IP Library Granted Patent US 12,410,244
Granted Patent B2
US 12,410,244 · App. 17/682,082 · Granted Sep 9, 2025

Anti-alpha-synuclein antibodies

Inventors: Patrick Downey (Brussels, BE); Kerry Louise Tyson (Slough, GB); Marco Kriek (Slough, GB); Lorenzo De Lichtervelde (Brussels, BE); Daniel John Lightwood (Slough, GB); David James Mcmillan (Slough, GB); Peter Charles Elliott (Slough, GB); Terence Seward Baker (Berkshire, GB)
Assignee: UCB Biopharma SRL
C07K16/18A61P25/16A61K2039/505C07K2317/24C07K2317/565C07K2317/92
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Quick Facts
Patent No.
US 12,410,244
App. No.
17/682,082
Granted
Sep 9, 2025
Kind
B2
Abstract

The present invention relates to alpha synuclein binding antibodies and fragments thereof capable of binding alpha synuclein as a monomer and in fibrils and preventing alpha synuclein aggregation induced by alpha synuclein fibrils. The antibodies of the present invention are for use in the treatment of alpha synucleinopathies, including Parkinson's disease.

Claims (21)

1. A method for detecting alpha synuclein in a biological sample, comprising:

a) contacting the biological sample with an anti-alpha synuclein antibody or antigen-binding fragment thereof, and

b) detecting binding of the anti-alpha synuclein antibody or antigen-binding fragment thereof to alpha synuclein;

wherein the antibody or antigen-binding fragment thereof comprises:

i. a light chain variable region comprising a CDR-L1 comprising SEQ ID NO: 1; a CDR-L2 comprising SEQ ID NO: 2 and a CDR-L3 comprising SEQ ID NO: 3; and a heavy chain variable region comprising a CDR-H1 comprising SEQ ID NO: 4; a CDR-H2 comprising SEQ ID NO: 5 and a CDR-H3 comprising SEQ ID NO: 6; or

ii. a light chain variable region comprising SEQ ID NO: 13 and a heavy chain variable region comprising SEQ ID NO: 25; or a light chain variable region comprising SEQ ID NO: 17 and a heavy chain variable region comprising SEQ ID NO: 25; or a light chain variable region comprising SEQ ID NO: 21 and a heavy chain variable region comprising SEQ ID NO: 25; or

iii. a light chain comprising SEQ ID NO: 14 and a heavy chain comprising SEQ ID SEQ ID NO: 26; or a light chain comprising SEQ ID NO: 18 and a heavy chain comprising SEQ ID SEQ ID NO: 26; or a light chain comprising SEQ ID NO: 22 and a heavy chain comprising SEQ ID SEQ ID NO: 26.

2. The method of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises: a light chain variable region comprising a CDR-L1 comprising SEQ ID NO: 1; a CDR-L2 comprising SEQ ID NO: 2 and a CDR-L3 comprising SEQ ID NO: 3; and a heavy chain variable region comprising a CDR-H1 comprising SEQ ID NO: 4; a CDR-H2 comprising SEQ ID NO: 5 and a CDR-H3 comprising SEQ ID NO: 6.

3. The method of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises: a light chain variable region comprising a CDR-L1 comprising SEQ ID NO: 1; a CDR-L2 comprising SEQ ID NO: 2 and a CDR-L3 comprising SEQ ID NO: 3; and a heavy chain variable region comprising a CDR-H1 comprising SEQ ID NO: 4; a CDR-H2 comprising SEQ ID NO: 5 and a CDR-H3 comprising SEQ ID NO: 6, wherein amino acid residue glycine (Gly; G) at position 6 with reference to SEQ ID NO: 3 is replaced by alanine (Ala; A).

4. The method of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises: a light chain variable region comprising SEQ ID NO: 13 and a heavy chain variable region comprising SEQ ID NO: 25.

5. The method of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises: a light chain variable region comprising SEQ ID NO: 17 and a heavy chain variable region comprising SEQ ID NO: 25.

6. The method of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises: a light chain variable region comprising SEQ ID NO: 21 and a heavy chain variable region comprising SEQ ID NO: 25.

7. The method of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises: a light chain comprising SEQ ID NO: 14 and a heavy chain comprising SEQ ID SEQ ID NO: 26.

8. The method of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises: a light chain comprising SEQ ID NO: 18 and a heavy chain comprising SEQ ID SEQ ID NO: 26.

9. The method of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises: a light chain comprising SEQ ID NO: 22 and a heavy chain comprising SEQ ID SEQ ID NO: 26.

10. The method of claim 1 , wherein the biological sample is from a subject suspected of having an alpha synucleinopathy, wherein the alpha synucleinopathy is selected from the group consisting of Parkinson's disease (PD), dementia with Lewy bodies (DLB), Diffuse Lewy Body Disease (DLBD), Lewy body variant of Alzheimer's disease (LBVAD), combined Alzheimer's and Parkinson's disease, multiple system atrophy (MSA), and neurodegeneration with brain iron accumulation type-1 (NBIA-1).

11. The method of claim 10 , wherein the Parkinson's disease comprises idiopathic or inherited forms of Parkinson's disease.

12. The method of claim 10 , wherein the alpha synucleinopathy is Parkinson's disease.

13. The method of claim 1 , wherein the biological sample comprises cerebrospinal fluid, blood plasma, blood serum, or solid tissue samples.

14. The method of claim 13 , wherein the sample is a solid tissue sample comprising a biopsy specimen, tissue cultures or cells derived therefrom, or the progeny thereof.

15. The method of claim 1 , wherein after (b), the method further comprises comparing the detected alpha synuclein or a post-translationally modified form of alpha synuclein with a suitable control.

Assignments (2)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 1, 2022
From: DOWNEY, PATRICK; DE LICHTERVELDE, LORENZO; TYSON, KERRY LOUISE; KRIEK, MARCO; LIGHTWOOD, DANIEL JOHN; MCMILLAN, DAVID JAMES; BAKER, TERENCE SEWARD; ELLIOT, PETER CHARLES
To: UCB BIOPHARMA SPRL
Reel/Frame 059135/0362 →
CHANGE OF NAME Recorded Mar 1, 2022
From: UCB BIOPHARMA SPRL
To: UCB BIOPHARMA SRL
Reel/Frame 059276/0108 →
Priority Claims (1)
GB 1720970 · Dec 15, 2017 · national
Continuity (2)
Continuation 16772043
Related Publication 20220340648A1 · Oct 27, 2022
References Cited (244)
US 6890535B1 · Schenk · 2005 [cited by applicant]
US 7306945B2 · Chilcote et al. · 2007 [cited by applicant]
US 7358331B2 · Chilcote et al. · 2008 [cited by applicant]
US 7727957B2 · Schenk et al. · 2010 [cited by applicant]
US 7910333B2 · Chilcote et al. · 2011 [cited by applicant]
US 7919088B2 · Schenk et al. · 2011 [cited by applicant]
US 7977316B2 · Schenk · 2011 [cited by applicant]
US 8092801B2 · Schenk et al. · 2012 [cited by applicant]
US 8147833B2 · Schenk et al. · 2012 [cited by applicant]
US 8506959B2 · Schenk et al. · 2013 [cited by applicant]
US 8609820B2 · Saldanha et al. · 2013 [cited by applicant]
US 8632776B2 · Nordström et al. · 2014 [cited by applicant]
US 8673593B2 · Chilcote et al. · 2014 [cited by applicant]
US 8741293B2 · Dodel et al. · 2014 [cited by applicant]
US 8790644B2 · Saldanha et al. · 2014 [cited by applicant]
US 8809506B2 · Lannfelt et al. · 2014 [cited by applicant]
US 8940276B2 · Weihofen et al. · 2015 [cited by applicant]
US 8968734B2 · Nordström et al. · 2015 [cited by applicant]
US 9315569B2 · Lannfelt et al. · 2016 [cited by applicant]
US 9493553B2 · Kaluza et al. · 2016 [cited by applicant]
US 9605056B2 · Barbour et al. · 2017 [cited by applicant]
US 9670274B2 · Kaluza et al. · 2017 [cited by applicant]
US 9732148B2 · Ayalon et al. · 2017 [cited by applicant]
US 9890209B2 · Kaluza et al. · 2018 [cited by applicant]
US 9896504B2 · Weihofen et al. · 2018 [cited by applicant]
US 10081674B2 · Barbour et al. · 2018 [cited by applicant]
US 11261242B2 · Adams et al. · 2022 [cited by applicant]
US 20030166558A1 · Frangione et al. · 2003 [cited by applicant]
US 20040136993A1 · Schenk et al. · 2004 [cited by applicant]
US 20050037013A1 · Schenk et al. · 2005 [cited by applicant]
US 20050196818A1 · Chilcote et al. · 2005 [cited by applicant]
US 20080014194A1 · Schenk et al. · 2008 [cited by applicant]
US 20110059093A1 · Bohrmann et al. · 2011 [cited by applicant]
US 20130072663A1 · Chilcote et al. · 2013 [cited by applicant]
US 20130108546A1 · Saldanha et al. · 2013 [cited by applicant]
US 20140241984A1 · El-Agnaf · 2014 [cited by applicant]
US 20140369940A1 · Weihofen et al. · 2014 [cited by applicant]
US 20150139937A1 · Gendelman et al. · 2015 [cited by applicant]
US 20150140003A1 · Kaluza et al. · 2015 [cited by applicant]
US 20160060331A1 · Schenk et al. · 2016 [cited by applicant]
US 20170320940A1 · Ayalon et al. · 2017 [cited by applicant]
US 20170349651A1 · Schenk et al. · 2017 [cited by applicant]
US 20180134775A1 · El-Agnaf et al. · 2018 [cited by applicant]
US 20180134776A1 · El-Agnaf et al. · 2018 [cited by applicant]
US 20180134777A1 · El-Agnaf et al. · 2018 [cited by applicant]
US 20180237510A1 · Kaluza et al. · 2018 [cited by applicant]
DE 102011008153A1 · 2012 [cited by applicant]
EP 1185296B1 · 2011 [cited by applicant]
EP 2371396B1 · 2014 [cited by applicant]
EP 2272539B1 · 2014 [cited by applicant]
EP 2807188B1 · 2014 [cited by applicant]
EP 2370466B1 · 2015 [cited by applicant]
EP 1578253B1 · 2015 [cited by applicant]
EP 2903648B1 · 2015 [cited by applicant]
EP 2949666B1 · 2015 [cited by applicant]
EP 2583978B1 · 2016 [cited by applicant]
EP 3067066B1 · 2016 [cited by applicant]
EP 2450056B1 · 2017 [cited by applicant]
EP 2361928B1 · 2017 [cited by applicant]
EP 1633189B1 · 2017 [cited by applicant]
EP 2539366B1 · 2017 [cited by applicant]
EP 2723379B1 · 2018 [cited by applicant]
EP 3369433A1 · 2018 [cited by applicant]
EP 2282758B1 · 2018 [cited by applicant]
WO 2002050121A1 · 2002 [cited by applicant]
WO 2004041067A3 · 2004 [cited by applicant]
WO 2005013889A3 · 2005 [cited by applicant]
WO 2005047860A3 · 2005 [cited by applicant]
WO 2006020581A3 · 2006 [cited by applicant]
WO 2006045037A3 · 2006 [cited by applicant]
WO 2007012061A3 · 2007 [cited by applicant]
WO 2007011907A2 · 2007 [cited by applicant]
WO 2007021255A1 · 2007 [cited by applicant]
WO 2008103472A3 · 2008 [cited by applicant]
WO 2009133521A3 · 2009 [cited by applicant]
WO 2010069603A1 · 2010 [cited by applicant]
WO 2011104696A1 · 2011 [cited by applicant]
WO 2011107544A1 · 2011 [cited by applicant]
WO 2012061785A3 · 2012 [cited by applicant]
WO 2012061786A1 · 2012 [cited by applicant]
WO 2012177972A1 · 2012 [cited by applicant]
WO 2013063516A1 · 2013 [cited by applicant]
WO 2013112945A1 · 2013 [cited by applicant]
WO 2013180201A1 · 2013 [cited by applicant]
WO 2014058924A3 · 2014 [cited by applicant]
WO 2014132210A1 · 2014 [cited by applicant]
WO 2015001504A2 · 2015 [cited by applicant]
WO 2015051159A1 · 2015 [cited by applicant]
WO 2015075011A1 · 2015 [cited by applicant]
WO 2015075635A2 · 2015 [cited by applicant]
WO 2015155694A1 · 2015 [cited by applicant]
WO 2015179867A1 · 2015 [cited by applicant]
WO 2015197772A1 · 2015 [cited by applicant]
WO 2016040903A1 · 2016 [cited by applicant]
WO 2016040905A1 · 2016 [cited by applicant]
WO 2016040907A1 · 2016 [cited by applicant]
WO 2016061389A3 · 2016 [cited by applicant]
WO 2017009312A1 · 2017 [cited by applicant]
WO 2017033152A1 · 2017 [cited by applicant]
WO 2017091512A1 · 2017 [cited by applicant]
WO 2017176835A2 · 2017 [cited by applicant]
WO 2017207739A1 · 2017 [cited by applicant]
WO 2018007817A1 · 2018 [cited by applicant]
WO 2018039147A1 · 2018 [cited by applicant]
WO 2018091444A1 · 2018 [cited by applicant]
WO 2018109058A1 · 2018 [cited by applicant]
WO 2018111670A3 · 2018 [cited by applicant]
WO 2018115225A1 · 2018 [cited by applicant]
WO 2018128454A1 · 2018 [cited by applicant]
WO 2018128722A1 · 2018 [cited by applicant]
WO 2018151821A1 · 2018 [cited by applicant]
WO 2018178950A1 · 2018 [cited by applicant]
WO 2018213440A1 · 2018 [cited by applicant]
WO 2018237338A1 · 2018 [cited by applicant]
WO 2019115674A1 · 2019 [cited by applicant]
Almandoz-Gil et al., “Low molar excess of 4-oxo-2-nonenal and 4-hydroxy-2-nonenal promote oligomerization of alpha-synuclein through different pathways,” Free Radical Biology and Medicine 110:421-431 (2017). [cited by applicant]
Anderson et al., “Phosphorylation of Ser-129 is the dominant pathological modification of alpha-synuclein in familial and sporadic Lewy body disease,” J Biol Chem 281:29739-29752 (2006). [cited by applicant]
Assayag et al., “Polyunsaturated fatty acids induce a-synuclein-related pathogenic changes in neuronal cells,” Am J Pathology 171(6):2000-2011 (2007). [cited by applicant]
Baba et al., “Aggregation of alpha-synuclein in Lewy bodies of sporadic Parkinson's disease and dementia with Lewy bodies,” Am J Pathology 152(4):879-884 (1998). [cited by applicant]
Bae et al., “Lipid peroxidation product 4-hydroxy-2-nonenal promotes seeding-capable oligomer formation and cell-to-cell transfer of α-synuclein,” Antioxid. Redox Signal 18(7):770-783 (2013). [cited by applicant]
Bengoa-Vergniory et al., “Alpha-synuclein oligomers: a new hope,” J. Acta Neuropathol 134:819-838 (2017). [cited by applicant]
Bergström et al., “Development of Passive Immunotherapies for Synucleinopathies,” Movement Disorders 31(2):203-213 (2016). [cited by applicant]
Bloch et al., “α-Synuclein pathology of the spinal and peripheral autonomic nervous system in neurologically unimpaired elderly subjects,” Neuropathology and Applied Neurobiology 32:284-295 (2006). [cited by applicant]
Bosco et al., “Elevated levels of oxidized cholesterol metabolites in Lewy body disease brains accelerate α-synuclein fibrilization,” Nature Chemical Biology 2(5):249-253 (2006). [cited by applicant]
Chen et al., “Enhancement and destruction of antibody function by somatic mutation: unequal occurrence is controlled byV gene combinatorial associations” EMBO 14(12):2784-2794 (1995). [cited by applicant]
Cole et al., “Lipid droplet binding and oligomerization properties of the Parkinson's disease protein α-synuclein,” JBC 277(8):6344-6352 (2002). [cited by applicant]
Cole et al., “Metal-catalyzed Oxidation of α-Synuclein Helping to Define the Relationship Between Oligomers, Protofibrils, and Filaments,” J Biol Chem 280(10):9678-9690 (2005). [cited by applicant]
Conway et al., “Accelerated in vitro fibril formation by a mutant α-synuclein linked to early-onset Parkinson disease,” Nature Medicine 4(11):1318-1320 (1998). [cited by applicant]
Cremades et al., “Chapter Three—Structural Characteristics of α-Synuclein Oligomers,” International Review of Cell and Molecular Biology 329:79-143 (2017). [cited by applicant]
Cremades et al., “Direct observation of the interconversion of normal and toxic forms of α-synuclein,” Cell 149:1048-1059 (2012). [cited by applicant]
Croisier et al., “Comparative study of commercially available anti α-synuclein antibodies,” Neuropathology and Applied Neurobiology 32:351-356 (2006). [cited by applicant]
Curtiss et al., “Selection of monoclonal antibodies for linear epitopes of an apolipoprotein yields antibodies with comparable affinity for lipid-free and lipid-associated apolipoprotein,” Journal of Lipid Research 37:8… [cited by applicant]
Danzer et al., “Different species of α-synuclein oligomers induce calcium influx and seeding,” J Neuroscience 27(34):9220-9232 (2007). [cited by applicant]
Dehay et al., “Targeting α-synuclein for treating Parkinson's disease: mechanistic and therapeutic considerations,” Lancet Neurol. 14(8): 855-866 (2015). [cited by applicant]
Deng et al., “Projecting human pharmacokinetics of therapeutic antibodies from nonclinical data. What have we learned?” mAbs 3:1, 61-66; (2011). [cited by applicant]
Dimitrov et al., “Therapeutic Antibodies: Current State and Future Trends—is a Paradigm Change Coming Soon?” Meth Mol Biol 525: Chapter 1, pp. 1-27 (2009). [cited by applicant]
Duda et al., “Immunohistochemical and Biochemical Studies Demonstrate a Distinct Profile of a-Synuclein Permutations in Multiple System Atrophy,” Journal of Neuropathology and Experimental Neurology 59:9 830-841 (2000). [cited by applicant]
El-Agnaf et al., “α-Synuclein implicated in Parkinson's disease is present in extracellular biological fluids, including human plasma,” FASEB J 17:1945-1947 (2003). [cited by applicant]
Emadi et al., “Inhibiting aggregation of α-synuclein with human single chain antibody fragments,” Biochem 43(10):2871-2878 (2004). [cited by applicant]
Emadi et al., “Isolation of a human single chain antibody fragment against oligomeric α-synuclein that inhibits aggregation and prevents α-synuclein-induced toxicity,” J. Mol. Biol. 368(4):1132-1144 (2007). [cited by applicant]
Fagerqvist et al., “Monoclonal antibodies selective for α-synuclein oligomers/protofibrils recognize brain pathology in Lewy body disorders and α-synuclein transgenic mice with the disease-causing A30P mutation,” Journa… [cited by applicant]
Fairfoul et al., “Alpha-synuclein RT-QuIC in the CSF of patients with alpha-synucleinopathies,” Annals of Clinical and Translational Neurology 3(10): 812-818 (2016). [cited by applicant]
Fernagut et al., “Behavioral and histopathological consequences of paraquat intoxication in mice: Effects of α-synuclein over-expression,” Synapse 61(12):991-1001 (2007). [cited by applicant]
Fjorback et al., “Determination of α-synuclein concentration in human plasma using ELISA,” Scandanavian Journal of Clinical & Laboratory Investigation 67:431-435 (2007). [cited by applicant]
Fujiwara et al., “α-Synuclein is phosphorylated in synucleinopathy lesions,” Nat Cell Biol 4: 160-164 (2002). [cited by applicant]
Games et al., “Reducing C-Terminal-Truncated Alpha-Synuclein by Immunotherapy Attenuates Neurodegeneration and Propagation in Parkinson's Disease-Like Models,” J. Neurosci 34(28):9441-9454 (2014). [cited by applicant]
Garambois et al., “Fully human IgG and IgM antibodies directed against the carcinoembryonic antigen (CEA) Gold 4 epitope and designed for radioimmunotherapy (RIT) of colorectal cancers,” BMC Cancer 4:75 (2004). [cited by applicant]
George et al., “Characterization of a novel protein regulated during the critical period for song learning in the zebra finch,” Neuron 15:361-372 (1995). [cited by applicant]
Giasson et al., “A panel of epitope-specific antibodies detects protein domains distributed throughout human a-synuclein in lewy bodies of Parkinson's disease,” J Neurosci Res 59:528-533 (2000). [cited by applicant]
Goedert, “α-synuclein and neurodegenerative diseases,” Nature Reviews Neuroscience 2:491-501 (2001). [cited by applicant]
Gomez-Tortosa et al., “α-Synuclein immunoreactivity in dementia with Lewy bodies: morphological staging and comparison with ubiquitin immunostaining,” Acta Neuropathologica 99(4):352-357 (2000). [cited by applicant]
Guilliams et al., “Nanobodies raised against monomeric alpha-synuclein distinguish between fibrils at different maturation stages,” Journal of Molecular Biology 425:2397-2411 (2013). [cited by applicant]
Jakes et al., “Epitope mapping of LB509, a monoclonal antibody directed against human a-synuclein,” Neuroscience Letters 269:13-16 (1999). [cited by applicant]
Jakobovits, “A Production of fully human antibodies by transgenic mice,” Current Opinion in Biotechnology 6:561-566 (1995). [cited by applicant]
Jankovic et al., “Safety and Tolerability of Multiple Ascending Doses of PRX002/RG7935, an Anti-α-Synuclein Monoclonal Antibody, in Patients with Parkinson Disease. A Randomized Clinical Trial,” JAMA Neurol. 75(10):1206… [cited by applicant]
Jensen et al., “α-Synuclein binds to tau and stimulates the protein kinase A—catalyzed tau phosphorylation of serine residues 262 and 356,” J. Biol. Chem 274(36):25481-25489 (1999). [cited by applicant]
Jensen et al., “Microtubule-associated protein 1B is a component of cortical Lewy bodies and binds α-synuclein filaments,” JBC 275(28):21500-21507 (2000). [cited by applicant]
Kahle et al., “Physiology and pathophysiology of alpha-synuclein. Cell culture and transgenic animal models based on a Parkinson's disease-associated protein,” Ann N Y Acad Sci 920:33-41 (2000). [cited by applicant]
Kahle et al., “Subcellular Localization of Wild-Type and Parkinson's Disease-Associated Mutant a-Synuclein in Human and Transgenic Mouse Brain,” J. Neuroscience 20(17):6365-6373 (2000). [cited by applicant]
Kawamata et al., “Interaction of α-synuclein and synphilin-1: effect of Parkinson's disease-associated mutations,” J. Neurochem. 77:929-934 (2001). [cited by applicant]
Kayed et al., “Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis,” Science 300:486-489 (2003). [cited by applicant]
Kim et al., “Transneuronal Propagation of Pathologic α-Synuclein from the Gut to the Brain Models Parkinson's Disease,” Neuron. 103(4):627-641 (2019). [cited by applicant]
Klos et al., “α-Synuclein pathology in the spinal cords of neurologically asymptomatic aged individuals,” Neurology 66:1100-1102 (2006). [cited by applicant]
Kramer et al., “Presynaptic alpha-Synuclein Aggregates, Not Lewy Bodies, Cause Neurodegeneration in Dementia with Lewy Bodies,” J. Neuroscience 27(6):1405-1410 (2007). [cited by applicant]
Kunik et al., “Structural Consensus among Antibodies defines the antigen binding site,” PLoS Comput Biol 8(2) (2012). [cited by applicant]
Kussie et al., “A Single Engineered Amino Acid Substitution Changes Antibody Fine Specificity,” J Immunol 152(1):146-52 (1994). [cited by applicant]
Lee et al., “Characterization of Cytoplasmic alpha-Synuclein Aggregates,” J Biol Chem 277(50):48976-48983 (2002). [cited by applicant]
Lee et al., “Intravesicular localization and exocytosis of α-synuclein and its aggregates,” J. Neuroscience 25(25):6016-6024 (2005). [cited by applicant]
Lee et al., “Real-time analysis of amyloid fibril formation of α-synuclein using a fibrillation-state-specific fluorescent probe of JC-1,” Biochem J 418:311-323 (2009). [cited by applicant]
Lipman et al., “Monoclonal versus polyclonal antibodies: distinguishing characteristics, applications, and information resources,” ILAR Journal 46:258-268 (2005). [cited by applicant]
Lynch et al., “An ScFv Intrabody Against the Non-Amyloid Component of Alpha Synuclein Reduces Intracellular Aggregation and Toxicity,” J Mol Biol 377(1):136-147 (2008). [cited by applicant]
Maguire-Zeiss et al., “Identification of human α-synuclein specific single chain antibodies,” Biochem Biophys Res Comm 349:1198-1205 (2006). [cited by applicant]
Margutti et al., “Autoantibodies to the C-terminal subunit of RLIP76 induce oxidative stress and endothelial cell apoptosis in immune-mediated vascular diseases and atherosclerosis,” Blood 111(9):4559-4570 (2007). [cited by applicant]
Mariuzza, R.A., “The Structural Basis of Antigen-Antibody Recognition,” Ann. Rev. Biophys. Biophys. Chem. 16:139-159 (1987). [cited by applicant]
Masliah et al., “Effects of α-synuclein immunization in a mouse model of Parkinson's disease,” Neuron 46:857-868 (2005). [cited by applicant]
Masliah et al., “Passive Immunization Reduces Behavioral and Neuropathological Deficits in an Alpha-Synuclein Transgenic Model of Lewy Body Disease,” PLoS One 4:1-17 (2011). [cited by applicant]
Mayo “Parkinson's disease,” accessed from mayoclinic.org on Nov. 7, 2018. [cited by applicant]
McLean et al., “Membrane Association and Protein Conformation of α-Synuclein in Intact Neurons Effect of Parkinson's Disease-Linked Mutations,” J. Biol. Chem 275(12):8812-8816 (2000). [cited by applicant]
Miller et al., “α-Synuclein in blood and brain from familial Parkinson disease with SNCA locus triplication,” Neurology 62:1835-1838 (2004). [cited by applicant]
Milne et al., “Heat-Labile Antigens of [cited by applicant]
Näsström et al., “P4-284: Oligomeric amorphous species of alpha-synuclein induce toxicity in a cellular model,” Alzh Dem: J Alzh Assoc 4(4):T754 (2008). [cited by applicant]
Näsström et al., “The lipid peroxidation metabolite 4-oxo-2-nonenal cross-links α-synuclein causing rapid formation of stable oligomers,” Biochem. Biophys. Res. Comm. 378:872-876 (2009). [cited by applicant]
Näsström et al., “Antibodies against α-synuclein reduce oligomerization in living cells,” PLoS One 6(10):e27230 (2011). [cited by applicant]
Okochi et al., “Constitutive phosphorylation of the Parkinson's disease associated alpha-synuclein,” J Biol Chem 275: 390-397 (2000). [cited by applicant]
Olanow et al., “Parkinson's Disease and Alpha Synuclein: Is Parkinson's Disease a Prion-Like Disorder?” Movement Disorders 28(1):31-40 (2013). [cited by applicant]
Oueslati, “Implication of Alpha-Synuclein Phosphorylation at S129 in Synucleinopathies: What Have We Learned in the Last Decade?” Journal of Parkinson's Disease 6:39-51 (2016). [cited by applicant]
Perez De La Lastra et al., “Epitope mapping of 10 monoclonal antibodies against the pig analogue of human membrane cofactor protein (MCP),” Immunology 96(4):663-670 (1999). [cited by applicant]
Qin et al., “Effect of 4-hydroxy-2-nonenal modification on α-synuclein aggregation,” J Biol Chem 282(8):5862-5870 (2007). [cited by applicant]
Reichmann et al., “Reshaping human antibodies for therapy,” Nature 332:323-327 (1988). [cited by applicant]
Ruesink et al., “Stabilization of α-synuclein oligomers using formaldehyde,” PLoS One 14(10): e0216764 (2019). [cited by applicant]
Schenk et al., “First in human assessment of PRX002, an anti-alpha-synuclein monoclonal antibody, in healthy volunteers,” Movement Disorders 32(2):211-218 (2017). [cited by applicant]
Schneider et al., “Over-expression of alpha-synuclein in human neural progenitors leads to specific changes in fate and differentiation,” Human Molecular Genetics 16(6):651-666 (2007). [cited by applicant]
Shen et al., “Identifying the Pathological Domain of Alpha-Synuclein as a Therapeutic for Parkinson's Disease,” Int J Mol Sci. 20(9):2338 (2019). [cited by applicant]
Seo et al., “α-Synuclein regulates neuronal survival via Bcl-2 family expression and PI3/Akt kinase pathway,” FASEB J 16(13):1826-1828 (2002). [cited by applicant]
Serpell et al., “Fiber diffraction of synthetic a-synuclein filaments shows amyloid-like cross-β conformation,” PNAS 97(9):4897-4902 (2000). [cited by applicant]
Shamoto-Nagai et al., “In parkinsonian substantia nigra, α-synuclein is modified by acrolein, a lipid-peroxidation product, and accumulates in the dopamine neurons with inhibition of proteasome activity,” J Neural Trans… [cited by applicant]
Sharma et al., “A close association of torsinA and α-synuclein in lewy bodies: a fluorescence resonance energy transfer study,” American J. Pathology 159(1):339-344 (2001). [cited by applicant]
Sharon et al., “The Formation of Highly Soluble Oligomers of alpha-Synuclein is Regulated by Fatty Acids and Enhanced in Parkinson's Disease,” Neuron 37:583-595 (2003). [cited by applicant]
Souza et al., “Dityrosine Cross-linking Promotes Formation of Stable a-Synuclein Polymers,” JBC 275:24 18344-18349 (2000). [cited by applicant]
Stefanis, “A-Synuclein in Parkinson's Disease,” Cold Spring Harb Perspect Med 4:a009399 (2012). [cited by applicant]
Sumikura et al., “Distribution of α-synuclein in the spinal cord and dorsal root ganglia in an autopsy cohort of elderly persons,” Acta neuropathologica communications 3(1):1-11 (2015). [cited by applicant]
Tickle et al., “A fully automated primary screening system for the discovery of therapeutic antibodies directly from B cells,” J Biomol Screen 20(4):492-497 (2015). [cited by applicant]
Toyokuni et al., “The monoclonal antibody specific for the 4-hydroxy-2-nonenal histidine adduct,” FEBS Letters 359:189-191 (1995). [cited by applicant]
Tran et al., “α-Synuclein Immunotherapy Blocks Uptake and Templated Propagation of Misfolded alpha-Synuclein and Neurodegeneration,” Cell Reports 7(6):2054-2065 (2014). [cited by applicant]
Trostchansky et al., “Interaction with phospholipids modulates α-synuclein nitration and lipid-protein adduct formation,” Biochem. J. 393: 343-349 (2006). [cited by applicant]
Vaikath et al., “Generation and Characterization of novel conformation-specific monoclonal antibodies for alpha-synuclein pathology,” Neurobiology of Disease 79: 81-99 (2015). [cited by applicant]
Van Der Putten et al., “Neuropathology in mice expressing human α-synuclein,” J. Neuroscience 20(16):6021-6029 (2000). [cited by applicant]
Van Diggelen et al., “Two conformationally distinct α-synuclein oligomers share common epitopes and the ability to impair long-term potentiation,” PLoS One 14(3):e0213663 (2019). [cited by applicant]
Msanji et al., “α-Synuclein-Based Animal Models of Parkinson's Disease: Challenges and Opportunities in a New Era,” Trends in Neurosciences, 39(11) 750-762 (2016). [cited by applicant]
Vogiatzi et al., “Wild type α-synuclein is degraded by chaperone-mediated autophagy and macroautophagy in neuronal cells,” JBC 283(35):23542-23556 (2008). [cited by applicant]
Volpicelli-Daley et al., “Exogenous a-Synuclein Fibrils Induce Lewy Body Pathology Leading to Synaptic Dysfunction and Neuron Death,” Neuron 72, 57-71 (2011). [cited by applicant]
Wahlberg et al., “Development of oligomer-specific alpha-synuclein antibodies,” Alzheimer's & Dementia 4(4) Suppl. T481-T482, P2-372 (2008). [cited by applicant]
Weber et al., “From rabbit antibody repertoires to rabbit monoclonal antibodies,” Experimental and Molecular Medicine 49: e305 (2017). [cited by applicant]
Yamashita et al., “Recent advances in the generation of human monoclonal Antibody,” Cytotechnology 55:55-60 (2007). [cited by applicant]
Zhou et al., “Intrabody and Parkinson's disease,” Biochim Biophys Acta 1792:634-642 (2009). [cited by applicant]
The International Search Report issued in PCT/EP2018/084689 dated Mar. 25, 2019. [cited by applicant]
Information on H3C Ab from U Iowa—D2 in Opposition of EP 2282758 submitted Aug. 16, 2019. [cited by applicant]
Datasheet for the 211 antibody—D14 in Opposition of EP 2282758 submitted Aug. 16, 2019. [cited by applicant]
Cosmo Bio News Topics Digest 2004—D17 in Opposition of EP 2282758 submitted Aug. 16, 2019. [cited by applicant]
Webpage for 610787 antibody—D20 in Opposition of EP 2282758 submitted Aug. 16, 2019. [cited by applicant]
Datasheet for 610787 antibody—D21 in Opposition of EP 2282758 submitted Aug. 16, 2019. [cited by applicant]
Screenshot for MAB3249 antibody—D29 in Opposition of EP 2282758 submitted Aug. 16, 2019. [cited by applicant]
MAb3249 Datasheet—D30 in Opposition of EP 2282758 submitted Aug. 16, 2019. [cited by applicant]
Screenshot for ab48506 antibody—D33 in Opposition of EP 2282758 submitted Aug. 16, 2019. [cited by applicant]
Screenshot of HNEJ-2 antibody—D34 in Opposition of EP 2282758 submitted Aug. 16, 2019. [cited by applicant]
Asano thesis 2007 Marshall University—D36 in Opposition of EP 2282758 submitted Aug. 16, 2019. [cited by applicant]
Experimental report for 8A5 antibody—D40 in Opposition of EP 2282758 submitted Aug. 16, 2019. [cited by applicant]
Product sheet for 8A5 producing cell line—D41 in Opposition of EP 2282758 submitted Aug. 16, 2019. [cited by applicant]
Patentee's letter of Jul. 9, 2014 re EP2539366—D45 in Opposition of EP 2282758 submitted Aug. 16, 2019. [cited by applicant]
Technical Report—Binding data of anti-alpha synuclein antibodies—D1 in Opposition of EP 2282758 submitted Aug. 21, 2019. [cited by applicant]
Tocris—Datasheet for DHA—D6 in Opposition of EP 2282758 submitted Aug. 21, 2019. [cited by applicant]
Exhibit 1 submitted by patentee Feb. 27, 2018—D12 in Opposition of EP 2282758 submitted Aug. 21, 2019. [cited by applicant]
EP Appl. No. 08022188—priority to WO2010069603—E6 in Opposition of EP 2282758 submitted Aug. 21, 2019. [cited by applicant]
Letter dated Mar. 14, 2017—D1 in Opposition of EP3067066 submitted Dec. 24, 2019. [cited by applicant]
Letter dated Jan. 8, 2018 filed during examination—D2 in Opposition of EP 3067066 submitted Dec. 24, 2019. [cited by applicant]
Letter dated Jul. 30, 2018 filed during examination—D3 in Opposition of EP 3067066 submitted Dec. 24, 2019. [cited by applicant]
Letter dated Aug. 24, 2018 filed during examination—D4 in Opposition of EP 3067066 submitted Dec. 24, 2019. [cited by applicant]
Response filed May 31, 2011 in U.S. Appl. No. 12/037,081—D5 in Opposition of EP 3067066 submitted Dec. 24, 2019. [cited by applicant]
ATCC deposit receipt for antibody 9E4 dated Feb. 26, 2007—D6 in Opposition of EP 3067066 submitted Dec. 24, 2019. [cited by applicant]
Declaration of E Masliah filed in U.S. Pat. No. 11,710,248—D27 in Opposition of EP 3067066 submitted Jun. 8, 2020. [cited by applicant]
Declaration of Leda Alfonso Trujillo filed in Ecuador Application SENADI-2020-39610, mailed May 5, 2021. [cited by applicant]
Declaration of Leda Alfonso Trujillo filed in Ecuador Application SENADI-2020-39623, mailed May 5, 2021. [cited by applicant]
Non-final Office Action in U.S. Appl. No. 16/771,993 dated May 5, 2021. [cited by applicant]
Notice of Allowance in U.S. Appl. No. 16/771,993 dated Nov. 5, 2021. [cited by applicant]