by applicant]
WO 2004100898A3 · 2004 [cited by applicant]
WO 2005017121A2 · 2005 [cited by applicant]
WO 2006002177A2 · 2006 [cited by applicant]
WO 2006002177A3 · 2006 [cited by applicant]
WO 2007010040A1 · 2007 [cited by applicant]
WO 2007064919A2 · 2007 [cited by applicant]
WO 2007064919A3 · 2007 [cited by applicant]
WO 2007137121A2 · 2007 [cited by applicant]
WO 2009017161A1 · 2009 [cited by applicant]
WO 2009085462A1 · 2009 [cited by applicant]
WO 2010144711A2 · 2010 [cited by applicant]
WO 2010142423A3 · 2011 [cited by applicant]
WO 2013096380A2 · 2013 [cited by applicant]
WO 2014011972A1 · 2014 [cited by applicant]
WO 2015122922A1 · 2015 [cited by applicant]
WO 2015197820A1 · 2015 [cited by applicant]
WO 2016112078A2 · 2016 [cited by applicant]
WO 2016196726A1 · 2016 [cited by applicant]
WO 2016196726A9 · 2017 [cited by applicant]
WO 2017191561A1 · 2017 [cited by applicant]
WO 2018022786A1 · 2018 [cited by applicant]
WO 2018170351A1 · 2018 [cited by applicant]
WO 2019171258A1 · 2019 [cited by applicant]
WO 2021205359A1 · 2021 [cited by applicant]
WO 2022013286A1 · 2022 [cited by applicant]
WO 2022090158A1 · 2022 [cited by applicant]
WO 2022090169A1 · 2022 [cited by applicant]
“Antibody Engineering”, Kontermann R and Dubel S eds., Springer-Verlag, Berlin, vol. 1, Second Edition, pp. 33-51, 2010. [cited by applicant]
“Immunoglobulin G1, anti-(human phosphorylated tau protein) (human-Mus musculus monoclonal JNJ-63733657 I 3 1-chain), disulfide with human-Mus musculus monoclonal JNJ-63733657 I 0-chain, dimer”, Database Accession No. 2… [cited by applicant]
“Remington's Pharmaceutical Science”, Edited by Osol A and Hoover JE., Mack Publishing Company, Easton, Pa., 15th edition, 1 page, 1975. [cited by applicant]
“The CCP4 Suite: Programs for Protein Crystallography”, Acta Crystallographica Section D Biological Crystallography, vol. D50, pp. 760-763, 1994. [cited by applicant]
Adams, et al., “PHENIX: a comprehensive Python-based system for macromolecular structure solution”, Acta Crystallographica, Section D, Biological Crystallography, vol. D66 Part 2, pp. 213-221, 2010. [cited by applicant]
Allen, et al., “Abundant Tau Filaments and Nonapoptotic Neurodegeneration in Transgenic Mice Expressing Human P301S Tau Protein”, The Journal of Neuroscience., vol. 22 Issue 21, pp. 9340-9351, Nov. 1, 2002. [cited by applicant]
Alonso A, et al., “Hyperphosphorylation induces self-assembly of T into tangles of paired helical filaments/straight filaments”, Proc. National Academy of Sciences USA, vol. 98 No. 12, pp. 6923-6928, Jun. 2001. [cited by applicant]
Bai S, et al., “A Guide to Rational Dosing of Monoclonal Antibodies”, Clin Pharmacokinet, vol. 51 No. 2, pp. 119-135, 2012. [cited by applicant]
Barthelemy et al., “A soluble phosphorylated tau signature links tau, amyloid and the evolution of stages of dominantly inherited Alzheimer's disease”, Nature Medicine, vol. 26, 24 pages, Mar. 2020. [cited by applicant]
Barthelemy et al., “Blood plasma phosphorylated-tau isoforms track CNS change in Alzheimer's disease”, Journal of Experimental Medicine, vol. 217, No. 11, e20200861, 12 pages, 2020. [cited by applicant]
Barthelemy et al., “Cerebrospinal fluid phospho-tau T217 outperforms T181 as a biomarker for the differential diagnosis of Alzheimer's disease and PET amyloid-positive patient identification”, Alzheimer's Research & The… [cited by applicant]
Barthelemy, et al., “Differential Mass Spectrometry Profiles of Tau Protein in the Cerebrospinal Fluid of Patients with Alzheimer's Disease, Progressive Supranuclear Palsy, and Dementia with Lewy Bodies”, Journal of Alz… [cited by applicant]
Barthélemy, N. R. et al., “Tau hyperphosphorylation on T217 in cerebrospinal fluid is specifically associated to amyloid-fβ pathology”, bioRxiv, 20 pages, 2017., URL: https://www.biorxiv.org/content/biorxiv/early/2017/1… [cited by applicant]
Berg L., “Clinical Dementia Rating (CDR)”, Psychopharmacol. Bull. 24, 1 page, 1988. [cited by applicant]
Bierer LM, et al., “Neocortical neurofibrillary tangles correlate with dementia severity in Alzheimer's disease”, Arch. Neurol., vol. 52, 4 pages, 1995. [cited by applicant]
Braak H et al., “Neuropathological stageing of Alzheimer-related changes”, Acta Neuropathologica, vol. 82, pp. 239-259, 1991. [cited by applicant]
Brion, Jean-Pierre et al., “Neurofilament Monoclonal Antibodies RT97 and 8D8 Recognize Different Modified Epitopes in Paired Helical Filament-τ In Alzheimer's Disease”, Journal of Neurochemistry, vol. 60, No. 4, pp. 137… [cited by applicant]
Butner et al., “Tau protein binds to microtubules through a flexible array of distributed weak sites”, The Journal of Cell Biology, vol. 115 No. 3, pp. 717-730, 1991. [cited by applicant]
Chen et al., “Enhancement and destruction of antibody function by somatic mutation: unequal occurrence is controlled by V gene combinatorial associations”, EMBO, vol. 14 No. 12, pp. 2784-2794, 1995. [cited by applicant]
Chothia, et al., “Structural Repertoire of the Human VH Segments”, J. Mol. Biol, vol. 227, pp. 799-817, Jun. 2, 1992. [cited by applicant]
Clavaguera, et al., “Brain homogenates from human tauopathies induce tau inclusions in mouse brain”, Proc Natl Acad Sci, vol. 110 No. 23, pp. 9535-9540, Jun. 2013. [cited by applicant]
Collin, et al., “Neuronal uptake of tau/pS 422 antibody and reduced progression of tau pathology in a mouse model of Alzheimer's disease”, Brain., vol. 137, pp. 2834-2846, 2014. [cited by applicant]
Condamines, O et al., “New immunoassay for the mapping of neurofibrillary degeneration in Alzheimer's disease using two monoclonal antibodies against human paired helical filament tau proteins”, Neuroscience Letters, vo… [cited by applicant]
D'Abramo, et al., “Detecting tau in serum of transgenic animal models after tau immunotherapy treatment”, Neurobiology of Aging, vol. 37, pp. 58-65, 2016. [cited by applicant]
Dai, et al., “Tau passive immunization blocks seeding and spread of Alzheimer hyperphosphorylated Tau-induced pathology in 3 × Tg-AD mice”, Alzheimer's Research & Therapy, vol. 10, No. 13, 14 pages, 2018. [cited by applicant]
Dall'Acqua et al., “Properties of Human IgG1s Engineered for Enhanced Binding to the Neonatal Fc Receptor (FoRn)”, The Journal of Biological Chemistry, vol. 281 No. 33, pp. 23514-23524, Aug. 18, 2006. [cited by applicant]
Decalignon, et al., “Propagation of Tau Pathology in a Model of Early Alzheimer's Disease”, Neuron, vol. 73, pp. 685-697, Feb. 23, 2012. [cited by applicant]
Delacourte A., “The molecular parameters of tau pathology, Tau as a killer and a witness”, Neuropathology and Genetics of Dementia, vol. 487, pp. 5-19, 2001. [cited by applicant]
Dickson W., “Neuropathology of progressive supranuclear palsy”, Handbook of Clinical Neurology, Dementias, vol. 89, 3rd Series, pp. 487-491, 2008. [cited by applicant]
Dubois et al., “Advancing research diagnostic criteria for Alzheimer's disease; the IWG-2 criteria”, Lancet Neurol, vol. 13, pp. 614-629, 2014. [cited by applicant]
Dubois et al., “Preclinical Alzheimer's disease: Definition, natural history, and diagnostic criteria”, Alzheimer's Dement., vol. 12, pp. 292-323, 2016. [cited by applicant]
Duka et al., “Identification of the Site of Tau Hyperphosphorylation and Activation of Tau Kinases in Synucleinopathies and Alzheimer's Diseases”, PLOS One, vol. 8 Issue 9, e75025, pp. 1-11, Sep. 2013. [cited by applicant]
Emsley, et al., “Coot: model-building tools for molecular graphics”, Acta Crystallographica, Section D Biological Crystallography, vol. D60, pp. 2126-2132, 2004. [cited by applicant]
Ercan E. et al., “A validated antibody panel for the characterization of tau post-translational modifications”, Molecular Neurodegeneration, vol. 12, No. 87, 19 pages, 2017. [cited by applicant]
Extended European Search Report received for EP Application No. 18767083.1, mailed on Dec. 14, 2020, 7 pages. [cited by applicant]
Extended European Search Report received for EP Application No. 19764468.5 dated Dec. 7, 2021, 9 pages. [cited by applicant]
Extended European Search Report received for European Application No. 19765110.2, dated Nov. 30, 2021, 15 pages. [cited by applicant]
Foote, et al., “Antibody framework residues affecting the conformation of the hypervariable loops”, Journal of Molecular Biology, vol. 224 Issue 2, 1 page, Mar. 20, 1992. [cited by applicant]
Friedhoff P. et al., “Structure of tau protein and assembly into paired helical filaments”, Biochim. Biophys. Acta., vol. 1502, pp. 122-132, 2000. [cited by applicant]
Funk, et al., “Distinct Therapeutic Mechanisms of Tau Antibodies-Promoting Microglial Clearance Versus Blocking Neuronal Uptake”, The Journal of Biological Chemistry, vol. 290 No. 35, pp. 21652-21662, Aug. 28, 2015. [cited by applicant]
Galpern et al., “A Single Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Anti-Phospho-Tau Antibody JNJ-63733657 in Healthy Subjects”, Alzheimer's and Dementia: T… [cited by applicant]
Goedert M, et al., “Neurofibrillary tangles and beta-amyloid deposits in Alzheimer's disease”, Curr Opin, Neurobiol., vol. 1, pp. 441-447, 1991. [cited by applicant]
Goedert, M. et al., “Epitope Mapping of Monoclonal Antibodies to the Paired Helical Filaments of Alzheimer's Disease: Identification of Phosphorylation sites in Tau Protein”, Biochemical Journal, Portland Press LTD, GB.… [cited by applicant]
Han, et al., “Beta amyloid, tau, neuroimaging, and cognition: sequence modeling of biomarkers for Alzheimer's Disease”, Brain Imaging and Behavior, vol. 6, pp. 610-620, 2012. [cited by applicant]
Hanger, et al., “Novel Phosphorylation Sites in Tau from Alzheimer Brain Support a Role for Casein Kinase 1 in Disease Pathogenesis”, The Journal of Biological Chemistry, vol. 282 No. 32, pp. 23645-23654, Aug. 10, 2007. [cited by applicant]
Hasegawa, et al., “Characterization of mAb AP 422, A Novel Phosphorylation-Dependent Monoclonal Antibody Against Tau Protein”, FEBS Letters, Elsevier, Amsterdam, NL., vol. 384, pp. 25-30, Mar. 1, 1996. [cited by applicant]
Hasegawa, et al., “Characterization of Two Distinct Monoclonal Antibodies to Paired Helical Filaments: Further Evidence for Fetal-Type Phosphorylation of the τ In Paired Helical Filaments”, Journal of Neurochemistry, vo… [cited by applicant]
Hoffmann, R. et al., “Unique Alzheimer's disease paired helical filament specific epitopes involve double phosphorylation at specific sites”, Biochemistry, American Chemical Society, US, vol. 36, No. 26, pp. 8114-8124, … [cited by applicant]
Iba, et al., “Tau pathology spread in PS19 tau transgenic mice following locus coeruleus (LC) injections of synthetic tau fibrils is determined by the LC's afferent and efferent connections”, Acta Neuropathol., vol. 130… [cited by applicant]
International Search Report and Written Opinion received for PCT Application No. PCT/EP2021/079543, Mailed on Mar. 10, 2022, 18 Pages. [cited by applicant]
International Search Report And Written Opinion received for PCT Application No. PCT/EP2021/079566, mailed on Mar. 4, 2022, 8 pages. [cited by applicant]
International Search Report and Written Opinion received for PCT Application No. PCT/IB 19/51747 dated Jul. 24, 2019, 26 pages. [cited by applicant]
International Search Report and Written Opinion received for PCT Application No. PCT/IB2019/051738, mailed on Jul. 10, 2019, 17 pages. [cited by applicant]
International Search Report And Written Opinion received for PCT Application No. PCT/IB2019/051748, mailed on Jul. 12, 2019, 16 pages. [cited by applicant]
International Search Report and Written Opinion received for PCT Application No. PCT/IB2021/052890, mailed on Aug. 17, 2021, 12 pages. [cited by applicant]
International Search Report and Written Opinion received for PCT Application No. PCT/US2018/022782, mailed on Aug. 3, 2018, 21 pages. [cited by applicant]
International Search Report and Written Opinion received for PCT Application No. PCT/EP2021/069595, Mailed on Nov. 16, 2021, 14 Pages. [cited by applicant]
Iqbal, et al., “Tau in Alzheimer Disease and Related Tauopathies”, Current Alzheimer Research, vol. 7 No. 8., pp. 656-664, 2010. [cited by applicant]
Jack Jr., et al., “NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease”, Alzheimer's Dement., vol. 14, pp. 535-562, 2018. [cited by applicant]
Janelidze et al., “Cerebrospinal fluid p-tau217 performs better than p-tau 181 as a biomarker of Alzheimer's disease”, Nature Communications, vol. 11, No. 1683, pp. 1-12, 2020. [cited by applicant]
Janelidze et al., “Plasma P-tau 181 in Alzheimer's disease: relationship to other biomarkers, differential diagnosis, neuropathology and longitudinal progression to Alzheimer's dementia”, Nature Medicine, vol. 26, pp. 3… [cited by applicant]
Jicha, G., et al., “A conformation- and phosphorylation-dependent antibody recognizing the paired helical filaments of Alzheimer's disease”, Journal of Neurochemistry, vol. 69, No. 5, pp. 2087-2095, 1997. [cited by applicant]
Julien, et al., “Biochemical Isolation of Insoluble Tau in Transgenic Mouse Models of Tauopathies”, Methods in Molecular Biology, vol. 849, Chapter 32, pp. 473-491, 2012. [cited by applicant]
Kabsch W, “XDS-Research Papers”, Acta Crystallographica Section D, Biological Crystallography, vol. D66, pp. 125-132, 2010. [cited by applicant]
Karikari et al., “Blood phosphorylated tau 181 as a biomarker for Alzheimer's disease: a diagnostic performance and prediction modelling study using data from four prospective cohorts”, The Lancet Neurology, vol. 19, pp… [cited by applicant]
Koenig, et al., “Mutational landscape of antibody variable domains reveals a switch modulating the interdomain conformational dynamics and antigen binding”, PNAS, pp. E486-E495, 2016. [cited by applicant]
Kussie et al., “A Single Engineered Amino Acid Substitution Changes Antibody Fine Specificity”, Jimmunol., vol. 152 No. 1, pp. 146-152, 1994. [cited by applicant]
Lee, et al., “Antibody-Mediated Targeting of Tau In Vivo Does Not Require Effector Function and Microglial Engagement”, Cell Reports, vol. 16, pp. 1690-1700, Aug. 9, 2016. [cited by applicant]
Lefranc et al., “IMGT unique numbering for immunoglobulin and T cell receptor variable domains and Ig superfamily V-like domains”, Developmental and Comparative Immunology, vol. 27, pp. 55-77, 2003. [cited by applicant]
Longo F., “Alzheimer's Prevention, Treatment and Research—A Q&A with Dr. Frank Longo”, Stanford Health Now, 2 pages, May 3, 2016. [cited by applicant]
Malia et al., “Epitope mapping and structural basis for the recognition of phosphorylated tau by the anti-tau antibody AT8”, Proteins, vol. 84, pp. 427-434, 2016. [cited by applicant]
Martin, et al., “Structural Families in Loops of Homologous Proteins: Automatic Classification, Modelling and Application to Antibodies”, J. Mol. Biol., vol. 263, pp. 800-815, 1996. [cited by applicant]
Matsuo, et al., “Biopsy-Derived Adult Human Brain Tau Is Phosphorylated at Many of the Same Sites as Alzheimer's Disease Paired Helical Filament Tau”, Neuron, vol. 13, pp. 989-1002, 1994. [cited by applicant]
McCoy, et al., “Phaser crystallographic software”, Journal of Applied Crystallography, vol. 40, pp. 658-674, 2007. [cited by applicant]
McEwan, et al., “Cytosolic Fc receptor TRIM21 inhibits seeded tau aggregation”, PNAS., vol. 114 No. 3, pp. 574-579, Jan. 17, 2017. [cited by applicant]
Mercken, et al., Monodonal antibodies with selective specificity for Alzheimer Tau are directed against phosphatase-sensitive epitopes, Acta Neuropathol, vol. 84, pp. 265-272, Mar. 17, 1992. [cited by applicant]
Meredith, et al., “Characterization of Novel CSF Tau and ptau Biomarkers for Alzheimer's Disease”, PLOS ONE, vol. 8 Issue 10, e76523, pp. 1-14, Oct. 2013. [cited by applicant]
Mocanu, et al., “The Potential for B-Structure in the Repeat Domain of Tau Protein Determines Aggregation, Synaptic Decay, Neuronal Loss, and Coassembly with Endogenous Tau in inducible Mouse Models of Tauopathy”, The J… [cited by applicant]
Morris G. E., “Epitope Mapping Protocols”, Methods in Molecular Biology, vol. 66, 1 page, 1996. [cited by applicant]
Morris, et al., “Tau post-translational modifications in wild-type and human amyloid precursor protein transgenic mice”, Nature Neuroscience, vol. 18 No. 8, 10 pages, Aug. 2015. [cited by applicant]
Muller et al., “Tau plasma levels in subjective cognitive decline: Results from the DELCODE study”, Nature Scientific Reports, vol. 7, No. 9529, pp. 1-6, 2017. [cited by applicant]
Murshudov, et al., “Refinement of Macromolecular Structures by the Maximum Likelihood Method”, Acta Crystallographica Section D Biological Crystallography, vol. D53, pp. 240-255, 1997. [cited by applicant]
Oddo, et al., “Genetically augmenting tau levels does not modulate the onset or progression of Aβ pathology in transgenic mice”, Journal of Neurochemistry, vol. 102, pp. 1053-1063, 2007. [cited by applicant]
Otvos, et al., “Monoclonal Antibody PHF-1 Recognizes Tau Protein Phosphorylated at Serine Residues 396 and 404”, Journal of Neuroscience Research, vol. 39, pp. 669-673, 1994. [cited by applicant]
Palmqvist et al., “Cerebrospinal fluid and plasma biomarker trajectories with increasing amyloid deposition in Alzheimer's disease”, EMBO Molecular Medicine, e11170, pp. 1-13, 2019. [cited by applicant]
Palmqvist et al., “Discriminative Accuracy of Plasma Phospho-tau217 for Alzheimer Disease vs Other Neurodegenerative Disorders”, JAMA, vol. 324 No. 8, pp. 772-781, Aug. 25, 2020. [cited by applicant]
Petry, Franck et al., “Specificity of Anti-Tau Antibodies when Analyzing Mice Models of Alzheimer's Disease: Problems and Solutions”, PLOS ONE, vol. 9, Issue 5, e94251, 12 pages, May 2014. [cited by applicant]
Porzig, R. et al., “Epitope mapping of mAbs AT8 and Tau5 directed against hyperphosphorylated regions of the human tau protein”; Biochemical and Biophysical Research Communications, Academic Press Inc, US, vol. 358, pp.… [cited by applicant]
Queen, et al. “A humanized antibody that binds to the interleukin 2 receptor”, Proc Natl Acad Sci USA, vol. 86, p. 10029-10033, Dec. 1989. [cited by applicant]
Reitz C., “Toward precision medicine in Alzheimer's disease”, Annals of Translational Medicine, vol. 4 No. 6, pp. 1-7, Mar. 2016. [cited by applicant]
Rowe et al., “Plasma p217+tau concordance with 18F-NAV4694 beta-amyloid and 18 F-MK6240 tau PET in mild Alzheimer's disease and cognitively unimpaired participants in the AIBL/ADNeT cohort”, Alzheimer's Dement., vol. 17… [cited by applicant]
Russell, et al., “Comprehensive Quantitative Profiling of Tau and Phosphorylated Tau Peptides in Cerebrospinal Fluid by Mass Spectrometry Provides New Biomarker Candidates”, Journal of Alzheimer's Disease, vol. 55, pp. … [cited by applicant]
Sanders, et al., “Distinct Tau Prion Strains Propagate in Cells and Mice and Define Different Tauopathies”, Neuron, vol. 82, pp. 1271-1288, Jun. 18, 2014. [cited by applicant]
Scattoni, et al., “Early behavioural markers of disease in P301S tau transgenic mice”, Behavioural Brain Research, vol. 208, pp. 250-257, 2010. [cited by applicant]
Schroeder et al., “Tau-directed immunotherapy: a promising strategy for treating Alzheimer's disease and other tauopathies”, J. Neuroimmune Pharmacol, vol. 11, pp. 9-25, 2016. [cited by applicant]
Seubert, et al., “Detection of Phosphorylated Ser262 in Fetal Tau, Adult Tau, and Paired Helical Filament Tau”, The Journal of Biological Chemistry, vol. 270 No. 32, pp. 18917-18922, 1995. [cited by applicant]
Sigurdsson EM., “Tau immunotherapy”, Neurodegener. Dis., vol. 16, pp. 34-38, 2016. [cited by applicant]
Singer, D., et al., “Neighbored phosphorylation sites as PHF-tau specific markers in Alzheimer's disease”, Biochemical and Biophysical Research Communications, Academic Press Inc., US, vol. 346, pp. 819-828, 2006. [cited by applicant]
Stokes, et al., “Stable Isotopes of Lithium: In Vivo Differential Distribution Between Plasma and Cerebrospinal Fluid”, Biological Psychiatry, vol. 17 No. 4, pp. 413-421, 1982. [cited by applicant]
Strohl, “Optimization of Fc-mediated effector functions of monoclonal antibodies”, Curr Opin Biotechnol, vol. 20, pp. 685-691, 2009. [cited by applicant]
Terwel, et al., “Changed Conformation of Mutant Tau-P301L Underlies the Moribund Tauopathy, Absent in Progressive, Nonlethal Axonopathy of Tau-4R/2N Transgenic Mice”, The Journal of Biological Chemistry, vol. 280 No. 5,… [cited by applicant]
Thijssen et al., “Diagnostic value of plasma phosphorylated tau 181 in Alzheimer's disease and frontotemporal lobar degeneration”, Nature Medicine, vol. 26, 25 pages, Mar. 2020. [cited by applicant]
Tramontano, et al., “Framework Residue 71 is a Major Determinant of the Position and Conformation of the Second Hypervariable Region in the VH Domains of Immunoglobulins”, J. Mol. Biol, vol. 215, pp. 175-182, 1990. [cited by applicant]
Triana-Baltzer et al., “Development and Validation of a High Sensitivity Assay for Measuring p217 + tau in Cerebrospinal Fluid”, Journal of Alzheimer's Disease, vol. 77, pp. 1417-1430, 2020. [cited by applicant]
Van Kolen et al., “Discovery and Functional Characterization of hPT3, a Humanized Anti-Phospho Tau Selective Monocional Antibody”, Journal of Alzheimer's Disease, vol. 77, pp. 1397-1416, 2020. [cited by applicant]
Vandermeeren M, et al., “Anti-Tau Monoclonal Antibodies Derived from Soluble and Filamentous Tau Show Diverse Functional Properties in vitro and in vivo”, J. Alzheimer's Disease, vol. 65, pp. 265-281, 2018. [cited by applicant]
Wischik, et al. “Structural characterization of the core of the paired helical filament of Alzheimer disease”, Proc Natl Acad Sci USA, vol. 85, pp. 4884-4888, Jul. 1988. [cited by applicant]
Wu, et al., “An Analysis of the Sequences of the Variable Regions of Bence Jones Proteins and Myeloma Light Chains and Their Implications for Antibody Complementarity”, Bence Jones Proteins and Myeloma Light Chains, pp.… [cited by applicant]
Yoshiyama, et al., “Synapse Loss and Microglial Activation Precede Tangles in a P301S Tauopathy Mouse Model”, Neuron, vol. 53, pp. 337-351, Feb. 1, 2007. [cited by applicant]
Zhao, et al., “Two routes for production and purification of Fab fragments in biopharmaceutical discovery research: Papain digestion of mAb and transient expression in mammalian cells”, Protein Expression and Purificati… [cited by applicant]
Abhinandan, et al., Analysis and improvements to Kabat and Structurally Correct Numbering of antibody Variable domains., Molelcular Immunology, Jul. 9, 2008, pp. 3832-3839, vol. 45. [cited by applicant]
Asuni, et al., Imnlunotherapy Targeting Pathological Tau Conformers in a Tangle Mouse Model Reduces Brain Pathology with Associated Functional Improvements, The Journal of Neuroscience, Aug. 22, 2007, pp. 9115-9129, vol… [cited by applicant]
Barbie, et al., The Human Immunoglobulin Kappa Variable (IGKV) Genes and Joining (IGKJ) Segments, Exp Clin Immunogenet, Jun. 13, 1998, pp. 171-183, vol. 15. [cited by applicant]
Boutajangout, et al., Immunotherapy Targeting Pathological Tau Prevents Cognitive Decline in a New Tangle Mouse Model, The Journal of Neuroscience, Dec. 8, 2010, pp. 16559-16566, vol. 30 Issue 49. [cited by applicant]
Boutajangout, et al., Passive immunization targeting pathological phospho-tau protein in a mouse model reduces functional decline and clears tau aggregates from the brain, Journal of Neurochemistry, Jun. 1, 2011, pp. 65… [cited by applicant]
Brunden, et al., Advances in tau-focused drug discovery for Alzheimer's disease and related tauopathies, Nature Reviews | Drug Discovery, 2009, pp. 783-793, vol. 8. [cited by applicant]
Chai, et al., Passive Immunization with Anti-Tau Antibodies in Two Transgenic Models, The Journal of Biological Chemistry, Sep. 30, 2011, pp. 34457-34467, vol. 286 Issue 39. [cited by applicant]
Chothia, et al., Canonical Structures for the Hypervariable Regions of Immunoglobulins, J. Mol. Biol.. , Apr. 23, 1987, pp. 901-917, vol. 196. [cited by applicant]
Clavaguera, et al., Transmission and spreading of tauopathy in transgenic mouse brain, Nature Cell Biology, Jun. 7, 2009, pp. 909-913, vol. 11 Issue 7. [cited by applicant]
Eduardo A. Padlan, A Possible Procedure for Reducing the Immunogenicity of Antibody Variable Domains While Preserving Theirligand-Binding Properties, Molecular Immunology, 1991, pp. 489-498, vol. 28 Issue 4/5. [cited by applicant]
Fishwild, et al., High-avidity human IgGK monoclonal antibodies from a novel strain of minilocus transgenic mice, Nature Biotechnology, May 1, 1996, pp. 845-851, vol. 14. [cited by applicant]
Fransson, et al., Human Framework Adaptation of a Mouse Anti-Human IL-13 Antibody., J. Mol. Biol., Mar. 10, 2010, pp. 214-231, vol. 398 Issue 2. [cited by applicant]
Frost, et al., Propagation of Tau Misfolding from the Outside to the Inside of a Cell, The Journal of Biological Chemistry, May 8, 2009, pp. 12845-12852, vol. 284 Issue 19. [cited by applicant]
Greenberg, et al., A preparation of Alzheimer paired helical filaments that displays distinct T proteins by polyacrylamide gel electrophoresis, Proc. Natl. Acad. Sci, Apr. 27, 1990, pp. 5827-5831, vol. 87. [cited by applicant]
Hanger, et al., Tau phosphorylation: the therapeutic challenge for neurodegenerative disease, Cell Press, Feb. 24, 2009, pp. 112-119, vol. 15 Issue 3. [cited by applicant]
Holmes, et al., Proteopathic tau seeding predicts tauopathy in vivo., Proc Natl Acad Sci, Sep. 26, 2014, pp. E4376- E4385, vol. 111 Issue 41. [cited by applicant]
Iba, et al., Synthetic Tau Fibrils Mediate Transmission of Neurofibrillary Tangles in a Transgenic Mouse Model of Alzheimer's-Like Tauopathy., The Journal of Neuroscience, Jan. 16, 2013, pp. 1024-1037, vol. 33 Issue 3. [cited by applicant]
Juan C. Almagro., Identification of differences in the specificity-determining residues of antibodies that recognize antigens of different size: implications for the rational design of antibody repertoires, Journal of Y… [cited by applicant]
Knappik, et al., Fully Synthetic Human Combinatorial Antibody Libraries (HuCAL) Based on Modular Consensus Frameworks and CDRs Randomized with Trinucleotides, J. Mol. Biol., 2000, pp. 57-86, vol. 296. [cited by applicant]
Knight, et al., Pharmacodynamic enhancement of the antiplatelet antibody Fab abciximab by site-specific pegylation, Platelets, 2004, pp. 409-418, vol. 15 Issue 7. [cited by applicant]
Kohler, et al., Continuous cultures of fused cells secreting antibody of predefined specificity, Nature, Aug. 7, 1975, pp. 495-497, vol. 256. [cited by applicant]
Krebs, et al., High-throughput generation and engineering of recombinant human antibodies, Journal of Immunological Methods, Apr. 6, 2001, pp. 67-84, vol. 254. [cited by applicant]
Leong, et al., Adapting Pharmacokinetic Properties of a Humanized Anti-Interleukin-8 Antibody for Therapeutic Applications Using Site-Specific Pegylation, Cytokine, 2001, pp. 106-119, vol. 16 Issue 3. [cited by applicant]
Li, et al., Characterization of Two VQIXXK Motifs for Tau Fibrillization in Vitro., Bio chemistry, Dec. 19, 2006, pp. 15692-15701, vol. 45 Issue 51. [cited by applicant]
Lonberg, et al., Antigen-specific human antibodies from mice comprising four distinct genetic modifications, Nature, Apr. 28, 1994, pp. 856-859, vol. 368. [cited by applicant]
Mendez, et al., Functional transplant of megabase human immunoglobulin loci recapitulates human antibody response in mice, nature genetics, 1997, pp. 146-156, vol. 15. [cited by applicant]
Mercken, et al., Affinity Purification of Human T Proteins and the Construction of a Sensitive Sandwich Enzyme-Linked Immunosorbent Assay for Hillman T Detection, J. Neurochem., Jun. 25, 1991, pp. 548-553, vol. 58. [cited by applicant]
Morris, et al., The Many Faces of Tau, Neuron, May 12, 2011, pp. 410-426, vol. 70. [cited by applicant]
Peeraer, et al., Intracerebral injection of preformed synthetic tau fibrils initiates widespread tauopathy and neuronal loss in the brains of tau transgenic mice., Neurobiology of Disease, 2015, pp. 83-95, vol. 73. [cited by applicant]
Shi, et al., De Novo Selection of High-Affinity Antibodies from Synthetic Fab Libraries Displayed on Phage as pIX Fusion Proteins, J. Mol. Biol., Jan. 28, 2010, pp. 385-396, vol. 397 Issue 2. [cited by applicant]
Spillantini, et al., Tau protein pathology in neurodegenerative diseases, Trends Neurosci, 1998, pp. 428-433, vol. 21 Issue 10. [cited by applicant]
Timmerman, et al., Functional reconstruction and synthetic mimicry of a conformational epitope using CLIPSTM technology, Journal of Molecular Recognition, Aug.1, 2007, pp. 283-299, vol. 20. [cited by applicant]
Yang, et al., Tailoring structure-function and pharmacokinetic properties of single-chain Fv proteins by site-specific PEGylation, Protein Engineering, 2003, pp. 761-770, vol. 16 Issue 10. [cited by applicant]
Alforum, “Therapeutics”, Janssen, 3 pages, 2021. [cited by applicant]
Clerc et al., “The B-cell-specific Oct-2 protein contains POU box- and homeo box-type domains”, Genes & Development, vol. 2, pp. 1570-1581, 1988. [cited by applicant]
Extended European Search Report received for European Application No. 19173615.6 dated Oct. 10, 2019, 19 pages□. [cited by applicant]
Galpern et al., “A multiple ascending dose study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of the anti-phospho-tau antibody JNJ-63733657”, Janssen Neuroscience, 1 page, 2020. [cited by applicant]
International Search Report and Written Opinion received for PCT Application No. PCT/US2012/070486 dated Jun. 19, 2013, 15 pages□. [cited by applicant]
Kabat, E. A. et al., “Sequences of Proteins of Immunological Interest”, 5th Ed. U.S. Dept. of Health and Human Services, Bethesda, Md., NIH Publication No. 9 1-3242, 2 pages, 1991. [cited by applicant]
Ksiezak-Reding et al., “Binding of Alz 50 depends on Phe8 in tau synthetic peptides and varies between native and denatured tau proteins”, Brain Res, vol. 697(1-2), 1 page, Oct. 1995. [cited by applicant]
NCT_03375697, “A Study to Investigate Safety and Tolerability, Pharmacokinetics and Pharmacodynamics of JNJ-63733657 in Healthy Subjects and Subjects With Alzheimer's Disease”, ClinicalTrials.gov, 9 pages, Dec. 18, 2017. [cited by applicant]
NCT_04619420, “A Study of JNJ-63733657 in Participants With Early Alzheimer's Disease (Autonomy)”, ClinicalTrials.gov, 11 pages, Nov. 6, 2020. [cited by applicant]
Plotkin et al., “Passive immunotherapies targeting Aβ and tau in Alzheimer's disease”, Neurobiology of Disease, vol. 144, 26 pages, 2020. [cited by applicant]
Xu et al., “Diversity in the CDR3 Region of VH Is Sufficient for Most Antibody Specificities”, Immunity, vol. 13, pp. 37-45, Jul. 2000. [cited by applicant]
Yanamandra et al., “Anti-tau antibody administration increases plasma tau in transgenic mice and patients with tauopathy”, Sci. Transl. Med., vol. 9, eaa12029, pp. 1-11, 2017. [cited by applicant]
Zanden et al., “Passive Immunotherapies Targeting Amyloid Beta and Tau Oligomers in Alzheimer's Disease”, Journal of Pharmaceutical Sciences, vol. 109, pp. 68-73, 2020. [cited by applicant]