Tau binding compounds

Abstract

To provide anti-tau antibodies and vectorization thereof (for example, into AAV particles), and to provide methods of using anti-tau antibodies and / or AAV particles for prevention, treatment, and / or diagnosis of neurological indications.SOLUTION: An isolated, for example recombinant, antibody that binds to tau and comprises a heavy chain variable region (VH) including HC CDR1, HC CDR2, and HC CDR3, and a light chain variable region (VL) including LC CDR1, LC CDR2, and LC CDR3 is provided.SELECTED DRAWING: None

Description

[Technical Field]

[0001] REFERENCE TO RELATED APPLICATIONS This application claims the benefit of the filing date of U.S. Provisional Patent Application No. 63 / 010261, filed April 15, 2020, and U.S. Provisional Patent Application No. 63 / 162976, filed March 18, 2021, the entire contents of the above-referenced applications are incorporated herein by reference, including any sequences in the tables and figures.

[0002] Sequence Listing This application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety.

[0003] The present disclosure provides tau-binding compounds and adeno-associated virus (AAV) particles comprising same. [Background technology]

[0004] Tauopathies are a group of neurodegenerative disorders characterized by dysfunction and / or aggregation of the microtubule-associated protein tau. Tau is a normally highly soluble protein known to associate with microtubules based on its degree of phosphorylation. Given its unique, extended structure, tau is considered a critical component of intracellular transport processes, particularly in neurons. Hyperphosphorylation of tau inhibits its binding to microtubules and microtubule assembly activity. Furthermore, hyperphosphorylation of tau predisposes it to misfolding and aggregation. In tauopathies, tau becomes hyperphosphorylated, misfolds, and aggregates into paired helical filaments (PHFs), twisted ribbons, or straight filament neurofibrillary tangles (NFTs). These NFTs are widely considered to signal impending neuronal death and contribute to widespread neuronal loss, leading to a variety of behavioral and cognitive impairments.

[0005] Genetically defined tauopathies were first reported when mutations in the tau gene were shown to lead to an autosomal dominant tauopathy known as frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). This provided evidence that alterations in tau can lead to neurodegenerative changes in the brain. These molecules are thought to be more amyloidogenic, i.e., more susceptible to hyperphosphorylation and more prone to aggregating into NFTs (Non-Patent Document 1).

[0006] Several approaches have been proposed to therapeutically interfere with the progression of tau pathology and prevent subsequent molecular and cellular consequences. Given that NFTs are composed of hyperphosphorylated, misfolded, and aggregated forms of tau, interference at each of these stages provides a target that can be pursued. Introduction of drugs that limit phosphorylation, block misfolding, or prevent aggregation are promising strategies. It has also been suggested that introduction of anti-tau antibodies could prevent the transneuronal spread of tau pathology.

[0007] There remains a need for anti-tau antibodies for use in the treatment, diagnosis, and other applications of tauopathies, and the present disclosure addresses this need through the related compounds and methods described herein. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Hutton, M. et al., 1998, Nature 393(6686):702-5 Summary of the Invention

[0009] The present disclosure relates, at least in part, to compositions and methods for modulating tau levels, e.g., tau aggregation and / or distribution, and / or delivery, e.g., vectored delivery, of antibodies that bind to tau, e.g., anti-tau antibodies, e.g., the anti-tau antibodies described herein. In some embodiments, tau levels, e.g., aggregation or distribution, are reduced or inhibited using an anti-tau antibody described herein, or an isolated, e.g., recombinant, AAV particle comprising a viral genome encoding an anti-tau antibody, such as the anti-tau antibodies described herein. In some embodiments, tau degradation is increased using an anti-tau antibody described herein, or an isolated, e.g., recombinant, AAV particle comprising a viral genome encoding an anti-tau antibody, such as the anti-tau antibodies described herein. Such inhibition and / or degradation may be useful for treating disorders and / or neurological disorders associated with tau expression, such as tauopathies.

[0010] Accordingly, in one aspect, the disclosure provides an isolated, e.g., recombinant, antibody that binds to tau, comprising a heavy chain variable region (VH) comprising one, two, or three of heavy chain complementarity determining region 1 (HC CDR1), heavy chain complementarity determining region 2 (HC CDR2), and / or heavy chain complementarity determining region 3 (HC CDR3) of any of the HC CDR sequences in Table 1, 6, 2A-2C, 4, or 5, and / or a light chain variable region (VL) comprising one, two, or three of light chain complementarity determining region 1 (LC CDR1), light chain complementarity determining region 2 (LC CDR2), and / or light chain complementarity determining region 3 (LC CDR3) of any of the LC CDR sequences in Table 1, 6, 2A-2B, 4, or 5.

[0011] In another aspect, the disclosure provides an isolated, e.g., recombinant, antibody that binds to human tau, wherein the antibody binds to the same or substantially the same epitope as a reference antibody, wherein the reference antibody comprises a VH comprising HC CDR1, HC CDR2, and HC CDR3, and a VL comprising light chain LC CDR1, LC CDR2, and LC CDR3, wherein the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 315, 341, 410, 474, 529, and 571, respectively; or wherein the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 314, 341, 410, 1154, 529, and 571, respectively; or wherein the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 314, 341, 410, 1154, 529, and 571, respectively. CDR3 comprises the amino acid sequences of SEQ ID NOs: 316, 341, 410, 475, 530, and 571, respectively.

[0012] In another aspect, the disclosure provides an isolated, e.g., recombinant, antibody that binds to human tau, which antibody competes for binding with a reference antibody, wherein the reference antibody comprises a VH comprising HC CDR1, HC CDR2, and HC CDR3, and a VL comprising light chain LC CDR1, LC CDR2, and LC CDR3, wherein HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 315, 341, 410, 474, 529, and 571, respectively; or wherein HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 314, 341, 410, 1154, 529, and 571, respectively; or wherein HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 314, 341, 410, 1154, 529, and 571, respectively. CDR3 comprises the amino acid sequences of SEQ ID NOs: 316, 341, 410, 475, 530, and 571, respectively.

[0013] In yet another aspect, the disclosure provides an isolated, e.g., recombinant, antibody that binds to a region of human tau protein comprising residues 409-436 numbered according to SEQ ID NO: 920. In some embodiments, the antibody comprises a VH comprising an HC CDR1, an HC CDR2, and an HC CDR3, wherein the HC CDR1, the HC CDR2, and the HC CDR3 comprise the amino acid sequences of SEQ ID NOs: 1180, 341, and 410, respectively; or the HC CDR1, the HC CDR2, and the HC CDR3 comprise the amino acid sequences of SEQ ID NOs: 1183, 1184, and 410, respectively; or the HC CDR1, the HC CDR2, and the HC CDR3 comprise the amino acid sequences of SEQ ID NOs: 1186, 1187, and 1167, respectively. In some embodiments, the antibody comprises a VL comprising an LC CDR1, an LC CDR2, and an LC CDR3, wherein the LC CDR1, the LC CDR2, and the LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 1181, 1182, and 571, respectively; or the LC CDR1, the LC CDR2, and the LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 1185, 1182, and 571, respectively; or the LC CDR1, the LC CDR2, and the LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 1188, 528, and 571, respectively.

[0014] In yet another aspect, the disclosure provides antibodies that bind, e.g., directly or indirectly, to a region of human tau protein including residues 32-49, 55-76, 159-194, 185-200, 219-247, 381-426, and / or 409-436 numbered according to SEQ ID NO:920.

[0015] In yet another aspect, the disclosure provides an isolated, e.g., recombinant, nucleic acid encoding an antibody described herein, e.g., an antibody comprising a VH that includes one, two, or three of the HC CDR1, HC CDR2, and / or HC CDR3 of any of the HC CDR sequences in Table 1, 6, 2A-2C, 4, or 5, and / or a VL that includes one, two, or three of the LC CDR1, LC CDR2, and / or LC CDR3 of any of the LC CDR sequences in Table 1, 6, 2A-2C, 4, or 5.

[0016] In yet another aspect, the present disclosure provides a viral genome comprising a promoter operably linked to a nucleic acid encoding an antibody that binds tau (e.g., an anti-tau antibody described herein). In some embodiments, the viral genome further comprises an internal terminal repeat (ITR) sequence (e.g., an ITR region described herein), an enhancer (e.g., an enhancer described herein), an intron region (e.g., an intron region described herein) and / or an exon region (e.g., an exon region described herein), a polyA signal region (e.g., a polyA signal sequence described herein), and / or an encoded miR binding site.

[0017] In yet another aspect, the present disclosure provides an isolated, e.g., recombinant, AAV particle comprising a capsid protein and a viral genome comprising a nucleic acid encoding an antibody that binds to tau (e.g., an anti-tau antibody described herein). In some embodiments, the capsid protein comprises an AAV capsid protein, e.g., a wild-type AAV capsid protein or a functional variant thereof. In some embodiments, the capsid protein comprises or is selected from an AAV9 capsid protein (e.g., a wild-type AAV9 capsid protein), a VOY101 capsid protein, a PHP.N capsid protein, or a PHP.B capsid protein, or a functional variant thereof.

[0018] In yet another aspect, the present disclosure provides a method for delivering an exogenous antibody molecule that binds to tau (e.g., an anti-tau antibody molecule described herein) to a subject, the method comprising administering an effective amount of an AAV particle or a plurality of AAV particles described herein, wherein the AAV particle comprises a viral genome described herein.

[0019] In yet another aspect, the present disclosure provides a method of treating a subject having or diagnosed as having a neurological disorder, a tauopathy, and / or a disease associated with tau expression, comprising administering to the subject an effective amount of an AAV particle or a plurality of AAV particles described herein that include a viral genome described herein.

[0020] In some embodiments, the present disclosure provides an antibody comprising: (1) a heavy chain variable domain (VH) comprising a complementarity determining region (CDR) H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 296-339, or a fragment thereof, a CDRH2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 340-391, or a fragment thereof, and a CDRH3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 392-456, or a fragment thereof, and (2) a light chain variable domain (VL) comprising a CDRL1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 457-514, or a fragment thereof, a CDRL2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 515-553, or a fragment thereof, and a CDRL3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 554-600, or a fragment thereof. The antibody may comprise a set of variable domain CDR amino acid sequences, wherein the set of variable domain CDR amino acid sequences is selected from Table 6.

[0021] The VH may include a framework region (FR) H1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 601 to 643, or a fragment thereof; FRH2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 644 to 696, or a fragment thereof; FRH3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 697 to 766, or a fragment thereof; and FRH4 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 767 to 775, or a fragment thereof.

[0022] The VL may include FRL1 or a fragment thereof having an amino acid sequence selected from the group consisting of SEQ ID NOs: 776 to 822, FRL2 or a fragment thereof having an amino acid sequence selected from the group consisting of SEQ ID NOs: 823 to 857, FRL3 or a fragment thereof having an amino acid sequence selected from the group consisting of SEQ ID NOs: 858 to 904, and FRL4 or a fragment thereof having an amino acid sequence selected from the group consisting of SEQ ID NOs: 905 to 919.

[0023] VH may comprise an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-74 and / or an amino acid sequence encoded by a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 147-220.

[0024] The VL may comprise an amino acid sequence selected from the group consisting of SEQ ID NOs: 75-146 and / or an amino acid sequence encoded by a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 221-295.

[0025] The antibody may comprise a variable domain pair selected from Table 3. CDRH1 may comprise an amino acid sequence selected from the group consisting of GFTFTRY (SEQ ID NO: 314), GYTFTIF (SEQ ID NO: 315), and GYTFTRF (SEQ ID NO: 316). CDRH2 may comprise the amino acid sequence of NPNNGG (SEQ ID NO: 341). CDRH3 may comprise the amino acid sequence of GTGTGAMDY (SEQ ID NO: 410).

[0026] CDRL1 may comprise an amino acid sequence selected from the group consisting of RSSQSLVHNNGITYLY (SEQ ID NO: 1154), RSSQSLVHSNGITHLY (SEQ ID NO: 474), and RSSQSLVHSNGNTHLY (SEQ ID NO: 475). CDRL2 may comprise an amino acid sequence selected from the group consisting of RVSNRFS (SEQ ID NO: 529) and RVSSRFS (SEQ ID NO: 530). CDRL3 may comprise the amino acid sequence of FQGTHVPRT (SEQ ID NO: 571).

[0027] CDRH1 may comprise an amino acid sequence selected from the group consisting of GFSLSTSAM (SEQ ID NO:325), GFSLNTSGM (SEQ ID NO:326), GFSLSTSGM (SEQ ID NO:321), and GFSLSTFGM (SEQ ID NO:327). CDRH2 may comprise an amino acid sequence of YWDDD (SEQ ID NO:362). CDRH3 may comprise an amino acid sequence selected from the group consisting of RRRGYGMDY (SEQ ID NO:435), RVRGYGMDY (SEQ ID NO:437), RVRYYAMDY (SEQ ID NO:438), RKRSYGMDY (SEQ ID NO:440), RSRRGNYDY (SEQ ID NO:421), and RGYYSNGNYFDY (SEQ ID NO:432).

[0028] CDRL1 may comprise an amino acid sequence selected from the group consisting of KASQSVSNDVA (SEQ ID NO:495), KSSQSLLNSGNQKNYLA (SEQ ID NO:496), KSSQSLLSSGNQKNYLA (SEQ ID NO:497), KSSQSLLDSDGKTYLN (SEQ ID NO:484), and SASSSISSTYLH (SEQ ID NO:493). CDRL2 may comprise an amino acid sequence selected from the group consisting of YASNRCT (SEQ ID NO:540), GTSTRES (SEQ ID NO:542), GASTRES (SEQ ID NO:543), LVSKLDS (SEQ ID NO:532), and RTSNLAS (SEQ ID NO:538). CDRL3 may comprise an amino acid sequence selected from the group consisting of QQDYRSPLT (SEQ ID NO:587), QNDHSHPYT (SEQ ID NO:588), WQGTHFPQT (SEQ ID NO:576), and QQGSSIPRYT (SEQ ID NO:585).

[0029] The antibodies of the present disclosure may include a format selected from the group consisting of monoclonal antibodies, multispecific antibodies, chimeric antibodies, antibody mimetics, single-chain Fv (scFv) formats, and antibody fragments. The antibodies may include an antibody class selected from the group consisting of IgA, IgD, IgE, IgG, and IgM. The antibodies may include mouse IgG, where the mouse IgG includes an isotype selected from the group consisting of IgG1, IgG2a, IgG2b, IgG2c, and IgG3. The antibodies may include human IgG, where the human IgG includes an isotype selected from the group consisting of IgG1, IgG2, IgG3, and IgG4. The antibodies may include one or more human constant domains. The one or more human constant domains may include human IgG constant domains. The antibodies may include humanized antibodies.

[0030] The antibodies of the present disclosure may bind to a tau protein epitope. The tau protein epitope may comprise or be contained within an amino acid sequence selected from the group consisting of SEQ ID NOs: 920-926. The antibody may compete for binding to the tau protein epitope with an antibody selected from one or more of AT100, AT120, PT3, C10.2, PT76, IPN002, 6C5, and UCBD. The tau protein epitope may comprise residues 409-436 of human tau (SEQ ID NO: 920). The tau protein epitope may comprise residues 413-430 of human tau (SEQ ID NO: 920). Antibodies that bind to a tau protein epitope have a K of about 0.1 nM to about 0.5 nM. D The tau protein epitope may include residues 55-76, 159-194, 219-247, and / or 381-426 of human tau (SEQ ID NO: 920). The tau protein epitope may include residues 57-72, 175-191, 223-238, and / or 383-400 of human tau (SEQ ID NO: 920). The tau protein epitope may include residues 223-238 of human tau (SEQ ID NO: 920). Antibodies that bind to tau protein epitopes may exhibit a K of about 0.5 nM to about 5 nM. DThe tau protein epitope may include a region formed by a complex of at least two tau proteins. The antibody may bind to concentrated paired helical fibrillar tau protein (ePHF) with a half-maximal effective concentration (EC50) of about 0.01 nM to about 100 nM. The antibody may not bind to non-pathological tau. The antibody may bind to pathological tau. The antibody may inhibit tau aggregation with a half-maximal inhibitory concentration (IC50) of about 1 nM to about 30 nM as determined by immunodepletion assay. The immunodepletion assay may be performed using Tau RD biosensor cells.

[0031] In some embodiments, the present disclosure provides an antibody that competes with a second antibody for binding to a tau protein epitope, the tau protein epitope comprising one or more of residues 32-49, 55-76, 57-72, 159-194, 175-191, 185-200, 219-247, 223-238, 381-426, 383-400, 409-436, and 413-430 of human tau (SEQ ID NO: 920). The tau protein epitope may comprise one or more of residues 409-436 and 413-430 of human tau (SEQ ID NO: 920). The second antibody may comprise a variable domain pair selected from the group consisting of a VH having the amino acid sequence of SEQ ID NO: 21 and a VL having the amino acid sequence of SEQ ID NO: 93, a VH having the amino acid sequence of SEQ ID NO: 22 and a VL having the amino acid sequence of SEQ ID NO: 94, and a VH having the amino acid sequence of SEQ ID NO: 23 and a VL having the amino acid sequence of SEQ ID NO: 95.

[0032] The antibodies of the present disclosure may comprise a conjugate. The conjugate may comprise a therapeutic agent. The conjugate may comprise a detectable label. In some embodiments, the present disclosure provides constructs encoding the antibodies disclosed herein.

[0033] In some embodiments, the present disclosure provides a method of treating a therapeutic indication in a subject by administering to the subject an antibody disclosed herein. The therapeutic indication can be a neurological indication. The neurological indication can be a neurodegenerative disease, Alzheimer's disease (AD), frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), frontotemporal lobar degeneration (FTLD), frontotemporal dementia (FTD), chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), Down syndrome, Pick's disease, corticobasal degeneration (CBD), corticobasal syndrome, amyotrophic lateral sclerosis (ALS), prion disease, Creutzfeldt-Jakob disease (CJD), multiple system atrophy, tangle-only dementia, stroke, or progressive subcortical gliosis.

[0034] In some embodiments, the present disclosure provides a method for diagnosing a therapeutic indication in a subject through the use of an antibody disclosed herein. The therapeutic indication may include a neurological indication. The neurological indication may be a neurodegenerative disease, AD, FTDP-17, FTLD, FTD, CTE, PSP, Down syndrome, Pick's disease, CBD, corticobasal syndrome, ALS, prion disease, CJD, multiple system atrophy, neurofibrillary senile dementia, stroke, or progressive subcortical gliosis. The antibody may be used to detect pathological tau in a target tissue. The target tissue may include CNS tissue. The target tissue may be a tissue slice. The tissue slice may be a cryopreserved tissue slice.

[0035] In some embodiments, the tau-binding compounds or antibodies of the present disclosure may be encoded by the viral genome of an adeno-associated virus (AAV). In some embodiments, the AAV viral genome may include one or more nucleic acid sequences encoding the antibodies described herein, or fragments thereof.

[0036] In some embodiments, the viral genome may include a 5' inverted terminal repeat (ITR) sequence region selected from SEQ ID NOs: 1035 and 1036, a promoter sequence region selected from 1039-1050, a polyadenylation (polyA) sequence region selected from 1134-1136, and a 3' ITR selected from SEQ ID NOs: 1037 and 1038.

[0037] In some embodiments, the viral genome may include one or more exon sequence regions selected from SEQ ID NOs: 1051-1055, one or more intron sequence regions selected from SEQ ID NOs: 1056-1070, one or more signal sequence regions selected from SEQ ID NOs: 1071-1089, one or more tag sequence regions selected from SEQ ID NOs: 1127-1133, and / or one or more filler sequence regions selected from SEQ ID NOs: 1137 and 1138.

[0038] In some embodiments, the viral genome may have a first nucleic acid sequence and a second nucleic acid sequence, wherein the first nucleic acid sequence encodes a VH and the second nucleic acid sequence encodes a VL. In some embodiments, the viral genome encodes a VH having an amino acid sequence selected from SEQ ID NOs: 1-74. In some embodiments, the viral genome encodes a VL having an amino acid sequence selected from SEQ ID NOs: 75-146. In some embodiments, the viral genome encodes a VH and VL pair selected from the pairings shown in Table 3.

[0039] In some embodiments, the first and second nucleic acid sequences of the viral genome are separated by one or more linker sequences, and the linker sequence(s) may be selected from SEQ ID NOs: 1090-1126.

[0040] In some embodiments, the viral genome comprises a VH nucleic acid sequence selected from SEQ ID NOs: 147 to 220. In some embodiments, the viral genome comprises a VL nucleic acid sequence selected from SEQ ID NOs: 221 to 295.

[0041] In some embodiments, the viral genome may encode one or more CDR sequences having an amino acid sequence selected from SEQ ID NOs: 296-600. In some embodiments, the viral genome may encode a set of CDRs selected from the CDR sets outlined in Table 6. In some embodiments, the viral genome may encode a CDR set pair selected from those outlined in Table 6.

[0042] In some embodiments, the viral genome may encode one or more FR amino acid sequences selected from SEQ ID NOs: 601-919. In some embodiments, the viral genome encodes, from 5' to 3', an antibody heavy chain, one or more linker sequences, and an antibody light chain. In other embodiments, the viral genome encodes, from 5' to 3', an antibody light chain, one or more linker sequences, and an antibody heavy chain.

[0043] In some embodiments, the AAV viral genomes described herein can be incorporated into AAV particles. In some embodiments, the AAV particles are VOY101, VOY201, AAVPHP.B(PHP.B), AAVPHP.A(PHP.A), AAVG2B-26, AAVG2B -13, AAVTH1.1-32, AAVTH1.1-35, AAVPHP.B2(PHP.B2), AAVPHP.B3(PHP.B3), AAVPHP.N / PHP.B-DGT , AAVPHP.B-EST, AAVPHP.B-GGT, AAVPHP.B-ATP, AAVPHP.B-ATT-T, AAVPHP.B-DGT-T, AAVPHP.B-GGT -T, AAVPHP.B-SGS, AAVPHP.B-AQP, AAVPHP.B-QQP, AAVPHP.B-SNP(3), AAVPHP.B-SNP, AAVPHP.B-QG T, AAVPHP.B-NQT, AAVPHP.B-EGS, AAVPHP.B-SGN, AAVPHP.B-EGT, AAVPHP.B-DST, AAVPHP.B-DST, AAVPHP.B-STP, AAVPHP.B-PQP, AAVPHP.B-SQP, AAVPHP.B-QLP, AAVPHP.B-TMP, AAVPHP.B-TTP, AAVPHP and a functional variant thereof.

[0044] In certain embodiments, the AAV particle comprises a VOY101 capsid. In some embodiments, the amino acid sequence of the VOY101 capsid is set forth in SEQ ID NO: 1023.

[0045] In some embodiments, the viral genome of an AAV particle described herein may further comprise a nucleotide sequence encoding an miR binding site, such as an miR binding site that modulates, e.g., reduces, expression of the payload encoded by the viral genome in cells or tissues in which the corresponding miRNA is expressed.

[0046] In some embodiments, the viral genome of the AAV particle may further comprise at least 1 to 5 copies of the encoded miR binding site, e.g., at least 1, 2, 3, 4, or 5 copies. In some embodiments, the viral genome may comprise at least 3 copies of the encoded miR binding site, optionally where all 3 copies are for the same miR binding site, or where at least 1, 2, or all copies are for different miR binding sites.

[0047] In some embodiments, the viral genome may further comprise a nucleotide sequence encoding a miR122 binding site, a miR183 binding site, miR-142-3p, or a combination thereof.

[0048] In some embodiments, the viral genome comprises an encoded miR122 binding site having the nucleotide sequence of SEQ ID NO: 1029, or a nucleotide sequence substantially identical thereto (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity), or a nucleic acid sequence having at least 1, 2, 3, 4, 5, 6, or 7 but not more than 10 modifications of SEQ ID NO: 1029.

[0049] In some embodiments, the viral genome comprises an encoded miR183 binding site having the nucleotide sequence of SEQ ID NO: 1032, or a nucleotide sequence substantially identical thereto (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity), or a nucleic acid sequence having at least 1, 2, 3, 4, 5, 6, or 7 but not more than 10 modifications of SEQ ID NO: 1032.

[0050] In some embodiments, the viral genome comprises an encoded miR-142-3p binding site having the nucleotide sequence of SEQ ID NO: 1031, or a nucleotide sequence substantially identical thereto (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity), or a nucleic acid sequence having at least 1, 2, 3, 4, 5, 6, or 7 but not more than 10 modifications of SEQ ID NO: 1031.

[0051] In some embodiments, the viral genome comprises at least four copies of the encoded miR binding site, optionally with all four copies comprising the same miR binding site, or with at least one, two, three, or all copies comprising different miR binding sites.

[0052] In some embodiments, the AAV particles disclosed herein can be formulated into pharmaceutical compositions. The present disclosure provides methods of producing antibodies in a subject by administering a pharmaceutical composition to the subject.

[0053] The present disclosure also provides a method for preventing or treating a tauopathy in a subject by administering to the subject a therapeutically effective amount of a pharmaceutical composition described herein. The pharmaceutical composition may be administered by any route of administration, including, but not limited to, intravenous, intramuscular, intraparenchymal, intracerebroventricular, intracisternal (ICM), intrathecal, or a combination thereof.

[0054] Tauopathies that may be treated by the methods and / or compositions of the disclosure include, but are not limited to, AD, FTDP-17, FTLD, FTD, CTE, PSP, Down syndrome, Pick's disease, CBD, corticobasal syndrome, ALS, prion disease, CJD, multiple system atrophy, neurofibrillary senile dementia, and progressive subcortical gliosis.

[0055] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein which equivalents are intended to be encompassed by the following recited embodiments.

[0056] Enumeration of Embodiments E1. an isolated, e.g., recombinant, antibody that binds to human tau, said antibody binding to the same or substantially the same epitope as a reference antibody, said reference antibody comprising a heavy chain variable region (VH) comprising heavy chain complementarity determining region 1 (HC CDR1), heavy chain complementarity determining region 2 (HC CDR2), and heavy chain complementarity determining region 3 (HC CDR3), and a light chain variable region (VL) comprising light chain complementarity determining region 1 (LC CDR1), light chain complementarity determining region 2 (LC CDR2), and light chain complementarity determining region 3 (LC CDR3); (i) the HC CDR1, the HC CDR2, the HC CDR3, the LC CDR1, the LC CDR2, and the LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 315, 341, 410, 474, 529, and 571, respectively; (ii) the HC CDR1, the HC CDR2, the HC CDR3, the LC CDR1, the LC CDR2, and the LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 314, 341, 410, 1154, 529, and 571, respectively; or (iii) the HC CDR1, the HC CDR2, the HC CDR3, the LC CDR1, the LC CDR2, and the LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 316, 341, 410, 475, 530, and 571, respectively; The antibody.

[0057] E2. an isolated, e.g., recombinant, antibody that binds to human tau, wherein the antibody competes for binding with a reference antibody, the reference antibody comprising a heavy chain variable region (VH) comprising heavy chain complementarity determining region 1 (HC CDR1), heavy chain complementarity determining region 2 (HC CDR2), and heavy chain complementarity determining region 3 (HC CDR3), and a light chain variable region (VL) comprising light chain complementarity determining region 1 (LC CDR1), light chain complementarity determining region 2 (LC CDR2), and light chain complementarity determining region 3 (LC CDR3); (i) the HC CDR1, the HC CDR2, the HC CDR3, the LC CDR1, the LC CDR2, and the LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 315, 341, 410, 474, 529, and 571, respectively; (ii) the HC CDR1, the HC CDR2, the HC CDR3, the LC CDR1, the LC CDR2, and the LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 314, 341, 410, 1154, 529, and 571, respectively; or (iii) the HC CDR1, the HC CDR2, the HC CDR3, the LC CDR1, the LC CDR2, and the LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 316, 341, 410, 475, 530, and 571, respectively; The antibody.

[0058] E3. The reference antibody (i) a VH comprising the amino acid sequence of SEQ ID NO: 22 and a VL comprising the amino acid sequence of SEQ ID NO: 94; (ii) a VH comprising the amino acid sequence of SEQ ID NO: 21 and a VL comprising the amino acid sequence of SEQ ID NO: 93, or (iii) VH comprising the amino acid sequence of SEQ ID NO: 23 and VL comprising the amino acid sequence of SEQ ID NO: 95 The antibody of embodiment E1 or E2, comprising:

[0059] E4. The antibody of any one of embodiments E1 to E3, which binds to an epitope that overlaps with the epitope recognized by said reference antibody.

[0060] E5. The antibody of any one of embodiments E1 to E4, which binds to a region of human tau protein comprising residues 409 to 436 numbered according to SEQ ID NO:920.

[0061] E6. The antibody of any one of embodiments E1 to E5, which binds to a region of human tau protein comprising residues 413 to 430 numbered according to SEQ ID NO:920.

[0062] E7. Dissociation constants (K) of about 0.1 to about 10 nM, or about 0.2 to 5 nM D The antibody of any one of embodiments E1 to E6, which binds to tau protein at

[0063] E8. (i) SEQ ID NOs: 1180, 341, and 410, respectively; (ii) SEQ ID NOs: 1183, 1184, and 410, respectively; or (iii) SEQ ID NOs: 1186, 1187, and 1167, respectively The antibody of any one of embodiments E1 to E7, comprising a heavy chain variable region comprising at least one, two, or three of HC CDR1, HC CDR2, and HC CDR3 comprising the amino acid sequences of:

[0064] E9. (i) SEQ ID NOs: 1181, 1182, and 571, respectively; (ii) SEQ ID NOs: 1185, 1182, and 571, respectively; or (iii) SEQ ID NOs: 1188, 528, and 571, respectively The antibody of any one of embodiments E1 to E8, comprising a light chain variable region (VL) comprising one, two, or three of the LC CDR1, LC CDR2, and / or LC CDR3 of:

[0065] E10. (i) the HC CDR1, the HC CDR2, the HC CDR3, the LC CDR1, the LC CDR2, and the LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 315, 341, 410, 474, 529, and 571, respectively; (ii) the HC CDR1, the HC CDR2, the HC CDR3, the LC CDR1, the LC CDR2, and the LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 1147, 1148, 410, 474, 529, and 571, respectively; or (iii) the HC CDR1, the HC CDR2, the HC CDR3, the LC CDR1, the LC CDR2, and the LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 1168, 1169, 1167, 1170, 528, and 571, respectively; The antibody of any one of embodiments E1 to E9.

[0066] E11. (i) the HC CDR1, the HC CDR2, the HC CDR3, the LC CDR1, the LC CDR2, and the LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 314, 341, 410, 1154, 529, and 571, respectively; (ii) the HC CDR1, the HC CDR2, the HC CDR3, the LC CDR1, the LC CDR2, and the LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 1144, 1145, 410, 1146, 529, and 571, respectively; or (iii) the HC CDR1, the HC CDR2, the HC CDR3, the LC CDR1, the LC CDR2, and the LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 1165, 1166, 1167, 473, 528, and 571, respectively; The antibody of any one of embodiments E1 to E9.

[0067] E12. (i) the HC CDR1, the HC CDR2, the HC CDR3, the LC CDR1, the LC CDR2, and the LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 316, 341, 410, 475, 530, and 571, respectively; (ii) the HC CDR1, the HC CDR2, the HC CDR3, the LC CDR1, the LC CDR2, and the LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 1149, 1150, 410, 475, 530, and 571, respectively; or (iii) the HC CDR1, the HC CDR2, the HC CDR3, the LC CDR1, the LC CDR2, and the LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 1171, 1166, 1167, 1172, 528, and 571, respectively; The antibody of any one of embodiments E1 to E9.

[0068] E13. (i) a VH comprising an amino acid sequence of SEQ ID NOs: 21 to 23, or an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or (ii) a VL comprising an amino acid sequence of SEQ ID NOs: 93 to 95, or an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; The antibody of any one of embodiments E1 to E12, comprising:

[0069] E14. 1. An isolated, e.g., recombinant, antibody that binds to a region of human tau protein comprising residues 409-436 numbered according to SEQ ID NO: 920, (i) a VH comprising HC CDR1, HC CDR2, and HC CDR3; (a) the HC CDR1, the HC CDR2, and the HC CDR3 comprise the amino acid sequences of SEQ ID NOs: 1180, 341, and 410, respectively; (b) the HC CDR1, the HC CDR2, and the HC CDR3 comprise the amino acid sequences of SEQ ID NOs: 1183, 1184, and 410, respectively; or (c) the VH, wherein the HC CDR1, the HC CDR2, and the HC CDR3 comprise the amino acid sequences of SEQ ID NOs: 1186, 1187, and 1167, respectively; (ii) a VL comprising an LC CDR1, an LC CDR2, and an LC CDR3; (a) the LC CDR1, the LC CDR2, and the LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 1181, 1182, and 571, respectively; (b) the LC CDR1, the LC CDR2, and the LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 1185, 1182, and 571, respectively; or (c) the LC CDR1, the LC CDR2, and the LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 1188, 528, and 571, respectively; The antibody comprising:

[0070] E15. An antibody that binds, e.g., directly or indirectly, to a region of human tau protein including residues 32-49, 55-76, 159-194, 185-200, 219-247, 381-426, and / or 409-436 numbered according to SEQ ID NO:920.

[0071] E16. The antibody of embodiment E14 or E15, which binds to a region of human tau protein comprising residues 55-76, 159-194, 219-247, and / or 381-426 numbered according to SEQ ID NO: 920.

[0072] E17. The antibody of embodiment E14 or E15, which binds to a region of human tau protein comprising residues 57-72, 175-191, 223-238, and / or 383-400 numbered according to SEQ ID NO: 920.

[0073] E18. The antibody of embodiment E14 or E15, which binds to a region of human tau protein comprising residues 223-238 numbered according to SEQ ID NO:920.

[0074] E19. The antibody of any one of embodiments E14 to E17, which binds to a conformational epitope comprising residues 55-76, 159-194, 219-247, and 381-426 numbered according to SEQ ID NO:920.

[0075] E20. (i) a VH comprising HC CDR1, HC CDR2, and HC CDR3 comprising the amino acid sequences of SEQ ID NOs: 325, 362, and 435, respectively, and / or a VL comprising LC CDR1, LC CDR2, and LC CDR3 comprising the amino acid sequences of SEQ ID NOs: 495, 540, and 587, respectively; (ii) a VH comprising HC CDR1, HC CDR2, and HC CDR3 comprising the amino acid sequences of SEQ ID NOs: 1152, 1153, and 435, respectively, and / or a VL comprising LC CDR1, LC CDR2, and LC CDR3 comprising the amino acid sequences of SEQ ID NOs: 495, 540, and 587, respectively; (iii) a VH comprising HC CDR1, HC CDR2, and HC CDR3 comprising the amino acid sequences of SEQ ID NOs: 1173, 1174, and 1175, respectively, and / or a VL comprising LC CDR1, LC CDR2, and LC CDR3 comprising the amino acid sequences of SEQ ID NOs: 1176, 1177, and 587, respectively; The antibody of any one of embodiments E15 to E19.

[0076] E21. Dissociation constant (K) of approximately 0.1 to approximately 1 nM D The antibody of any one of embodiments E14 to E20, which binds to tau protein at

[0077] E22. (i) a heavy chain variable region (VH) comprising one, two, or three of the HC CDR1, HC CDR2, and / or HC CDR3 of any of the HC CDR sequences in Tables 1, 6, 2A-2C, 4, or 5; and / or (ii) a light chain variable region (VL) comprising one, two, or three of the LC CDR1, LC CDR2, and / or LC CDR3 of any of the LC CDR sequences in Tables 1, 6, 2A-2C, 4, or 5; An isolated, e.g., recombinant, antibody that binds to tau, comprising:

[0078] E23. The antibody of embodiment E22, comprising a VH comprising the HC CDR1, HC CDR2, and HC CDR3 of any one of the antibodies of Tables 1, 6, 2A-2C, 4, or 5.

[0079] E24. The antibody of embodiment E22 or E23, comprising a VL comprising the LC CDR1, LC CDR2, and LC CDR3 of any one of the antibodies of Tables 1, 6, 2A-2C, 4, or 5.

[0080] E25. An antibody described in any one of embodiments E22 to E24, comprising a VH comprising the HC CDR1, HC CDR2, and HC CDR3 of any one of the antibodies in Tables 1, 6, 2A to 2C, 4, or 5, and a VL comprising the LC CDR1, LC CDR2, and LC CDR3 of any one of the antibodies in Tables 1, 6, 2A to 2C, 4, or 5.

[0081] E26. (i) HC CDR1, HC CDR2, and HC CDR3 comprising the amino acid sequences of SEQ ID NOs: 931 or 932, 341, and 410, respectively; and / or (ii) LC CDR1, LC CDR2, and LC CDR3 comprising the amino acid sequences of SEQ ID NOs: 933 or 934, 935 or 936, and 571, respectively. The antibody of any one of embodiments E22 to E25, comprising:

[0082] E27. (i) HC CDR1, HC CDR2, and HC CDR3 comprising the amino acid sequences of SEQ ID NOs: 1180, 341, and 410, respectively, and / or LC CDR1, LC CDR2, and LC CDR3 comprising the amino acid sequences of SEQ ID NOs: 1181, 1182, and 571, respectively; (ii) HC CDR1, HC CDR2, and HC CDR3 comprising the amino acid sequences of SEQ ID NOs: 1183, 1184, and 410, respectively, and / or LC CDR1, LC CDR2, and LC CDR3 comprising the amino acid sequences of SEQ ID NOs: 1185, 1182, and 571, respectively; or (iii) HC CDR1, HC CDR2, and HC CDR3 comprising the amino acid sequences of SEQ ID NOs: 1186, 1187, and 1167, respectively, and / or LC CDR1, LC CDR2, and LC CDR3 comprising the amino acid sequences of SEQ ID NOs: 1188, 528, and 571, respectively. The antibody of any one of embodiments E22 to E26, comprising:

[0083] E28. (i) HC CDR1, HC CDR2, and HC CDR3 comprising the amino acid sequences of SEQ ID NOs: 315, 341, and 410, respectively, and / or LC CDR1, LC CDR2, and LC CDR3 comprising the amino acid sequences of SEQ ID NOs: 474, 529, and 571, respectively; (ii) HC CDR1, HC CDR2, and HC CDR3 comprising the amino acid sequences of SEQ ID NOs: 1147, 1148, and 410, respectively, and / or LC CDR1, LC CDR2, and LC CDR3 comprising the amino acid sequences of SEQ ID NOs: 474, 529, and 571, respectively; or (iii) HC CDR1, HC CDR2, and HC CDR3 comprising the amino acid sequences of SEQ ID NOs: 1168, 1169, and 1167, respectively, and / or LC CDR1, LC CDR2, and LC CDR3 comprising the amino acid sequences of SEQ ID NOs: 1170, 528, and 571, respectively. The antibody of any one of embodiments E22 to E27, comprising:

[0084] E29. (i) HC CDR1, HC CDR2, and HC CDR3 comprising the amino acid sequences of SEQ ID NOs: 314, 341, and 410, respectively, and / or LC CDR1, LC CDR2, and LC CDR3 comprising the amino acid sequences of SEQ ID NOs: 1154, 529, and 571, respectively; (ii) HC CDR1, HC CDR2, and HC CDR3 comprising the amino acid sequences of SEQ ID NOs: 1144, 1145, and 410, respectively, and / or LC CDR1, LC CDR2, and LC CDR3 comprising the amino acid sequences of SEQ ID NOs: 1146, 529, and 571, respectively; or (iii) HC CDR1, HC CDR2, and HC CDR3 comprising the amino acid sequences of SEQ ID NOs: 1165, 1166, and 1167, respectively, and / or LC CDR1, LC CDR2, and LC CDR3 comprising the amino acid sequences of SEQ ID NOs: 473, 528, and 571, respectively. The antibody of any one of embodiments E22 to E27, comprising:

[0085] E30. (i) HC CDR1, HC CDR2, and HC CDR3 comprising the amino acid sequences of SEQ ID NOs: 316, 341, and 410, respectively, and / or LC CDR1, LC CDR2, and LC CDR3 comprising the amino acid sequences of SEQ ID NOs: 475, 530, and 571, respectively; (ii) HC CDR1, HC CDR2, and HC CDR3 comprising the amino acid sequences of SEQ ID NOs: 1149, 1150, and 410, respectively, and / or LC CDR1, LC CDR2, and LC CDR3 comprising the amino acid sequences of SEQ ID NOs: 475, 1151, and 571, respectively; or (iii) HC CDR1, HC CDR2, and HC CDR3 comprising the amino acid sequences of SEQ ID NOs: 1171, 1166, and 1167, respectively, and / or LC CDR1, LC CDR2, and LC CDR3 comprising the amino acid sequences of SEQ ID NOs: 1172, 528, and 571, respectively. The antibody of any one of embodiments E22 to E27, comprising:

[0086] E31. (i) HC CDR1, HC CDR2, and HC CDR3 comprising the amino acid sequences of SEQ ID NOs: 325, 362, and 435, respectively, and / or LC CDR1, LC CDR2, and LC CDR3 comprising the amino acid sequences of SEQ ID NOs: 495, 540, and 587, respectively; (ii) HC CDR1, HC CDR2, and HC CDR3 comprising the amino acid sequences of SEQ ID NOs: 1152, 1153, and 435, respectively, and / or LC CDR1, LC CDR2, and LC CDR3 comprising the amino acid sequences of SEQ ID NOs: 495, 540, and 587, respectively; or (iii) HC CDR1, HC CDR2, and HC CDR3 comprising the amino acid sequences of SEQ ID NOs: 1173, 1174, and 1175, respectively, and / or LC CDR1, LC CDR2, and LC CDR3 comprising the amino acid sequences of SEQ ID NOs: 1176, 1177, and 587, respectively. The antibody of any one of embodiments E22 to E27, comprising:

[0087] E32. (i) HC CDR1, HC CDR2, and HC CDR3 comprising the amino acid sequences of SEQ ID NOs: 304, 347, and 400, respectively, and / or LC CDR1, LC CDR2, and LC CDR3 comprising the amino acid sequences of SEQ ID NOs: 464, 523, and 562, respectively; (ii) HC CDR1, HC CDR2, and HC CDR3 comprising the amino acid sequences of SEQ ID NOs: 1142, 1143, and 400, respectively, and / or LC CDR1, LC CDR2, and LC CDR3 comprising the amino acid sequences of SEQ ID NOs: 464, 523, and 562, respectively; or (iii) HC CDR1, HC CDR2, and HC CDR3 comprising the amino acid sequences of SEQ ID NOs: 1160, 1161, and 1162, respectively, and / or LC CDR1, LC CDR2, and LC CDR3 comprising the amino acid sequences of SEQ ID NOs: 1163, 1164, and 562, respectively. The antibody of any one of embodiments E22 to E27, comprising:

[0088] E33. (i) HC CDR1, HC CDR2, and HC CDR3 comprising the amino acid sequences of SEQ ID NOs: 299, 343, and 395, respectively, and / or LC CDR1, LC CDR2, and LC CDR3 comprising the amino acid sequences of SEQ ID NOs: 460, 518, and 557, respectively; (ii) HC CDR1, HC CDR2, and HC CDR3 comprising the amino acid sequences of SEQ ID NOs: 1140, 1141, and 395, respectively, and / or LC CDR1, LC CDR2, and LC CDR3 comprising the amino acid sequences of SEQ ID NOs: 460, 518, and 557, respectively; or (iii) HC CDR1, HC CDR2, and HC CDR3 comprising the amino acid sequences of SEQ ID NOs: 1155, 1156, and 1157, respectively, and / or LC CDR1, LC CDR2, and LC CDR3 comprising the amino acid sequences of SEQ ID NOs: 1158, 1159, and 557, respectively. The antibody of any one of embodiments E22 to E27, comprising:

[0089] E34. (i) one, two, three, or all of heavy chain framework region 1 (FRH1), heavy chain framework region 2 (FRH2), heavy chain framework region 3 (FRH3), and / or heavy chain framework region 4 (FRH4) comprising the amino acid sequence of any of the heavy chain framework regions of an antibody listed in Table 7 or 4; or (ii) one, two, three, or all of heavy chain framework region 1 (FRH1), heavy chain framework region 2 (FRH2), heavy chain framework region 3 (FRH3), and / or heavy chain framework region 4 (FRH4), comprising an amino acid sequence having at least one, two, or three, but not more than four, modifications, e.g., substitutions, relative to the amino acid sequence of any of the heavy chain framework regions of an antibody listed in Table 7 or 4; 10. The antibody of any one of the preceding embodiments, comprising:

[0090] E35. (i) one, two, three, or all of FRH1 comprising the amino acid sequence of SEQ ID NO: 603, FRH2 comprising the amino acid sequence of SEQ ID NO: 664, FRH3 comprising the amino acid sequence of SEQ ID NO: 718, and / or FRH4 comprising the amino acid sequence of SEQ ID NO: 771, or an amino acid sequence having at least one, two, or three, but not more than four, modifications, e.g., substitutions, relative to each of the amino acid sequences of SEQ ID NOs: 603, 664, 718, and / or 771; (ii) one, two, three, or all of FRH1 comprising the amino acid sequence of SEQ ID NO: 619, FRH2 comprising the amino acid sequence of SEQ ID NO: 663, FRH3 comprising the amino acid sequence of SEQ ID NO: 717, and / or FRH4 comprising the amino acid sequence of SEQ ID NO: 771, or an amino acid sequence having at least one, two, or three, but not more than four, modifications, e.g., substitutions, relative to each of the amino acid sequences of SEQ ID NOs: 619, 663, 717, and / or 771; (iii) one, two, three, or all of FRH1 comprising the amino acid sequence of SEQ ID NO: 603, FRH2 comprising the amino acid sequence of SEQ ID NO: 665, FRH3 comprising the amino acid sequence of SEQ ID NO: 719, and / or FRH4 comprising the amino acid sequence of SEQ ID NO: 771, or an amino acid sequence having at least one, two, or three, but not more than four, modifications, e.g., substitutions, relative to each of the amino acid sequences of SEQ ID NOs: 603, 665, 719, and / or 771; (iv) one, two, three, or all of FRH1 comprising the amino acid sequence of SEQ ID NO: 633, FRH2 comprising the amino acid sequence of SEQ ID NO: 682, FRH3 comprising the amino acid sequence of SEQ ID NO: 745, and / or FRH4 comprising the amino acid sequence of SEQ ID NO: 771, or an amino acid sequence having at least one, two, or three, but not more than four, modifications, e.g., substitutions, relative to each of the amino acid sequences of SEQ ID NOs: 663, 682, 745, and / or 771; (v) one, two, three, or all of FRH1 comprising the amino acid sequence of SEQ ID NO: 608, FRH2 comprising the amino acid sequence of SEQ ID NO: 652, FRH3 comprising the amino acid sequence of SEQ ID NO: 705, and / or FRH4 comprising the amino acid sequence of SEQ ID NO: 767, or an amino acid sequence having at least one, two, or three, but not more than four, modifications, e.g., substitutions, relative to each of the amino acid sequences of SEQ ID NOs: 608, 652, 705, and / or 767; or (vi) one, two, three, or all of FRH1 comprising the amino acid sequence of SEQ ID NO: 604, FRH2 comprising the amino acid sequence of SEQ ID NO: 647, FRH3 comprising the amino acid sequence of SEQ ID NO: 700, and / or FRH4 comprising the amino acid sequence of SEQ ID NO: 770, or an amino acid sequence having at least one, two, or three, but not more than four, modifications, e.g., substitutions, relative to each of the amino acid sequences of SEQ ID NOs: 604, 647, 700, and / or 770. 10. The antibody of any one of the preceding embodiments, comprising:

[0091] E36. (i) one, two, three, or all of light chain framework region 1 (FRL1), light chain framework region 2 (FRL2), light chain framework region 3 (FRL3), and / or light chain framework region 4 (FRL4) comprising the amino acid sequence of any of the light chain framework regions of an antibody listed in Table 7 or 4; or (ii) one, two, three, or all of light chain framework region 1 (FRL1), light chain framework region 2 (FRL2), light chain framework region 3 (FRL3), and / or light chain framework region 4 (FRL4), comprising an amino acid sequence having at least one, two, or three, but not more than four, modifications, e.g., substitutions, relative to the amino acid sequence of any of the light chain framework regions of an antibody listed in Table 7 or 4; 10. The antibody of any one of the preceding embodiments, comprising:

[0092] E37. (i) one, two, three, or all of FRL1 comprising the amino acid sequence of SEQ ID NO: 793, FRL2 comprising the amino acid sequence of SEQ ID NO: 836, FRL3 comprising the amino acid sequence of SEQ ID NO: 874, and / or FRL4 comprising the amino acid sequence of SEQ ID NO: 910, or an amino acid sequence having at least one, two, or three, but not more than four, modifications, e.g., substitutions, relative to each of the amino acid sequences of SEQ ID NOs: 793, 836, 874, and / or 910; (ii) one, two, three, or all of FRL1 comprising the amino acid sequence of SEQ ID NO: 1178, FRL2 comprising the amino acid sequence of SEQ ID NO: 831, FRL3 comprising the amino acid sequence of SEQ ID NO: 1179, and / or FRL4 comprising the amino acid sequence of SEQ ID NO: 906, or an amino acid sequence having at least one, two, or three, but not more than four, modifications, e.g., substitutions, relative to each of the amino acid sequences of SEQ ID NOs: 1178, 831, 1179, and / or 906; (iii) one, two, three, or all of FRL1 comprising the amino acid sequence of SEQ ID NO: 787, FRL2 comprising the amino acid sequence of SEQ ID NO: 831, FRL3 comprising the amino acid sequence of SEQ ID NO: 870, and / or FRL4 comprising the amino acid sequence of SEQ ID NO: 906, or an amino acid sequence having at least one, two, or three, but not more than four, modifications, e.g., substitutions, relative to each of the amino acid sequences of SEQ ID NOs: 787, 831, 870, and / or 906; or (iv) one, two, three, or all of FRL1 comprising the amino acid sequence of SEQ ID NO: 807, FRL2 comprising the amino acid sequence of SEQ ID NO: 830, FRL3 comprising the amino acid sequence of SEQ ID NO: 888, and / or FRL4 comprising the amino acid sequence of SEQ ID NO: 908, or an amino acid sequence having at least one, two, or three, but not more than four, modifications, e.g., substitutions, relative to each of the amino acid sequences of SEQ ID NOs: 807, 830, 888, and / or 908; (v) one, two, three, or all of FRL1 comprising the amino acid sequence of SEQ ID NO: 783, FRL2 comprising the amino acid sequence of SEQ ID NO: 830, FRL3 comprising the amino acid sequence of SEQ ID NO: 866, and / or FRL4 comprising the amino acid sequence of SEQ ID NO: 906, or an amino acid sequence having at least one, two, or three, but not more than four, modifications, e.g., substitutions, relative to each of the amino acid sequences of SEQ ID NOs: 783, 830, 866, and / or 906; or (vi) one, two, three, or all of FRL1 comprising the amino acid sequence of SEQ ID NO: 779, FRL2 comprising the amino acid sequence of SEQ ID NO: 825, FRL3 comprising the amino acid sequence of SEQ ID NO: 861, and / or FRL4 comprising the amino acid sequence of SEQ ID NO: 908, or an amino acid sequence having at least one, two, or three, but not more than four, modifications, e.g., substitutions, relative to each of the amino acid sequences of SEQ ID NOs: 779, 825, 861, and / or 908. 10. The antibody of any one of the preceding embodiments, comprising:

[0093] E38. (i) the amino acid sequence of any VH listed in Table 3 or 4, or an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; (ii) an amino acid sequence having at least one, two, or three modifications of any VH amino acid sequence listed in Table 3 or 4, but no more than 30, no more than 20, or no more than 10 modifications; or (iii) an amino acid sequence encoded by the nucleotide sequence of any VH listed in Table 3 or 4, or a nucleotide sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; The antibody of any one of embodiments E22 to E37, comprising a VH comprising:

[0094] E39. (i) an amino acid sequence of SEQ ID NO: 4, 9, 21-23, or 51, or an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; (ii) an amino acid sequence having at least one, two, or three modifications of the amino acid sequence of SEQ ID NO: 4, 9, 21-23, or 51, but not more than 30, not more than 20, or not more than 10 modifications; or (iii) an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 150, 155, 167-169, or 197, or a nucleotide sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; The antibody of any one of embodiments E22 to E38, comprising a VH comprising:

[0095] E40. From the N-terminus to the C-terminus, (i) FRH1 comprising the amino acid sequence of any of the FRH1 antibodies in Table 7; (ii) an HC CDR1 comprising the amino acid sequence of an HC CDR1 of an antibody of Table 6 or 5; (iii) FRH2 comprising the amino acid sequence of FRH2 of an antibody of Table 7 or 4; (iv) an HC CDR2 comprising the amino acid sequence of the HC CDR2 of an antibody of Table 6 or 5; (v) an FRH3 comprising the amino acid sequence of an FRH3 of an antibody of Table 7 or 4; (vi) an HC CDR3 comprising the amino acid sequence of an HC CDR3 of an antibody of Table 6 or 5; and (vii) FRH4 comprising the amino acid sequence of FRH4 of an antibody in Table 7 or 4

[0023] 1. The isolated antibody of any preceding embodiment, comprising a VH comprising:

[0096] E41. a VH comprising, from N-terminus to C-terminus, FRH1, HC CDR1, FRH2, HC CDR2, FRH3, HC CDR3, and FRH4; (i) the FRH1, the HC CDR1, the FRH2, the HC CDR2, the FRH3, the HC CDR3, and the FRH4 comprise the amino acid sequences of SEQ ID NOs: 603, 315, 664, 341, 718, 410, and 771, respectively; (ii) the FRH1, the HC CDR1, the FRH2, the HC CDR2, the FRH3, the HC CDR3, and the FRH4 comprise the amino acid sequences of SEQ ID NOs: 619, 314, 663, 341, 717, 410, and 771, respectively; (iii) the FRH1, the HC CDR1, the FRH2, the HC CDR2, the FRH3, the HC CDR3, and the FRH4 comprise the amino acid sequences of SEQ ID NOs: 603, 316, 665, 341, 719, 410, and 771, respectively; (vi) the FRH1, the HC CDR1, the FRH2, the HC CDR2, the FRH3, the HC CDR3, and the FRH4 comprise the amino acid sequences of SEQ ID NOs: 663, 325, 682, 362, 745, 435, and 771, respectively; (v) the FRH1, the HC CDR1, the FRH2, the HC CDR2, the FRH3, the HCDR3, and the FRH4 comprise the amino acid sequences of SEQ ID NOs: 608, 304, 652, 347, 705, 400, and 767, respectively; or (vi) the FRH1, the HC CDR1, the FRH2, the HC CDR2, the FRH3, the HC CDR3, and the FRH4 comprise the amino acid sequences of SEQ ID NOs: 604, 299, 647, 343, 700, 395, and 770, respectively; The antibody of any one of the preceding embodiments.

[0097] E42. The antibody of any one of embodiments E22 to E41, wherein the nucleotide sequence encoding the VH comprises the nucleotide sequence of any VH presented in Table 3 or 4, or a nucleotide sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0098] E43. The antibody of any one of embodiments E22 to E42, wherein the nucleotide sequence encoding the VH comprises the nucleotide sequence of SEQ ID NO: 150, 155, 167-169, or 197, or a nucleotide sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0099] E44. (i) the amino acid sequence of any VL listed in Table 3 or 4, or an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; (ii) an amino acid sequence having at least one, two, or three modifications of any VL amino acid sequence listed in Table 3 or 4, but no more than 30, no more than 20, or no more than 10 modifications; or (iii) an amino acid sequence encoded by the nucleotide sequence of any VL listed in Table 3 or 4, or a nucleotide sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; The antibody of any one of embodiments E22 to E43, comprising a VL comprising:

[0100] E45. (i) an amino acid sequence of SEQ ID NO: 78, 83, 93-95, or 122, or an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; (ii) an amino acid sequence having at least one, two, or three modifications of the amino acid sequence of SEQ ID NO: 78, 83, 93-95, or 122, but not more than 30, not more than 20, or not more than 10 modifications; or (iii) an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 224, 229, 241-243, or 270, or a nucleotide sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; The antibody of any one of embodiments E22 to E44, comprising a VL comprising:

[0101] E46. From the N-terminus to the C-terminus, (i) FRL1 comprising the amino acid sequence of FRL1 of any of the antibodies in Table 7 or 4; (ii) an LC CDR1 comprising the amino acid sequence of the LC CDR1 of an antibody of Table 6 or 5; (iii) FRL2 comprising the amino acid sequence of FRL2 of an antibody of Table 7 or 4; (iv) an LC CDR2 comprising the amino acid sequence of an LC CDR2 of an antibody of Table 6 or 5; (v) FRL3 comprising the amino acid sequence of FRL3 of an antibody of Table 7 or 4; (vi) an LC CDR3 comprising the amino acid sequence of the LC CDR3 of an antibody of Table 6 or 5, and (vii) FRL4 comprising the amino acid sequence of FRL4 of an antibody in Table 7 or 4

[0023] 1. The antibody of any preceding embodiment, comprising a VL comprising:

[0102] E47. a VL comprising, from N-terminus to C-terminus, FRL1, LC CDR1, FRL2, LC CDR2, FRL3, LC CDR3, and FRL4; (i) the FRL1, the LC CDR1, the FRL2, the LC CDR2, the FRL3, the LC CDR3, and the FRL4 comprise the amino acid sequences of SEQ ID NOs: 793, 474, 836, 529, 874, 571, and 910, respectively; (ii) the FRL1, the LC CDR1, the FRL2, the LC CDR2, the FRL3, the LC CDR3, and the FRL4 comprise the amino acid sequences of SEQ ID NOs: 1178, 1154, 831, 529, 1179, 571, and 906, respectively; (iii) the FRL1, the LC CDR1, the FRL2, the LC CDR2, the FRL3, the LC CDR3, and the FRL4 comprise the amino acid sequences of SEQ ID NOs: 787, 475, 831, 530, 870, 571, and 906, respectively; (iv) the FRL1, the LC CDR1, the FRL2, the LC CDR2, the FRL3, the LC CDR3, and the FRL4 comprise the amino acid sequences of SEQ ID NOs: 807, 495, 830, 540, 888, 587, and 908, respectively; (v) the FRL1, the LC CDR1, the FRL2, the LC CDR2, the FRL3, the LC CDR3, and the FRL4 comprise the amino acid sequences of SEQ ID NOs: 783, 464, 830, 523, 866, 562, and 906, respectively; or (vi) the FRL1, the LC CDR1, the FRL2, the LC CDR2, the FRL3, the LC CDR3, and the FRL4 comprise the amino acid sequences of SEQ ID NOs: 779, 460, 825, 518, 861, 557, and 908, respectively; The antibody of any one of the preceding embodiments.

[0103] E48. The antibody of any one of embodiments E22 to E47, wherein the nucleotide sequence encoding the VL comprises the nucleotide sequence of any VL presented in Table 3 or 4, or a nucleotide sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0104] E49. The antibody of any one of embodiments E22 to E48, wherein the nucleotide sequence encoding the VL comprises the nucleotide sequence of SEQ ID NO: 224, 229, 241-243, or 270, or a nucleotide sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0105] E50. (i) VH, (a) the amino acid sequence of any VH listed in Table 3 or 4, or an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; (b) an amino acid sequence having at least one, two, or three modifications of any VH amino acid sequence listed in Table 3 or 4, but no more than 30, no more than 20, or no more than 10 modifications; or (c) any VH listed in Table 3 or 4, comprising an amino acid sequence encoded by a nucleotide sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and (ii) VL, (a) the amino acid sequence of any VL listed in Table 3 or 4, or an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; (b) an amino acid sequence having at least one, two, or three modifications of any VL amino acid sequence listed in Table 3 or 4, but no more than 30, no more than 20, or no more than 10 modifications; or (c) any VL comprising an amino acid sequence encoded by the nucleotide sequence of any VL listed in Table 3 or 4, or a nucleotide sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. 10. The antibody of any one of the preceding embodiments, comprising:

[0106] E51. 10. The antibody of any one of the preceding embodiments, comprising the amino acid sequence of the VH of any of the antibodies listed in Tables 3 and 4 and the amino acid sequence of the VL of an antibody listed in Tables 3 or 4.

[0107] E52. (i) a VH comprising the amino acid sequence of SEQ ID NO: 22, or an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; (ii) a VL comprising the amino acid sequence of SEQ ID NO: 94, or an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; The antibody of any one of embodiments E22 to E28 and E34 to E51, comprising:

[0108] E53. (i) a VH comprising the amino acid sequence of SEQ ID NO: 21, or an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; (ii) a VL comprising the amino acid sequence of SEQ ID NO: 93, or an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; The antibody of any one of embodiments E22 to E27, E29, and E34 to E51, comprising:

[0109] E54. (i) a VH comprising the amino acid sequence of SEQ ID NO: 23, or an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; (ii) a VL comprising the amino acid sequence of SEQ ID NO: 95, or an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; The antibody of any one of embodiments E22 to E27, E30, and E34 to E51, comprising:

[0110] E55. (i) a VH comprising the amino acid sequence of SEQ ID NO: 51, or an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; (ii) a VL comprising the amino acid sequence of SEQ ID NO: 122, or an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; The antibody of any one of embodiments E22 to E27, E31, and E44 to E51, comprising:

[0111] E56. (i) a VH comprising the amino acid sequence of SEQ ID NO: 9, or an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; (ii) a VL comprising the amino acid sequence of SEQ ID NO: 83, or an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; The antibody of any one of embodiments E22 to E27, E32, and E44 to E51, comprising:

[0112] E57. (i) a VH comprising the amino acid sequence of SEQ ID NO: 4, or an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; (ii) a VL comprising the amino acid sequence of SEQ ID NO: 78, or an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; The antibody of any one of embodiments E22 to E27, and E33 to E51, comprising:

[0113] E58. The nucleotide sequence encoding the antibody (i) the nucleotide sequence of SEQ ID NO: 150, or a nucleotide sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or the nucleotide sequence of SEQ ID NO: 224, or a nucleotide sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; (ii) the nucleotide sequence of SEQ ID NO: 155, or a nucleotide sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or the nucleotide sequence of SEQ ID NO: 229, or a nucleotide sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; (iii) the nucleotide sequence of SEQ ID NO: 167, or a nucleotide sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or the nucleotide sequence of SEQ ID NO: 241, or a nucleotide sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; (iv) the nucleotide sequence of SEQ ID NO: 168, or a nucleotide sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or the nucleotide sequence of SEQ ID NO: 242, or a nucleotide sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; (v) the nucleotide sequence of SEQ ID NO: 169, or a nucleotide sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or the nucleotide sequence of SEQ ID NO: 243, or a nucleotide sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; or (vi) the nucleotide sequence of SEQ ID NO: 197, or a nucleotide sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or the nucleotide sequence of SEQ ID NO: 270, or a nucleotide sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. 10. The antibody of any one of the preceding embodiments, comprising:

[0114] E59. The antibody of any one of the preceding embodiments, which is a full-length antibody, a bispecific antibody, a Fab, a F(ab')2, an Fv, or a single-chain Fv fragment (scFv).

[0115] E60. 10. The antibody of any one of the preceding embodiments, comprising a heavy chain constant region selected from human IgG1, human IgG2, human IgG3, human IgG4, murine IgG1, murine IgG2a, murine IgG2b, murine IgG2c, and murine IgG3, and / or a light chain constant region selected from a kappa or lambda light chain constant region.

[0116] E61. 10. The antibody of any one of the preceding embodiments, comprising a heavy chain constant region comprising an amino acid sequence of a heavy chain constant region set out in Table X, or an amino acid sequence with at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or a light chain constant region comprising an amino acid sequence of a light chain constant region set out in Table X, or an amino acid sequence with at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0117] E62. 10. The antibody of any one of the preceding embodiments, wherein the nucleotide sequence encoding the heavy chain constant region comprises the nucleotide sequence of a heavy chain constant region set out in Table X, or a nucleotide sequence with at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or wherein the nucleotide sequence encoding the light chain constant region comprises the nucleotide sequence of a light chain constant region set out in Table X, or a nucleotide sequence with at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

[0118] E63. (i) a VH comprising the amino acid sequence of any VH set forth in Table 3 or 4, or an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and a heavy chain constant region comprising the amino acid sequence of a heavy chain constant region set forth in Table X, or an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or (ii) a VL comprising the amino acid sequence of any VL listed in Table 3 or 4, or an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and a light chain constant region comprising the amino acid sequence of a light chain constant region listed in Table X, or an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. 10. The antibody of any one of the preceding embodiments, comprising:

[0119] E64. (i) a VH comprising the amino acid sequence of SEQ ID NO: 4, 9, 21-23, or 51, or an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and a heavy chain constant region comprising the amino acid sequence of the heavy chain constant region amino acids set forth in Table X, or an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or (ii) a VL comprising the amino acid sequence of SEQ ID NO: 78, 83, 93-95, or 122, or an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and a light chain constant region comprising the amino acid sequence of the light chain constant region amino acids set forth in Table X, or an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. 10. The antibody of any one of the preceding embodiments, comprising:

[0120] E65. 10. The antibody of any one of the preceding embodiments, which binds to the C-terminus of tau protein, e.g., residues 409-436 numbered according to SEQ ID NO: 920.

[0121] E66. 10. The antibody of any one of the preceding embodiments, which binds to the microtubule binding domain of tau protein.

[0122] E67. 10. The antibody of any one of the preceding embodiments, which binds to the proline-rich domain of tau protein.

[0123] E68. A dissociation constant (K) of less than about 120 nM, as measured, for example, by Octet, as described, for example, in Example 8. D2. The antibody of any one of the preceding embodiments, wherein the antibody binds to tau protein at

[0124] E69. K of approximately 0.1 nM to approximately 0.5 nM D 10. The antibody of any one of the preceding embodiments, wherein the antibody binds to tau protein at

[0125] E70. K of approximately 0.5 nM to approximately 5 nM D 2. The antibody of any one of the preceding embodiments, wherein the antibody is capable of binding to tau protein at

[0126] E71. K of approximately 5 nM to approximately 30 nM D 2. The antibody of any one of the preceding embodiments, wherein the antibody is capable of binding to tau protein at

[0127] E72. 10. The antibody of any one of the preceding embodiments, which binds to a tau protein comprising at least one, two, three, or more phosphorylated residues, e.g., residues T212, T217, S396, S404, S409, numbered according to SEQ ID NO: 920, or a combination thereof.

[0128] E73. 10. The antibody of any one of the preceding embodiments, which binds to concentrated paired helical fibrillar tau protein (ePHF), e.g., with a half-maximal effective concentration (EC50) of about 0.01 nM to about 100 nM.

[0129] E74. 10. The antibody of any one of the preceding embodiments, which reduces, e.g., inhibits, the aggregation of tau. E75. The antibody of any one of the preceding embodiments, which inhibits tau aggregation with a half-maximal inhibitory concentration (IC50) of about 1 nM to about 30 nM, e.g., as measured by an immunodepletion assay (e.g., using tau RD biosensor cells), e.g., as described in Example 6.

[0130] E76. 10. The antibody of any one of the preceding embodiments, which binds to an epitope comprising a region formed by a complex of at least two tau proteins, e.g., a tau dimer.

[0131] E77. An antibody that competes for binding to tau with the antibody of any one of the preceding embodiments. E78. An antibody that binds to the same epitope as, substantially the same epitope as, or an overlapping epitope with, the epitope of the antibody of any one of the preceding embodiments.

[0132] E79. An isolated, e.g., recombinant, nucleic acid encoding the antibody of any one of the preceding embodiments.

[0133] E80. 1. An isolated, e.g., recombinant, nucleic acid encoding an antibody that binds to tau, said antibody comprising: (i) a heavy chain variable region (VH) comprising at least one, two, or three of the HC CDR1, HC CDR2, and / or HC CDR3 of an antibody of Table 1, 6, 2A-2C, 4, or 5; and / or (ii) a light chain variable region (VL) comprising at least one, two, or three of the LC CDR1, LC CDR2, and / or LC CDR3 of an antibody of Table 1, 6, 2A-2C, 4, or 5; The nucleic acid comprising:

[0134] E81. (i) the HC CDR1, the HC CDR2, the HC CDR3, the LC CDR1, the LC CDR2, and the LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 315, 341, 410, 474, 529, and 571, respectively; (ii) the HC CDR1, the HC CDR2, the HC CDR3, the LC CDR1, the LC CDR2, and the LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 314, 341, 410, 1154, 529, and 571, respectively; (iii) the HC CDR1, the HC CDR2, the HC CDR3, the LC CDR1, the LC CDR2, and the LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 316, 341, 410, 475, 530, and 571, respectively; (iv) the HC CDR1, the HC CDR2, the HC CDR3, the LC CDR1, the LC CDR2, and the LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 325, 362, 435, 495, 540, and 587, respectively; (v) the HC CDR1, the HC CDR2, the HC CDR3, the LC CDR1, the LC CDR2, and the LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 304, 347, 400, 464, 523, and 562, respectively; or (vi) the HC CDR1, the HC CDR2, the HC CDR3, the LC CDR1, the LC CDR2, and the LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 299, 343, 395, 460, 518, and 557, respectively; The nucleic acid of embodiment E80.

[0135] E82. The antibody (i) a VH comprising the amino acid sequence of any VH listed in Table 3 or 4, an amino acid sequence with at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity to any VH listed in Table 3 or 4, or an amino acid sequence that has at least one, two, or three modifications of the amino acid sequence of any VH listed in Table 3 or 4, but not more than 30, not more than 20, or not more than 10 modifications; and / or (ii) a VL that comprises an amino acid sequence of any VL listed in Table 3 or 4, an amino acid sequence that has at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity to any VL listed in Table 3 or 4, or an amino acid sequence that has at least one, two, or three modifications of the amino acid sequence of any VL listed in Table 3 or 4, but not more than 30, not more than 20, or not more than 10 modifications. The nucleic acid of embodiment E80, comprising:

[0136] E83. The antibody (i) a VH comprising the amino acid sequence of SEQ ID NO: 4, 9, 21-23, or 51, or an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, or an amino acid sequence having at least one, two, or three modifications of the amino acid sequence of SEQ ID NO: 4, 9, 21-23, or 51, but not more than 30, not more than 20, or not more than 10 modifications; and / or (ii) a VL comprising an amino acid sequence of SEQ ID NO: 78, 83, 93-95, or 122, or an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, or an amino acid sequence having at least one, two, or three modifications of the amino acid sequence of SEQ ID NO: 78, 83, 93-95, or 122, but not more than 30, not more than 20, or not more than 10 modifications. The nucleic acid of any one of embodiments E80 to E82, comprising:

[0137] E84. The antibody (i) a heavy chain constant region comprising an amino acid sequence set out in Table X, or an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or (ii) a light chain constant region comprising an amino acid sequence set forth in Table X, or an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; The nucleic acid of any one of embodiments E80 to E83, comprising:

[0138] E85. (i) the nucleotide sequence of any VH listed in Table 3 or 4, or a nucleotide sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or (ii) the nucleotide sequence of any VL listed in Table 3 or 4, or a nucleotide sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. The nucleic acid of any one of embodiments E80 to E84, comprising:

[0139] E86. (i) the nucleotide sequence of SEQ ID NO: 150, 155, 167-169, or 197, or a nucleotide sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or (ii) the nucleotide sequence of SEQ ID NO: 224, 229, 241-243, or 270, or a nucleotide sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. The nucleic acid of any one of embodiments E80 to E85, comprising:

[0140] E87. The isolated nucleic acid sequence of any one of embodiments E79 to E86, wherein the nucleic acid sequence encoding the heavy chain variable region and / or the light chain variable region is codon-optimized.

[0141] E88. An isolated, eg recombinant, antibody encoded by a nucleic acid according to any one of embodiments E79 to E87.

[0142] E89. A vector comprising a nucleic acid according to any one of embodiments E79 to E87, or a nucleic acid encoding an antibody according to any one of embodiments E1 to E78 and E88.

[0143] E90. A host cell comprising a nucleic acid according to any one of embodiments E79 to E87, a nucleic acid encoding an antibody according to any one of embodiments E1 to E78 and E88, or a vector (e.g., an expression vector) according to embodiment E89.

[0144] E91. The host cell of embodiment E90, which is an insect cell, a bacterial cell, or a mammalian cell. E92. A method for producing an antibody, comprising culturing a host cell of embodiment E90 or E91 under conditions suitable for gene expression.

[0145] E93. An isolated nucleic acid encoding a payload, wherein the encoded payload comprises an antibody of any one of embodiments E1 to E78 and E88.

[0146] E94. The nucleic acid of embodiment E93, further encoding a signal sequence, wherein optionally the nucleotide sequence encoding said signal sequence comprises the nucleotide sequence of any of the signal sequences listed in Table 14, or a nucleotide sequence with at least 95% sequence identity thereto.

[0147] E95. The nucleic acid of any one of embodiments E93-E94, further encoding a second signal sequence, optionally wherein the nucleotide sequence encoding said signal sequence comprises the nucleotide sequence of any of the signal sequences listed in Table 14, or a nucleotide sequence having at least 95% sequence identity thereto.

[0148] E96. (i) the nucleotide sequence encoding the signal sequence is located 5' to the nucleotide sequence encoding the VH; and / or (ii) the nucleotide sequence encoding the signal sequence is located 5' to the nucleotide sequence encoding the VL; The nucleic acid of any one of embodiments E93 to E95.

[0149] E97. The nucleic acid of any one of embodiments E93 to E96, wherein the encoded VH and VL sequences are directly joined, eg, without a linker.

[0150] E98. The nucleic acid of any one of embodiments E93 to E97, wherein the encoded VH and VL sequences are connected via a linker.

[0151] E99. The nucleic acid of embodiment E98, wherein said linker comprises the nucleotide sequence of any of the linker sequences provided in Table 15, or a nucleotide sequence having at least 95% sequence identity thereto.

[0152] E100. The nucleic acid of any one of embodiments E93 to E99, wherein the encoded payload is a full-length antibody, a bispecific antibody, a Fab, a F(ab')2, an Fv, a single-chain Fv fragment (scFv), a single-domain antibody, or a camelid antibody.

[0153] E101. A viral genome comprising a promoter operably linked to said nucleic acid encoding a payload comprising the antibody of any one of embodiments E1 to E78 and E88.

[0154] E102. The promoter is (i) human elongation factor 1 α-subunit (EF1α), cytomegalovirus (CMV) immediate early enhancer and / or promoter, chicken β-actin (CBA) and its derivatives CAG, β-glucuronidase (GUSB), or ubiquitin C (UBC), neuron-specific enolase (NSE), platelet-derived growth factor (PDGF), platelet-derived growth factor B chain (PDGF-β), intercellular adhesion molecule 2 (ICAM-2), synapsin (Syn), methyl-CpG-binding protein 2 (MeCP2), Ca2+ / calmodulin and / or are selected from: dependent protein kinase II (CaMKII), metabotropic glutamate receptor 2 (mGluR2), neurofilament light chain (NFL) or neurofilament heavy chain (NFH), beta-globin minigene nβ2, preproenkephalin (PPE), enkephalin (Enk) and excitatory amino acid transporter 2 (EAAT2), glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), or fragments, e.g. truncations, or functional variants thereof; and / or (ii) comprises the nucleotide sequence of any of the promoter sequences listed in Table 11, or a nucleotide sequence that is at least 95% identical thereto; The viral genome of embodiment E101.

[0155] E103. The viral genome of any one of embodiments E101 to E102, further comprising an enhancer, optionally wherein said enhancer is a CMV immediate early (CMVie) enhancer.

[0156] E104. The viral genome of any one of embodiments E101 to E103, further comprising a polyadenylation (polyA) signal region.

[0157] E105. The viral genome of embodiment E104, wherein the polyA signal region comprises a nucleotide sequence of any of SEQ ID NOs: 1134 to 1136, or a nucleotide sequence having at least 95% identity thereto.

[0158] E106. The viral genome of any one of embodiments E101 to E105, further comprising an inverted terminal repeat (ITR) sequence.

[0159] E107. (i) the ITR sequences are positioned 5' to the encoded payload, and / or (ii) the ITR sequence is positioned 3' to the encoded payload; The viral genome of embodiment E106.

[0160] E108. The viral genome of any one of embodiments E101 to E107, comprising an ITR sequence positioned 5' to the encoded payload and an ITR sequence positioned 3' to the encoded payload.

[0161] E109. The viral genome of any one of embodiments E101 to E108, wherein the ITR sequence comprises the nucleotide sequence of any one of SEQ ID NOs: 1035 to 1038, or a nucleotide sequence having at least 80%, 85%, 90%, or 95% sequence identity thereto.

[0162] E110. The viral genome of any one of embodiments E101 to E109, further comprising an intron region.

[0163] E111. The viral genome of embodiment E110, wherein the intron region comprises the nucleotide sequence of any of the intron regions listed in Table 13, or a nucleotide sequence having at least 95% identity thereto.

[0164] E112. The viral genome of any one of embodiments E101 to E111, comprising at least one, two, or three intron regions.

[0165] E113. The viral genome of any one of embodiments E101 to E112, further comprising an exon region.

[0166] E114. The viral genome of embodiment E113, wherein the exon region comprises a nucleotide sequence of any of the exon sequences in Table 12, or a nucleotide sequence having at least 95% identity thereto.

[0167] E115. The viral genome of any one of embodiments E101 to E114, comprising at least one, two, or three exon regions.

[0168] E116. The viral genome of any one of embodiments E101 to E115, further comprising a Kozak sequence, optionally wherein said Kozak sequence comprises the nucleotide sequence GCCGCCACCATG (SEQ ID NO: 1079) or GAGGAGCCACC (SEQ ID NO: 1089).

[0169] E117. The viral genome of any one of embodiments E101 to E116, further comprising a nucleotide sequence encoding an miR binding site, such as an miR binding site that modulates, e.g., reduces, expression of the payload encoded by the viral genome in cells or tissues in which the corresponding miRNA is expressed.

[0170] E118. The viral genome of embodiment E117, comprising at least 1 to 5 copies of the encoded miR binding site, such as at least 1, 2, 3, 4, or 5 copies.

[0171] E119. The viral genome of any one of embodiments E117-E118, comprising at least three copies of the encoded miR binding site, optionally wherein all three copies comprise the same miR binding site, or wherein at least one, two, or all copies comprise different miR binding sites.

[0172] E120. The viral genome of any one of embodiments E117 to E119, comprising at least four copies of the encoded miR binding site, optionally wherein all four copies comprise the same miR binding site, or wherein at least one, two, three, or all copies comprise different miR binding sites.

[0173] E121. the encoded miR binding site comprises a miR122 binding site, a miR183 binding site, a miR-142-3p, or a combination thereof, and optionally (i) the encoded miR122 binding site comprises the nucleotide sequence of SEQ ID NO: 1029, or a nucleotide sequence substantially identical thereto (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity), or a nucleotide sequence having at least 1, 2, 3, 4, 5, 6, or 7, but not more than 10, modifications of SEQ ID NO: 1029; (ii) the encoded miR183 binding site comprises the nucleotide sequence of SEQ ID NO: 1032, or a nucleotide sequence substantially identical thereto (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity), or a nucleotide sequence having at least one, two, three, four, five, six, or seven, but not more than ten, modifications of SEQ ID NO: 1032; and / or (iii) the encoded miR-142-3p binding site comprises the nucleotide sequence of SEQ ID NO: 1031, or a nucleotide sequence substantially identical thereto (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity), or a nucleotide sequence having at least one, two, three, four, five, six, or seven, but not more than ten, modifications of SEQ ID NO: 1031; The viral genome of any one of embodiments E117 to E120.

[0174] E122. The viral genome of any one of embodiments E101 to E121, which is single-stranded. E123. The viral genome of any one of embodiments E101 to E122, further comprising a nucleotide sequence encoding a Rep protein, such as a nonstructural protein, wherein the Rep protein comprises a Rep78 protein, a Rep68 protein, a Rep52 protein, and / or a Rep40 protein.

[0175] E124. The viral genome of embodiment E123, wherein the Rep78 protein, the Rep68 protein, the Rep52 protein, and / or the Rep40 protein are encoded by at least one Rep gene.

[0176] E125. The viral genome of any one of embodiments E101 to E124, further comprising a nucleic acid sequence encoding a capsid protein, such as a structural protein, wherein the capsid protein comprises a VP1 polypeptide, a VP2 polypeptide, and / or a VP3 polypeptide.

[0177] E126. The viral genome of embodiment E125, wherein the VP1 polypeptide, the VP2 polypeptide, and / or the VP3 polypeptide are encoded by at least one Cap gene.

[0178] E127. A vector comprising the viral genome of any one of embodiments E101 to E126. E128. (i) a capsid protein, and (ii) a nucleic acid according to any one of embodiments E79 to E87 and E93 to E100, or a viral genome according to any one of embodiments E101 to E126. An isolated, e.g., recombinant, AAV particle comprising:

[0179] E129. (i) the capsid protein comprises the amino acid sequence of SEQ ID NO: 1003, or an amino acid sequence having at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto; (ii) the capsid protein comprises an amino acid sequence having at least one, two, or three modifications of the amino acid sequence of SEQ ID NO: 1003, but not more than 30, not more than 20, or not more than 10 modifications; (iii) the capsid protein comprises the amino acid sequence of SEQ ID NO: 1011, or an amino acid sequence having at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto; (iv) the capsid protein comprises an amino acid sequence having at least one, two, or three modifications of the amino acid sequence of SEQ ID NO: 1011, but not more than 30, not more than 20, or not more than 10 modifications; (v) the capsid protein comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 1002, or a sequence having at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto; and / or (vi) the nucleotide sequence encoding the capsid protein comprises the nucleotide sequence of SEQ ID NO: 1002, or a sequence having at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto; An isolated AAV particle described in embodiment E128.

[0180] E130. The capsid protein comprises: (i) an amino acid substitution at position K449 numbered according to SEQ ID NO: 1003, e.g., a K449R substitution; (ii) an insert comprising the amino acid sequence of TLAVPFK (SEQ ID NO: 1151), optionally located immediately after position 588 relative to the reference sequence numbered according to SEQ ID NO: 1003; (iii) an amino acid other than "A" at position 587 and / or an amino acid other than "Q" at position 588, numbered according to SEQ ID NO: 1003; and / or (iv) an amino acid substitution of A587D and / or Q588G numbered according to SEQ ID NO: 1003 The isolated AAV particle of embodiment E128 or E129, comprising:

[0181] E131. An AAV particle described in any one of embodiments E128 to E130, wherein the capsid protein comprises (i) an amino acid substitution of K449R numbered according to SEQ ID NO: 1003, and (ii) an insert comprising the amino acid sequence of TLAVPFK (SEQ ID NO: 1151), optionally located immediately after position 588 of SEQ ID NO: 1003.

[0182] E132. An AAV particle described in any one of embodiments E128 to E130, wherein the capsid protein comprises (i) an amino acid substitution of K449R numbered according to SEQ ID NO: 1003, (ii) an insert comprising the amino acid sequence of TLAVPFK (SEQ ID NO: 1151), optionally located immediately after position 588 relative to the reference sequence numbered according to SEQ ID NO: 1003, and (iii) amino acid substitutions of A587D and Q588G numbered according to SEQ ID NO: 1003.

[0183] E133. An AAV particle described in any one of embodiments E128 to E130, wherein the capsid protein comprises (i) an insert comprising the amino acid sequence of TLAVPFK (sequence number 1151), optionally located immediately after position 588 relative to the reference sequence numbered according to SEQ ID NO: 1003, and (ii) amino acid substitutions A587D and Q588G numbered according to SEQ ID NO: 1003.

[0184] E134. The AAV particle of any one of embodiments E128 to E133, wherein the capsid protein comprises any of the capsid proteins listed in Table 9, or a functional variant thereof.

[0185] E135. The capsid proteins include VOY101, VOY201, AAVPHP.B (PHP.B), AAVPHP.A (PHP.A), AAVG2B-26, AAVG2B-13, AA VTH1.1-32, AAVTH1.1-35, AAVPHP.B2(PHP.B2), AAVPHP.B3(PHP.B3), AAVPHP.N / PHP.B-DGT, AAVP HP.B-EST, AAVPHP.B-GGT, AAVPHP.B-ATP, AAVPHP.B-ATT-T, AAVPHP.B-DGT-T, AAVPHP.B-GGT-T, AAVPHP.B-SGS, AAVPHP.B-AQP, AAVPHP.B-QQP, AAVPHP.B-SNP(3), AAVPHP.B-SNP, AAVPHP.B-QGT, A AVPHP.B-NQT, AAVPHP.B-EGS, AAVPHP.B-SGN, AAVPHP.B-EGT, AAVPHP.B-DST, AAVPHP.B-DST, AAVPHP.B-STP, AAVPHP.B-PQP, AAVPHP.B-SQP, AAVPHP.B-QLP, AAVPHP.B-TMP, AAVPHP.B-TTP, AAVPHP. S / G2A12, AAVG2A15 / G2A3(G2A3), AAVG2B4(G2B4), AAVG2B5(G2B5), AAVPHP.N(PHP.N), PHP.S, AAV 1, AAV2, AAV2 variant, AAV2 / 3 variant, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9.47, AAV9(hu14), AAV9, AAV9 An AAV particle described in any one of embodiments E128 to E134, comprising a K449R, AAV10, AAV11, AAV12, AAVrh8, AAVrh10, AAVDJ, AAVDJ8, or AAV2G9 capsid protein, or a functional variant thereof.

[0186] E136. An AAV particle described in any of embodiments E128 to E135, wherein the capsid protein comprises a VOY101 capsid protein.

[0187] E137. The capsid protein is (i) the amino acid sequence of SEQ ID NO: 1023, or an amino acid sequence substantially identical thereto (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity); (ii) an amino acid sequence that contains at least one, two, or three modifications, but no more than 30, no more than 20, or no more than 10 modifications, e.g., substitutions, relative to the amino acid sequence of SEQ ID NO: 1023; or (iii) an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 1022, or a nucleotide sequence substantially identical thereto (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity). The AAV particle of embodiment E136, comprising:

[0188] E138. The AAV particle of embodiment E136 or E137, wherein the nucleotide sequence encoding the capsid protein comprises the nucleotide sequence of SEQ ID NO: 1022, or a nucleotide sequence substantially identical thereto (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity).

[0189] E139. The capsid protein is (i) a VP1 polypeptide, a VP2 polypeptide, a VP3 polypeptide, or a combination thereof; (ii) positions 138 to 743 of SEQ ID NO: 1023, e.g., an amino acid sequence corresponding to VP2, or a sequence having at least 80% (e.g., at least about 85, 90, 92, 95, 96, 97, 98, or 99%) sequence identity thereto; (iii) positions 203 to 743 of SEQ ID NO: 1023, e.g., an amino acid sequence corresponding to VP3, or a sequence having at least 80% (e.g., at least about 85, 90, 92, 95, 96, 97, 98, or 99%) sequence identity thereto; and / or (iv) positions 1 to 743 of SEQ ID NO: 1023, e.g., an amino acid sequence corresponding to VP1, or a sequence having at least 80% (e.g., at least about 85, 90, 92, 95, 96, 97, 98, or 99%) sequence identity thereto An AAV particle described in any one of embodiments E128 to E138, comprising:

[0190] E140. A host cell comprising a nucleic acid described in any one of embodiments E79 to E87 and E93 to E100, a viral genome described in any one of embodiments E101 to E126, or an AAV particle described in any one of embodiments E128 to E139, wherein the host cell is optionally an insect cell, a bacterial cell, or a mammalian cell.

[0191] E141. A nucleic acid encoding a viral genome according to any one of embodiments E101 to E126 and a scaffold region suitable for replication of the viral genome in a cell, such as a bacterial cell (e.g., the scaffold region comprises one or both of a bacterial origin of replication and a selectable marker).

[0192] E142. 1. A method for producing a viral genome, comprising: (i) providing a nucleic acid molecule comprising a viral genome according to any one of embodiments E101 to E126; (ii) excising the viral genome from the backbone region, for example, by cleaving the nucleic acid molecule upstream and downstream of the viral genome; The method comprising:

[0193] E143. 1. A method of producing isolated, e.g., recombinant, AAV particles, comprising: (i) providing a host cell containing the viral genome of embodiment E140; (ii) incubating the host cell under conditions suitable for encapsulating the viral genome into a capsid protein, such as a VOY101 capsid protein; This results in the production of the isolated AAV particles.

[0194] E144. The method of embodiment E143, further comprising, prior to step (i), introducing into said host cell a first nucleic acid molecule comprising said viral genome.

[0195] E145. The method of embodiment E143 or E144, wherein said host cell comprises a second nucleic acid encoding a capsid protein, such as a VOY101 capsid protein.

[0196] E146. The method of any one of embodiments E143-E144, wherein said second nucleic acid molecule is introduced into said host cell before, simultaneously with, or after said first nucleic acid molecule.

[0197] E147. A pharmaceutical composition comprising an antibody described in any one of embodiments E1 to E78 and E88, an AAV particle described in any one of embodiments E128 to E139, or an AAV particle comprising a viral genome described in any one of embodiments E101 to E126, or an isolated nucleic acid described in any one of embodiments E79 to E87 and E93 to E100, and a pharmaceutically acceptable excipient.

[0198] E148. A method for delivering an exogenous antibody that binds to tau to a subject, the method comprising administering an effective amount of the pharmaceutical composition of embodiment S1, the antibody of any one of embodiments E1 to E78 and E88, the AAV particle of any one of embodiments E128 to E139, e.g., a plurality of AAV particles, or an AAV particle comprising a viral genome of any one of embodiments E101 to E126, e.g., a plurality of AAV particles, or the isolated nucleic acid of any one of embodiments E79 to E87 and E93 to E100.

[0199] E149. The method of embodiment E148, wherein the subject has, has been diagnosed with, or is at risk of having a disease associated with tau expression.

[0200] E150. The method of embodiment E148 or E149, wherein the subject has, has been diagnosed with, or is at risk of having a neurological disorder, e.g., a neurodegenerative disorder.

[0201] E151. The method of embodiment E148, E149, or E150, wherein the subject has, has been diagnosed with, or is at risk of having a tauopathy.

[0202] E152. A method of treating a subject having or diagnosed as having a disease associated with tau expression, comprising administering to the subject an effective amount of the pharmaceutical composition of embodiment E147, the antibody of any one of embodiments E1 to E78 and E88, the AAV particle of any one of embodiments E128 to E139, e.g., a plurality of AAV particles, or an AAV particle comprising a viral genome of any one of embodiments E101 to E126, e.g., a plurality of AAV particles, or the isolated nucleic acid of any one of embodiments E79 to E87 and E93 to E100.

[0203] E153. A method of treating a subject having or diagnosed as having a neurological disorder, such as a neurodegenerative disorder, comprising administering to the subject an effective amount of the pharmaceutical composition of embodiment E147, the antibody of any one of embodiments E1 to E78 and E88, the AAV particle of any one of embodiments E128 to E139, e.g., a plurality of AAV particles, or an AAV particle comprising a viral genome of any one of embodiments E101 to E126, e.g., a plurality of AAV particles, or the isolated nucleic acid of any one of embodiments E79 to E87 and E93 to E100.

[0204] E154. A method of treating a subject having or diagnosed as having a tauopathy, comprising administering to the subject an effective amount of the pharmaceutical composition of embodiment E147, the antibody of any one of embodiments E1 to E78 and E88, the AAV particle of any one of embodiments E128 to E139, e.g., a plurality of AAV particles, or an AAV particle comprising a viral genome of any one of embodiments E101 to E126, e.g., a plurality of AAV particles, or the isolated nucleic acid of any one of embodiments E79 to E87 and E93 to E100.

[0205] E155. The method of any one of embodiments E152 to E154, wherein the disease, neurological disorder, or tauopathy associated with tau expression comprises AD, FTDP-17, FTLD, FTD, CTE, PSP, Down syndrome, Pick's disease, CBD, corticobasal syndrome, ALS, prion disease, CJD, multiple system atrophy, neurofibrillary senile dementia, or progressive subcortical gliosis.

[0206] E156. The method of any one of embodiments E152 to E155, wherein treating comprises preventing progression of said disease in said subject.

[0207] E157. The method of any one of embodiments E152 to E156, wherein the subject is a human. E158. The method of any one of embodiments E152 to E157, wherein the AAV particles are administered to the subject intravenously, intramuscularly, via intraparenchymal administration, intracerebroventricularly, via intracisternal (ICM) injection, intrathecally, via focused ultrasound (FUS), e.g., in combination with intravenous administration of microbubbles (FUS-MB), or via MRI-guided FUS in combination with intravenous administration.

[0208] E159. The method of any one of embodiments E152 to E158, wherein the AAV particles are administered intravenously to the subject.

[0209] E160. The method of any one of embodiments E152 to E158, wherein the AAV particles are administered to the subject via intracisternal injection (ICM).

[0210] E161. The method of any one of embodiments E152 to E160, further comprising assessing, e.g., measuring, the level of antibodies produced in the subject, e.g., in cells or tissues of said subject.

[0211] E162. The method of any one of embodiments E152 to E161, wherein said administering results in the production of antibodies in said subject, eg, in cells or tissues of said subject, of 0.001 ug / mL to 100 mg / mL.

[0212] E163. The method of embodiment E162, wherein said cell is a neuronal cell. E164. The method of embodiment E162, wherein said tissue is central nervous system tissue, e.g., brain tissue.

[0213] E165. The method of any one of embodiments E152 to E164, further comprising performing a blood test, an imaging test, a CNS biopsy sample, or an aqueous cerebrospinal fluid biopsy.

[0214] E166. The method of any one of embodiments E161 to E165, wherein measuring the level of antibodies is performed before, during, or after treatment with the AAV particles, e.g., a plurality of AAV particles.

[0215] E167. The method of any one of embodiments E152 to E166, wherein the subject has a level of antibodies that is higher than a reference level, e.g., a subject that has not received treatment, e.g., a subject that has not been administered the AAV particle or plurality of AAV particles.

[0216] E168. The plurality of AAV particles is about 1×10 6 VG / mL ~ approx. 1×10 16 The method of any one of embodiments E152 to E167, wherein the medicament is administered at a dose of about 0.0001 mg / kg to about 100 mg / kg VG / mL.

[0217] E169. The method of any one of embodiments E152 to E168, further comprising the administration of an additional therapeutic agent and / or therapy suitable for the treatment or prevention of a disorder associated with tau expression, a neurological disorder, such as a neurodegenerative disorder.

[0218] E170. The method of embodiment E169, wherein the additional therapeutic agent and / or therapy comprises a cholinesterase inhibitor (e.g., donepezil, rivastigmine, and / or galantamine), an N-methyl D-aspartate (NMDA) antagonist (e.g., memantine), an antipsychotic, anxiolytic, an anticonvulsant, a dopamine agonist (e.g., pramipexole, ropinirole, rotigotine, and / or apomorphine), an MAO B inhibitor (e.g., selegiline, rasagiline, and / or safinamide), a catechol O-methyltransferase (COMT) inhibitor (entacapone, opicapone, and / or tolcapone), an anticholinergic (e.g., benztropine and / or trihexyphenidyl), amantadine, carbidopa-levodopa, deep brain stimulation (DBS), or a combination thereof.

[0219] E171. An antibody according to any one of embodiments E1 to E78 and E88, a nucleic acid according to any one of embodiments E79 to E87 and E93 to E100, a viral genome according to any one of embodiments E101 to E126, a pharmaceutical composition according to embodiment E147, or an AAV particle according to any one of embodiments E128 to E139, for use in the manufacture of a medicament.

[0220] E172. An antibody according to any one of embodiments E1 to E78 and E88, a nucleic acid according to any one of embodiments E79 to E87 and E93 to E100, a viral genome according to any one of embodiments E101 to E126, a pharmaceutical composition according to embodiment E147, or an AAV particle according to any one of embodiments E128 to E139 for use in the treatment of a disease associated with tau expression.

[0221] E173. An antibody according to any one of embodiments E1 to E78 and E88, a nucleic acid according to any one of embodiments E79 to E87 and E93 to E100, a viral genome according to any one of embodiments E101 to E126, a pharmaceutical composition according to embodiment E147, or an AAV particle according to any one of embodiments E128 to E139 for use in the treatment of a neurological disorder, such as a neurodegenerative disorder.

[0222] E174. An antibody according to any one of embodiments E1 to E78 and E88, a nucleic acid according to any one of embodiments E79 to E87 and E93 to E100, a viral genome according to any one of embodiments E101 to E126, a pharmaceutical composition according to embodiment E147, or an AAV particle according to any one of embodiments E128 to E139 for use in the treatment of a tauopathy.

[0223] E175. Use of an effective amount of an antibody described in any one of embodiments E1 to E78 and E88, a nucleic acid described in any one of embodiments E79 to E87 and E93 to E100, a viral genome described in any one of embodiments E101 to E126, a pharmaceutical composition described in embodiment E147, or an AAV particle described in any one of embodiments E128 to E139 in the manufacture of a medicament for treating a disease associated with tau expression, a neurological disorder, such as a neurodegenerative disorder, or a tauopathy in a subject. [Brief explanation of the drawings]

[0224] [Figure 1] A and B show alignments of the variable light chain or VL region (A) and variable heavy chain or VH region (B) of selected antibodies V0004, V0009, V0022, V0023, V0024, and V0052, with the CDR sequences highlighted according to the Kabat numbering system. The corresponding framework region sequences, including FRH1-FRH4 and FRL1-FRL4 in the Kabat numbering system, are defined by the boundaries of the CDR regions. [Figure 2] A and B show alignments of the variable light chain (A) and variable heavy chain (B) regions of selected antibodies V0004, V0009, V0022, V0023, V0024, and V0052, with the CDR sequences highlighted according to the Chothia numbering system. The corresponding framework region sequences, including FRH1-FRH4 and FRL1-FRL4 in the Chothia numbering system, are defined by the boundaries of the CDR regions. [Figure 3] A and B show alignments of the variable light chain (A) and variable heavy chain (B) regions of selected antibodies V0004, V0009, V0022, V0023, V0024, and V0052, with the CDR sequences highlighted according to the IMGT numbering system. The corresponding framework region sequences, including FRH1-FRH4 and FRL1-FRL4 in the IMGT numbering system, are defined by the boundaries of the CDR regions. DETAILED DESCRIPTION OF THE INVENTION

[0225] I. Composition In some embodiments, the present disclosure provides compositions that interact with the human microtubule-associated protein tau. Such compositions can be antibodies that bind to tau protein epitopes, referred to herein as "anti-tau antibodies." Tau dysfunction and / or aggregation are found in a class of neurodegenerative diseases called tauopathies. Hyperphosphorylation of tau leads to aggregation and inhibition of tau-dependent microtubule assembly. In tauopathies, tau aggregates form paired helical filaments (PHFs) found in neurofibrillary tangles (NFTs). These aggregates lead to neuronal loss and cognitive decline. The anti-tau antibodies of the present disclosure can be useful for the treatment and / or diagnosis of tauopathies, as well as other uses described herein.

[0226] antibody In some embodiments, the compounds (e.g., anti-tau antibodies) and compositions of the present disclosure comprise an antibody or fragment thereof. In some embodiments, the antibodies described herein bind to tau. For example, the antibody binds to an epitope on tau, e.g., a conformational epitope, a phosphorylated epitope, or a linear epitope, e.g., as described herein.

[0227] As used herein, the term "antibody" is used in the broadest sense and specifically encompasses a variety of embodiments, including, but not limited to, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies formed from at least two intact antibodies), single-chain Fv (scFv) formats, and antibody fragments (e.g., Fab, F(ab'), F(ab'), Fv, etc.), so long as they exhibit the desired functional or biological activity. Antibodies are primarily amino acid-based molecules, but may contain one or more modifications (including, but not limited to, the addition of a sugar moiety, a fluorescent moiety, a chemical tag, etc.).

[0228] Antibodies (including antigen-binding fragments thereof) of the present disclosure may include, but are not limited to, polyclonal, monoclonal, multispecific, bispecific, trispecific, human, humanized, chimeric, single-chain, diabodies, linear antibodies, Fab fragments, F(ab') fragments, F(ab')2 fragments, Fv fragments, fragments produced by an Fab expression library, variable domains, anti-idiotypic (anti-Id) antibodies (including, for example, anti-Id antibodies to antibodies of the invention), intracellularly produced antibodies (i.e., intrabodies), codon-optimized antibodies, scFv fragments, tandem scFv antibodies, bispecific T cell engagers, mAb2 antibodies, chimeric antigen receptors (CARs), tetravalent bispecific antibodies, biosynthetic antibodies, natural antibodies, miniaturized antibodies, unibodies, maxibodies, and epitope-binding fragments of any of the above.

[0229] In some embodiments, an antibody comprises at least one immunoglobulin variable domain sequence. Antibodies can include, for example, full-length mature antibodies and antigen-binding fragments of antibodies. For example, an antibody can comprise a heavy (H) chain variable domain sequence (abbreviated herein as VH) and a light (L) chain variable domain sequence (abbreviated herein as VL). In another example, an antibody comprises two heavy (H) chain variable domain sequences and two light (L) chain variable domain sequences, thereby forming two antigen-binding sites, such as Fab, Fab', F(ab')2, Fc, Fd, Fd', Fv, single-chain antibodies (e.g., scFv), single variable domain antibodies, diabodies (Dab) (bivalent and bispecific), and chimeric (e.g., humanized) antibodies, which can be produced by modification of whole antibodies or those synthesized de novo using recombinant DNA technology. These functional antibody fragments retain the ability to selectively bind to their respective antigens or receptors. The antibodies and antibody fragments may be from any class of antibody, including, but not limited to, IgG, IgA, IgM, IgD, and IgE, and any subclass of antibody (e.g., human IgG1, IgG2, IgG3, and IgG4, and mouse IgG1, IgG2a, IgG2b, IgG2c, and IgG3). The antibodies of the present disclosure may be monoclonal or polyclonal. The antibodies may also be human, humanized, CDR-grafted, or in vitro-generated. The antibodies may have a heavy chain constant region selected from, for example, IgG1, IgG2, IgG3, or IgG4. The antibodies may have a light chain selected from, for example, kappa or lambda.

[0230] In some embodiments, the antibodies of the present disclosure include functional fragments or variants thereof. The constant region of the antibody can be altered, e.g., mutated, to modify the properties of the antibody (e.g., to increase or decrease one or more of Fc receptor binding, antibody glycosylation, the number of cysteine ​​residues, effector cell function, or complement function).

[0231] As used herein, the term "antibody fragment" refers to a portion of an intact antibody or a fusion protein thereof, optionally comprising at least one antigen-binding region. Examples of antigen-binding fragments include: (i) a Fab fragment, i.e., a monovalent fragment consisting of the VL, VH, CL, and CH1 domains; (ii) a F(ab')2 fragment, i.e., a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CH1 domains; (iv) a Fv fragment consisting of the VL and VH domains of one arm of an antibody; (v) a diabody (dAb) fragment consisting of a VH domain; (vi) a camelid or camelized variable domain; (vii) a single-chain Fv (scFv) (see, e.g., Bird et al. (1988) Science 242:423-426, and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883); and (viii) a single-domain antibody. These antibody fragments are obtained using conventional techniques known to those of skill in the art, and the fragments are screened for utility in the same manner as intact antibodies. Antibody fragments can also be assembled into single-domain antibodies, maxibodies, minibodies, nanobodies, intrabodies, diabodies, triabodies, tetrabodies, v-NARs, and bis-scFvs (see, e.g., Hollinger and Hudson, Nature Biotechnology 23:1126-1136, 2005). In some embodiments, papain digestion of antibodies produces two identical antigen-binding fragments, called "Fab" fragments, each with a single antigen-binding site. A residual "Fc" fragment is also produced, the name reflecting its ability to readily crystallize. Pepsin treatment yields an F(ab')2 fragment, which has two antigen-binding sites and is still capable of cross-linking antigen. Antibodies of the present disclosure may comprise one or more of these fragments and can be produced, for example, by enzymatic digestion of whole antibodies or by recombinant expression.

[0232] In some embodiments, the antibody may be a single-domain antibody. Single-domain antibodies may include antibodies whose complementarity-determining regions are part of a single-domain polypeptide. Examples include, but are not limited to, heavy-chain antibodies, antibodies naturally devoid of light chains, single-domain antibodies derived from conventional four-chain antibodies, engineered antibodies, and single-domain scaffolds other than those derived from antibodies. The single-domain antibody may be any known or future single-domain antibody in the art. The single-domain antibody may be derived from any species, including, but not limited to, mouse, human, camel, llama, fish, shark, goat, rabbit, and cow. According to another aspect of the present invention, the single-domain antibody is a naturally occurring single-domain antibody known as a heavy-chain antibody devoid of light chains. Such single-domain antibodies are disclosed, for example, in WO9404678. For clarity, this variable domain derived from a heavy-chain antibody naturally devoid of light chains is referred to herein as a VHH or nanobody to distinguish it from the conventional VH of four-chain immunoglobulins. Such VHH molecules may be derived from antibodies produced in Camelidae species, such as camel, llama, dromedary, alpaca, and guanaco. Non-Camelidae species may also produce heavy chain antibodies that are naturally devoid of light chains, and such VHHs are within the scope of the present invention.

[0233] "Native antibodies" are typically heterotetrameric glycoproteins of about 150,000 daltons composed of two identical light (L) chains and two identical heavy (H) chains. The genes encoding antibody heavy and light chains are known, and the constituent segments of each have been well characterized and described (Matsuda, F. et al., 1998, The Journal of Experimental Medicine. 188(11); 2151-62 and Li, A. et al., 2004, Blood. 103(12:4602-9, the contents of each of which are incorporated herein by reference in their entirety). Each light chain is linked to a heavy chain by one covalent disulfide bond, while the number of disulfide linkages varies among the heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide bridges. Each heavy chain contains a variable domain (V) at one end and a variable domain (V) at the other end. H ) followed by several constant domains. Each light chain has a variable domain (V L ) at its other end and a constant domain. The constant domain of the light chain is aligned with the first constant domain of the heavy chain, and the light chain variable domain is aligned with the variable domain of the heavy chain.

[0234] As used herein, the term "variable domain" refers to specific antibody domains found in both the heavy and light chains of antibodies, which vary significantly in sequence among antibodies, and which are used in the binding and specificity of each particular antibody for its particular antigen. In some embodiments, the VH and VL regions of antibodies described herein can be subdivided into regions of hypervariability, called complementarity-determining regions (CDRs), interspersed with highly conserved regions called framework regions (FRs).

[0235] As used herein, the term "hypervariable region" refers to a region within a variable domain that contains amino acid residues involved in antigen binding. The amino acids present in the hypervariable region determine the structure of the complementarity-determining region (CDR), which becomes part of the antigen-binding site of an antibody.

[0236] As used herein, the term "CDR" refers to the region of an antibody that contains the structure complementary to its target antigen or epitope. The CDR region generally confers antigen specificity and binding affinity. The other parts of the variable domain that do not interact with the antigen are each called the "framework region" (FR). The antigen-binding site (also known as the antigen combining site or paratope) contains the amino acid residues necessary for interacting with a specific antigen. The exact residues that make up the antigen-binding site can be determined by CDR analysis.

[0237] As used herein, the term "CDR analysis" refers to any process used to determine which antibody variable domain residues make up the CDRs. The extent of the framework regions and CDRs have been precisely defined by several methods (see Kabat, E. A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, US Department of Health and Human Services, NIH Publication No. 91-3242; Chothia, C. et al. (1987) J. Mol. Biol. 196:901-917; and the AbM definitions used by Oxford Molecular's AbM antibody modeling software. Generally, see, e.g., Protein Sequence and Structure Analysis of Antibody Variable Domains. In: Antibody Engineering Lab Manual (Ed.: Duebel, S. and Kontermann, R., Springer-Verlag, Heidelberg). CDR analysis can be performed by co-crystallography with bound antigen. In some embodiments, CDR analysis can include computational evaluation based on comparison with other antibodies (Strohl, W. R. Therapeutic Antibody Engineering. Woodhead, Publishing, Philadelphia PA. 2012. Ch. 3, pp. 47-54, the contents of which are incorporated herein by reference in their entirety).CDR analysis and / or precise amino acid sequence boundaries may be performed using methods such as those described by Kabat [Wu, TT et al., 1970, JEM, 132(2):211-50 and Johnson, G. et al., 2000, Nucleic Acids Res. 28(1):214-8, the contents of each of which are incorporated herein by reference in their entirety], Chothia [Chothia and Lesk, J. Mol. Biol. 196, 901(1987); Chothia et al., Nature 342, 877(1989); and Al-Lazikani, B. et al., 1997, J. Mol. Biol. 273(4):927-48, the contents of each of which are incorporated herein by reference in their entirety], Lefranc [Lefranc, MP et al., 2005, Immunome Res. 1:3), and Honegger (Honegger, A. and Pluckthun, A. 2001. J. Mol. Biol. 309(3):657-70, the contents of which are incorporated herein by reference in their entirety). In some embodiments, CDRs defined according to the Chothia numbering scheme may also be referred to as hypervariable loops.

[0238] For example, in Kabat, the CDR amino acid residues of the heavy chain variable domain (VH) are numbered 31 to 35 (HCDR1), 50 to 65 (HCDR2), and 95 to 102 (HCDR3), and the CDR amino acid residues of the light chain variable domain (VL) are numbered 24 to 34 (LCDR1), 50 to 56 (LCDR2), and 89 to 97 (LCDR3).

[0239] In Chothia, the CDR amino acids of the VH are numbered 26-32 (HCDR1), 52-56 (HCDR2), and 95-102 (HCDR3), and the amino acid residues of the VL are numbered 26-32 (LCDR1), 50-52 (LCDR2), and 91-96 (LCDR3).

[0240] Combining the CDR definitions of both Kabat and Chothia, the CDRs consist of amino acid residues 26-35 (HCDR1), 50-65 (HCDR2), and 95-102 (HCDR3) in human VH, and amino acid residues 24-34 (LCDR1), 50-56 (LCDR2), and 89-97 (LCDR3) in human VL.

[0241] For a particular antibody of the present invention, the equivalent CDR and framework region sequences based on the Kabat, Chothia, and IMGT numbering systems can be readily obtained based at least on the tables and sequences provided herein, which provide the SEQ ID NOs of the equivalent CDR regions based on the Kabat, Chothia, and IMGT numbering systems, respectively. See also Figures 1A-3B.

[0242] Generally, the VH and VL domains each have three CDRs. The VL CDRs are referred to herein as CDRL1, CDRL2, and CDRL3, in order of their appearance when moving from the N-terminus to the C-terminus along the variable domain polypeptide. The VH CDRs are referred to herein as CDRH1, CDRH2, and CDRH3, in order of their appearance when moving from the N-terminus to the C-terminus along the variable domain polypeptide. Each CDR has a preferred canonical structure, with the exception of CDRH3, which is highly variable in sequence and length between antibodies and contains an amino acid sequence that can result in various three-dimensional structures of the antigen-binding domain (Nikoloudis, D. et al., 2014. Peer J. 2:e456). In some cases, CDRH3 may be analyzed in a panel of related antibodies to assess antibody diversity. Various methods of determining CDR sequences are known in the art and can be applied to known antibody sequences (Strohl, WR Therapeutic Antibody Engineering. Woodhead Publishing, Philadelphia PA. 2012. Ch. 3, p47-54, the contents of which are incorporated herein by reference in their entirety).

[0243] In some embodiments, the VH and VL domains each have four framework regions (FRs) located before, after, and between the CDR regions. The VH framework regions are referred to herein as FRH1, FRH2, FRH3, and FRH4, and the VL framework regions are referred to herein as FRL1, FRL2, FRL3, and FRL4. In some embodiments, in a VH domain, the FRs and CDRs are arranged, from N-terminus to C-terminus, as follows: FRH1-CDRH1-FRH2-CDRH2-FRH3-CDRH3-FRH4. In some embodiments, in a VL domain, the FRs and CDRs are arranged, from N-terminus to C-terminus, as follows: FRL1-CDRL1-FRL2-CDRL2-FRL3-CDRL3-FRL4.

[0244] In some embodiments, the antigen-binding domain of an antibody of the present disclosure is the portion of the antibody that contains determinants that form an interface that binds to a tau polypeptide or its epitope. For proteins (or protein mimetics), the antigen-binding site typically includes one or more loops (consisting of at least four amino acids or amino acid mimetics) that form an interface that binds to the tau polypeptide. Typically, the antigen-binding site of an antibody includes at least one or two CDRs and / or hypervariable loops, and more typically includes at least three, four, five, or six CDRs and / or hypervariable loops.

[0245] In yet other embodiments, the antibody has a heavy chain constant region chosen from, e.g., the heavy chain constant regions of IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE, particularly, the human heavy chain constant regions of, e.g., IgG1, IgG2, IgG3, and IgG4, or the murine heavy chain constant regions of IgG1, IgG2a, IgG2b, IgG2c, and IgG3. In another embodiment, the antibody has a light chain constant region chosen from, e.g., the kappa or lambda (e.g., murine or human) light chain constant regions.

[0246] The constant region can be altered, e.g., mutated, to modify the properties of the antibody (e.g., to increase or decrease one or more of Fc receptor binding, antibody glycosylation, the number of cysteine ​​residues, effector cell function, and / or complement function). In some embodiments, the antibody has effector function and is capable of fixing complement. In other embodiments, the antibody neither recruits effector cells nor fixes complement. In other embodiments, the ability of the antibody to bind to Fc receptors is reduced or absent. For example, the antibody is an isotype or subtype, fragment, or other variant that does not support binding to Fc receptors, e.g., the Fc receptor binding region thereof is mutated or deleted.

[0247] Methods for altering antibody constant regions are known in the art. Antibodies with altered function, e.g., altered affinity for effector ligands such as FcR on cells or the C1 component of complement, can be produced by substituting at least one amino acid residue in the constant portion of the antibody with a different residue (see, e.g., EP 388,151 A1, U.S. Pat. No. 5,624,821, and U.S. Pat. No. 5,648,260, the contents of all of which are incorporated herein by reference). Similar types of alterations may be described that, when applied to immunoglobulins of mice or other species, reduce or eliminate these functions.

[0248] As used herein, the term "Fv" refers to an antibody fragment that contains the minimum fragment of an antibody necessary to form a complete antigen-binding site. This region consists of a dimer of one heavy-chain variable domain and one light-chain variable domain in tight, non-covalent association. Fv fragments can be generated by proteolytic cleavage, but most are unstable. Recombinant methods for generating stable Fv fragments are known in the art, typically by inserting a flexible linker between the light-chain variable domain and the heavy-chain variable domain (thereby forming a single-chain Fv (scFv)) or by introducing a disulfide bridge between the heavy-chain variable domain and the light-chain variable domain (Strohl, WR Therapeutic Antibody Engineering. Woodhead Publishing, Philadelphia PA. 2012. Ch. 3, p. 46-47, the contents of which are incorporated herein by reference in their entirety).

[0249] Antibody "light chains" from any vertebrate species can be assigned to one of two clearly distinct types, called kappa and lambda, based on the amino acid sequence of their constant domain. Antibodies can be assigned to different classes depending on the amino acid sequence of the constant domain of their heavy chain.

[0250] As used herein, the term "single-chain Fv" or "scFv" refers to a fusion protein of a VH antibody domain and a VL antibody domain, linked together by a flexible peptide linker into a single polypeptide chain. In some embodiments, the Fv polypeptide linker allows the scFv to form the desired structure for antigen binding. In some embodiments, scFvs are utilized in conjunction with phage display, yeast display, or other display methods, where the scFvs are expressed in association with a surface member (e.g., a phage coat protein) and can be used to identify high-affinity peptides against a given antigen. In some embodiments, antibodies of the present disclosure are prepared as scFvFc antibodies. The term "scFvFc" refers to an antibody format comprising a fusion of one or more scFvs with an antibody Fc domain.

[0251] The term "chimeric antibody" refers to an antibody having portions derived from more than one source. A chimeric antibody may contain portions derived from different species. For example, a chimeric antibody may contain an antibody having a murine variable domain and a human constant domain. Further examples of chimeric antibodies and methods for producing them include those described in Morrison, SL, Transfectomas provide novel chimeric antibodies. Science. 1985 Sep 20;229(4719):1202-7; Gillies, SD et al., High-level expression of chimeric antibodies using adapted cDNA variable region cassettes. J Immunol Methods. 1989 Dec 20;125(1-2):191-202; and U.S. Patent Nos. 5,807,715, 4,816,567, and 4,816,397, all of which are incorporated herein by reference in their entirety.

[0252] The term "diabody" refers to a small antibody fragment that has two antigen-binding sites, one light-chain variable domain V, in the same polypeptide chain. L heavy chain variable domain V connected to H Diabodies refer to fragments comprising the following: (a) a diabody fragment (or fragments) comprising: (a) a diabody fragment (or fragments) comprising: (a) a diabody fragment (or fragments) comprising: (b ...b) a diabody fragment (or fragments) comprising: (a) a diabody fragment (or fragments) comprising: (b) a diabody fragment (or fragments) comprising: (a) a diabody fragment (or fragments) comprising: (b) a diabody fragment (or fragments) comprising: (b) a diabody fragment (or fragments) comprising: (a) a diabody fragment (or fragments) comprising: (b) a diabody fragment (or fragments) comprising: (b) a diabody fragment (or fragments) comprising: (a) a diabody fragment (or fragments) comprising: (b) a diabody fragment (or fragments) comprising: (b) a diabody fragment (or fragments) comprising: (c) a diabody fragment (or fragments) comprising: (c) a diabody fragment (or fragments) comprising: (a) a diabody fragment (or fragments) comprising: (a) a diabody fragment (or fragments) comprising: (b) a diabody fragment (or fragments) comprising: (c) a

[0253] The term "intrabody" refers to a form of antibody that is not secreted from the cell in which it is produced, but instead targets one or more intracellular protein(s). Intrabodies can be used to affect numerous cellular processes, including, but not limited to, intracellular trafficking, transcription, translation, metabolic processes, proliferative signaling, and cell division. In some embodiments, methods of the invention can involve intrabody-based therapy. In some such embodiments, the variable domain sequences and / or CDR sequences disclosed herein can be incorporated into one or more constructs for intrabody-based therapy. In some cases, intrabodies of the invention can target one or more glycosylated intracellular proteins or modulate the interaction of one or more glycosylated intracellular proteins with alternative proteins.

[0254] As used herein, the term "chimeric antigen receptor" or "CAR" refers to an artificial receptor that is engineered to be expressed on the surface of immune effector cells and to specifically target cells that express an entity that binds to the artificial receptor with high affinity. CARs can be designed to contain one or more segments of an antibody, antibody variable domain, and / or antibody CDR, such that when such a CAR is expressed on an immune effector cell, the immune effector cell binds to and eliminates cells recognized by the antibody portion of the CAR. In some cases, CARs are designed to specifically bind to cancer cells, resulting in their immune-modulatory clearance.

[0255] The antibodies of the present invention may be monoclonal or polyclonal. As used herein, the term "monoclonal antibody" refers to an antibody obtained from a population of substantially homogeneous cells (or clones), i.e., the individual antibodies comprising the population are identical and / or bind to the same epitope, excluding possible variants that may arise during monoclonal antibody production, which are generally present in minor amounts. Unlike polyclonal antibody preparations, which typically contain different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen.

[0256] The modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method.

[0257] In some embodiments, the antibody comprises a variable region or portion thereof, e.g., a CDR, comprising the amino acid sequence of an antibody generated in a non-human organism, e.g., a rat or a mouse. Antibodies, including chimeric antibodies, CDR-grafted antibodies, and humanized antibodies, are within the scope of the present invention. Antibodies comprising the sequence of an antibody generated in a non-human organism, e.g., a rat or a mouse, and then modified, e.g., in the variable framework or constant region, to reduce antigenicity in humans are within the scope of the present invention.

[0258] As used herein, monoclonal antibodies include "chimeric" antibodies (immunoglobulins) in which a portion of the heavy and / or light chain is identical or homologous to corresponding sequences in antibodies from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical or homologous to corresponding sequences in antibodies from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies.

[0259] Antibodies of the present disclosure may be from any animal origin, including mammals, birds, reptiles, and insects. Mammalian antibodies may be, for example, of human, murine (e.g., mouse or rat), donkey, sheep, rabbit, goat, guinea pig, camel, bovine, or equine origin.

[0260] In some embodiments, the antibody of the present disclosure may be an antibody mimetic. The term "antibody mimetic" refers to any molecule that mimics the function or effect of an antibody and binds specifically and with high affinity to its molecular target. In some embodiments, the antibody mimetic may be a monobody designed to incorporate a fibronectin type III domain (Fn3) as a protein scaffold (US Pat. No. 6,673,901, US Pat. No. 6,348,584). In some embodiments, the antibody mimetic may be any known in the art, including, but not limited to, affibody molecules, affilins, affitins, anticalins, avimers, DARPins, Fynomers, and Kunitz, as well as domain peptides. In other embodiments, the antibody mimetic may include one or more non-peptide regions.

[0261] As used herein, the term "antibody variant" refers to a biomolecule that is similar in structure, sequence and / or function to an antibody, but contains some differences in its amino acid sequence, composition or structure compared to another antibody or a naturally occurring antibody.

[0262] multispecific antibody In some embodiments, the antibody is a multispecific antibody, e.g., comprises a plurality of immunoglobulin variable domain sequences, wherein a first immunoglobulin variable domain sequence of the plurality has binding specificity for a first epitope and a second immunoglobulin variable domain sequence of the plurality has binding specificity for a second epitope. In some embodiments, the first and second epitopes are on the same antigen, e.g., the same protein (or subunit of a multimeric protein). In some embodiments, the first and second epitopes overlap. In some embodiments, the first and second epitopes do not overlap. In some embodiments, the first and second epitopes are on different antigens, e.g., different proteins (or different subunits of a multimeric protein). In some embodiments, the multispecific antibody comprises a third, fourth, or fifth immunoglobulin variable domain. In some embodiments, the multispecific antibody is a bispecific antibody, a trispecific antibody, or a tetraspecific antibody. In some embodiments, the anti-tau antibody is a multispecific antibody.

[0263] In some embodiments, a multispecific antibody is a bispecific antibody. A bispecific antibody does not have specificity for more than two antigens. A bispecific antibody is characterized by a first immunoglobulin variable domain sequence that has binding specificity for a first epitope and a second immunoglobulin variable domain sequence that has binding specificity for a second epitope. In some embodiments, the first and second epitopes are on the same antigen, e.g., the same protein (or subunit of a multimeric protein). In some embodiments, the first and second epitopes overlap. In some embodiments, the first and second epitopes do not overlap. In some embodiments, the first and second epitopes are on different antigens, e.g., different proteins (or different subunits of a multimeric protein). In some embodiments, a bispecific antibody comprises heavy and light chain variable domain sequences that have binding specificity for a first epitope and heavy and light chain variable domain sequences that have binding specificity for a second epitope. In some embodiments, the bispecific antibody comprises a half antibody having binding specificity for a first epitope and a half antibody having binding specificity for a second epitope. In some embodiments, the bispecific antibody comprises a half antibody, or fragment thereof, having binding specificity for a first epitope and a half antibody, or fragment thereof, having binding specificity for a second epitope. In some embodiments, the bispecific antibody comprises an scFv, or fragment thereof, having binding specificity for a first epitope and an scFv, or fragment thereof, having binding specificity for a second epitope. In certain embodiments, the anti-tau antibody is a bispecific antibody.

[0264] In some embodiments, antibody sequences of the present disclosure can be generated from bispecific or heterodimeric antibodies produced using protocols known in the art, such as the "knobs-in-holes" approach described, for example, in U.S. Pat. No. 5,731,168; electrostatic steering Fc pairing described, for example, in WO 09 / 089004, WO 06 / 106905, and WO 2010 / 129304; or Strand Exchange Engineered (SEED) technology described, for example, in WO 07 / 110205. Fab arm exchange, as described, for example, in WO 08 / 119353, WO 2011 / 131746, and WO 2013 / 060867; biantibody conjugates, for example, by crosslinking antibodies using heterobifunctional reagents with amine-reactive groups and sulfhydryl-reactive groups to generate bispecific structures, as described, for example, in US 4,433,059; bispecific antibody determinants generated by recombining half antibodies (heavy chain-light chain pairs or Fab) from different antibodies through cycles of reduction and oxidation of the disulfide bond between the two heavy chains, as described, for example, in US 4,444,878; trifunctional antibodies, for example, three Fab' fragments crosslinked via sulfhydryl-reactive groups, as described, for example, in US 5,273,743; biosynthetic binding proteins, for example, as described, for example, in US 5,534,254 for example, pairs of scFvs cross-linked through their C-terminal tails, preferably via disulfide or amine-reactive chemical cross-linking; bifunctional antibodies, e.g., Fab fragments with different binding specificities dimerized via leucine zippers (e.g., c-fos and c-jun) replacing the constant domains, as described, for example, in US Pat. No. 5,582,996; bispecific and oligospecific monovalent and oligovalent receptors, e.g., the VH-CH1 regions of two antibodies (two Fab fragments) linked via a polypeptide spacer between the CH1 region of one antibody and the VH region of the other antibody, typically with an associated light chain, as described, for example, in US Pat. No. 5,591,828; bispecific DNA-antibody conjugates, e.g., cross-linking of antibodies or Fab fragments via a double-stranded portion of DNA, as described, for example, in US Pat. No. 5,635,602;Bispecific fusion proteins, such as those described in US Pat. No. 5,637,481, include expression constructs comprising two scFvs and a complete constant region with a hydrophilic helical peptide linker between them; multivalent and multispecific binding proteins, such as those described in US Pat. No. 5,837,242, include polypeptide dimers, commonly referred to as diabodies, having a first domain with an Ig heavy chain variable region binding region and a second domain with an Ig light chain variable region binding region (higher order structures creating bispecific, trispecific, or tetraspecific molecules are also disclosed); minibody constructs, such as those described in US Pat. No. 5,837,821, including those having linked VL and VH chains further connected by a peptide spacer to antibody hinge and CH3 regions, which can be dimerized to form bispecific / multivalent molecules; and short peptide linkers (e.g., 5 or 10 amino acids). These include, but are not limited to, VH and VL domains linked via a peptide bond, or with no linker at all in either orientation, which can dimerize to form bispecific diabodies; trimers and tetramers, as described, for example, in US 5,844,094; consecutive VH domains (or VL domains of family members) connected at their C-termini by a peptide bond to a crosslinking group and further associated with a VL domain to form a series of FVs (or scFvs), as described, for example, in US 5,864,019; and single-chain binding polypeptides, as described, for example, in US 5,869,620, in which both VH and VL domains linked via peptide linkers are joined into multivalent structures via non-covalent or chemical crosslinking to form, for example, homobivalent, heterobivalent, trivalent, and tetravalent structures using both scFV or diabody-type formats.

[0265] Antibody development Antibodies according to the present disclosure can be developed using standard methods in the art. Two primary antibody preparation techniques are immunization and antibody display. In both cases, the desired antibody is identified from a larger pool of candidates based on its affinity for a particular target or epitope. An immune response is characterized by the reaction of an organism's cells, tissues, and / or organs to the presence of a foreign substance. Such an immune response typically leads to the organism producing one or more antibodies against the foreign substance, such as an antigen or a portion of an antigen.

[0266] antigen Antibodies can be developed (e.g., via immunization) or selected (e.g., from a pool of candidates) using, for example, any naturally occurring or synthetic antigen. As used herein, an "antigen" is an entity that induces or elicits an immune response in an organism and may also refer to an antibody binding partner. An immune response is characterized by the reaction of an organism's cells, tissues, and / or organs to the presence of a foreign substance. Such an immune response typically leads to the organism producing one or more antibodies against the foreign substance. In some embodiments, the antigen comprises tau protein.

[0267] As used herein, the term "tau protein" refers to a protein or protein complex containing the microtubule-associated protein tau or a peptide fragment thereof. Tau proteins may include condensed paired helical fibrillar tau protein (ePHF), also known as "sarkosyl-insoluble tau," or fragments thereof. Tau proteins may contain one or more phosphorylated residues. Such phosphorylated residues may correspond to disease-associated tau proteins (also referred to herein as "pathological tau").

[0268] immunization In some embodiments, antibodies can be prepared by immunizing a host with an antigen of interest. Immunizing a host animal (e.g., a mouse, rabbit, goat, or llama) with an antigenic protein can induce lymphocytes that specifically bind to the antigen. The lymphocytes can be collected and fused with an immortalized cell line to generate hybridomas, which can be cultured in a suitable culture medium to promote growth (see, e.g., Kohler, G. et al., Continuous cultures of fused cells secreting antibody of predefined specificity. Nature. 1975 Aug 7;256(5517):495-7, the contents of which are incorporated herein by reference in their entirety). Alternatively, lymphocytes can be immunized in vitro.

[0269] Lymphocytes may be fused with an immortalized cell line using a suitable fusing agent (e.g., polyethylene glycol) to form hybridoma cells (see, e.g., Goding, JW, Monoclonal Antibodies: Principles and Practice. Academic Press. 1986; 59-1031, the contents of which are incorporated herein by reference in their entirety). The immortalized cell line may be transformed mammalian cells, particularly myeloma cells of rodent, rabbit, bovine, or human origin. In some embodiments, rat or mouse myeloma cell lines are used. The hybridoma cells may be cultured in a suitable culture medium that typically contains one or more substances that inhibit the growth or survival of unfused cells. For example, parental cells lacking the enzyme hypoxanthine guanine phosphoribosyltransferase (HGPRT or HPRT) may be used, and the culture medium for the resulting hybridoma cells may be supplemented with hypoxanthine, aminopterin, and thymidine ("HAT medium") to prevent growth of HGPRT-deficient (unfused) cells.

[0270] Desirable properties of immortalized cell lines include, but are not limited to, efficient fusion, support of high levels of antibody expression by the selected antibody-producing cells, and sensitivity to a medium that inhibits unfused cells (e.g., HAT medium). In some embodiments, the immortalized cell line is a mouse myeloma line. Such cell lines can be obtained, for example, from the Salk Institute Cell Distribution Center (San Diego, CA) or the American Type Culture Collection (Manassas, VA). Human myeloma and mouse-human heteromyeloma cell lines can also be used to produce human monoclonal antibodies (see, e.g., Kozbor, D. et al., A human hybrid myeloma for production of human monoclonal antibodies. J Immunol. 1984 December;133(6):3001-5 and Brodeur, B. et al., Monoclonal Antibody Production Techniques and Applications. Marcel Dekker, Inc., New York. 1987;33:51-63, the contents of each of which are incorporated herein by reference in their entirety).

[0271] Hybridoma cell culture medium can be assayed for the presence of monoclonal antibodies with the desired binding specificity. Assays can include, but are not limited to, immunoprecipitation assays, in vitro binding assays, radioimmunoassays (RIA), surface plasmon resonance (SPR) assays, and / or enzyme-linked immunosorbent assays (ELISA). In some embodiments, the binding specificity of a monoclonal antibody can be determined by Scatchard analysis (Munson, PJ et al., Ligand: a versatile computerized approach for characterization of ligand-binding systems. Anal Biochem. 1980 Sep 1;107(1):220-39, the contents of which are incorporated herein by reference in their entirety).

[0272] Antibodies produced by cultured hybridomas may be analyzed to determine their binding specificity for the target antigen. Once antibodies with desirable characteristics are identified, the corresponding hybridomas may be subcloned by limiting dilution procedures and grown by standard methods. Antibodies produced by hybridomas may be isolated and purified using standard immunoglobulin purification procedures, such as, for example, protein A-Sepharose, hydroxyapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography. Alternatively, hybridoma cells may be grown in vivo as ascites in a mammal. In some embodiments, antibodies may be isolated directly from the serum of an immunized host.

[0273] In some embodiments, recombinant versions of antibodies generated by immunization may be prepared. Such antibodies may be prepared using genomic antibody sequences from selected hybridomas. The genomic antibody sequence of a hybridoma may be obtained by extracting RNA molecules from antibody-producing hybridoma cells and producing cDNA by reverse transcriptase polymerase chain reaction (PCR). PCR may be used to amplify the cDNA using primers specific for the antibody heavy and light chains. The PCR product may then be subcloned into a plasmid for sequence analysis. Antibodies may be produced by inserting the resulting antibody sequence into an expression vector. Some recombinant antibodies may be prepared using synthetic nucleic acid constructs encoding amino acid sequences corresponding to those obtained from isolated hybridoma antibodies.

[0274] antibody display In some embodiments, antibodies can be developed using antibody display technology. "Display technology" refers to systems and methods for expressing amino acid-based candidate compounds in a format accessible to a target or ligand, where the compounds are linked to a nucleic acid encoding the compound. In most systems, candidate compounds are expressed on the surface of a host capsid or cell, although some host-free systems exist (e.g., ribosome display). Display technology can be used to generate a display "library" containing a set of candidate compound library members. A display library that includes antibodies (or variants or fragments thereof) as library members is referred to herein as an "antibody display library." Antibodies can be designed, selected, or optimized by screening target antigens using an antibody display library. An antibody display library can contain millions to billions of members, each expressing a unique antibody domain. The displayed antibody fragments can be expressed as V H and V L The antibody variable domains or CDRs obtained from display library selection may be directly incorporated into antibody sequences for recombinant antibody production or may be mutated and utilized for further optimization via in vitro affinity maturation.

[0275] Antibody display libraries can include antibody phage display libraries. Antibody phage display libraries utilize phage virus particles as hosts, with millions to billions of members, each expressing a unique antibody domain. Such libraries can provide a diverse source that can be used to select potentially hundreds of antibody fragments with varying levels of affinity for one or more antigens of interest (McCafferty, et al., 1990. Nature. 348:552-4; Edwards, BM et al., 2003. JMB. 334:103-18; Schofield, D. et al., 2007. Genome Biol. 8, R254; and Pershad, K. et al., 2010. Protein Engineering Design and Selection. 23:279-88; the contents of each are incorporated herein by reference in their entirety). The displayed antibody fragments can be scFv antibody fragments. Phage display library members can be expressed as fusion proteins linked to a viral coat protein (e.g., the N-terminus of the viral pIII coat protein). L The V chains are expressed separately and expressed in the periplasm. H After assembly with the chain, the complex may be incorporated into a viral coat. The precipitated library members may be sequenced from the bound phage to obtain cDNAs encoding the desired antibody domains.

[0276] In some embodiments, antibody display libraries can be generated using yeast surface display technology. Antibody yeast display libraries are composed of yeast cells with surface-displayed antibodies or antibody fragments. Antibody yeast display libraries can contain antibody variable domains expressed on the surface of Saccharomyces cerevisiae cells. Yeast display libraries can be expanded by displaying antibody fragments of interest as fusion proteins with yeast surface proteins (e.g., Aga2p protein). Yeast cells displaying antibodies or antibody fragments with affinity for a particular target can be isolated according to standard methods. Such methods can include, but are not limited to, magnetic separation and flow cytometry.

[0277] Recombinant synthesis Antibodies of the present disclosure can be prepared using recombinant DNA technology and related processes. Constructs (e.g., DNA expression plasmids) encoding antibodies can be prepared and used to synthesize complete antibodies or portions thereof. In some embodiments, DNA sequences encoding antibody variable domains of the present disclosure can be inserted into expression vectors (e.g., mammalian expression vectors) encoding other antibody domains and used to prepare antibodies with the inserted variable domains. DNA sequences encoding antibody variable domains can be inserted downstream of an upstream expression vector region having a promoter / enhancer element and / or encoding an immunoglobulin signal sequence. DNA sequences encoding antibody variable domains can be inserted upstream of a downstream expression vector region encoding an immunoglobulin constant domain. The encoded constant domain can be derived from any class (e.g., IgG, IgA, IgD, IgE, and IgM) or species (e.g., human, mouse, rabbit, rat, and non-human primate). In some embodiments, the encoded constant domain encodes the constant domain of human IgG (e.g., IgG1, IgG2, IgG3, or IgG4). In some embodiments, the encoded constant domain encodes the constant domain of a mouse IgG (eg, IgG1, IgG2a, IgG2b, IgG2c, or IgG3).

[0278] An expression vector encoding an antibody of the present disclosure can be used to transfect cells for antibody production. Such cells can be mammalian cells. Cell lines stably transfected with the antibody expression vector can be prepared and used to establish stable cell lines. The antibody-producing cell line can be expanded to express the antibody, which can be isolated or purified from the cell culture medium.

[0279] Antibody characterization In some embodiments, antibodies of the present disclosure can be identified, selected, or excluded based on different characteristics. Such characteristics can include, but are not limited to, physical and functional characteristics. Physical characteristics can include antibody structural properties (e.g., amino acid sequence or residues; secondary, tertiary, or quaternary protein structure; post-translational modifications (e.g., glycosylation); chemical bonds, and stability). Functional characteristics can include, but are not limited to, antibody affinity (i.e., for a particular epitope and / or antigen) and antibody activity (e.g., the ability of an antibody to activate or inhibit a target, process, or pathway).

[0280] Antibody Binding and Affinity In some embodiments, antibodies of the present disclosure can be identified, selected, or excluded based on the level of binding and / or affinity for a particular epitope and / or antigen. The level of antibody binding and / or affinity can be assessed using different antigen formats. In some embodiments, antibody affinity for different antigen formats can be tested in vitro (e.g., by ELISA). In vitro testing of anti-tau antibodies can be performed using brain samples or fragments. Such samples or fragments can be obtained from subjects with AD (e.g., human AD patients). In some embodiments, brain samples or fragments can be obtained from non-human subjects. Such non-human subjects can include non-human animals (e.g., mice, rats, and primates) used in AD disease model studies. In some embodiments, brain samples or fragments used in antibody affinity testing can be derived from the TG4510 / P301S mouse strain. Antibody affinity can be compared to a control sample lacking the particular antigen for which affinity is being analyzed. In some embodiments, the control sample used in anti-tau antibody testing can include a brain sample or fragment from a non-diseased human subject. In some embodiments, brain samples or sections from wild-type and / or tau knockout mouse strains may be used as control samples.

[0281] In vitro affinity testing may be performed using recombinant or isolated protein antigens (e.g., by ELISA). For example, recombinant or isolated ePHF may be used for anti-tau antibody affinity testing. In some embodiments, an anti-tau antibody of the present disclosure may exhibit a half-maximal effective concentration (EC50) of about 0.01 nM to about 100 nM for binding to ePHF as assessed by ELISA. In some embodiments, the exhibited EC50 may be less than about 50 nM, less than about 20 nM, less than about 10 nM, or less than about 1 nM. In some embodiments, an anti-tau antibody of the present disclosure may exhibit an EC50 of about 0.01 nM to about 100 nM for binding to any of the antigens listed in Table 8, or an epitope (including, but not limited to, a conformational epitope) comprising or contained in any of the antigens, as assessed by ELISA. In some embodiments, the exhibited EC50 may be less than about 50 nM, less than about 20 nM, less than about 10 nM, or less than about 1 nM.

[0282] In some embodiments, the anti-tau antibodies of the present disclosure bind to pathological tau but not to non-pathological tau. Such antibodies are sometimes referred to herein as being "selective" for pathological forms of tau. In some embodiments, the anti-tau antibodies of the present disclosure bind to tau tangles.

[0283] In some embodiments, antibody affinity analysis can be used to identify, select, or exclude multispecific antibodies. As used herein, the term "multispecific antibody" refers to an antibody that has affinity for multiple epitopes or antigens. In some embodiments, multispecific antibodies can be identified, selected, or excluded based on the relative affinity for each recognized epitope or antigen. For example, a multispecific antibody can be selected for use or further development based on its higher affinity for one epitope or antigen to which it exhibits affinity compared to a second epitope or antigen.

[0284] In some embodiments, anti-tau antibodies may be tested for competition with other anti-tau antibodies. Such testing can be performed to provide information about the specific epitope recognized by the antibody and can yield information related to the level of epitope affinity compared to competing antibodies. In some embodiments, the anti-tau antibody used in antibody binding and / or affinity analyses may include the anti-tau antibody PT3 described in U.S. Pat. No. 9,371,376, the anti-tau antibody C10.2 described in U.S. Pat. No. 10,196,439 (referred to therein as antibody "C10-2"), the anti-tau antibody IPN002 described in U.S. Pat. No. 10,040,847, the anti-tau antibody AT8 (ThermoFisher, Waltham, MA), the anti-tau antibody AT100 (ThermoFisher, Waltham, MA), the anti-tau antibody AT120 described in U.S. Pat. No. 5,843,779, or the anti-tau antibody PT76 described in Vandermeeren, M. et al., J Alzheimers Dis. 2018;65(1):265-281.

[0285] antibody activity In some embodiments, antibodies of the present disclosure can be identified, selected, or excluded based on their ability to promote or reduce a particular activity. Antibody activity can be assessed using analytical assays. Such assays can be selected or designed to detect, screen, measure, and / or rank antibodies based on such antibody activity.

[0286] Anti-tau antibodies can be characterized by their ability to inhibit tau aggregation. Inhibition can be based on physical disruption of tau aggregates or on anti-tau antibody-dependent depletion (immunodepletion) of tau protein. Characterization based on tau aggregation inhibition can be evaluated using one or more assays of tau aggregation. In some embodiments, anti-tau antibodies can be characterized by a tau seeding assay. A tau seeding assay typically involves initiating tau aggregation in vitro and evaluating aggregation inhibition by a candidate compound being tested. The tau seeding assay can be performed using tau aggregation biosensor cells. The tau aggregation biosensor cells generate a detectable signal (e.g., a fluorescent signal) in response to tau aggregation. The tau aggregation biosensor cells can be cultured with recombinant or isolated tau, or with a sample from tau-rich brain tissue or fluid (to promote tau aggregation), and treated with or without a candidate compound to evaluate tau aggregation inhibition. In some embodiments, anti-tau antibodies can be used to deplete tau from the culture medium prior to incubation with biosensor cells. The level of aggregation in the depleted medium can be compared to the level of aggregation in the non-depleted medium to assess the inhibitory function of the anti-tau antibody. Tau aggregation biosensor cells can include, but are not limited to, tau RD biosensor cells. In some embodiments, neurons expressing human tau can be used.

[0287] In some embodiments, anti-tau antibodies of the present disclosure may inhibit tau aggregation with a half-maximal inhibitory concentration (IC50) of about 1 nM to about 30 nM, as determined by immunodepletion assays (e.g., using TauRD biosensor cells).

[0288] Antibody Structure and Variation Antibodies of the present disclosure may exist as whole polypeptides, multiple polypeptides, or fragments of polypeptides, which may be independently encoded by one or more nucleic acids, multiple nucleic acids, fragments of nucleic acids, or variants of any of the foregoing.

[0289] As used herein, "polypeptide" refers to a polymer of amino acid residues (natural or unnatural) linked together, most often by peptide bonds. The term, as used herein, refers to proteins, polypeptides, and peptides of any size, structure, or function. Polypeptides smaller than about 50 amino acids may be referred to using the term "peptide." Peptides can be at least about 2, 3, 4, or at least 5 amino acid residues in length. Polypeptides of the present disclosure can include gene products, naturally occurring polypeptides, synthetic polypeptides, homologs, orthologs, paralogs, fragments, or other equivalents, variants, and analogs of the foregoing. Polypeptides can be single molecules or multimolecular complexes, such as dimers, trimers, or tetramers. Polypeptides can include single-chain or multi-chain polypeptides, which can be associated or linked. Polypeptides can also include amino acid polymers in which one or more amino acid residues are artificial chemical analogs of the corresponding naturally occurring amino acids.

[0290] The term "polypeptide variant" refers to a molecule whose amino acid sequence differs from a native or reference sequence. Amino acid sequence variants may have substitutions, deletions, and / or insertions at certain positions within the amino acid sequence when compared to the native or reference sequence. Typically, variants will have at least about 50% identity (homology) to the native or reference sequence, and preferably will be at least about 80%, and more preferably at least about 90% identical (homological) to the native or reference sequence.

[0291] In some embodiments, "variant mimetics" are provided. As used herein, the term "variant mimetics" includes one or more amino acids that mimic an activated sequence. For example, glutamate can function as a mimic of phosphorylated threonine and / or phosphorylated serine. Alternatively, variant mimetics can result in inactivated or inactivated products containing the mimic; for example, phenylalanine can act as an inactivating substitute for tyrosine, or alanine can act as an inactivating substitute for serine.

[0292] The term "amino acid sequence variant" refers to a molecule that has some differences in the amino acid sequence compared to a native or starting sequence. An amino acid sequence variant may have substitutions, deletions, and / or insertions at certain positions within the amino acid sequence. A "native" or "starting" sequence should not be confused with a wild-type sequence. As used herein, a native or starting sequence is a relative term that refers to the original molecule to which a comparison can be made. A "native" or "starting" sequence or molecule can represent a wild-type (a sequence found in nature), but need not be a wild-type sequence.

[0293] Typically, variants have at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, at least 99.5%, at least 99.8%, or at least 99.9% sequence identity compared to the native sequence.

[0294] "Homolog" as applied to an amino acid sequence means a corresponding sequence in another species that has substantial identity to a second sequence in the second species. "Analog" is intended to include polypeptide variants that differ by one or more amino acid changes, eg, substitution, addition, or deletion of amino acid residues, but still retain the properties of the parent polypeptide.

[0295] The present disclosure contemplates variants and derivatives of the antibodies presented herein. These include substitution, insertion, deletion, and covalent variants and derivatives. For example, a sequence tag or one or more amino acids, such as lysines, can be added to the antibody peptide sequence (e.g., at the N- or C-terminus). The sequence tag can be used for peptide purification or localization. Lysines can be used to increase the solubility of the peptide or to enable biotinylation. Alternatively, amino acid residues located in the carboxy- and amino-terminal regions of the amino acid sequence of a peptide or polypeptide can be optionally deleted to produce a truncated sequence. Alternatively, certain amino acids (e.g., C- or N-terminal residues) can be deleted depending on the use of the sequence, for example, as part of a larger soluble sequence or for expression of the sequence linked to a solid support.

[0296] "Substitutional variants," when referring to polypeptides, are those in which at least one amino acid residue in a native or starting sequence has been removed and a different amino acid inserted in its place at the same position. The substitutions may be single, where only one amino acid in the molecule has been substituted, or multiple, where two or more amino acids have been substituted in the same molecule.

[0297] As used herein, the term "conservative amino acid substitution" refers to the substitution of an amino acid normally present in a sequence with a different amino acid of similar size, charge, or polarity. Examples of conservative substitutions include the substitution of a nonpolar (hydrophobic) residue, such as isoleucine, valine, and leucine, for another nonpolar residue. Similarly, examples of conservative substitutions include the substitution of one polar (hydrophilic) residue for another, such as arginine for lysine, glutamine for asparagine, and glycine for serine. Furthermore, the substitution of a basic residue, such as lysine, arginine, or histidine, for another, or the substitution of one acidic residue, such as aspartic acid or glutamic acid, for another, are further examples of conservative substitutions. Examples of non-conservative substitutions include the substitution of a nonpolar (hydrophobic) amino acid residue, such as isoleucine, valine, leucine, alanine, or methionine, for a polar (hydrophilic) residue, such as cysteine, glutamine, glutamic acid, or lysine, and / or the substitution of a polar residue for a nonpolar residue.

[0298] "Insertional variants," when referring to polypeptides, are those that have one or more amino acids inserted immediately adjacent to an amino acid at a particular position in the native or starting sequence. "Immediately adjacent" to an amino acid means connected to either the alpha-carboxy or alpha-amino functional group of the amino acid.

[0299] "Deletion variants," when referring to polypeptides, are those in which one or more amino acids in the native or starting amino acid sequence have been removed. Typically, deletion variants have one or more amino acids deleted within a particular region of the molecule.

[0300] As used herein, the term "derivative" is used interchangeably with the term "variant" and refers to a molecule that is modified or altered in some way relative to a reference or starting molecule. In some embodiments, derivatives include native or starting polypeptides that have been modified with proteinaceous or non-proteinaceous organic derivatizing agents and post-translational modifications. Covalent modifications are traditionally introduced by reacting targeted amino acid residues in a polypeptide with organic derivatizing agents capable of reacting with selected side chains or terminal residues, or by exploiting post-translational modification mechanisms operative in selected recombinant host cells. The resulting covalent derivatives are useful in programs aimed at identifying residues important for biological activity, immunoassays, or the preparation of antibodies for immunoaffinity purification.

[0301] Certain post-translational modifications are the result of the action of recombinant host cells on expressed polypeptides. Glutaminyl and asparaginyl residues are frequently post-translationally deamidated to the corresponding glutamyl and aspartyl residues. Alternatively, these residues are deamidated under mildly acidic conditions. Either form of these residues may be present in polypeptides used in accordance with the present disclosure.

[0302] Other post-translational modifications include hydroxylation of proline and lysine, phosphorylation of the hydroxyl groups of seryl or threonyl residues, and methylation of the alpha-amino groups of lysine, arginine, and histidine side chains (TECreighton, Proteins: Structure and Molecular Properties, W.H. Freeman & Co., San Francisco, pp. 79-86 (1983)).

[0303] Covalent derivatives specifically include fusion molecules in which a polypeptide is covalently linked to a nonproteinaceous polymer. The nonproteinaceous polymer may include hydrophilic synthetic polymers, i.e., polymers not otherwise found in nature. However, naturally occurring polymers produced by recombinant or in vitro methods are useful, as are polymers isolated from nature. Hydrophilic polyvinyl polymers may include polyvinyl alcohol and / or polyvinylpyrrolidone. Particularly useful are polyvinyl alkylene ethers such as polyethylene glycol and polypropylene glycol. Polypeptides may be linked to various nonproteinaceous polymers, such as polyethylene glycol, polypropylene glycol, or polyoxyalkylenes, in the manner described in U.S. Pat. Nos. 4,640,835, 4,496,689, 4,301,144, 4,670,417, 4,791,192, or 4,179,337, the contents of each of which are incorporated herein by reference in their entirety.

[0304] As used herein in reference to a polypeptide, the term "loop" refers to a structural feature of a peptide or polypeptide that reverses the direction of the peptide or polypeptide backbone and contains four or more amino acid residues. Oliva et al. (J. Mol Biol 266(4):814-830; 1997, the contents of which are incorporated herein by reference in their entirety) have identified at least five classes of polypeptide loops.

[0305] As used herein in reference to polypeptides, the term "half-loop" refers to a portion of an identified loop that has at least half of the amino acid residues present in the original loop. It is understood that a loop does not necessarily contain an even number of amino acid residues. Thus, if a loop contains or is identified as containing an odd number of amino acids, a half-loop of an odd-numbered loop will contain an integer or next integer portion of the loop (number of amino acids in the loop / 2±0.5 amino acids). For example, a loop identified as a 7-amino acid loop can generate a half-loop of 3 or 4 amino acids (7 / 2=3.5±0.5 is 3 or 4).

[0306] The term "domain," as used herein in reference to a polypeptide, refers to a motif in a polypeptide that has one or more identifiable structural and / or functional characteristics or properties (e.g., binding ability), e.g., serves as a site of protein-protein interaction.

[0307] As used herein in reference to a polypeptide, the term "site" is synonymous with "amino acid residue" and "amino acid side chain." A site represents a location on a polypeptide that can be modified, manipulated, altered, derivatized, or changed within the polypeptide.

[0308] As used herein, the term "terminus" refers to the end of a peptide or polypeptide when referring to a polypeptide. Such termini are not limited to the first or last position of a peptide or polypeptide, but may include additional amino acids within the terminal region. Polypeptide-based molecules of the present disclosure may be characterized as having both an N-terminus (terminating in an amino acid with a free amino group) and a C-terminus (terminating in an amino acid with a free carboxyl group). Proteins of the present disclosure are optionally composed of multiple polypeptide chains held together by disulfide bonds or non-covalent forces (multimers, oligomers). These types of proteins have multiple N- and C-termini. Alternatively, the termini of a polypeptide may optionally be modified to begin or end with a non-polypeptide-based moiety, such as an organic conjugate.

[0309] Antibody Modification Antibodies can be modified to produce variants with one or more altered properties. Such properties may include or relate to the antibody's structure, function, affinity, specificity, protein folding, stability, production, expression, and / or immunogenicity (i.e., immune response in a subject treated with such an antibody). In some embodiments, antibody fragments or variants may be used to modify another antibody or incorporated into a synthetic antibody.

[0310] Antibody modifications may include amino acid sequence modifications. Such modifications may include, but are not limited to, amino acid deletions, additions, and / or substitutions. Modification information may be obtained by amino acid sequence analysis. Such analysis may include alignment of amino acid sequences between different antibodies or antibody variants. Two or more antibodies may be compared to identify residues or regions suitable for modification. The antibodies compared may include those that bind to the same epitope. The antibodies compared may also bind to different (distinct or overlapping) epitopes of the same protein or target (e.g., to identify residues or regions that confer specificity for a particular epitope). Comparison may include analysis of light and / or heavy chain sequence variation, analysis of CDR sequence variation, analysis of germline sequences, and / or analysis of framework sequences. Information obtained from such analysis can be used to identify amino acid residues, amino acid segments, amino acid side chains, CDR lengths, and / or other properties or characteristics that are conserved or variable between antibodies that bind the same or different epitopes.

[0311] In some embodiments, modified versions of the above-described anti-tau antibodies may be prepared by adding, deleting, or substituting one or more CDR amino acid residues. In some embodiments, anti-tau antibodies may be modified by aligning the amino acid sequences of antibodies that bind to similar targets and preparing modified antibodies with one or more amino acid deletions, substitutions, or insertions based on analysis of the aligned sequences.

[0312] The present disclosure includes amino acid consensus sequences for CDR region sequences and indicates specific amino acids that may be modified (indicated in square brackets), or more commonly, amino acid residue positions that may be deleted or substituted (indicated using the variable "X") in antibody amino acid sequences, e.g., as set forth in Table 1A or Z.

[0313] Related CDR sequences that may appear in the same VH and / or VL sequence of an antibody are grouped in the same row. For example, an antibody of the invention may comprise one each of CDRH1-CDRH3 and CDRL1-CDRL3, where said CDRH1-CDRH3 and CDRL1-CDRL3 are represented by SEQ ID NOs: 928, 930, 409, 472, 525, and 570, respectively.

[0314] Further, in Table 5, for example, each odd-numbered row under a table heading and the even-numbered row immediately below it are related (if not identical) consensus sequences (e.g., SEQ ID NOs: 927 and 928 are related, and SEQ ID NOs: 933 and 934 are related). It is contemplated that an antibody of the invention may comprise one each of CDRH1-CDRH3 and CDRL1-CDRL3, where each of said CDRH1-CDRH3 and CDRL1-CDRL3 may independently be represented by one of two related consensus sequences. For example, an antibody of the invention may comprise one each of CDRH1-CDRH3 and CDRL1-CDRL3, where said CDRH1-CDRH3 and CDRL1-CDRL3 are represented by SEQ ID NOs: 931, 341, 410, 934, 935, and 571, respectively.

[0315] Furthermore, the amino acid at each X or Xi position (where i is 1, 2, 3, ...) can be any naturally occurring amino acid or a selected subset of the amino acids specified in each consensus sequence X / Xi position. It is contemplated that any one or more of the specific amino acids listed at each X or Xi position can be excluded as a permissible value for the X or Xi position. For example, in SEQ ID NO: 947, X4 can be any residue such as T, S, A, V, I, or L. In some embodiments, X4 is T, L, or V, or S, A, or V, etc.

[0316] [Table 1-1]

[0317]

Table 1-2

[0318]

Table 1-3

[0319]

Table 1-4

[0320]

Table 1-5

[0321]

Table 1-6

[0322]

Table 1-7

[0323]

Table 1-8

[0324]

Table 2-1

[0325]

Table 2-2

[0326] In some embodiments, an anti-tau antibody of the disclosure may comprise a CDRH1 comprising the amino acid sequence GYTFTS[Y / N] (SEQ ID NO: 927), or a CDRH1 comprising the amino acid sequence GYTFTSX (SEQ ID NO: 928), where X can be any amino acid, e.g., X is Y / F / N / Q; a CDRH2 comprising the amino acid sequence NPNNS[D / E] (SEQ ID NO: 929), or a CDRH2 comprising the amino acid sequence NPNNSX (SEQ ID NO: 930), where X can be any amino acid, e.g., an amino acid with a negatively charged side chain; and a CDRH3 comprising the amino acid sequence ANYYGGSQFAY (SEQ ID NO: 409); a CDRL1 comprising the amino acid sequence RSSQSLVHSNGKTYLH (SEQ ID NO: 472); a CDRL2 comprising the amino acid sequence KVSNRFS (SEQ ID NO: 525); and / or a CDRL3 comprising the amino acid sequence SQSTHVPFT (SEQ ID NO: 570).

[0327] In some embodiments, the anti-tau antibody comprises a CDRH1 comprising the amino acid sequence G[F / Y]TFT[R / I][Y / F] (SEQ ID NO: 931), or a CDRH1 comprising the amino acid sequence G-X1-TFT-X2-X3 (SEQ ID NO: 932) (wherein each of Xi, X2, and X3 can be any amino acid, e.g., Xi and / or X3 can be an amino acid having a hydrophobic and / or aromatic side chain, such as F or Y, and / or X2 can be a positively charged residue (e.g., R, K, H) or a residue having an aliphatic side chain (e.g., A, V, I, or L)); a CDRH2 comprising the amino acid sequence NPNNGG (SEQ ID NO: 341); a CDRH3 comprising the amino acid sequence GTGTGAMDY (SEQ ID NO: 410); or the amino acid sequence RSSQSLVH a CDRL1 comprising the amino acid sequence [N / S]NG[I / N]T[H / Y]LY (SEQ ID NO: 933), or the amino acid sequence RSSQSLVH-X1-NG-X2-T-X3-LY (SEQ ID NO: 934) (wherein X1, X2, and X3 can be any amino acid, e.g., X1 is Q / N / S / T, and / or X2 is A / V / I / L / Q / N, and / or X3 is H / R / K / Y / F); a CDRL2 comprising the amino acid sequence RVS[N / S]RFS (SEQ ID NO: 935), or the amino acid sequence RVSXRFS (SEQ ID NO: 936) (wherein X can be any amino acid, e.g., X is Q / N / S / T); and / or a CDRL3 comprising the amino acid sequence FQGTHVPRT (SEQ ID NO: 571).

[0328] In some embodiments, the anti-tau antibody comprises a CDRH1 comprising the amino acid sequence G[F / Y]TFT[R / I / D][Y / F] (SEQ ID NO: 937), or a CDRH1 comprising the amino acid sequence G-X1-TFT-X2-X3 (SEQ ID NO: 938), where X1, X2, and X3 can be any amino acid, e.g., X1 and X3 are each independently F / Y, and / or X2 is any residue (e.g., R / K / H / D / E / G / A / I / L / V); a CDRH2 comprising the amino acid sequence NPNNG[G / E] (SEQ ID NO: 939), or a CDRH2 comprising the amino acid sequence NPNNGX (SEQ ID NO: 940), where X is any amino acid, e.g., , E / D / G / A / V / I / L; a CDRH3 comprising the amino acid sequence of G[T / R]G[T / M]G[absent / Y][absent / Y]A[M / L]DY (SEQ ID NO: 941), or a CDRH3 comprising the amino acid sequence G-X1-G-X2-G-X3-X4-A-X5-DY (SEQ ID NO: 942) (wherein each of X1-X5 can be any amino acid, and / or X3 and / or X4 can be absent, e.g., X1 is S / T / R / K / H, and / or X2 is S / T / V / L / A / I / M, and / or X3 and X4 are each independently Y / F / absent, and / or X5 is A / V / I / L / M);a CDRL1 comprising the amino acid sequence [R / G][S / A]S[Q / E][S / N][L / V][V / Y][H / G][S / A / N][N / T / L][G / N][I / N / absent][T / absent][H / Y / absent][L / absent][Y / absent] (SEQ ID NO: 943), or a CDRL1 comprising the amino acid sequence X1-X2-S-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15 (SEQ ID NO: 944) (wherein X1 to X15 may be any amino acid, and / or X11, X12 may be any amino acid, and / or X13, X14, X15 may be any amino acid, and / or X16, X17, X18, X19, X20, X21, X22, X23, X24, X25, X26, X27, X28, X29, X30, X31, X32, X33, X34, X35, X36, X37, X38, X39, X40, X41, X42, X43, X44, X45, X46, X47, X48, X49, X50, X51, X52, X53, X54, X55, X56, X57, X58, X59, X60, X61, X62, X63, X64, X65, X66, X67, X68, X69, X70, X71, X72, X73, X74, X75, X76, X77, X78, X79, X80, X81, X82, X83, X84, X85, X86 , X13, X14, and / or X15 may be absent, for example, X1 is R / K / H / G / A / V / I / L, and / or X2 is S / T / A / V / I / L, and / or X3 is Q / N / E / D, and / or X4 is S / T / N / Q, and / or X5 is L / V / A / I, and / or X6 is A / V / I / L / Y / F, and / or X7 is H / R / K / G / A, and / or X8 is S / T / A / V / I / L / N / Q, and / or X9 is N / Q / A / I / L / V / M. X10 is G / A / N / Q and / or X11 is Q / N / A / V / I / L / absent and / or X12 is T / S / absent and / or X13 is H / R / K / Y / F / absent and / or X14 is A / V / I / L / absent and / or X15 is Y / F / absent); a CDRL2 consensus sequence having about 3 to about 7 amino acids of the amino acid sequence of [R / G][V / A][S / T][N / T / S][R / L][F / A][S / D] (SEQ ID NO: 945), or a CDRL2 comprising the amino acid sequence X1-X2-X3-X4-X5-X6-X7 (SEQ ID NO: 946), where X1, X2, X3, X4, X5, X6, and X7 can be any amino acid, e.g., X1 is R / K / H / G / A, and / or X2 is V / A / I / L, and / or X3 is S / T, and / or X4 is N / Q / T / S, and / or X5 is R / K / H / A / V / I / L, and / or X6 is F / Y / A / V / I / L / G, and / or X7 is S / T / D / E;and / or a CDRL3 comprising the amino acid sequence [F / Q][G / N][G / V][T / L][H / T][V / I]P[R / W]T (SEQ ID NO: 947), or a CDRL3 comprising the amino acid sequence X1-X2-X3-X4-X5-X6-P-X7-T (SEQ ID NO: 948) (wherein X1, X2, X3, X4, X5, X6, and X7 can be any amino acid, e.g., X1 is F / Y / Q / N, and / or X2 is G / A / Q / N, and / or X3 is G / A / V / I / L, and / or X4 is T / S / A / V / I / L, and / or X5 is H / R / K / T / S, and / or X6 is V / I / A / L, and / or X7 is R / K / H / W / F / Y);

[0329] In some embodiments, the anti-tau antibody comprises a CDRH1 comprising the amino acid sequence GY[S / T]FT[D / E]Y (SEQ ID NO: 949), or a CDRH1 comprising the amino acid sequence GY-X1-FT-X2-Y (SEQ ID NO: 950) (wherein X1 and X2 can be any amino acid, e.g., X1 is S / T and / or X2 is D / E / S / T); a CDRH2 comprising the amino acid sequence [F / Y]PG[S / R][D / G][S / N] (SEQ ID NO: 951), or a CDRH2 comprising the amino acid sequence X1-PG-X2-X3-X4 (SEQ ID NO: a CDRH2 comprising the amino acid sequence P[T / A][V / I / Y][V / Y][A / S][R / K]DYAM[D / E]Y (SEQ ID NO: 953), or a CDRH3 comprising the amino acid sequence P-X1-X2-X3-X4-X5-DYAM-X6-Y (SEQ ID NO: 954) (wherein X1 to X4 can be any amino acid, e.g., X1 is F / Y, and / or X2 is S / T / R / K / H, and / or X3 is D / E / G / A, and / or X4 is S / T / N / Q); a CDRH3 comprising the amino acid sequence P[T / A][V / I / Y][V / Y][A / S][R / K]DYAM[D / E]Y (SEQ ID NO: 953), or a CDRH3 comprising the amino acid sequence P-X1-X2-X3-X4-X5-DYAM-X6-Y (SEQ ID NO: 954) (wherein wherein X1 to X6 may be any amino acid, for example, X1 is T / S / A / V / I / L, and / or X2 is V / I / A / L / Y / F, and / or X3 is V / I / A / L / Y / F, and / or X4 is A / V / I / L / S / T, and / or X5 is R / K / H, and / or X6 is D / E; a CDRL1 comprising the amino acid sequence RSSQSIV[Y / H][S / R / T]NGNTYLE (SEQ ID NO: 955), or the amino acid sequence RSSQSIV-X1-X2-NGNTYLE ( and / or a CDRL1 comprising the amino acid sequence KVSNRFS (SEQ ID NO: 525); and / or a CDRL3 comprising the amino acid sequence FQGSHVP[Y / F]T (SEQ ID NO: 957), or a CDRL3 comprising the amino acid sequence FQGSHVPXT (SEQ ID NO: 958) (wherein X can be any amino acid, for example, X is Y / F).

[0330] In some embodiments, the anti-tau antibody comprises a CDRH1 comprising the amino acid sequence GY[S / T]FT[D / E / S]Y (SEQ ID NO: 959), or a CDRH1 comprising the amino acid sequence GY-X1-FT-X2-Y (SEQ ID NO: 950) (wherein X1 and X2 can be any amino acid, e.g., X1 is S / T and / or X2 is E / D / S / T); a CDRH2 comprising the amino acid sequence [F / Y]P[G / S][S / R / N][D / G][S / G / N] (SEQ ID NO: 960), or a CDRH2 comprising the amino acid sequence CDRH2 comprising the sequence X1-P-X2-X3-X4-X5 (SEQ ID NO: 961) (wherein X1 through X5 can be any amino acid, e.g., X1 is F / Y, and / or X2 is S / T / G / A / V / I / L, and / or X3 is S / T / R / K / H / N / Q, and / or X4 is D / E / G / A, and / or X5 is S / T / N / Q / G / A); a CDRH3 comprising the amino acid sequence X1-X2-X3-X4-X5-X6-DYAM-X7-Y (SEQ ID NO: 962), or a CDRH3 comprising the amino acid sequence X1-X2-X3-X4-X5-X6-DYAM-X7-Y (SEQ ID NO: 963), where X1 to X7 can be any amino acid, e.g., X1 is S / T / P / A / I / L / V, and / or X2 is T / S / A / V / I / L, and / or X3 is A / V / I / L / Y / F, and / or X4 is A / V / I / L / Y / F, and / or X5 is A / V / I / L / G / S / T, and / or X6 is A / V / I / L / G / S / T, and / or is R / K / H and / or X7 is E / D; a CDRL1 comprising the amino acid sequence RSSQSIV[Y / H][S / R / T]NGNTYLE (SEQ ID NO: 955), or a CDRL1 comprising the amino acid sequence RSSQSIV-X1-X2-NGNTYLE (SEQ ID NO: 956) (wherein X1 and X2 can be any amino acid, for example, X1 is Y / F / H / R / K and / or X2 is S / T / R / K / H); a CDRL2 comprising the amino acid sequence KVSNRFS (SEQ ID NO: 525);and / or a CDRL3 comprising the amino acid sequence FQGSHVP[Y / F]T (SEQ ID NO: 957), or a CDRL3 comprising the amino acid sequence FQGSHVPXT (SEQ ID NO: 958), where X can be any amino acid, e.g., X is F / Y;

[0331] In some embodiments, the anti-tau antibody is a CDRH1 comprising the amino acid sequence GFSL[S / N]T[S / F][A / G]M (SEQ ID NO: 964), or a CDRH1 comprising the amino acid sequence GFSL-X1-T-X2-X3-M (SEQ ID NO: 965) (wherein X1-X3 can be any amino acid, e.g., X1 is S / T / N / Q and / or X2 is S / T / F / Y and / or X3 is A / V / I / L / G); a CDRH2 comprising the amino acid sequence YWDDD (SEQ ID NO: 362); a CDRH3 comprising the amino acid sequence R[R / V / K]R[G / Y / S]Y[G / A]MDY (SEQ ID NO: 966), or a CDRH3 comprising the amino acid sequence R-X1-R-X2-Y-X3-MDY (SEQ ID NO: 967) (wherein X1 to X3 may be any amino acid, e.g., X1 is R / K / H / A / V / I / L and / or X2 is G / A / V / I / L / S / T / Y / F and / or X3 is A / V / I / L / G); or an amino acid sequence K[A / S]SQS[V / L][S / L][N / S] a CDRL1 comprising the amino acid sequence K-X1-SQS-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-A (SEQ ID NO: 969), wherein X1 through X12 can be any amino acid and / or one or more of X5 through X10 can be absent, e.g., X1 is S / T / A / V / I / L, and / or or X2 is A / V / I / L, and / or X3 is S / T / A / V / I / L, and / or X4 is N / Q / S / T, and / or X5 is S / T / absent, and / or X6 is G / A / V / I / L / absent, and / or X7 is N / Q / absent, and / or X8 is N / Q / absent, and / or X9 is K / R / H / absent, and / or X10 is N / Q / absent, and / or X11 is E / D / Y / F, and / or X12 is A / V / I / L);a CDRL2 comprising the amino acid sequence [Y / G][A / T]S[N / T]R[C / E][T / S] (SEQ ID NO: 970), or a CDRL2 comprising the amino acid sequence X1-X2-S-X3-R-X4-X5 (SEQ ID NO: 971) (wherein X1 to X5 can be any amino acid, e.g., X1 is Y / F / G / A / V / I / L and / or X2 is A / V / I / L / T / S and / or X3 is N / Q / T / S and / or X4 is C / S / E / D and / or X5 is T / S); and / or or a CDRL3 comprising the amino acid sequence Q[Q / N]D[Y / H][R / S][S / H]P[L / Y]T (SEQ ID NO: 972), or a CDRL3 comprising the amino acid sequence Q-X1-D-X3-X4-X5-P-X6-T (SEQ ID NO: 973) (wherein X1 to X6 can be any amino acid, e.g., X1 is Q / N, and / or X2 is Y / F / H / R / K, and / or X3 is R / K / H / S / T, and / or X4 is S / T / H / K / R and / or A / V / I / L / Y / F);

[0332] In some embodiments, the anti-tau antibody is a CDRH1 comprising the amino acid sequence GFSL[S / N]T[S / F][A / G]M (SEQ ID NO: 964), or a CDRH1 comprising the amino acid sequence GFSL-X1-T-X2-X3-M (SEQ ID NO: 965) (wherein X1-X3 can be any amino acid, e.g., X1 is S / T / N / Q and / or X2 is S / T / F / Y and / or X3 is G / A / I / L / V); a CDRH2 comprising the amino acid sequence YWDDD (SEQ ID NO: 362); a CDRH3 comprising the amino acid sequence R[R / V / K / S / G][Y / R][Y / absent][S / absent][absent / N][G / S / Y / R][Y / N / G][G / A / Y / N][M / F / Y]DY (SEQ ID NO: 974), or a CDRH4 comprising the amino acid sequence R-X a CDRH3 comprising 1-X2-X3-X4-X5-X6-X7-X8-X9-DY (SEQ ID NO: 975), where each of X1 through X9 can be any amino acid and / or one or more of X3 through X5 can be absent, e.g., X1 is R / K / H / A / V / I / L / G / S / T and / or X2 is Y / F / R / K / H, and / or X3 is Y / F / absent, and / or X4 is S / T / absent, and / or X5 is N / Q / absent, and / or X6 is G / A / V / I / L / S / T / Y / F / R / K / H, and / or X7 is Y / F / N / Q / G / A / V / I / L, and / or X8 is G / A / V / I / L / Y / F / N / Q, and / or X9 is M / F / Y);a CDRL1 comprising the amino acid sequence [K / S][S / A]S[Q / S]S[L / I / V][L / S][N / S / D][D / S / T][V / G / D / Y][N / G / absent][Q / absent][K / absent][N / T / absent][Y / absent][L / absent][A / H / N] (SEQ ID NO: 976); or a CDRL1 comprising the amino acid sequence X1-X2-S-X3-S-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15 (SEQ ID NO: 977), where each of X1 to X15 is any amino acid. and / or one or more of X9 to X14 may be absent, for example, X1 is K / R / H / S / T, and / or X2 is S / T / A / V / I / L, and / or X3 is Q / N / S / T, and / or X4 is L / I / V / A, and / or X5 is A / V / I / L / S / T, and / or X6 is N / Q / S / T / D / E, and / or X7 is D / E / S / T, and / or X8 is G / A / V / I / L / D / E / Y / F, and and / or X9 is N / Q / G / A / absent, and / or X10 is Q / N / absent, and / or X11 is K / R / H / absent, and / or X12 is N / Q / T / S / absent, and / or X13 is Y / F / absent, and / or X14 is A / V / I / L / absent, and / or X15 is A / V / I / L / H / K / R / N / Q); a CD comprising the amino acid sequence [Y / G / L / R][A / T / V]S[N / T / K][R / L][C / E / D / A][T / S] (SEQ ID NO: 978). RL2, or CDRL2 comprising the amino acid sequence X1-X2-S-X3-X4-X5-X6 (SEQ ID NO: 979) (wherein X1-X6 can be any amino acid, e.g., X1 is Y / F / G / A / V / I / L / R / K / H and / or X2 is A / V / I / L / T / S and / or X3 is N / Q / T / S / K / R / H and / or X4 is R / K / H / A / V / I / L and / or X5 is C / S / E / D / A / V / I / L and / or X6 is T / S);and / or a CDRL3 comprising the amino acid sequence [W / Q][Q / N][G / D][T / S / Y / H][H / S / R][F / I / S / H]P[Q / R / L / Y][absent / Y]T (SEQ ID NO: 980), or a CDRL3 comprising the amino acid sequence X1-X2-X3-X4-X5-X6-P-X7-X8-T (SEQ ID NO: 981) (wherein each of X1 to X8 may be any amino acid and / or X8 may be absent, e.g., X1 is Q / N / W / F / Y, and / or X2 is Q / N, and / or X3 is G / A / V / I / L / D / E, and / or X4 is T / S / Y / F / H / K / R, and / or X5 is H / K / R / S / T, and / or X6 is F / Y / A / V / I / L / S / T / H / K / R, and / or X7 is Q / N / R / K / H / A / V / I / L / Y / F, and / or X8 is Y / F / absent);

[0333] Functional modification In some embodiments, antibodies of the present disclosure may be modified to optimize one or more functional properties (e.g., antibody affinity or activity). Non-limiting examples of antibody functional properties include epitope or antigen affinity, ability to recruit or immobilize a target, and ability to activate or inhibit a target, process, or pathway. In some embodiments, functional properties include or relate to protein-protein interactions, protein aggregation, enzymatic activity, receptor-ligand interactions, cell signaling pathways, proteolytic cascades, and / or the ability to modulate a biological or physiological response.

[0334] Antibody modification can optimize antibodies by adjusting epitope affinity. Such modifications can be performed by affinity maturation. Affinity maturation techniques are used to identify CDR-encoding sequences with the highest affinity for the target antigen. In some embodiments, antibody display technologies (e.g., phage or yeast) can be used. Such methods can involve mutating the nucleotide sequence encoding the parent antibody to be optimized. The nucleotide sequence can be mutated entirely randomly or at specific amino acid residues to alter expression, generating millions to billions of variants. Sites or residues can be selected for mutation based on the frequency of the sequence or amino acid observed in the natural human antibody repertoire. Variants can be subjected to multiple rounds of affinity screening for target antigen binding (e.g., using display library screening techniques, surface plasmon resonance techniques, fluorescence-associated cell sorting (FACS) analysis, enzyme-linked immunosorbent assay (ELISA), etc.). Multiple rounds of selection, mutation, and expression can be performed to identify antibody fragment sequences with the highest affinity for the target antigen. Such sequences can be directly incorporated into antibody sequences for production. In some cases, the goal of affinity maturation is to increase antibody affinity by at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 20-fold, at least 30-fold, at least 40-fold, at least 50-fold, at least 100-fold, at least 500-fold, at least 1,000-fold, or more than 1,000-fold compared to the affinity of the original or starting antibody. If the affinity is lower than desired, the process can be repeated.

[0335] In some embodiments, antibody affinity may be assessed using different antigen formats. In some embodiments, antibody affinity to different antigen formats may be tested in vitro (e.g., by ELISA). In vitro testing may be performed using brain samples or fragments. Such samples or fragments may be obtained from subjects with AD (e.g., human AD patients). In some embodiments, brain samples or fragments may be obtained from non-human subjects. Such non-human subjects may include non-human animals (e.g., mice, rats, and primates) used in AD disease model studies. In some embodiments, brain samples or fragments used in antibody affinity testing may be derived from the TG4510 / P301S mouse strain. Antibody affinity may be compared to a control sample lacking the specific antigen for which affinity is being analyzed. In some embodiments, the control sample may include a brain sample or fragment from a non-diseased human subject. In some embodiments, brain samples or fragments from wild-type and / or tau knockout mouse strains may be used as control samples. In vitro affinity testing may be performed using recombinant or isolated protein antigens (e.g., by ELISA). In some embodiments, recombinant or isolated ePHFs are used for antibody affinity testing. In some embodiments, the antigens listed in Table 8 may be used.

[0336] In some embodiments, antibody affinity analysis can be used to adjust the multispecificity of an antibody (e.g., to reduce or increase the multispecificity of an antibody). Such adjustment can include adjusting the relative affinity for two or more epitopes or antigens. For example, an antibody can be optimized to have higher affinity for one epitope or antigen compared to a second epitope or antigen.

[0337] Antibodies can be modified to optimize the functional properties of the antibody. Such functional properties can be evaluated or engineered based on analytical assay results related to one or more functional properties of the antibody. Assays can be used to screen multiple antibodies and identify or rank antibodies based on functional criteria. Anti-tau antibodies can be modified to optimize tau aggregation inhibition. Such inhibition can be based on the physical disruption of tau aggregates or the ability of the anti-tau antibody to deplete tau protein from the assay sample. Optimization based on tau aggregation inhibition can be assessed using one or more assays of tau aggregation (e.g., by tau seeding assays).

[0338] Modification of production In some embodiments, modifications may be made to optimize antibody production. Such modifications may include or relate to one or more of protein folding, stability, expression, and / or immunogenicity. Modifications may be made to address one or more antibody characteristics that adversely affect production. Such characteristics may include, but are not limited to, unpaired cysteines or irregular disulfides; glycosylation sites (e.g., N-linked NXS / T sites); acid cleavage sites, amino acid oxidation sites, compatibility with mouse germline sequences; asparagine deamidation sites; aspartic acid isomerization sites; N-terminal pyroglutamate formation sites; and aggregation-prone amino acid sequence regions (e.g., within CDR sequences).

[0339] In some embodiments, antibodies of the present disclosure can be prepared using recombinant DNA technology (see, e.g., U.S. Pat. No. 4,816,567, incorporated herein by reference in its entirety). DNA encoding the antibody can be isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes capable of specifically binding to genes encoding the heavy and light chains of a murine antibody). In some embodiments, hybridoma cells can be used as a preferred source of DNA. Once isolated, the DNA can be placed into an expression vector, which is then transfected into host cells. Host cells can include, but are not limited to, HEK293 cells, HEK293T cells, monkey COS cells, Chinese hamster ovary (CHO) cells, and myeloma cells, which do not otherwise produce immunoglobulin proteins, for the synthesis of monoclonal antibodies in recombinant host cells. The DNA can also be modified, for example, by substituting the coding sequence for human heavy and light chain constant domains for the homologous murine sequences (U.S. Pat. No. 4,816,567), or by covalently linking all or part of the coding sequence for a non-immunoglobulin polypeptide to the immunoglobulin coding sequence.

[0340] Antibody humanization In some embodiments, the anti-tau antibodies of the present disclosure may be prepared as humanized antibodies. A "humanized" antibody is a chimeric antibody that contains minimal sequence (e.g., variable domain or CDR) derived from a non-human immunoglobulin (e.g., a murine immunoglobulin). A humanized antibody may be prepared from a human (recipient) immunoglobulin in which hypervariable region residues are substituted by hypervariable region residues derived from one or more non-human "donor" antibodies (e.g., a mouse, rat, rabbit, or non-human primate). The donor antibody may be selected based on the desired specificity, affinity, and / or potency. A humanized antibody may contain one or more back mutations, including the restoration of one or more amino acids to those found in the donor antibody. Conversely, donor antibody residues in a humanized antibody may be mutated to match those present in the human recipient antibody. Back mutations may be introduced to reduce the human immune response to the humanized antibody. In some embodiments, back mutations are introduced to avoid problems with antibody manufacturing (e.g., protein aggregation or post-translational modifications).

[0341] To construct an expression plasmid encoding a fully humanized antibody with a human constant region, DNA sequences encoding the antibody variable region can be inserted into an expression vector (e.g., a mammalian expression vector) between an upstream promoter / enhancer and immunoglobulin signal sequence and a downstream immunoglobulin constant region gene. The DNA sample can then be transfected into mammalian cells for antibody production. Constant domains from any class of human antibody can be used. There are five major classes of intact human antibodies: IgA, IgD, IgE, IgG, and IgM, some of which can be further divided into subclasses (isotypes), e.g., IgG1 (human and mouse), IgG2 (human), IgG2a (mouse), IgG2b (mouse), IgG2c (mouse), IgG3 (human and mouse), IgG4 (human), IgA (mouse), IgA1 (human), and IgA2 (human).

[0342] Cell lines stably transfected with DNA encoding the humanized antibody may be prepared and used to establish stable cell lines. The humanized antibody-producing cell lines may be expanded to express the humanized antibody, which may be harvested and purified from the cell culture medium.

[0343] In some embodiments, the humanized antibodies of the present disclosure may have cross-reactivity with non-human species. Species cross-reactivity may allow the antibody to be used in different animals for various purposes. For example, cross-reactive antibodies may be used in preclinical animal studies to provide information about the efficacy and / or toxicity of the antibody. Non-human species may include, but are not limited to, mice, rats, rabbits, dogs, pigs, goats, sheep, and non-human primates (e.g., cynomolgus monkeys).

[0344] antibody conjugates In some embodiments, the antibodies of the present disclosure may be or may be prepared as antibody conjugates. As used herein, the term "conjugate" refers to any agent, cargo, or chemical moiety attached to a receptor entity, or the process of attaching such an agent, cargo, or chemical moiety. As used herein, the term "antibody conjugate" refers to any antibody having an attached agent, cargo, or chemical moiety. Conjugates used to prepare antibody conjugates may include a therapeutic agent. Such therapeutic agents may include drugs. Antibody conjugates containing a conjugated drug are referred to herein as "antibody-drug conjugates." Antibody-drug conjugates may be used to target a conjugated drug to a particular target based on the affinity of the associated antibody for a protein or epitope associated with such a target. Such antibody-drug conjugates may be used to localize the biological activity associated with such a conjugated drug to a target cell, tissue, organ, or other targeting entity. In some embodiments, the conjugates used to prepare antibody conjugates include a detectable label. The antibody can be conjugated with a detectable label for detection purposes. Such detectable labels can include, but are not limited to, radioisotopes, fluorophores, chromophores, chemiluminescent compounds, enzymes, enzyme cofactors, dyes, metal ions, ligands, biotin, avidin, streptavidin, haptens, quantum dots, or any other detectable labels known in the art or described herein.

[0345] The conjugate may be attached to the antibody directly or via a linker. Direct attachment may be by covalent bonding or by non-covalent association (e.g., ionic, electrostatic, hydrophobic, hydrogen bonding, hybridization, etc.). The linker used to attach the conjugate may comprise any chemical structure capable of connecting the antibody to the conjugate. In some embodiments, the linker comprises a polymer (e.g., a nucleic acid, a polypeptide, polyethylene glycol, a carbohydrate, a lipid, or a combination thereof). The antibody conjugate linker may be cleavable (e.g., via contact with an enzyme, a change in pH, or a change in temperature).

[0346] Exemplary Anti-Tau Antibodies In some embodiments, the anti-tau antibody comprises at least one antigen-binding domain, e.g., a variable region or antigen-binding fragment thereof, from an antibody described herein, e.g., an antibody selected from V0001-V0065, V1001-V1005, or V2001-V2005, as described in Tables 1, 3, 6, 2A-2C, 4, or 5, or a sequence substantially identical (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences.

[0347] In some embodiments, the anti-tau antibody comprises a heavy chain variable region from an antibody described herein, e.g., selected from V0001-V0065, V1001-V1005, or V2001-V2005, e.g., as described in Table 3, 6, or 4, or a sequence substantially identical (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences. In some embodiments, the heavy chain variable region comprises an amino acid sequence having at least one, two, or three modifications (e.g., substitutions, e.g., conservative substitutions) of the amino acid sequence of a heavy chain variable region presented in Table 3, 6, or 4, but no more than 30, no more than 20, or no more than 10 modifications (e.g., substitutions, e.g., conservative substitutions).

[0348] In some embodiments, the nucleotide sequence encoding the anti-tau antibody comprises the nucleotide sequence of a heavy chain variable region from an antibody described herein, e.g., as described in Table 3 or 4, e.g., selected from V0001-V0065, V1001-V1005, or V2001-V2005, or a nucleotide sequence substantially identical (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences.

[0349] In some embodiments, the anti-tau antibody comprises a light chain variable region from an antibody described herein, e.g., selected from V0001-V0065, V1001-V1005, or V2001-V2005, as described in Tables 3, 6, or 4, or a sequence substantially identical (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences. In some embodiments, the light chain variable region comprises an amino acid sequence that has at least one, two, or three modifications (e.g., substitutions, e.g., conservative substitutions) of the amino acid sequence of a light chain variable region presented in Tables 3, 6, or 4, but no more than 30, no more than 20, or no more than 10 modifications (e.g., substitutions, e.g., conservative substitutions).

[0350] In some embodiments, the nucleotide sequence encoding the anti-tau antibody comprises the nucleotide sequence of a light chain variable region from an antibody described herein, e.g., as described in Table 3 or 4, e.g., selected from V0001-V0065, V1001-V1005, or V2001-V2005, or a nucleotide sequence substantially identical (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences.

[0351] In some embodiments, the anti-tau antibody comprises a heavy chain variable region and a light chain variable region from an antibody described herein, e.g., as described in Tables 3, 6, or 4, e.g., selected from V0001-V0065, V1001-V1005, or V2001-V2005, or sequences substantially identical (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences. In some embodiments, an anti-tau antibody comprises a heavy chain variable region comprising an amino acid sequence having at least one, two, or three modifications (e.g., substitutions, e.g., conservative substitutions) of the heavy chain variable region amino acid sequence presented in Table 3, 6, or 4, but no more than 30, no more than 20, or no more than 10 modifications (e.g., substitutions, e.g., conservative substitutions); and a light chain variable region comprising an amino acid sequence having at least one, two, or three modifications (e.g., substitutions, e.g., conservative substitutions) of the light chain variable region amino acid sequence presented in Table 3, 6, or 4, but no more than 30, no more than 20, or no more than 10 modifications (e.g., substitutions, e.g., conservative substitutions).

[0352] In some embodiments, the anti-tau antibody comprises a heavy chain constant region, e.g., a human IgG1, IgG2, IgG3, or IgG4 constant region, or a murine IgG1, IgG2A, IgG2B, IgG2C, or IgG3 constant region. In some embodiments, the heavy chain constant comprises an amino acid sequence set forth in Table X, or a sequence substantially identical (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences. In some embodiments, the nucleic acid encoding the heavy chain constant region comprises a nucleotide sequence set forth in Table X, or a nucleotide sequence substantially identical (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences.

[0353] In some embodiments, the anti-tau antibody comprises a light chain constant region, e.g., a kappa light chain constant region, e.g., a human kappa or lambda light chain constant region, or a mouse kappa or lambda light chain constant region. In some embodiments, the light chain constant comprises an amino acid sequence set forth in Table X, or a sequence substantially identical (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences. In some embodiments, the nucleic acid encoding the light chain constant region comprises a nucleotide sequence set forth in Table X, or a nucleotide sequence substantially identical (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences.

[0354] In some embodiments, the anti-tau antibody comprises a heavy chain constant region and a light chain constant region. In some embodiments, the heavy chain constant region and the light chain constant region comprise an amino acid sequence set forth in Table X, or a sequence substantially identical thereto (e.g., having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity). In some embodiments, the nucleotide sequence encoding the anti-tau antibody comprises a nucleotide sequence of a heavy chain constant region and a nucleotide sequence of a kappa or lambda light chain constant region. In some embodiments, the nucleotide sequence encoding the heavy chain constant region and the light chain constant region comprises a nucleotide sequence set forth in Table X, or a nucleotide sequence substantially identical thereto (e.g., having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity).

[0355] In some embodiments, the anti-tau antibody comprises a heavy chain variable and constant region, a light chain variable and constant region, or both, that comprise an amino acid sequence of Table 3, 6, or 4 for the variable region and an amino acid sequence of Table X for the constant region, or that are encoded by a nucleic acid sequence of Table 3, 6, or 4, and X, or a sequence substantially identical (e.g., having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences.

[0356] In some embodiments, the anti-tau antibody comprises at least one, two, three, or four framework regions from the heavy chain variable region of an antibody described herein, e.g., selected from V0001-V0065, V1001-V1005, or V2001-V2005, as described in Table 7 or 4, or a sequence substantially identical (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences. In some embodiments, one or more of the framework regions (or collectively all of the framework regions) have one, two, three, four, five, or more changes, e.g., amino acid substitutions, insertions, or deletions, relative to the amino acid sequence set forth in Table 7 or 4. In some embodiments, the anti-tau antibody comprises substitutions in the heavy chain framework regions, eg, one or more substitutions in FRH1, FRH2, FRH3, and / or FRH4 of the heavy chain.

[0357] In some embodiments, the anti-tau antibody comprises at least one, two, three, or four framework regions from the light chain variable region of an antibody described herein, e.g., selected from V0001-V0065, V1001-V1005, or V2001-V2005, as described in Table 7 or 4, or a sequence substantially identical (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences. In some embodiments, one or more of the framework regions (or collectively all of the framework regions) have one, two, three, four, five, or more changes, e.g., amino acid substitutions, insertions, or deletions, relative to the amino acid sequence set forth in Table 7 or 4. In some embodiments, the anti-tau antibody comprises substitutions in the light chain framework region, eg, one or more substitutions in FRL1, FRL2, FRL3, and / or FRL4 of the light chain.

[0358] In some embodiments, the anti-tau antibody comprises at least one, two, or three complementarity determining regions (CDRs) from a heavy chain variable region comprising an amino acid sequence of Table 2A-2C, 3, 6, 4, or 5, or encoded by a nucleic acid sequence of Table 4, or a sequence substantially identical (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, or more changes, e.g., amino acid substitutions, insertions, or deletions, relative to the amino acid sequence set forth in Table 2A-2C, 6, 4, or 5, or encoded by the nucleotide sequence set forth in Table 4. In some embodiments, the encoded anti-tau antibody comprises substitutions in the heavy chain CDRs, for example, one or more substitutions in CDR1, CDR2 and / or CDR3 of the heavy chain.

[0359] In some embodiments, the anti-tau antibody comprises at least one, two, or three complementarity determining regions (CDRs) from a light chain variable region comprising an amino acid sequence of Table 2A-2C, 6, 4, or 5, or encoded by a nucleic acid sequence of Table 4, or a sequence substantially identical (e.g., having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, or more alterations, e.g., amino acid substitutions, insertions, or deletions, relative to the amino acid sequence set forth in Table 2A-2C, 6, 4, or 5, or encoded by the nucleotide sequence set forth in Table 4. In some embodiments, the anti-tau antibody comprises substitutions in the light chain CDRs, e.g., one or more substitutions in CDR1, CDR2, and / or CDR3 of the light chain.

[0360] In some embodiments, the anti-tau antibody comprises at least one, two, three, four, five, or six CDRs (or collectively all of the CDRs) from heavy and light chain variable regions comprising the amino acid sequences shown in Tables 2A-2C, 6, 4, or 5, or encoded by the nucleotide sequences shown in Table 4. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six, or more alterations, e.g., amino acid substitutions, insertions, or deletions, relative to the CDRs shown in Tables 2A-2C, 6, 4, or 5, or encoded by the nucleotide sequences shown in Table 4.

[0361] In some embodiments, the anti-tau antibody comprises all three CDRs from a heavy chain variable region, all three CDRs from a light chain variable region, or both (e.g., all six CDRs from the heavy and light chain variable regions) comprising the amino acid sequence set forth in Tables 2A-2C, 6, 4, or 5, or encoded by the nucleotide sequence set forth in Table 4.

[0362] In some embodiments, anti-tau antibodies of the present disclosure may comprise CDRs identified by CDR analysis of the variable domain sequences presented herein via co-crystal structure analysis with bound antigen, by computational evaluation based on comparison with other antibodies (see, e.g., Strohl, WR Therapeutic Antibody Engineering. Woodhead Publishing, Philadelphia PA. 2012. Ch. 3, p47-54), or by the Kabat, Chothia, Al-Lazikani, Lefranc, or Honegger numbering schemes, as previously described.

[0363] [Table 3]

[0364] [Table 4]

[0365] [Table 5]

[0366] [Table 6-1]

[0367] [Table 6-2]

[0368] [Table 6-3]

[0369] [Table 7-1]

[0370]

Table 7-2

[0371]

Table 7-3

[0372]

Table 7-4

[0373]

Table 7-5

[0374]

Table 7-6

[0375]

Table 7-7

[0376]

Table 7-8

[0377]

Table 7-9

[0378]

Table 7-10

[0379]

Table 7-11

[0380]

Table 7-12

[0381]

Table 7-13

[0382]

Table 7-14

[0383]

Table 8-1

[0384]

Table 8-2

[0385]

Table 8-3

[0386]

Table 9-1

[0387]

Table 9-2

[0388]

Table 10-1

[0389]

Table 10-2

[0390]

Table 10-3

[0391] [Table 10-4]

[0392] [Table 10-5]

[0393] [Table 10-6]

[0394] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of heavy chain complementarity determining region 1 (HC CDR1), HC CDR2, and / or HC CDR3, wherein the HC CDR1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NOs: 299, 343, and 395, respectively. In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of LC CDR1, LC CDR2, and / or LC CDR3, wherein the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NOs: 460, 518, and 557, respectively. In some embodiments, the anti-tau antibody comprises HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3, wherein the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences respectively comprise the sequences of SEQ ID NOs: 299, 343, 395, 460, 518, and 557. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, or more changes, e.g., amino acid substitutions, insertions, or deletions, relative to the amino acid sequence of any of SEQ ID NOs: 299, 343, 395, 460, 518, or 557.

[0395] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of heavy chain complementarity determining region 1 (HC CDR1), HC CDR2, and / or HC CDR3, wherein the HC CDR1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NOs: 1140, 1141, and 395, respectively. In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of LC CDR1, LC CDR2, and / or LC CDR3, wherein the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NOs: 460, 518, and 557, respectively. In some embodiments, the anti-tau antibody comprises HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3, wherein the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences respectively comprise the sequences of SEQ ID NOs: 1140, 1141, 395, 460, 518, and 557. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, or more changes, e.g., amino acid substitutions, insertions, or deletions, relative to the amino acid sequence of any of SEQ ID NOs: 1140, 1141, 395, 460, 518, and 557.

[0396] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of heavy chain complementarity determining region 1 (HC CDR1), HC CDR2, and / or HC CDR3, wherein the HC CDR1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NOs: 1155, 1156, and 1157, respectively. In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of LC CDR1, LC CDR2, and / or LC CDR3, wherein the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NOs: 1158, 1159, and 557, respectively. In some embodiments, the anti-tau antibody comprises HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3, wherein the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences respectively comprise the sequences of SEQ ID NOs: 1155, 1156, 1157, 1158, 1159, and 557. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, or more changes, e.g., amino acid substitutions, insertions, or deletions, relative to the amino acid sequence of any of SEQ ID NOs: 1155, 1156, 1157, 1158, 1159, and 557.

[0397] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of heavy chain complementarity determining region 1 (HC CDR1), HC CDR2, and / or HC CDR3, wherein the HC CDR1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NOs: 304, 347, and 400, respectively. In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of LC CDR1, LC CDR2, and / or LC CDR3, wherein the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NOs: 464, 523, and 562, respectively. In some embodiments, the anti-tau antibody comprises HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3, wherein the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences respectively comprise the sequences of SEQ ID NOs: 304, 347, 400, 464, 523, and 562. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, or more changes, e.g., amino acid substitutions, insertions, or deletions, relative to the amino acid sequence of any of SEQ ID NOs: 304, 347, 400, 464, 523, and 562.

[0398] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of heavy chain complementarity determining region 1 (HC CDR1), HC CDR2, and / or HC CDR3, wherein the HC CDR1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NOs: 1142, 1143, and 400, respectively. In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of LC CDR1, LC CDR2, and / or LC CDR3, wherein the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NOs: 464, 523, and 562, respectively. In some embodiments, the anti-tau antibody comprises HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3, wherein the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences respectively comprise the sequences of SEQ ID NOs: 1142, 1143, 400, 464, 523, and 562. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, or more changes, e.g., amino acid substitutions, insertions, or deletions, relative to the amino acid sequence of any of SEQ ID NOs: 1142, 1143, 400, 464, 523, and 562.

[0399] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of heavy chain complementarity determining region 1 (HC CDR1), HC CDR2, and / or HC CDR3, wherein the HC CDR1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NOs: 1160, 1161, and 1162, respectively. In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of LC CDR1, LC CDR2, and / or LC CDR3, wherein the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NOs: 1163, 1164, and 562, respectively. In some embodiments, the anti-tau antibody comprises HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3, wherein the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NOs: 1160, 1161, 1162, 1163, 1164, and 562, respectively. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, or more changes, e.g., amino acid substitutions, insertions, or deletions, relative to the amino acid sequence of any of SEQ ID NOs: 1160, 1161, 1162, 1163, 1164, and 562.

[0400] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of heavy chain complementarity determining region 1 (HC CDR1), HC CDR2, and / or HC CDR3, wherein the HC CDR1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NOs: 314, 341, and 410, respectively. In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of LC CDR1, LC CDR2, and / or LC CDR3, wherein the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NOs: 1154, 529, and 571, respectively. In some embodiments, the anti-tau antibody comprises HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3, wherein the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences respectively comprise the sequences of SEQ ID NOs: 314, 341, 410, 1154, 529, and 571. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, or more changes, e.g., amino acid substitutions, insertions, or deletions, relative to the amino acid sequence of any of SEQ ID NOs: 314, 341, 410, 1154, 529, and 571.

[0401] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of heavy chain complementarity determining region 1 (HC CDR1), HC CDR2, and / or HC CDR3, wherein the HC CDR1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NOs: 1144, 1145, and 410, respectively. In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of LC CDR1, LC CDR2, and / or LC CDR3, wherein the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NOs: 1146, 529, and 571, respectively. In some embodiments, the anti-tau antibody comprises HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3, wherein the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences respectively comprise the sequences of SEQ ID NOs: 1144, 1145, 410, 1146, 529, and 571. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, or more changes, e.g., amino acid substitutions, insertions, or deletions, relative to the amino acid sequence of any of SEQ ID NOs: 1144, 1145, 410, 1146, 529, and 571.

[0402] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of heavy chain complementarity determining region 1 (HC CDR1), HC CDR2, and / or HC CDR3, wherein the HC CDR1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NOs: 1165, 1166, and 1167, respectively. In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of LC CDR1, LC CDR2, and / or LC CDR3, wherein the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NOs: 473, 528, and 571, respectively. In some embodiments, the anti-tau antibody comprises HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3, wherein the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences respectively comprise the sequences of SEQ ID NOs: 1165, 1166, 1167, 473, 528, and 571. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, or more changes, e.g., amino acid substitutions, insertions, or deletions, relative to the amino acid sequence of any of SEQ ID NOs: 1165, 1166, 1167, 473, 528, and 571.

[0403] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of heavy chain complementarity determining region 1 (HC CDR1), HC CDR2, and / or HC CDR3, wherein the HC CDR1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NOs: 315, 341, and 410, respectively. In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of LC CDR1, LC CDR2, and / or LC CDR3, wherein the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NOs: 474, 529, and 571, respectively. In some embodiments, the anti-tau antibody comprises HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3, wherein the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences respectively comprise the sequences of SEQ ID NOs: 315, 341, 410, 474, 529, and 571. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, or more changes, e.g., amino acid substitutions, insertions, or deletions, relative to the amino acid sequence of any of SEQ ID NOs: 315, 341, 410, 474, 529, and 571.

[0404] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of heavy chain complementarity determining region 1 (HC CDR1), HC CDR2, and / or HC CDR3, wherein the HC CDR1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NOs: 1147, 1148, and 410, respectively. In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of LC CDR1, LC CDR2, and / or LC CDR3, wherein the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NOs: 474, 529, and 571, respectively. In some embodiments, the anti-tau antibody comprises HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3, wherein the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences respectively comprise the sequences of SEQ ID NOs: 1147, 1148, 410, 474, 529, and 571. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, or more changes, e.g., amino acid substitutions, insertions, or deletions, relative to the amino acid sequence of any of SEQ ID NOs: 1147, 1148, 410, 474, 529, and 571.

[0405] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of heavy chain complementarity determining region 1 (HC CDR1), HC CDR2, and / or HC CDR3, wherein the HC CDR1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NOs: 1168, 1169, and 1167, respectively. In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of LC CDR1, LC CDR2, and / or LC CDR3, wherein the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NOs: 1170, 528, and 571, respectively. In some embodiments, the anti-tau antibody comprises HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3, wherein the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences respectively comprise the sequences of SEQ ID NOs: 1168, 1169, 1167, 1170, 528, and 571. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, or more changes, e.g., amino acid substitutions, insertions, or deletions, relative to the amino acid sequence of any of SEQ ID NOs: 1168, 1169, 1167, 1170, 528, and 571.

[0406] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of heavy chain complementarity determining region 1 (HC CDR1), HC CDR2, and / or HC CDR3, wherein the HC CDR1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NOs: 316, 341, and 410, respectively. In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of LC CDR1, LC CDR2, and / or LC CDR3, wherein the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NOs: 475, 530, and 571, respectively. In some embodiments, the anti-tau antibody comprises HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3, wherein the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences respectively comprise the sequences of SEQ ID NOs: 316, 341, 410, 475, 530, and 571. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, or more changes, e.g., amino acid substitutions, insertions, or deletions, relative to the amino acid sequence of any of SEQ ID NOs: 316, 341, 410, 475, 530, and 571.

[0407] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of heavy chain complementarity determining region 1 (HC CDR1), HC CDR2, and / or HC CDR3, wherein the HC CDR1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NOs: 1149, 1150, and 410, respectively. In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of LC CDR1, LC CDR2, and / or LC CDR3, wherein the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NOs: 475, 530, and 571, respectively. In some embodiments, the anti-tau antibody comprises HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3, wherein the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences respectively comprise the sequences of SEQ ID NOs: 1149, 1150, 410, 475, 530, and 571. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, or more changes, e.g., amino acid substitutions, insertions, or deletions, relative to the amino acid sequence of any of SEQ ID NOs: 1149, 1150, 410, 475, 530, and 571.

[0408] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of heavy chain complementarity determining region 1 (HC CDR1), HC CDR2, and / or HC CDR3, wherein the HC CDR1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NOs: 1171, 1166, and 1167, respectively. In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of LC CDR1, LC CDR2, and / or LC CDR3, wherein the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NOs: 1172, 528, and 571, respectively. In some embodiments, the anti-tau antibody comprises HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3, wherein the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences respectively comprise the sequences of SEQ ID NOs: 1171, 1166, 1167, 1172, 528, and 571. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, or more changes, e.g., amino acid substitutions, insertions, or deletions, relative to the amino acid sequence of any of SEQ ID NOs: 1171, 1166, 1167, 1172, 528, and 571.

[0409] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of heavy chain complementarity determining region 1 (HC CDR1), HC CDR2, and / or HC CDR3, wherein the HC CDR1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NOs: 325, 362, and 435, respectively. In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of LC CDR1, LC CDR2, and / or LC CDR3, wherein the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NOs: 495, 540, and 587, respectively. In some embodiments, the anti-tau antibody comprises HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3, wherein the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences respectively comprise the sequences of SEQ ID NOs: 325, 362, 435, 495, 540, and 587. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, or more changes, e.g., amino acid substitutions, insertions, or deletions, relative to the amino acid sequence of any of SEQ ID NOs: 325, 362, 435, 495, 540, and 587.

[0410] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of heavy chain complementarity determining region 1 (HC CDR1), HC CDR2, and / or HC CDR3, wherein the HC CDR1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NOs: 1152, 1153, and 435, respectively. In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of LC CDR1, LC CDR2, and / or LC CDR3, wherein the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NOs: 495, 540, and 587, respectively. In some embodiments, the anti-tau antibody comprises HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3, wherein the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences respectively comprise the sequences of SEQ ID NOs: 1152, 1153, 435, 495, 540, and 587. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, or more changes, e.g., amino acid substitutions, insertions, or deletions, relative to the amino acid sequence of any of SEQ ID NOs: 1152, 1153, 435, 495, 540, and 587.

[0411] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of heavy chain complementarity determining region 1 (HC CDR1), HC CDR2, and / or HC CDR3, wherein the HC CDR1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NOs: 1173, 1174, and 1175, respectively. In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of LC CDR1, LC CDR2, and / or LC CDR3, wherein the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NOs: 1176, 1177, and 587, respectively. In some embodiments, the anti-tau antibody comprises HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3, wherein the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences respectively comprise the sequences of SEQ ID NOs: 1173, 1174, 1175, 1176, 1177, and 587. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, or more changes, e.g., amino acid substitutions, insertions, or deletions, relative to the amino acid sequence of any of SEQ ID NOs: 1173, 1174, 1175, 1176, 1177, and 587.

[0412] In some embodiments, the anti-tau antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:4, or encoded by the nucleotide sequence of SEQ ID NO:150, or a sequence substantially identical (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences. In some embodiments, the anti-tau antibody comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:78, or encoded by the nucleotide sequence of SEQ ID NO:224, or a sequence substantially identical (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences. In some embodiments, the anti-tau antibody comprises heavy and light chain variable regions that comprise the amino acid sequences of SEQ ID NOs: 4 and 78, respectively, or that are encoded by the nucleotide sequences of SEQ ID NOs: 150 and 224, respectively, or sequences substantially identical (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences. In some embodiments, the nucleotide sequence encoding the heavy chain variable region of the anti-tau antibody comprises the nucleotide sequence of SEQ ID NO: 150, or a sequence substantially identical thereto (e.g., having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity), and / or the nucleotide sequence encoding the light chain variable region comprises the nucleotide sequence of SEQ ID NO: 224, or a sequence substantially identical thereto (e.g., having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity).

[0413] In some embodiments, the anti-tau antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:9, or encoded by the nucleotide sequence of SEQ ID NO:155, or a sequence substantially identical (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences. In some embodiments, the anti-tau antibody comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:83, or encoded by the nucleotide sequence of SEQ ID NO:229, or a sequence substantially identical (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences. In some embodiments, the anti-tau antibody comprises heavy chain and light chain variable regions that comprise the amino acid sequences of SEQ ID NOs: 9 and 83, respectively, or encoded by the nucleotide sequences of SEQ ID NOs: 155 and 229, respectively, or sequences substantially identical (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences. In some embodiments, the nucleotide sequence encoding the heavy chain variable region of the anti-tau antibody comprises the nucleotide sequence of SEQ ID NO: 155, or a sequence substantially identical thereto (e.g., having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity), and / or the nucleotide sequence encoding the light chain variable region comprises the nucleotide sequence of SEQ ID NO: 229, or a sequence substantially identical thereto (e.g., having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity).

[0414] In some embodiments, the anti-tau antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:21, or encoded by the nucleotide sequence of SEQ ID NO:167, or a sequence substantially identical (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences. In some embodiments, the anti-tau antibody comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:93, or encoded by the nucleotide sequence of SEQ ID NO:241, or a sequence substantially identical (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences. In some embodiments, the anti-tau antibody comprises heavy chain and light chain variable regions that comprise the amino acid sequences of SEQ ID NOs: 21 and 93, respectively, or that are encoded by the nucleotide sequences of SEQ ID NOs: 167 and 241, respectively, or sequences substantially identical (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences. In some embodiments, the nucleotide sequence encoding the heavy chain variable region of the anti-tau antibody comprises the nucleotide sequence of SEQ ID NO: 167, or a sequence substantially identical thereto (e.g., having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity), and / or the nucleotide sequence encoding the light chain variable region comprises the nucleotide sequence of SEQ ID NO: 241, or a sequence substantially identical thereto (e.g., having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity).

[0415] In some embodiments, the anti-tau antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 22, or encoded by the nucleotide sequence of SEQ ID NO: 168, or a sequence substantially identical (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences. In some embodiments, the anti-tau antibody comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 94, or encoded by the nucleotide sequence of SEQ ID NO: 242, or a sequence substantially identical (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences. In some embodiments, the anti-tau antibody comprises heavy chain and light chain variable regions that comprise the amino acid sequences of SEQ ID NOs: 22 and 94, respectively, or that are encoded by the nucleotide sequences of SEQ ID NOs: 168 and 242, respectively, or sequences substantially identical (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences. In some embodiments, the nucleotide sequence encoding the heavy chain variable region of the anti-tau antibody comprises the nucleotide sequence of SEQ ID NO: 168, or a sequence substantially identical thereto (e.g., having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity), and / or the nucleotide sequence encoding the light chain variable region comprises the nucleotide sequence of SEQ ID NO: 242, or a sequence substantially identical thereto (e.g., having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity).

[0416] In some embodiments, the anti-tau antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:23, or encoded by the nucleotide sequence of SEQ ID NO:169, or a sequence substantially identical (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences. In some embodiments, the anti-tau antibody comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:95, or encoded by the nucleotide sequence of SEQ ID NO:243, or a sequence substantially identical (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences. In some embodiments, the anti-tau antibody comprises heavy chain and light chain variable regions that comprise the amino acid sequences of SEQ ID NOs: 23 and 95, respectively, or that are encoded by the nucleotide sequences of SEQ ID NOs: 169 and 243, respectively, or sequences substantially identical (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences. In some embodiments, the nucleotide sequence encoding the heavy chain variable region of the anti-tau antibody comprises the nucleotide sequence of SEQ ID NO: 169, or a sequence substantially identical thereto (e.g., having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity), and / or the nucleotide sequence encoding the light chain variable region comprises the nucleotide sequence of SEQ ID NO: 243, or a sequence substantially identical thereto (e.g., having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity).

[0417] In some embodiments, the anti-tau antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:51, or encoded by the nucleotide sequence of SEQ ID NO:197, or a sequence substantially identical (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences. In some embodiments, the anti-tau antibody comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:122, or encoded by the nucleotide sequence of SEQ ID NO:270, or a sequence substantially identical (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences. In some embodiments, the anti-tau antibody comprises heavy chain and light chain variable regions that comprise the amino acid sequences of SEQ ID NOs: 51 and 122, respectively, or encoded by the nucleotide sequences of SEQ ID NOs: 197 and 270, respectively, or sequences substantially identical (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences. In some embodiments, the nucleotide sequence encoding the heavy chain variable region of the anti-tau antibody comprises the nucleotide sequence of SEQ ID NO: 197, or a sequence substantially identical thereto (e.g., having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity), and / or the nucleotide sequence encoding the light chain variable region comprises the nucleotide sequence of SEQ ID NO: 270, or a sequence substantially identical thereto (e.g., having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity).

[0418] In some embodiments, the anti-tau antibody comprises a VH and / or VL encoded by a codon-optimized nucleic acid sequence. Codon optimization can be achieved by any method known to those of skill in the art, including, but not limited to, methods by Genescript, EMBOSS, Bioinformatics, NUS, NUS2, Geneinfinity, IDT, NUS3, GregThatcher, Insilico, Molbio, N2P, Snapgene, and / or VectorNTI.

[0419] Anti-tau antibodies according to the present disclosure can be prepared using any of the antibody sequences presented herein (e.g., variable domain amino acid sequences, variable domain amino acid sequence pairs, CDR amino acid sequences, variable domain CDR amino acid sequence sets, variable domain CDR amino acid sequence set pairs, and / or framework region amino acid sequences), any of which can be prepared, for example, as a monoclonal antibody, multispecific antibody, chimeric antibody, antibody mimetic, scFv, or antibody fragment.

[0420] In some embodiments, anti-tau antibodies using any of the antibody sequences presented herein may be prepared as IgA, IgD, IgE, IgG, or IgM antibodies. When prepared as a mouse IgG antibody, the anti-tau antibody may be prepared as an IgG1, IgG2a, IgG2b, IgG2c, or IgG3 isotype. When prepared as a human IgG antibody, the anti-tau antibody may be prepared as an IgG1, IgG2, IgG3, or IgG4 isotype. Anti-tau antibodies prepared as human or humanized antibodies may contain one or more human constant domains.

[0421] The present disclosure provides, in some embodiments, nucleic acids (e.g., isolated nucleic acids) encoding any of the above-described antibodies, as well as viral genomes, vectors, AAV particles, and cells comprising same.

[0422] Tau protein antigen In some embodiments, the anti-tau antibody binds to a tau protein antigen, e.g., an epitope on a tau protein. The tau protein antigen may include human microtubule-associated protein tau, isoform 2 (SEQ ID NO: 920) or a fragment thereof. The tau protein antigen may include ePHF or a fragment thereof. The tau protein antigen may include one or more phosphorylated residues. Such phosphorylated residues may correspond to those found in pathological tau. In some embodiments, the tau protein antigen includes any of those listed in Table 8. In the table, the phosphorylated residue associated with each antigen is double underlined. In some embodiments, the tau protein may include a variant (e.g., a phosphorylated or non-phosphorylated variant) or fragment of the listed sequence.

[0423] [Table 11]

[0424] In some embodiments, the anti-tau antibodies of the present disclosure bind to a tau protein epitope on a tau protein antigen described herein. Such a tau protein epitope may comprise or be contained within a tau protein antigen amino acid sequence listed in Table 8. In some embodiments, the anti-tau antibodies of the present disclosure bind to a tau protein epitope that includes a region formed by a complex of at least two tau proteins.

[0425] In some embodiments, disclosed herein are encoded antibodies that compete with the aforementioned antibodies for binding to tau, hi some embodiments, disclosed herein are antibodies that bind to the same epitope as, substantially the same epitope as, an epitope that overlaps with, or an epitope that substantially overlaps with, the epitope of the aforementioned anti-tau antibodies.

[0426] In some embodiments, competition or cross-competition refers to the ability of an antibody to interfere with the binding of an anti-tau antibody, such as the anti-tau antibody provided herein, to a target, such as a tau protein. Interference with binding can be direct or indirect (e.g., through allosteric modulation of the antibody or the target). The extent to which an antibody can interfere with the binding of another antibody to a target, and therefore whether it can be said to compete, can be determined using a competitive binding assay, such as a FACS assay, ELISA, or BIACORE assay. In some embodiments, the competitive binding assay is a quantitative competitive assay. In some embodiments, a first anti-tau antibody is said to compete with a second anti-tau antibody for binding to a target if it reduces binding of the first antibody to the target by 10% or more, e.g., 20% or more, 30% or more, 40% or more, 50% or more, 55% or more, 60% or more, 65% or more, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more, 95% or more, 98% or more, 99% or more in a competitive binding assay (e.g., a competitive assay described herein).

[0427] In some embodiments, an epitope comprises a portion of an antigen (e.g., a tau protein antigen) that specifically interacts with an antibody. Such a portion is referred to herein as an epitopic determinant and typically comprises or is a portion of an element such as an amino acid side chain or a sugar side chain. Epitopes can be defined by methods known in the art or disclosed herein, for example, by crystallography or hydrogen-deuterium exchange. At least one or some of the portions on an antibody that specifically interact with an epitopic determinant are typically located within a CDR(s). Typically, an epitope has specific three-dimensional structural characteristics. Typically, an epitope has specific charge characteristics. Some epitopes are linear epitopes, while others are conformational epitopes.

[0428] In one embodiment, an epitopic determinant is a moiety on an antigen, such as an amino acid side chain or sugar side chain, or portion thereof, that is within a predetermined distance, e.g., within 5 angstroms, of a moiety on an antibody when the antigen and antibody are co-crystallized, and is referred to herein as a crystallographic epitopic determinant. In some embodiments, the crystallographic epitopic determinants of an epitope are collectively referred to as a crystallographic epitope.

[0429] A first antibody binds to the same epitope as a second antibody (e.g., a reference antibody, e.g., an antibody disclosed herein) when the first antibody specifically interacts with the same epitopic determinant on the antigen as the second or reference antibody specifically interacts with, e.g., when the interaction is measured using the same method for both the antibody and the second or reference antibody. Overlapping epitopes share at least one epitopic determinant. A first antibody binds to an overlapping epitope with a second antibody (e.g., a reference antibody, e.g., an antibody disclosed herein) when both antibodies specifically interact with a common epitopic determinant. A first antibody and a second antibody (e.g., a reference antibody, e.g., an antibody disclosed herein) bind to substantially overlapping epitopes when at least half of the epitopic determinants of the second or reference antibody are found as epitopic determinants within the epitope of the first antibody. A first antibody and a second antibody (e.g., a reference antibody, e.g., an antibody disclosed herein) bind to substantially the same epitope if the first antibody binds to at least half of the core epitopic determinants of the epitope of the second antibody or the reference antibody, where the core epitopic determinants are defined by crystal structure analysis.

[0430] Epitope specificity Antibodies of the present disclosure may bind to a tau protein epitope that may include or be contained within residues of SEQ ID NOs: 920-926. The antibodies may compete for binding to the tau protein epitope with other anti-tau antibodies, including, but not limited to, AT100, AT120, PT3, C10.2, PT76, IPN002, 6C5, and UCBD. The tau protein epitope may include C-terminal residues 409-436 of human tau (SEQ ID NO: 920). Such an epitope may include residues 413-430 of human tau (SEQ ID NO: 920). Antibodies that bind to such residues have a K of about 0.1 nM to about 0.5 nM. D In some embodiments, tau protein epitopes may include residues 55-76, 159-194, 219-247, and / or 381-426 of human tau (SEQ ID NO: 920). Such epitopes may include residues 57-72, 175-191, 223-238, and / or 383-400 of human tau (SEQ ID NO: 920). Antibodies that bind to such residues may exhibit a K of about 0.5 nM to about 5 nM. D may be present.

[0431] In some embodiments, the present disclosure provides an antibody that competes with a second antibody for binding to a tau protein epitope. Such epitope may include one or more of residues 32-49, 55-76, 57-72, 159-194, 175-191, 185-200, 219-247, 223-238, 381-426, 383-400, 409-436, and 413-430 of human tau (SEQ ID NO: 920).

[0432] The tau protein epitope may comprise one or more of residues 409-436 and 413-430 of human tau (SEQ ID NO: 920). A second antibody that competes for binding to such an epitope may comprise a variable domain pair selected from the group consisting of a VH having the amino acid sequence of SEQ ID NO: 21 and a VL having the amino acid sequence of SEQ ID NO: 93, a VH having the amino acid sequence of SEQ ID NO: 22 and a VL having the amino acid sequence of SEQ ID NO: 94, and a VH having the amino acid sequence of SEQ ID NO: 23 and a VL having the amino acid sequence of SEQ ID NO: 95.

[0433] Antibodies that compete for tau epitope binding with such second antibodies include CDRH1 comprising the amino acid sequence G[F / Y]TFT[R / I][Y / F] (SEQ ID NO: 931), or more commonly G-X1-TFT-X2-X3 (SEQ ID NO: 932) (where X1, X2, and X3 can be any amino acid, e.g., X1 and / or X3 can be an amino acid having a hydrophobic and / or aromatic side chain, such as F or Y, and / or X2 can be a positively charged residue (e.g., R, K, H) or a residue having an aliphatic side chain (e.g., A, V, I, or L)); CDRH2 comprising the amino acid sequence NPNNGG (SEQ ID NO: 341); CDRH3 comprising the amino acid sequence GTGTGAMDY (SEQ ID NO: 410); and / or a CDRL3 comprising the amino acid sequence FQGTHVPRT (SEQ ID NO: 571).

[0434] In some embodiments, CDRH1 may comprise the amino acid sequence G[F / Y]TFT[R / I][Y / F] (SEQ ID NO: 931). CDRH2 may comprise the amino acid sequence NPNNGG (SEQ ID NO: 341). CDRH3 may comprise the amino acid sequence GTGTGAMDY (SEQ ID NO: 410). CDRL1 may comprise the amino acid sequence RSSQSLVH[N / S]NG[I / N]T[H / Y]LY (SEQ ID NO: 933). CDRL2 may comprise the amino acid sequence RVS[N / S]RFS (SEQ ID NO: 935). CDRL3 may comprise the amino acid sequence FQGTHVPRT (SEQ ID NO: 571).

[0435] In some embodiments, the tau protein epitope may include one or more of residues 57-72, 175-191, 223-238, and 383-400 of human tau (SEQ ID NO: 920). A second antibody that competes for binding to such an epitope may comprise a variable domain pair selected from the group consisting of a VH having the amino acid sequence of SEQ ID NO: 51 and a VL having the amino acid sequence of SEQ ID NO: 122, a VH having the amino acid sequence of SEQ ID NO: 53 and a VL having the amino acid sequence of SEQ ID NO: 124, a VH having the amino acid sequence of SEQ ID NO: 54 and a VL having the amino acid sequence of SEQ ID NO: 125, a VH having the amino acid sequence of SEQ ID NO: 56 and a VL having the amino acid sequence of SEQ ID NO: 125, a VH having the amino acid sequence of SEQ ID NO: 57 and a VL having the amino acid sequence of SEQ ID NO: 126, a VH having the amino acid sequence of SEQ ID NO: 35 and a VL having the amino acid sequence of SEQ ID NO: 107, and a VH having the amino acid sequence of SEQ ID NO: 48 and a VL having the amino acid sequence of SEQ ID NO: 120.

[0436] Antibodies that compete for tau epitope binding with such a second antibody include CDRH1 comprising the amino acid sequence of GFSL[S / N]T[S / F][A / G]M (SEQ ID NO: 964), or more commonly GFSL-X1-T-X2-X3-M (SEQ ID NO: 965) (wherein X1-X3 can be any amino acid, e.g., X1 is S / T / N / Q and / or X2 is S / T / F / Y and / or X3 is G / A / I / L / V); CDRH2 comprising the amino acid sequence YWDDD (SEQ ID NO: 362); CDRH3 comprising X2-X3-X4-X5-X6-X7-X8-X9-DY (SEQ ID NO: 975), where each of X1-X9 can be any amino acid and / or one or more of X3-X5 can be absent, e.g., X1 is R / K / H / A / V / I / L / G / S / T and / or X2 is Y / F / R / K / H and / or X 3 is Y / F / Absent, and / or X4 is S / T / Absent, and / or X5 is N / Q / Absent, and / or X6 is G / A / V / I / L / S / T / Y / F / R / K / H, and / or X7 is Y / F / N / Q / G / A / V / I / L, and / or X8 is G / A / V / I / L / Y / F / N / Q, and / or X9 is M / F / Y);A CDRL1 comprising the amino acid sequence [K / S][S / A]S[Q / S]S[L / I / V][L / S][N / S / D][D / S / T][V / G / D / Y][N / G / absent][Q / absent][K / absent][N / T / absent][Y / absent][L / absent][A / H / N] (SEQ ID NO: 976), or more commonly X1-X2-S-X3-S-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15 (SEQ ID NO: 977), where each of X1 through X15 is any amino acid. and / or one or more of X9 to X14 may be absent, for example, X1 is K / R / H / S / T, and / or X2 is S / T / A / V / I / L, and / or X3 is Q / N / S / T, and / or X4 is L / I / V / A, and / or X5 is A / V / I / L / S / T, and / or X6 is N / Q / S / T / D / E, and / or X7 is D / E / S / T, and / or X8 is G / A / V / I / L / D / E / Y / F, and and / or X9 is N / Q / G / A / absent, and / or X10 is Q / N / absent, and / or X11 is K / R / H / absent, and / or X12 is N / Q / T / S / absent, and / or X13 is Y / F / absent, and / or X14 is A / V / I / L / absent, and / or X15 is A / V / I / L / H / K / R / N / Q); the amino acid sequence [Y / G / L / R][A / T / V]S[N / T / K][R / L][C / E / D / A][T / S] (SEQ ID NO: 978), also or more generally a CDRL2 comprising X1-X2-S-X3-X4-X5-X6 (SEQ ID NO: 979), where X1 through X6 can be any amino acid, e.g., X1 is Y / F / G / A / V / I / L / R / K / H and / or X2 is A / V / I / L / T / S and / or X3 is N / Q / T / S / K / R / H and / or X4 is R / K / H / A / V / I / L and / or X5 is C / S / E / D / A / V / I / L and / or X6 is T / S;and / or a CDRL3 comprising the amino acid sequence [W / Q][Q / N][G / D][T / S / Y / H][H / S / R][F / I / S / H]P[Q / R / L / Y][Absent / Y]T (SEQ ID NO: 980), or more generally X1-X2-X3-X4-X5-X6-P-X7-X8-T (SEQ ID NO: 981), where each of X1 through X8 can be any amino acid and / or X8 can be absent, e.g., X1 is Q / N X1 is / W / F / Y, and / or X2 is Q / N, and / or X3 is G / A / V / I / L / D / E, and / or X4 is T / S / Y / F / H / K / R, and / or X5 is H / K / R / S / T, and / or X6 is F / Y / A / V / I / L / S / T / H / K / R, and / or X7 is Q / N / R / K / H / A / V / I / L / Y / F, and / or X8 is Y / F / absent);

[0437] CDRH1 can comprise the amino acid sequence GFSL[S / N]T[S / F][A / G]M (SEQ ID NO: 964). CDRH2 can comprise the amino acid sequence YWDDD (SEQ ID NO: 362). CDRH3 can comprise the amino acid sequence R[R / V / K / S / G][Y / R][Y / absent][S / absent][absent / N][G / S / Y / R][Y / N / G][G / A / Y / N][M / F / Y]DY (SEQ ID NO: 974). CDRL1 can comprise the amino acid sequence [K / S][S / A]S[Q / S]S[L / I / V][L / S][N / S / D][D / S / T][V / G / D / Y][N / G / absent][Q / absent][K / absent][N / T / absent][Y / absent][L / absent][A / H / N] (SEQ ID NO: 976). CDRL2 can comprise the amino acid sequence [Y / G / L / R][A / T / V]S[N / T / K][R / L][C / E / D / A][T / S] (SEQ ID NO: 978). CDRL3 can comprise the amino acid sequence [W / Q][Q / N][G / D][T / S / Y / H][H / S / R][F / I / S / H]P[Q / R / L / Y][absent / Y]T (SEQ ID NO: 980).

[0438] II. Vectorization According to the present disclosure, compositions for delivering an anti-tau antibody or functional variant thereof by adeno-associated virus particles (AAV) are provided. In some embodiments, an AAV particle, e.g., an AAV particle described herein, or multiple particles, can be provided, e.g., delivered, to a cell, tissue, organ, or organism in vivo, ex vivo, or in vitro via any of several administration routes.

[0439] As used herein, an "AAV particle" is a virus that comprises a capsid and a viral genome having at least one payload region and at least one inverted terminal repeat (ITR) region.

[0440] As used herein, "viral genome" or "vector genome" refers to the nucleic acid sequence(s) packaged in an AAV particle. The viral genome includes at least one payload region that encodes a polypeptide, such as an antibody, antibody-based composition, or fragment thereof.

[0441] As used herein, a "payload" or "payload region" is any nucleic acid molecule that encodes one or more polypeptides. At a minimum, the payload region includes a nucleic acid sequence encoding an antibody, antibody-based composition, or fragment thereof, and may optionally include one or more functional or regulatory elements that facilitate transcriptional expression and / or polypeptide translation.

[0442] In some embodiments, the AAV particles, viral genome, and / or payload, and methods of their use, may be as described in WO2017189963 or WO2020223276, the contents of each of which are incorporated herein by reference in their entirety.

[0443] The nucleic acid sequences, viral genomes, and polypeptides disclosed herein may be engineered to contain modular elements and / or sequence motifs assembled to enable expression of an antibody or functional variant thereof, e.g., an antibody described herein. In some embodiments, the nucleic acid sequence encodes an antibody comprising one or more of the antibody CDRs (e.g., heavy and / or light chain CDRs), variable heavy (VH) and / or variable light (VL) chain regions, heavy and / or light chain constant regions, or combinations thereof. In some embodiments, the nucleic acid sequence encoding the antibody may encode a linker, e.g., such that the VH / heavy and VL / light chains of the antibody are connected via a linker. In some embodiments, the viral genome may further comprise a promoter region, an intron, a Kozak sequence, an enhancer, or a polyadenylation sequence. The order of expression, structural position, or number of concatemers (e.g., VH, VL, heavy chain, light chain, and / or linker) may vary within or between different payload regions. The identity, location, and number of linkers expressed by the payload region can also vary. In some embodiments, the payload is a region comprising one or more humanized antibody sequences, such as, but not limited to, a humanized antibody VL, light chain domain, and / or a humanized antibody VH, heavy chain domain, or fragments thereof.

[0444] In some embodiments, the present disclosure provides methods of delivering an antibody (e.g., an anti-tau antibody described herein) and / or a nucleic acid sequence encoding an antibody (e.g., an anti-tau antibody described herein) contained within a viral genome contained within a recombinant AAV particle (e.g., an AAV particle described herein) to a cell, tissue, organ, or subject.

[0445] Adeno-associated virus (AAV) and AAV particles In some embodiments, adeno-associated viruses (AAVs) are small, non-enveloped, icosahedral-capsid viruses of the Parvoviridae family, characterized by a single-stranded DNA viral genome. The Parvoviridae family consists of two subfamilies: the Parvovirinae subfamily, which infect vertebrates, and the Densovirinae subfamily, which infect invertebrates. The Parvoviridae family includes the Dependovirus genus, which includes AAVs. In some embodiments, AAVs can replicate in vertebrate hosts, including, but not limited to, humans, primates, bovine, canine, equine, and ovine species.

[0446] Parvoviruses and other members of the Parvoviridae family are reviewed in Kenneth I. Berns, "Parvoviridae: The Viruses and Their Replication," Chapter 69 in FIELDS VIROLOGY (3d Ed. 1996), the contents of which are incorporated by reference in their entirety.

[0447] AAVs have proven useful as biological tools due to their relatively simple structure, ability to infect a wide range of cells (including resting and dividing cells) without integrating into the host genome or replicating, and a relatively mild immunogenicity profile. The viral genome can be engineered to contain minimal components for the assembly of functional recombinant viruses or viral particles loaded with a desired payload or engineered to express or deliver a desired payload to specific tissues.

[0448] The wild-type AAV vector genome is a linear, single-stranded DNA (ssDNA) molecule approximately 5,000 nucleotides (nt) long. Inverted terminal repeats (ITRs) traditionally cap the viral genome at both the 5' and 3' ends, providing origins of replication for the viral genome. Without wishing to be bound by theory, the AAV viral genome typically contains two ITR sequences. These ITRs have a characteristic T-shaped hairpin structure defined by self-complementary regions (145 nt in wild-type AAV) at the 5' and 3' ends of the ssDNA, which form an energetically stable double-stranded region. The double-stranded hairpin structure has multiple functions, including, but not limited to, acting as an origin of DNA replication by serving as a primer for the endogenous DNA polymerase complex of the host viral replicating cell.

[0449] The wild-type AAV viral genome further contains nucleotide sequences for two open reading frames, one for four nonstructural Rep proteins (Rep78, Rep68, Rep52, and Rep40, encoded by the Rep genes) and one for three capsid or structural proteins (VP1, VP2, and VP3, encoded by the capsid or Cap genes). The Rep proteins are important for replication and packaging, and the capsid proteins assemble to create the protein coat of AAV, i.e., the AAV capsid. Alternative splicing and alternative start codons and promoters result in the production of four different Rep proteins from a single open reading frame and the production of three capsid proteins from a single open reading frame. While this varies depending on the AAV serotype, as a non-limiting example, for AAV9 / hu.14 (SEQ ID NO: 123 of US Pat. No. 7,906,111 , the entire contents of which are incorporated herein by reference), VP1 refers to amino acids 1-736, VP2 refers to amino acids 138-736, and VP3 refers to amino acids 203-736. In other words, VP1 is the full-length capsid sequence, while VP2 and VP3 are shorter components. As a result, a sequence change within the VP3 region will result in a change to both VP1 and VP2, but because VP3 is the shortest of the three, the percent difference compared to the parent sequence will be greatest for VP3. While this discussion is focused on amino acid sequences, the same discussion applies to the nucleic acid sequences encoding these proteins. The three capsid proteins assemble together to create the AAV capsid protein. Without wishing to be bound by theory, AAV capsid proteins typically comprise a 1:1:10 molar ratio of VP1:VP2:VP3. As used herein, "AAV serotype" is primarily defined by the AAV capsid. In some cases, the ITRs are also specifically described by the AAV serotype (e.g., AAV2 / 9).

[0450] For use as a biological tool, the wild-type AAV viral genome can be modified to replace the rep / cap sequence with a nucleic acid sequence containing a payload region with at least one ITR region. Typically, there are two ITR regions in a recombinant AAV viral genome. The rep / cap sequence can be provided in trans during production to generate AAV particles.

[0451] In addition to an encoded heterologous payload, AAV vectors can contain all or part of the viral genome of any naturally occurring and / or recombinant AAV serotype nucleotide sequence or variant. AAV variants can have sequences with significant homology at the nucleic acid level (genome or capsid) and amino acid level (capsid) to produce constructs that are generally physically equivalent and functionally functional, replicate by similar mechanisms, and assemble by similar mechanisms. Chiorini et al., J. Vir. 71:6823-33 (1997), Srivastava et al., J. Vir. 45:555-64 (1983), Chiorini et al., J. Vir. 73:1309-1319 (1999), Rutledge et al., J. Vir. 72:309-319 (1998), and Wu et al., J. Vir. 74:8635-47 (2000), the contents of each of which are incorporated herein by reference in their entireties.

[0452] In some embodiments, the AAV particles of the present disclosure are recombinant AAV viral vectors that are replication-deficient and lack sequences encoding functional Rep and Cap proteins within their viral genome. These defective AAV vectors lack most or all of the parent coding sequences and can essentially retain only one or two AAV ITR sequences and a nucleic acid of interest for delivery to a cell, tissue, organ, or organism.

[0453] In some embodiments, the viral genome of an AAV particle of the present disclosure comprises at least one control element that provides for the replication, transcription, and translation of the coding sequence encoded therein. Not all control elements need always be present, so long as the coding sequence is replicable, transcribable, and / or translatable in an appropriate host cell. Non-limiting examples of expression control elements include sequences for transcription initiation and / or termination, promoter and / or enhancer sequences, efficient RNA processing signals such as splicing and polyadenylation signals, sequences that stabilize cytoplasmic mRNA, sequences that enhance translation efficiency (e.g., Kozak consensus sequences), sequences that enhance protein stability, and / or sequences that enhance protein processing and / or secretion.

[0454] According to the present disclosure, AAV particles for use in therapeutic and / or diagnostic agents comprise a virus that has been distilled or reduced to the minimum components necessary for transduction of a desired nucleic acid payload or cargo. In this manner, the AAV particle is engineered as a vehicle for specific delivery without the deleterious replication and / or integration properties seen in wild-type virus.

[0455] The AAV vectors of the present disclosure can be recombinantly produced and can be based on the parent or reference sequence of an adeno-associated virus (AAV). As used herein, a "vector" is any molecule or moiety that transports, transduces, or otherwise acts as a carrier of a heterologous molecule, such as a nucleic acid, as described herein.

[0456] In addition to single-stranded AAV viral genomes (e.g., ssAAV), the present disclosure also provides self-complementary AAV (scAAV) viral genomes. scAAV vector genomes contain DNA strands that anneal together to form double-stranded DNA. scAAV allows for rapid expression in transduced cells by omitting second-strand synthesis.

[0457] In some embodiments, the AAV particles of the present disclosure are scAAV. In some embodiments, the AAV particles of the present disclosure are ssAAV. Methods for producing and / or modifying AAV particles have been disclosed in the art, such as pseudotyped AAV vectors (PCT Patent Publication Nos. WO200028004, WO200123001, WO2004112727, WO2005005610, and WO2005072364, the contents of each of which are incorporated herein by reference in their entirety).

[0458] AAV particles can be modified to enhance delivery efficiency. Such modified AAV particles can be efficiently packaged and used to successfully infect target cells with high frequency and extremely low toxicity. In some embodiments, the capsid of the AAV particle is engineered according to the method described in U.S. Publication No. US20130195801, the entire contents of which are incorporated herein by reference.

[0459] In some embodiments, AAV particles comprising a payload region encoding a polypeptide can be introduced into mammalian cells. AAV serotype In some embodiments, AAV particles, e.g., AAV particles for vectored delivery of an antibody (e.g., an anti-tau antibody) described herein, can comprise or be derived from any natural or recombinant AAV serotype. The AAV particles of the present disclosure can comprise or be derived from any natural or recombinant AAV serotype. According to the present disclosure, the AAV particles include VOY101, VOY201, AAVPHP.B (PHP.B), AAVPHP.A (PHP.A), AAVG2B-26, AAVG2B-13, A AVTH1.1-32, AAVTH1.1-35, AAVPHP.B2(PHP.B2), AAVPHP.B3(PHP.B3), AAVPHP.N / PHP.B-DGT, AAVPH P.B-EST, AAVPHP.B-GGT, AAVPHP.B-ATP, AAVPHP.B-ATT-T, AAVPHP.B-DGT-T, AAVPHP.B-GGT-T, AAVP HP.B-SGS, AAVPHP.B-AQP, AAVPHP.B-QQP, AAVPHP.B-SNP(3), AAVPHP.B-SNP, AAVPHP.B-QGT, AAVPHP .B-NQT, AAVPHP.B-EGS, AAVPHP.B-SGN, AAVPHP.B-EGT, AAVPHP.B-DST, AAVPHP.B-DST, AAVPHP.B-S TP, AAVPHP.B-PQP, AAVPHP.B-SQP, AAVPHP.B-QLP, AAVPHP.B-TMP, AAVPHP.B-TTP, AAVPHP.S / G2A12, AAVG2A15 / G2A3(G2A3), AAVG2B4(G2B4), AAVG2B5(G2B5), PHP.S, AAV1, AAV2, AAV2G9, AAV3, AAV3a, A AV3b, AAV3-3, AAV4, AAV4-4, AAV5, AAV6, AAV6.1, AAV6.2, AAV6.1.2, AAV7, AAV7.2, AAV8, AAV9, AAV9 K449R, AAV9.11, AAV9.13, AAV9.16, AAV9.24, AAV9.45, AAV9.47, AAV9.61, AAV9.68, AAV9.84, AAV9.9, AAV10, AAV11, AAV12, AAV16.3, AAV24.1, AAV27.3, AAV42.12、AAV42-1b、AAV42-2、AAV42-3a、AAV42-3b、AAV42-4、AAV42-5a、AAV42-5b、AAV42-6b、AAV42-8、AAV42-10、AAV42-11、AAV42-12、AAV42-13、AAV42-1 5、AAV42-aa、AAV43-1、AAV43-12、AAV43-20、AAV43-21、AAV43-23、AAV43-25、AAV43-5、AAV44.1、AAV44.2、AAV44.5、AAV223.1、AAV223.2、AAV223.4、AA V223.5、AAV223.6、AAV223.7、AAV1-7 / rh.48、AAV1-8 / rh.49、AAV2-15 / rh.62、AAV2-3 / rh.61、AAV2-4 / rh.50、AAV2-5 / rh.51、AAV3.1 / rh.6、AAV3.1 / rh.61 .9、AAV3-9 / rh.52、AAV3-11 / rh.53、AAV4-8 / r11.64、AAV4-9 / rh.54、AAV4-19 / rh.55、AAV5-3 / rh.57、AAV5-22 / rh.58、AAV7.3 / hu.7、AAV16.8 / hu.10 AV16.12 / hu.11、AAV29.3 / bb.1、AAV29.5 / bb.2、AAV106.1 / hu.37、AAV114.3 / hu.40、AAV127.2 / hu.41、AAV127.5 / hu.42、AAV128.3 / hu.44、AAV130.4 / hu.48、AAV145.1 / hu.53、AAV145.5 / hu.54、AAV145.6 / hu.55、AAV161.10 / hu.60、AAV161.6 / hu.61、AAV33.12 / hu.17、AAV33.4 / hu.15、AAV33.8 / hu.16、A AV52 / hu.19、AAV52.1 / hu.20、AAV58.2 / hu.25、AAVA3.3、AAVA3.4、AAVA3.5、AAVA3.7、AAVC1、AAVC2、AAVC5、AAV-DJ、AAV-DJ8、AAV3、AAV5、AAV2 rh.72、AAVhu.8、AAVrh.68、AAVrh.70、AAVpi.1、AAVpi.3、AAVpi.2、AAVrh.60、AAVrh.44、AAVrh.65、AAVrh.55、AAVrh.47、AAVrh.69、AAVrh.45、AAVrh.59、AAVhu.12、AAVH6、AAVLK03、AAVH-1 / hu.1、AAVH-5 / hu.3、AAVLG-10 / rh.40、AAVLG-4 / rh.38、AAVLG-9 / hu.39、AAV N721-8 / rh.43、AAVCh.5、AAVCh.5R1、AAVcy.2、AAVcy.3、AAVcy.4、AAVcy.5、AAVCy.5R1、AAVCy.5R2、AAVCy.5R3、AAVC y.5R4、AAVcy.6、AAVhu.1、AAVhu.2、AAVhu.3、AAVhu.4、AAVhu.5、AAVhu.6、AAVhu.7、AAVhu.9、AAVhu.10、AAVhu.11、 AAVhu.13、AAVhu.15、AAVhu.16、AAVhu.17、AAVhu.18、AAVhu.20、AAVhu.21、AAVhu.22、AAVhu.23.2、AAVhu.24、AAVhu .25、AAVhu.27、AAVhu.28、AAVhu.29、AAVhu.29R、AAVhu.31、AAVhu.32、AAVhu.34、AAVhu.35、AAVhu.37、AAVhu.39、A AVhu.40、AAVhu.41、AAVhu.42、AAVhu.43、AAVhu.44、AAVhu.44R1、AAVhu.44R2、AAVhu.44R3、AAVhu.45、AAVhu.46、AA Vhu.47、AAVhu.48、AAVhu.48R1、AAVhu.48R2、AAVhu.48R3、AAVhu.49、AAVhu.51、AAVhu.52、AAVhu.54、AAVhu.55、AA Vhu.56、AAVhu.57、AAVhu.58、AAVhu.60、AAVhu.61、AAVhu.63、AAVhu.64、AAVhu.66、AAVhu.67、AAVhu.14 / 9、AAVhu.t 19、AAVrh.2、AAVrh.2R、AAVrh.8、AAVrh.8R、AAVrh.10、AAVrh.12、AAVrh.13、AAVrh.13R、AAVrh.14、AAVrh.17、AAVrh.18、AAVrh.19、AA Vrh.20、AAVrh.21、AAVrh.22、AAVrh.23、AAVrh.24、AAVrh.25、AAVrh.31、AAVrh.32、AAVrh.33、AAVrh.34、AAVrh.35、AAVrh.36、AAVrh.37、AAVrh.37R2、AAVrh.38、AAVrh.39、AAVrh.40、AAVrh.46、AAVrh.48、AAVrh.48.1、AAVrh.48.1.2、AAVrh.48.2、AAVrh.49、AAVrh.51、AAVrh.52、AAVrh. rh.53、AAVrh.54、AAVrh.56、AAVrh.57、AAVrh.58、AAVrh.61、AAVrh.64、AAVrh.64R1、AAVrh.64R2、AAVrh.67、AAVrh.73、AAVrh.74、AAVrh.8R、AAVrh.8R. A586R mutation、AAVrh8R R533A mutation、AAAV、BAAV、ヤギAAV、ウシAAV、AAVhE1.1、AAVhEr1.5、AAVhEr1.14、AAVhEr1.8、AAVhEr1.16、AAVhEr1.18、AAVhEr1.35、AAVhEr1.7、AAVhEr1.36、AAVhEr r2.29、AAVhEr2.4、AAVhEr2.16、AAVhEr2.30、AAVhEr2.31、AAVhEr2.36、AAVhER1.23、AAVhEr3.1、AAV2.5T、AAV-PAEC、AAV-LK01、AAV-LK02、AAV-LK03、AAV-L K04、AAV-LK05、AAV-LK06、AAV-LK07、AAV-LK08、AAV-LK09、AAV-LK10、AAV-LK11、AAV-LK12、AAV-LK13、AAV-LK14、AAV-LK15、AAV-LK16、AAV-LK17、AAV-LK18 AAV-LK19、AAV-PAEC2、AAV-PAEC4、AAV-PAEC6、AAV-PAEC7、AAV-PAEC8、AAV-PAEC11、AAV-PAEC12、AAV-2-pre-miRNA-101、AAV-8h、AAV-8b、AAV-h、AAV-b、AAV SM 10-2、AAVシャッフル100-1、AAVシャッフル100-3、AAVシャッフル100-7、AAVシャッフル10-6、AAVシャッフル10-8、AAV SM 10-1、AAV SM 10-8、AAV SM 100-3 100-10、BNP61 AAV、BNP62 AAV、BNP63 AAV、AAVrh.50、AAVrh.43、AAVrh.62, AAVrh.48, AAVhu.19, AAVhu.11, AAVhu.53, AAV4-8 / rh.64, AAVLG-9 / hu.39, AAV54.5 / hu.23, AAV54.2 / hu.22, AAV54.7 / hu.24, AAV54.1 / hu.21, AAV54.4R / hu.27, AAV46.2 / hu.28, AAV46.6 / hu.29, AAV128.1 / hu.43, authentic AAV (ttAAV), UPENN AAV 10, Japanese AAV 10 serotype, AAV CBr-7.1, AAV CBr-7.10, AAV CBr-7.2, AAV CBr-7.3, AAV CBr-7.4, AAV CBr-7.5, AAV CBr-7.7, AAV CBr-7.8, AAV CBr-B7.3, AAV CBr-B7.4, AAV CBr-E1, AAV CBr-E2, AAV CBr-E3, AAV CBr-E4, AAV CBr-E5, AAV CBr-e5, AAV CBr-E6, AAV CBr-E7, AAV CBr-E8, AAV CHt-1, AAV CHt-2, AAV CHt-3, AAV CHt-6.1, AAV CHt-6.10, AAV CHt-6.5, AAV CHt-6.6, AAV CHt-6.7, AAV CHt-6.8、AAV CHt-P1、AAV CHt-P2、AAV CHt-P5、AAV CHt-P6、AAV CHt-P8、AAV CHt-P9、AAV CKd-1、AAV CKd-10、AAV CKd-2、AAV CKd-3、AAV CKd-4、AAV CKd-6、AAV CKd-7、AAV CKd-8、AAV CKd-B1、AAV CKd-B2、AAV CKd-B3、AAV CKd-B4、AAV CKd-B5、AAV CKd-B6、AAV CKd-B7、AAV CKd-B8、AAV CKd-H1、AAV CKd-H2、AAV CKd-H3、AAV CKd-H4、AAV CKd-H5、AAV CKd-H6、AAV CKd-N3、AAV CKd-N4、AAV CKd-N9、AAV CLg-F1、AAV CLg-F2、AAV CLg-F3、AAV CLg-F4、AAV CLg-F5、AAV CLg-F6、AAV CLg-F7、AAV CLg-F8、AAV CLv-1、AAV CLv1-1、AAV CLv1-10、AAV CLv1-2、AAV CLv-12、AAV CLv1-3、AAV CLv-13、AAV CLv1-4、AAV Clv1-7、AAV Clv1-8、AAV Clv1-9、AAV CLv-2、AAV CLv-3、AAV CLv-4、AAV CLv-6、AAV CLv-8、AAV CLv-D1、AAV CLv-D2、AAV CLv-D3、AAV CLv-D4、AAV CL. v-D5, AAV CLv-D6, AAV CLv-D7, AAV CLv-D8, AAV CLv-E1, AAV CLv-K1, AAV CLv-K3, AAV CLv-K6, AAV CLv-L4, AAV CLv-L5, AAV CLv-L6, AAV CLv-M1, AAV CLv-M11, AAV CLv-M2, AAV CLv-M5, AAV CLv-M6, AAV CLv-M7, AAV CLv-M8, AAV CLv-M9, AAV CLv-R1, AAV CLv-R2, AAV CLv-R3, AAV CLv-R4, AAV CLv-R5, AAV CLv-R6, AAV CLv-R7, AAV CLv-R8, AAV CLv-R9. CSp-8.6, AAV CSp-8.7, AAV CSp-8.8, AAV CSp-8.9, AAV The peptides may utilize or be based on a serotype selected from any of: CSp-9, AAV.hu.48R3, AAV.VR-355, AAV3B, AAV4, AAV5, AAVF1 / HSC1, AAVF11 / HSC11, AAVF12 / HSC12, AAVF13 / HSC13, AAVF14 / HSC14, AAVF15 / HSC15, AAVF16 / HSC16, AAVF17 / HSC17, AAVF2 / HSC2, AAVF3 / HSC3, AAVF4 / HSC4, AAVF5 / HSC5, AAVF6 / HSC6, AAVF7 / HSC7, AAVF8 / HSC8, and / or AAVF9 / HSC9, and variants thereof.

[0460] In some embodiments, the AAV serotype is selected from the group consisting of sequences set forth in U.S. Publication No. US20030138772, the entire contents of which are incorporated herein by reference, including, but not limited to, AAV1 (SEQ ID NOs: 6 and 64 in US20030138772), AAV2 (SEQ ID NOs: 7 and 70 in US20030138772), AAV3 (SEQ ID NOs: 8 and 71 in US20030138772), AAV4 (SEQ ID NOs: 9 and 10 in US20030138772), AAV5 (SEQ ID NOs: 11 and 12 in US20030138772), AAV6 (SEQ ID NOs: 13 and 14 in US20030138772), AAV7 (SEQ ID NOs: 15 and 16 in US20030138772), AAV8 (SEQ ID NOs: 17 and 18 in US20030138772), AAV9 (SEQ ID NOs: 19 and 20 in US20030138772), AAV10 (SEQ ID NOs: 21 and 22 in US20030138772), AAV11 (SEQ ID NOs: 23 and 24 in US20030138772), AAV12 (SEQ ID NOs: 25 and 26 in US20030138772), AAV13 (SEQ ID NOs: 26 and 27 in US20030138772), AAV14 (SEQ ID NOs: 27 and 28 in US20030138772), AAV15 (SEQ ID NOs: 28 and 4 (SEQ ID NO: 63 in US20030138772), AAV5 (SEQ ID NO: 114 in US20030138772), AAV6 (SEQ ID NO: 65 in US20030138772), AAV7 (SEQ ID NOs: 1 to 3 in US20030138772), AAV8 (SEQ ID NOs: 4 and 95 in US20030138772), AAV9 (SEQ ID NOs: 5 and 100 in US20030138772), AAV10 (SEQ ID NOs: 113 and 114 in US20030138772), and AAV11 (SEQ ID NOs: 115 and 116 in US20030138772). AAV11 (SEQ ID NO: 118 of US20030138772), AAV12 (SEQ ID NO: 119 of US20030138772), AAVrh10 (amino acids 1 to 738 of SEQ ID NO: 81 of US20030138772), AAV16.3 (SEQ ID NO: 10 of US20030138772), AAV29.3 / bb.1 (SEQ ID NO: 11 of US20030138772), AA V29.4 (US20030138772 SEQ ID NO: 12), AAV29.5 / bb.2 (US20030138772 SEQ ID NO: 13), AAV1.3 (US20030138772 SEQ ID NO: 14), AAV13.3 (US20030138772 SEQ ID NO: 15), AAV24.1 (US20030138772 SEQ ID NO: 16), AAV27.3 (US20030138772 SEQ ID NO: 17), AAV7.2 (US20030138772 SEQ ID NO: 18), AAVC1 (US20030138772 SEQ ID NO: 19), AAVC3 (US20030138772 SEQ ID NO: 20), AAVC5 (US20030138772 SEQ ID NO: 21), AAVF1 (US20030138772 SEQ ID NO: 22), AAVF3 (US20030138772 SEQ ID NO: 23), AAVF5 (US20030138772 SEQ ID NO: 24), AAVH6 (US20030138772 SEQ ID NO: 25), AAVH2 (US20030138772 SEQ ID NO: 26), AAV42-8 ( US20030138772 SEQ ID NO: 27), AAV42-15 (US20030138772 SEQ ID NO: 28), AAV42-5b (US20030138772 SEQ ID NO: 29), AAV42-lb (US20030138772 SEQ ID NO: 30), AAV42-13 (US20030138772 SEQ ID NO: 31), AAV42-3a (US20030138772 SEQ ID NO: 32), AAV42-4 (US20030138772 SEQ ID NO: 33), AAV42-5a (US20030138772 SEQ ID NO: 34), AAV42-10 (US2003013 8772 SEQ ID NO: 35), AAV42-3b (US20030138772 SEQ ID NO: 36), AAV42-11 (US20030138772 SEQ ID NO: 37), AAV42-6b (US20030138772 SEQ ID NO: 38), AAV43-1 (US20030138772 SEQ ID NO: 39), AAV43-5 (US20030138772 SEQ ID NO: 40), AAV43-12 (US20030138772 SEQ ID NO: 41), AAV43-20 (US20030138772 SEQ ID NO: 42), AAV43-21 (US20030138772 SEQ ID NO: 4 3), AAV43-23 (US20030138772 SEQ ID NO: 44), AAV43-25 (US20030138772 SEQ ID NO: 45), AAV44.1 (US20030138772 SEQ ID NO: 46), AAV44.5 (US20030138772 SEQ ID NO: 47), AAV223.1 (US20030138772 SEQ ID NO: 48), AAV223.2 (US20030138772 SEQ ID NO: 49), AAV223.4 (US20030138772 SEQ ID NO: 50), AAV223.5 (US20030138772 SEQ ID NO: 51), AAV223.The vector may be or have AAV223.6 (US20030138772 SEQ ID NO:52), AAV223.7 (US20030138772 SEQ ID NO:53), AAVA3.4 (US20030138772 SEQ ID NO:54), AAVA3.5 (US20030138772 SEQ ID NO:55), AAVA3.7 (US20030138772 SEQ ID NO:56), AAVA3.3 (US20030138772 SEQ ID NO:57), AAV42.12 (US20030138772 SEQ ID NO:58), AAV44.2 (US20030138772 SEQ ID NO:59), AAV42-2 (US20030138772 SEQ ID NO:9), or a variant thereof.

[0461] In some embodiments, the AAV serotype is selected from the group consisting of sequences set forth in U.S. Publication No. US20150159173, the contents of which are incorporated herein by reference in their entirety, including, but not limited to, AAV2 (SEQ ID NOs: 7 and 23 of US20150159173), rh20 (SEQ ID NO: 1 of US20150159173), rh32 / 33 (SEQ ID NO: 2 of US20150159173), rh39 (SEQ ID NOs: 3, 20, and 36 of US20150159173), rh46 (SEQ ID NOs: 4 and 22 of US20150159173), rh73 (SEQ ID NOs: 5 and 6 of US20150159173), and the like. US20150159173 SEQ ID NO: 5), rh74 (US20150159173 SEQ ID NO: 6), AAV6.1 (US20150159173 SEQ ID NO: 29), rh.8 (US20150159173 SEQ ID NO: 41), rh.48.1 (US20150159173 SEQ ID NO: 44), hu.44 (US20150159173 SEQ ID NO: 45), hu.29 (US20150159173 SEQ ID NO: 42), hu.48 (US20150159173 SEQ ID NO: 38), rh54 (US20150159173 SEQ ID NO: 49), AAV 2 (SEQ ID NO: 7 in US20150159173), cy.5 (SEQ ID NO: 8 and 24 in US20150159173), rh.10 (SEQ ID NO: 9 and 25 in US20150159173), rh.13 (SEQ ID NO: 10 and 26 in US20150159173), AAV1 (SEQ ID NO: 11 and 27 in US20150159173), AAV3 (SEQ ID NO: 12 and 28 in US20150159173), AAV6 (SEQ ID NO: 13 and 29 in US20150159173), AAV7 (SEQ ID NO: 14 and 30 in US20150159173), AAV8 (SEQ ID NOs: 15 and 31 in US20150159173), hu.13 (SEQ ID NOs: 16 and 32 in US20150159173), hu.26 (SEQ ID NOs: 17 and 33 in US20150159173), hu.37 (SEQ ID NOs: 18 and 34 in US20150159173), hu.53 (SEQ ID NOs: 19 and 35 in US20150159173), rh.43 (SEQ ID NOs: 21 and 37 in US20150159173), rh2 (SEQ ID NO: 39 in US20150159173), rh.37 (SEQ ID NO: 40 in US20150159173), rh.64 (SEQ ID NO: 43 in US20150159173), rh.48 (SEQ ID NO: 44 in US20150159173), ch.5 (SEQ ID NO: 46 in US20150159173), rh.67 (SEQ ID NO: 47 in US20150159173), rh.58 (SEQ ID NO: 48 in US20150159173), or Cy5R1, Cy5R2, Cy5R3, Cy5R4, rh.13R, rh.37R The antibody may be or have a variant thereof, including, but not limited to, AAV6.2, rh.2R, rh.8R, rh.48.1, rh.48.2, rh.48.1.2, hu.44R1, hu.44R2, hu.44R3, hu.29R, ch.5R1, rh64R1, rh64R2, AAV6.2, AAV6.1, AAV6.12, hu.48R1, hu.48R2, and hu.48R3.

[0462] In some embodiments, the AAV serotype may be or have a sequence set forth in U.S. Patent No. US7198951, the entire contents of which are incorporated herein by reference, such as, but not limited to, AAV9 (SEQ ID NOs: 1-3 of US7198951), AAV2 (SEQ ID NO: 4 of US7198951), AAV1 (SEQ ID NO: 5 of US7198951), AAV3 (SEQ ID NO: 6 of US7198951), and AAV8 (SEQ ID NO: 7 of US7198951).

[0463] In some embodiments, the AAV serotype can be or have a mutation of the AAV9 sequence described by N Pulicherla et al. (Molecular Therapy 19(6):1070-1078 (2011), which is incorporated herein by reference in its entirety), such as, but not limited to, AAV9.9, AAV9.11, AAV9.13, AAV9.16, AAV9.24, AAV9.45, AAV9.47, AAV9.61, AAV9.68, AAV9.84.

[0464] In some embodiments, the AAV serotype may be or have a sequence described in U.S. Pat. No. 6,156,303, the entire contents of which are incorporated herein by reference, such as, but not limited to, AAV3B (SEQ ID NOs: 1 and 10 of U.S. Pat. No. 6,156,303), AAV6 (SEQ ID NOs: 2, 7, and 11 of U.S. Pat. No. 6,156,303), AAV2 (SEQ ID NOs: 3 and 8 of U.S. Pat. No. 6,156,303), AAV3A (SEQ ID NOs: 4 and 9 of U.S. Pat. No. 6,156,303), or derivatives thereof.

[0465] In some embodiments, the AAV serotype may be or have a sequence set forth in U.S. Publication No. US20140359799, the contents of which are incorporated herein by reference in their entirety, such as, but not limited to, AAV8 (SEQ ID NO: 1 of US20140359799), AAVDJ (SEQ ID NOs: 2 and 3 of US20140359799), or a variant thereof.

[0466] In some embodiments, the serotype may be AAVDJ or a variant thereof, such as AAVDJ8 (or AAV-DJ8) described by Grimm et al. (Journal of Virology 82(12):5887-5911 (2008), which is incorporated herein by reference in its entirety). The amino acid sequence of AAVDJ8 may contain two or more mutations to remove the heparin-binding domain (HBD). As a non-limiting example, the AAV-DJ sequence set forth as SEQ ID NO:1 in U.S. Pat. No. 7,588,772, the contents of which are incorporated herein by reference in their entirety, may contain two mutations: (1) R587Q, which changes arginine (R; Arg) at amino acid 587 to glutamine (Q; Gln), and (2) R590T, which changes arginine (R; Arg) at amino acid 590 to threonine (T; Thr). As another non-limiting example, the mutations may include three mutations: (1) K406R, which changes lysine (K; Lys) at amino acid 406 to arginine (R; Arg); (2) R587Q, which changes arginine (R; Arg) at amino acid 587 to glutamine (Q; Gln); and (3) R590T, which changes arginine (R; Arg) at amino acid 590 to threonine (T; Thr).

[0467] In some embodiments, the AAV serotype is or can have the sequence of AAV4 described in International Publication No. WO1998011244, the contents of which are incorporated herein by reference in their entirety, such as, but not limited to, AAV4 (SEQ ID NOs: 1-20 of WO1998011244).

[0468] In some embodiments, the AAV serotype may be that described in International Publication No. WO2014144229, which is incorporated herein by reference in its entirety, or may have a mutation in the AAV2 sequence to produce AAV2G9.

[0469] In some embodiments, the AAV serotype is selected from the group consisting of sequences set forth in International Publication No. WO2005033321, the entire contents of which are incorporated herein by reference, including, but not limited to, AAV3-3 (SEQ ID NO: 217 in WO2005033321), AAV1 (SEQ ID NOs: 219 and 202 in WO2005033321), AAV106.1 / hu.37 (SEQ ID NO: 10 in WO2005033321), AAV114.3 / hu.40 (SEQ ID NO: 11 in WO2005033321), AAV127.2 / hu.41 (SEQ ID NO: 12 in WO2005033321), AAV130.1 / hu.37 (SEQ ID NO: 13 in WO2005033321), AAV140.1 / hu.40 (SEQ ID NO: 14 in WO2005033321), AAV150.1 / hu.41 (SEQ ID NO: 15 in WO2005033321), AAV160.1 / hu.41 (SEQ ID NO: 16 in WO2005033321), AAV170.1 / hu.41 (SEQ ID NO: 17 in WO2005033321), AAV180.1 / hu.41 (SEQ ID NO: 18 in WO2005033321), AAV190.1 / hu.41 (SEQ ID NO: 19 in WO2005033321), AAV191.1 / hu.41 (SEQ ID NO: 19 in WO2005033321), AAV192.1 1 (SEQ ID NOs: 6 and 8), AAV128.3 / hu.44 (SEQ ID NO: 81 in WO2005033321), AAV130.4 / hu.48 (SEQ ID NO: 78 in WO2005033321), AAV145.1 / hu.53 (SEQ ID NOs: 176 and 177 in WO2005033321), AAV145.6 / hu.56 (SEQ ID NOs: 168 and 192 in WO2005033321), AAV16.12 / hu.11 (SEQ ID NOs: 153 and 57 in WO2005033321), AAV16.8 / hu.10 (SEQ ID NOs: 156 and 57 in WO2005033321), AAV16.11 / hu.12 (SEQ ID NOs: 157 and 58 in WO2005033321), AAV16.12 / hu.13 (SEQ ID NOs: 158 and 59 in WO2005033321), AAV16.13 / hu.14 (SEQ ID NOs: 169 and 170 in WO2005033321), AAV16.14 / hu.15 (SEQ ID NOs: 169 and 171 in WO2005033321), AAV16.14 / hu.16 (SEQ ID NOs: 169 and 180 in WO2005033321), AAV16.14 / hu.17 (SEQ ID NOs: 171 and 172 in WO2005033321), AAV16.14 / hu.1 6), AAV161.10 / hu.60 (SEQ ID NO: 170 in WO2005033321), AAV161.6 / hu.61 (SEQ ID NO: 174 in WO2005033321), AAV1-7 / rh.48 (SEQ ID NO: 32 in WO2005033321), AAV1-8 / rh.49 (SEQ ID NOs: 103 and 25 in WO2005033321), AAV2 (SEQ ID NOs: 211 and 221 in WO2005033321), AAV2-15 / rh.62 (SEQ ID NOs: 33 and 114 in WO2005033321), AAV2-3 / rh.61 (WO2005033321), 321), AAV2-4 / rh.50 (SEQ ID NOs: 23 and 108 in WO2005033321), AAV2-5 / rh.51 (SEQ ID NOs: 104 and 22 in WO2005033321), AAV3.1 / hu.6 (SEQ ID NOs: 5 and 84 in WO2005033321), AAV3.1 / hu.9 (SEQ ID NOs: 155 and 58 in WO2005033321), AAV3-11 / rh.53 (SEQ ID NOs: 186 and 176 in WO2005033321), AAV3-3 (SEQ ID NO: 200 in WO2005033321), AAV33.12 / hu.17 (SEQ ID NO: 4 in WO2005033321), AAV33.4 / hu.15 (SEQ ID NO: 50 in WO2005033321), AAV33.8 / hu.16 (SEQ ID NO: 51 in WO2005033321), AAV3-9 / rh.52 (SEQ ID NOs: 96 and 18 in WO2005033321), AAV4-19 / rh.55 (SEQ ID NO: 117 in WO2005033321), AAV4-4 (SEQ ID NOs: 201 and 218 in WO2005033321), AAV4-9 / rh.54 (SEQ ID NO: 116 in WO2005033321), AAV5 (WO2005 AAV5-3 / rh.57 (SEQ ID NO: 105 of WO2005033321), AAV5-3 / rh.57 (SEQ ID NO: 26 of WO2005033321), AAV58.2 / hu.25 (SEQ ID NO: 49 of WO2005033321), AAV6 (SEQ ID NO: 105 of WO2005033321), AAV5-3 / rh.57 (SEQ ID NO: 105 of WO2005033321), AAV5-3 / rh.57 (SEQ ID NO: 105 of WO2005033321), AAV58.2 / hu.25 (SEQ ID NO: 105 of WO2005033321), AAV6 (SEQ ID NO: 105 of WO2005033321), AAV5-3 / rh.57 ... sequence numbers 203 and 220), AAV7 (SEQ ID NOs: 222 and 213 in WO2005033321), AAV7.3 / hu.7 (SEQ ID NO: 55 in WO2005033321), AAV8 (SEQ ID NOs: 223 and 214 in WO2005033321), AAVH-1 / hu.1 (SEQ ID NO: 46 in WO2005033321), AAVH-5 / hu.3 (SEQ ID NO: 44 in WO2005033321), AAVhu.1 (SEQ ID NO: 144 in WO2005033321), AAVhu.10 (SEQ ID NO: 156 in WO2005033321), AAVhu.11 (WO 2005033321), AAVhu.12 (SEQ ID NO: 59 in WO2005033321), AAVhu.13 (SEQ ID NO: 129 in WO2005033321), AAVhu.14 / AAV9 (SEQ ID NOs: 123 and 3 in WO2005033321), AAVhu.15 (SEQ ID NO: 147 in WO2005033321), AAVhu.16 (SEQ ID NO: 148 in WO2005033321), AAVhu.17 (SEQ ID NO: 83 in WO2005033321), AAVhu.18 (SEQ ID NO: 149 in WO2005033321), AAVhu.19 (SEQ ID NO: 133 in WO2005033321), AAVhu.2 (SEQ ID NO: 143 in WO2005033321), AAVhu.20 (SEQ ID NO: 134 in WO2005033321), AAVhu.21 (SEQ ID NO: 135 in WO2005033321), AAVhu.22 (SEQ ID NO: 138 in WO2005033321), AAVhu.23.2 (SEQ ID NO: 137 in WO2005033321), AAVhu.24 (SEQ ID NO: 136 in WO2005033321), AAVhu.25 (SEQ ID NO: 146 in WO2005033321), AAV hu.27 (SEQ ID NO: 140 in WO2005033321), AAVhu.29 (SEQ ID NO: 132 in WO2005033321), AAVhu.3 (SEQ ID NO: 145 in WO2005033321), AAVhu.31 (SEQ ID NO: 121 in WO2005033321), AAVhu.32 (SEQ ID NO: 122 in WO2005033321), AAVhu.34 (SEQ ID NO: 125 in WO2005033321), AAVhu.35 (SEQ ID NO: 164 in WO2005033321), AAVhu.37 (SEQ ID NO: 8 ... (SEQ ID NO: 145 in WO2005033321), AAVhu.35 (SEQ ID NO: 164 in WO2005033321), AAVhu.37 (S u.39 (SEQ ID NO: 102 in WO2005033321), AAVhu.4 (SEQ ID NO: 141 in WO2005033321), AAVhu.40 (SEQ ID NO: 87 in WO2005033321), AAVhu.41 (SEQ ID NO: 91 in WO2005033321), AAVhu.42 (SEQ ID NO: 85 in WO2005033321), AAVhu.43 (SEQ ID NO: 160 in WO2005033321), AAVhu.44 (SEQ ID NO: 144 in WO2005033321), AAVhu.45 (SEQ ID NO: 127 in WO2005033321), AAVhu.4 6 (SEQ ID NO: 159 in WO2005033321), AAVhu.47 (SEQ ID NO: 128 in WO2005033321), AAVhu.48 (SEQ ID NO: 157 in WO2005033321), AAVhu.49 (SEQ ID NO: 189 in WO2005033321), AAVhu.51 (SEQ ID NO: 190 in WO2005033321), AAVhu.52 (SEQ ID NO: 191 in WO2005033321), AAVhu.53 (SEQ ID NO: 186 in WO2005033321), AAVhu.54 (SEQ ID NO: 188 in WO2005033321), AAVhu.AAVhu.55 (SEQ ID NO: 187 in WO2005033321), AAVhu.56 (SEQ ID NO: 192 in WO2005033321), AAVhu.57 (SEQ ID NO: 193 in WO2005033321), AAVhu.58 (SEQ ID NO: 194 in WO2005033321), AAVhu.6 (SEQ ID NO: 84 in WO2005033321), AAVhu.60 (SEQ ID NO: 184 in WO2005033321), AAVhu.61 (SEQ ID NO: 185 in WO2005033321), AAVhu.63 (SEQ ID NO: 195 in WO2005033321), AAVhu.64 (SEQ ID NO: 196 in WO2005033321), AAVhu.66 (SEQ ID NO: 197 in WO2005033321), AAVhu.67 (SEQ ID NO: 198 in WO2005033321), AAVhu.7 (SEQ ID NO: 150 in WO2005033321), AAVhu.8 (SEQ ID NO: 12 in WO2005033321), AAVhu.9 (SEQ ID NO: 155 in WO2005033321), AAVLG-10 / rh.40 (SEQ ID NO: 14 in WO2005033321), AAVLG-4 / rh.38 (SEQ ID NO: 86 in WO2005033321), AAVL G-4 / rh.38 (SEQ ID NO: 7 in WO2005033321), AAVN721-8 / rh.43 (SEQ ID NO: 163 in WO2005033321), AAVN721-8 / rh.43 (SEQ ID NO: 43 in WO2005033321), AAVpi.1 (SEQ ID NO: 28 in WO2005033321), AAVpi.2 (SEQ ID NO: 30 in WO2005033321), AAVpi.3 (SEQ ID NO: 29 in WO2005033321), AAVrh.38 (SEQ ID NO: 86 in WO2005033321), AAVrh.40 (SEQ ID NO: 92 in WO2005033321) , AAVrh.43 (SEQ ID NO: 163 in WO2005033321), AAVrh.44 (SEQ ID NO: 34 in WO2005033321), AAVrh.45 (SEQ ID NO: 41 in WO2005033321), AAVrh.47 (SEQ ID NO: 38 in WO2005033321), AAVrh.48 (SEQ ID NO: 115 in WO2005033321), AAVrh.49 (SEQ ID NO: 103 in WO2005033321), AAVrh.50 (SEQ ID NO: 108 in WO2005033321), AAVrh.51 (SEQ ID NO: 104 in WO2005033321), AAVrh.52 (SEQ ID NO: 96 in WO2005033321), AAVrh.53 (SEQ ID NO: 97 in WO2005033321), AAVrh.55 (SEQ ID NO: 37 in WO2005033321), AAVrh.56 (SEQ ID NO: 152 in WO2005033321), AAVrh.57 (SEQ ID NO: 105 in WO2005033321), AAVrh. AAVrh.58 (SEQ ID NO: 106 in WO2005033321), AAVrh.59 (SEQ ID NO: 42 in WO2005033321), AAVrh.60 (SEQ ID NO: 31 in WO2005033321), AAVrh.61 (SEQ ID NO: 107 in WO2005033321), AAVrh.62 (SEQ ID NO: 114 in WO2005033321), AAVrh.6 AAVrh.4 (SEQ ID NO: 99 in WO2005033321), AAVrh.65 (SEQ ID NO: 35 in WO2005033321), AAVrh.68 (SEQ ID NO: 16 in WO2005033321), AAVrh.69 (SEQ ID NO: 39 in WO2005033321), AAVrh.70 (SEQ ID NO: 20 in WO2005033321), AAVrh.72 (SEQ ID NO: 9 in WO2005033321), or AAVcy.2, AAVcy.3, AAVcy.4, AAVcy.5, AAVcy.6, AAVrh.12, AAVrh.17, AAVrh.18, AAVrh.19, AAVrh.21, AAVrh.22, AAVrh.23, AAVrh.24, AAVrh.25, AAVrh.25 / 42 The vector may be or have a variant thereof, including but not limited to AAVrh.15, AAVrh.31, AAVrh.32, AAVrh.33, AAVrh.34, AAVrh.35, AAVrh.36, AAVrh.37, AAVrh14. Non-limiting examples of variants include SEQ ID NOs: 13, 15, 17, 19, 24, 36, 40, 45, 47, 48, 51-54, 60-62, 64-77, 79, 80, 82, 89, 90, 93-95, 98, 100, 101, 109-113, 118-120, 124, 126, 131, 139, 142, 151, 154, 158, 161, 162, 165-183, 202, 204-212, 215, 219, and 224-236 of WO2005033321, the contents of which are incorporated herein by reference in their entirety.

[0470] In some embodiments, the AAV serotype may be or have a sequence set forth in International Publication No. WO2015168666, the contents of which are incorporated herein by reference in their entirety, such as, but not limited to, AAVrh8R (SEQ ID NO: 9 of WO2015168666), AAVrh8R A586R mutant (SEQ ID NO: 10 of WO2015168666), AAVrh8R R533A mutant (SEQ ID NO: 11 of WO2015168...

Claims

1. 1. An isolated, e.g., recombinant, antibody that binds to tau, comprising a heavy chain variable region (VH) comprising HC CDR1, HC CDR2, and HC CDR3, and a light chain variable region (VL) comprising LC CDR1, LC CDR2, and LC CDR3, (i) the HC CDR1, the HC CDR2, and the HC CDR3 comprise the amino acid sequences of SEQ ID NOs: 315, 341, and 410, respectively, and the LC CDR1, the LC CDR2, and the LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 474, 529, and 571, respectively; or (ii) the HC CDR1, the HC CDR2, and the HC CDR3 comprise the amino acid sequences of SEQ ID NOs: 314, 341, and 410, respectively, and the LC CDR1, the LC CDR2, and the LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 1154, 529, and 571, respectively; or (iii) the HC CDR1, the HC CDR2, and the HC CDR3 comprise the amino acid sequences of SEQ ID NOs: 316, 341, and 410, respectively, and the LC CDR1, the LC CDR2, and the LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 475, 530, and 571, respectively; or (iv) the HC CDR1, the HC CDR2, and the HC CDR3 comprise the amino acid sequences of SEQ ID NOs: 325, 362, and 435, respectively, and the LC CDR1, the LC CDR2, and the LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 495, 540, and 587, respectively; or (v) the HC CDR1, the HC CDR2, and the HC CDR3 comprise the amino acid sequences of SEQ ID NOs: 304, 347, and 400, respectively, and the LC CDR1, the LC CDR2, and the LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 464, 523, and 562, respectively; or (vi) the HC CDR1, the HC CDR2, and the HC CDR3 comprise the amino acid sequences of SEQ ID NOs: 299, 343, and 395, respectively, and the LC CDR1, the LC CDR2, and the LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 460, 518, and 557, respectively; or (vii) the HC CDR1, the HC CDR2, and the HC CDR3 comprise the amino acid sequence of any of the HC CDR sequences in Table 1, 6, 2A-2C, 4, or 5, and the LC CDR1, the LC CDR2, and the LC CDR3 comprise the amino acid sequence of any of the LC CDR sequences in Table 1, 6, 2A-2C, 4, or 5. The antibody.

2. 1. An isolated, e.g., recombinant, antibody that binds to tau, comprising a heavy chain variable region (VH) comprising HC CDR1, HC CDR2, and HC CDR3, and a light chain variable region (VL) comprising LC CDR1, LC CDR2, and LC CDR3, (i) the HC CDR1, the HC CDR2, the HC CDR3, the LC CDR1, the LC CDR2, and the LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 1180, 341, 410, 1181, 1182, and 571, respectively; (ii) the HC CDR1, the HC CDR2, the HC CDR3, the LC CDR1, the LC CDR2, and the LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 1183, 1184, 410, 1185, 1182, and 571, respectively; or (iii) the HC CDR1, the HC CDR2, the HC CDR3, the LC CDR1, the LC CDR2, and the LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 1186, 1187, 1167, 1188, 528, and 571, respectively; Optionally, the antibody binds to a region of human tau protein comprising residues 409-436 numbered according to SEQ ID NO:

920. The antibody.

3. the antibody binds to the region of the human tau protein comprising residues 409-436 numbered according to SEQ ID NO:920; (i) the HC CDR1, the HC CDR2, and the HC CDR3 comprise the amino acid sequences of SEQ ID NOs: 1180, 341, and 410, respectively; (ii) the LC CDR1, the LC CDR2, and the LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 1181, 1182, and 571, respectively; The antibody described in claim 2.

4. (i) the VH comprises an amino acid sequence of SEQ ID NO: 22, 21, 23, 51, 9, or 4, or an amino acid sequence having at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; or (ii) the VH comprises an amino acid sequence having at least one, two, or three modifications of the amino acid sequence of SEQ ID NO: 22, 21, 23, 51, 9, or 4, but not more than 30, not more than 20, or not more than 10 modifications; or (iii) the VH comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 168, 167, 169, 197, 155, or 150, or a nucleotide sequence having at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; or (iv) the VH comprises an amino acid sequence of any VH listed in Table 3 or 4, or an amino acid sequence with at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, or an amino acid sequence that has at least one, two, or three modifications, but no more than 30, no more than 20, or no more than 10 modifications, of any VH amino acid sequence listed in Table 3 or 4. The antibody according to any one of claims 1 to 3.

5. (i) the VL comprises an amino acid sequence of SEQ ID NO: 94, 93, 95, 122, 83, or 78, or an amino acid sequence having at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; or (ii) the VL comprises an amino acid sequence having at least one, two, or three modifications, but no more than 30, no more than 20, or no more than 10 modifications, of the amino acid sequence of SEQ ID NO: 94, 93, 95, 122, 83, or 78; or (iii) the VL comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 242, 241, 243, 270, 229, or 224, or a nucleotide sequence having at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; or (iv) the VL comprises an amino acid sequence of any VL listed in Table 3 or 4, or an amino acid sequence with at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, or an amino acid sequence that has at least one, two, or three modifications, but no more than 30, no more than 20, or no more than 10 modifications, of the amino acid sequence of any VL listed in Table 3 or 4. The antibody according to any one of claims 1 to 4.

6. (i) the VH comprises an amino acid sequence of SEQ ID NO: 22, or an amino acid sequence having at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, or having at least one, two, or three but not more than ten modifications thereof; and the VL comprises an amino acid sequence of SEQ ID NO: 94, or an amino acid sequence having at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, or having at least one, two, or three but not more than ten modifications thereof; (ii) the VH comprises an amino acid sequence of SEQ ID NO: 21, or an amino acid sequence having at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, or having at least one, two, or three but not more than ten modifications thereof; and the VL comprises an amino acid sequence of SEQ ID NO: 93, or an amino acid sequence having at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, or having at least one, two, or three but not more than ten modifications thereof; (iii) the VH comprises an amino acid sequence of SEQ ID NO: 23, or an amino acid sequence having at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, or having at least one, two, or three but not more than ten modifications thereof; and the VL comprises an amino acid sequence of SEQ ID NO: 95, or an amino acid sequence having at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, or having at least one, two, or three but not more than ten modifications thereof; (iv) the VH comprises an amino acid sequence of SEQ ID NO: 51, or an amino acid sequence having at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, or having at least one, two, or three but not more than ten modifications thereof; and the VL comprises an amino acid sequence of SEQ ID NO: 122, or an amino acid sequence having at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, or having at least one, two, or three but not more than ten modifications thereof; (v) the VH comprises an amino acid sequence of SEQ ID NO: 9, or an amino acid sequence having at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, or having at least one, two, or three but not more than ten modifications thereof; and the VL comprises an amino acid sequence of SEQ ID NO: 83, or an amino acid sequence having at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, or having at least one, two, or three but not more than ten modifications thereof; or (vi) the VH comprises an amino acid sequence of SEQ ID NO: 4, or an amino acid sequence having at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, or having at least one, two, or three but not more than ten modifications thereof; and the VL comprises an amino acid sequence of SEQ ID NO: 78, or an amino acid sequence having at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, or having at least one, two, or three but not more than ten modifications thereof. The antibody according to any one of claims 1 to 5.

7. (i) the nucleotide sequence encoding the VH comprises the nucleotide sequence of SEQ ID NO: 168, 167, 169, 197, 155, or 150, or a nucleotide sequence having at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or (ii) the nucleotide sequence encoding the VL comprises the nucleotide sequence of SEQ ID NO: 242, 241, 243, 270, 229, or 224, or a nucleotide sequence having at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; The antibody according to any one of claims 1 to 6.

8. Full length antibody, bispecific antibody, Fab, F(ab') ２ 8. The antibody of any one of claims 1 to 7, which is a single-chain Fv fragment (scFv).

9. 9. The antibody of any one of claims 1 to 8, comprising a heavy chain constant region selected from human IgG1, human IgG2, human IgG3, and human IgG4, mouse IgG1, mouse IgG2a, mouse IgG2b, mouse IgG2c, and mouse IgG3, and / or a light chain constant region selected from a kappa or lambda light chain constant region, such as human or mouse kappa or human or mouse lambda.

10. 10. The antibody of any one of claims 1 to 9, comprising a heavy chain constant region comprising an amino acid sequence of a heavy chain constant region set out in Table X, or an amino acid sequence with at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and / or a light chain constant region comprising an amino acid sequence of a light chain constant region set out in Table X, or an amino acid sequence with at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

11. (1) the C-terminus of a tau protein, e.g., residues 409-436 numbered according to SEQ ID NO: 920; (2) the microtubule-binding domain of tau protein; (3) the proline-rich domain of tau protein; (4) a tau protein comprising at least one, two, three, or more phosphorylated residues, e.g., residues T212, T217, S396, S404, S409, numbered according to SEQ ID NO: 920, or a combination thereof; (5) condensed paired helical fibrillar tau protein (ePHF), and / or (6) An epitope comprising a region formed by a complex of at least two tau proteins, for example, a tau dimer. The antibody according to any one of claims 1 to 10, which binds to

12. a dissociation constant (K) of less than about 120 nM (e.g., as measured by Octet, e.g., as described in Example 8); Ｄ The antibody according to any one of claims 1 to 11, which binds to tau protein at the site of

13. 13. The antibody of any one of claims 1 to 12, which reduces or inhibits tau aggregation, e.g., inhibits tau aggregation with a half-maximal inhibitory concentration (IC50) of about 1 nM to about 30 nM (e.g., as measured by an immunodepletion assay (e.g., using tau RD biosensor cells), e.g., as described in Example 6).

14. An isolated, eg recombinant, antibody that competes with an antibody of any one of claims 1 to 13 for binding to tau.

15. An isolated, e.g., recombinant, antibody that binds to the same epitope as, substantially the same epitope as, or an epitope that overlaps with, the epitope of an antibody of any one of claims 1 to 14.

16. An isolated, eg recombinant, nucleic acid encoding an antibody according to any one of claims 1 to 15.

17. An isolated, e.g., recombinant, nucleic acid encoding an antibody comprising a VH comprising HC CDR1, HC CDR2, and HC CDR3, and a VL comprising LC CDR1, LC CDR2, and LC CDR3, (i) the HC CDR1, the HC CDR2, and the HC CDR3 comprise the amino acid sequences of SEQ ID NOs: 315, 341, and 410, respectively, and the LC CDR1, the LC CDR2, and the LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 474, 529, and 571, respectively; or (ii) the HC CDR1, the HC CDR2, and the HC CDR3 comprise the amino acid sequences of SEQ ID NOs: 314, 341, and 410, respectively, and the LC CDR1, the LC CDR2, and the LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 1154, 529, and 571, respectively; or (iii) the HC CDR1, the HC CDR2, and the HC CDR3 comprise the amino acid sequences of SEQ ID NOs: 316, 341, and 410, respectively, and the LC CDR1, the LC CDR2, and the LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 475, 530, and 571, respectively; or (iv) the HC CDR1, the HC CDR2, and the HC CDR3 comprise the amino acid sequences of SEQ ID NOs: 325, 362, and 435, respectively, and the LC CDR1, the LC CDR2, and the LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 495, 540, and 587, respectively; or (v) the HC CDR1, the HC CDR2, and the HC CDR3 comprise the amino acid sequences of SEQ ID NOs: 304, 347, and 400, respectively, and the LC CDR1, the LC CDR2, and the LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 464, 523, and 562, respectively; or (vi) the HC CDR1, the HC CDR2, and the HC CDR3 comprise the amino acid sequences of SEQ ID NOs: 299, 343, and 395, respectively, and the LC CDR1, the LC CDR2, and the LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 460, 518, and 557, respectively; or (vii) the HC CDR1, the HC CDR2, and the HC CDR3 comprise the amino acid sequence of any of the HC CDR sequences in Table 1, 6, 2A-2C, 4, or 5, and the LC CDR1, the LC CDR2, and the LC CDR3 comprise the amino acid sequence of any of the LC CDR sequences in Table 1, 6, 2A-2C, 4, or 5; The nucleic acid.

18. (i) the VH comprises an amino acid sequence of SEQ ID NO: 22, 21, 23, 51, 9, or 4, or an amino acid sequence having at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, or having at least one, two, or three but not more than ten amino acid sequence modifications thereof; and / or (ii) the VL comprises an amino acid sequence of SEQ ID NO: 94, 93, 95, 122, 83, or 78, or an amino acid sequence having at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, or having at least one, two, or three but not more than 10 modifications of said amino acid sequence; The nucleic acid of claim 17.

19. (i) the nucleotide sequence of any VH listed in Table 3 or 4, or a nucleotide sequence having at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or (ii) the nucleotide sequence of any VL listed in Table 3 or 4, or a nucleotide sequence having at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

19. The nucleic acid of claim 17 or 18, comprising:

20. (i) the nucleotide sequence of SEQ ID NO: 168, 167, 169, 197, 155, or 150, or a nucleotide sequence having at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or (ii) the nucleotide sequence of SEQ ID NO: 242, 241, 243, 270, 229, or 224, or a nucleotide sequence having at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. The nucleic acid according to any one of claims 17 to 19, comprising:

21. The antibody (i) a heavy chain constant region comprising an amino acid sequence set out in Table X, or an amino acid sequence having at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; and / or (ii) a light chain constant region comprising an amino acid sequence of a light chain constant region set forth in Table X, or an amino acid sequence having at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; The nucleic acid according to any one of claims 17 to 20, comprising:

22. 22. The isolated nucleic acid sequence of any one of claims 17 to 21, wherein the nucleic acid sequence encoding the heavy chain variable region and / or the light chain variable region is codon-optimized.

23. An isolated, eg recombinant, antibody encoded by a nucleic acid according to any one of claims 17 to 22.

24. 24. An isolated nucleic acid encoding a payload, wherein the encoded payload comprises an antibody of any one of claims 1-15 or 23, or an antibody encoded by a nucleic acid of any one of claims 17-22.

25. 25. The nucleic acid of Claim 24, further encoding a signal sequence and optionally a second signal sequence, wherein optionally the nucleotide sequence encoding the signal sequence and / or the second signal sequence (if present) comprises the nucleotide sequence of any of the signal sequences listed in Table 14, or a nucleotide sequence having at least 95% sequence identity thereto.

26. (i) the nucleotide sequence encoding the signal sequence is located 5' to the nucleotide sequence encoding the VH; and / or (ii) the nucleotide sequence encoding the signal sequence is located 5' to the nucleotide sequence encoding the VL; 26. The nucleic acid of claim 24 or 25.

27. (i) the encoded VH and VL sequences are directly connected (e.g., without a linker), or (ii) the encoded VH and VL sequences are connected via a linker, and optionally the linker comprises the nucleotide sequence of any of the linker sequences presented in Table 15, or a nucleotide sequence with at least 95% sequence identity thereto. The nucleic acid according to any one of claims 24 to 26.

28. The encoded payload may be a full-length antibody, a bispecific antibody, a Fab, a F(ab') ２ , Fv, single chain Fv fragment (scFv), single domain antibody or camelid antibody.

29. 24. A viral genome comprising a promoter operably linked to the nucleic acid encoding a payload comprising the antibody of any one of claims 1 to 15 and 23, optionally wherein the promoter (i) human elongation factor 1 α-subunit (EF1α), cytomegalovirus (CMV) immediate early enhancer and / or promoter, chicken β-actin (CBA) and its derivatives CAG, β-glucuronidase (GUSB), or ubiquitin C (UBC), neuron-specific enolase (NSE), platelet-derived growth factor (PDGF), platelet-derived growth factor B chain (PDGF-β), intercellular adhesion molecule 2 (ICAM-2), synapsin (Syn), methyl-CpG binding protein 2 (MeCP2), Ca2+ / calmodulin dependent protein kinase II (CaMKII), metabotropic glutamate receptor 2 (mGluR2), neurofilament light chain (NFL) or neurofilament heavy chain (NFH), β-globin minigene nβ2, preproenkephalin (PPE), enkephalin (Enk) and excitatory amino acid transporter 2 (EAAT2), glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), or fragments, e.g. truncations, or functional variants thereof; and / or (ii) comprises the nucleotide sequence of any of the promoter sequences listed in Table 11, or a nucleotide sequence that is at least 95% identical thereto; The viral genome.

30. 30. The viral genome of claim 29, further comprising an enhancer, optionally wherein the enhancer is a CMV immediate early (CMVie) enhancer.

31. (i) a polyadenylation (polyA) signal region, optionally comprising the nucleotide sequence of any of SEQ ID NOs: 1134-1136, or a nucleotide sequence having at least 95% identity thereto; (ii) ITR sequences, optionally (a) the ITR sequences are located 5' to the encoded payload, and / or the ITR sequences are located 3' to the encoded payload, and / or (b) the ITR sequence comprises the nucleotide sequence of any one of SEQ ID NOs: 1035-1038, or a nucleotide sequence having at least 80%, 85%, 90%, or 95% sequence identity thereto; (iii) at least one, two, or three intron regions, optionally each intron region independently comprising the nucleotide sequence of any of the intron regions listed in Table 13, or a nucleotide sequence having at least 95% identity thereto; (iv) at least one, two, or three exon regions, optionally each exon region independently comprising the nucleotide sequence of any of the exon sequences in Table 12, or a nucleotide sequence having at least 95% identity thereto; and / or (v) a Kozak sequence, optionally comprising the nucleotide sequence GCCGCCACCATG (SEQ ID NO: 1079) or GAGGAGCCACC (SEQ ID NO: 1089).

31. The viral genome of claim 29 or 30, further comprising:

32. 32. The viral genome of any one of claims 29 to 31, further comprising a nucleotide sequence encoding a miR binding site, such as a miR binding site that modulates, e.g., reduces, expression of the payload encoded by the viral genome in cells or tissues in which the corresponding miRNA is expressed.

33. 33. The viral genome of claim 32, comprising at least 1 to 5 copies, such as at least 1, 2, 3, 4, or 5 copies, of the encoded miR binding site.

34. 34. The viral genome of claim 32 or 33, comprising at least three or four copies of the encoded miR binding site, optionally wherein all copies contain the same miR binding site, or wherein at least one, two, three, or all copies contain different miR binding sites.

35. the encoded miR binding site comprises a miR122 binding site, a miR183 binding site, a miR-142-3p, or a combination thereof, and optionally (i) the encoded miR122 binding site comprises the nucleotide sequence of SEQ ID NO: 1029, or a nucleotide sequence substantially identical thereto (e.g., having at least 90%, 92%, 95%, 97%, 98%, or 99% sequence identity), or a nucleotide sequence having at least 1, 2, 3, 4, 5, 6, or 7, but not more than 10, modifications of SEQ ID NO: 1029; (ii) the encoded miR183 binding site comprises the nucleotide sequence of SEQ ID NO: 1032, or a nucleotide sequence substantially identical thereto (e.g., having at least 90%, 92%, 95%, 97%, 98%, or 99% sequence identity), or a nucleotide sequence having at least one, two, three, four, five, six, or seven, but not more than ten, modifications of SEQ ID NO: 1032; and / or (iii) the encoded miR-142-3p binding site comprises the nucleotide sequence of SEQ ID NO: 1031, or a nucleotide sequence substantially identical thereto (e.g., having at least 90%, 92%, 95%, 97%, 98%, or 99% sequence identity), or a nucleotide sequence having at least one, two, three, four, five, six, or seven, but not more than ten, modifications of SEQ ID NO: 1031; A viral genome according to any one of claims 32 to 34.

36. The viral genome of any one of claims 29 to 35, which is single-stranded.

37. A vector comprising the viral genome according to any one of claims 29 to 36, optionally comprising: (i) a nucleotide sequence encoding a Rep protein, such as a non-structural protein, wherein the Rep protein comprises a Rep78 protein, a Rep68 protein, a Rep52 protein, and / or a Rep40 protein, and optionally the Rep78 protein, the Rep68 protein, the Rep52 protein, and / or the Rep40 protein are encoded by at least one Rep gene; and / or (ii) a nucleotide sequence encoding a capsid protein, such as a structural protein, wherein the capsid protein comprises a VP1 polypeptide, a VP2 polypeptide, and / or a VP3 polypeptide, and optionally the VP1 polypeptide, the VP2 polypeptide, and / or the VP3 polypeptide are encoded by at least one Cap gene. The vector further comprises:

38. (i) a capsid protein, and (ii) a nucleic acid according to any one of claims 16 and 17 to 28, a viral genome according to any one of claims 29 to 36, or a vector according to claim 37 An isolated, e.g., recombinant, AAV particle comprising:

39. (i) the capsid protein comprises the amino acid sequence of SEQ ID NO: 1003, or an amino acid sequence having at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto; (ii) the capsid protein comprises an amino acid sequence having at least one, two, or three modifications of the amino acid sequence of SEQ ID NO: 1003, but not more than 30, not more than 20, or not more than 10 modifications; (iii) the capsid protein comprises the amino acid sequence of SEQ ID NO: 1011, or an amino acid sequence having at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto; (iv) the capsid protein comprises an amino acid sequence having at least one, two, or three modifications of the amino acid sequence of SEQ ID NO: 1011, but not more than 30, not more than 20, or not more than 10 modifications; (v) the capsid protein comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 1002, or a sequence having at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto; and / or (vi) the nucleotide sequence encoding the capsid protein comprises the nucleotide sequence of SEQ ID NO: 1002, or a sequence having at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto; 39. The isolated AAV particle of claim 38.

40. The capsid protein is (i) an amino acid substitution at position K449 numbered according to SEQ ID NO: 1003, e.g., a K449R substitution; (ii) an insert comprising the amino acid sequence of TLAVPFK (SEQ ID NO: 1151), optionally located immediately after position 588 relative to the reference sequence numbered according to SEQ ID NO: 1003; (iii) an amino acid other than "A" at position 587 and / or an amino acid other than "Q" at position 588, numbered according to SEQ ID NO: 1003; and / or (iv) an amino acid substitution of A587D and / or Q588G numbered according to SEQ ID NO: 1003.

40. The isolated AAV particle of claim 38 or 39, comprising:

41. The capsid protein is (i) (a) an amino acid substitution of K449R numbered according to SEQ ID NO: 1003, and (b) an insert comprising the amino acid sequence of TLAVPFK (SEQ ID NO: 1151), optionally located immediately after position 588 of SEQ ID NO: 1003; (ii) (a) an amino acid substitution of K449R numbered according to SEQ ID NO: 1003; (b) an insert comprising the amino acid sequence of TLAVPFK (SEQ ID NO: 1151), optionally located immediately after position 588 relative to the reference sequence numbered according to SEQ ID NO: 1003; and (c) amino acid substitutions of A587D and Q588G numbered according to SEQ ID NO: 1003; or (iii) (a) an insert comprising the amino acid sequence of TLAVPFK (SEQ ID NO: 1151), optionally located immediately after position 588 with respect to a reference sequence numbered according to SEQ ID NO: 1003, and (b) amino acid substitutions A587D and Q588G numbered according to SEQ ID NO: 1003. The isolated AAV particle of any one of claims 38 to 40, comprising:

42. The capsid protein is (i) VOY101, VOY201, AAVPHP. B (PHP.B), AAVPHP. A (PHP.A), AAVG2B-26, AAVG2B-13, AAVTH1.1-32, AAVTH1.1-35, AAVPHP. B2 (PHP.B2), AAVPHP. B3 (PHP.B3), AAVPHP. N / PHP. B-DGT, AAVPHP. B-EST, AAVPHP. B-GGT, AAVPHP. B-ATP, AAVPHP. B-ATT-T, AAVPHP. B-DGT-T, AAVPHP. B-GGT-T, AAVPHP. B-SGS, AAVPHP. B-AQP, AAVPHP. B-QQP, AAVPHP. B-SNP (3), AAVPHP. B-SNP, AAVPHP. B-QGT, AAVPHP. B-NQT, AAVPHP. B-EGS, AAVPHP. B-SGN, AAVPHP. B-EGT, AAVPHP. B-DST, AAVPHP. B-DST, AAVPHP. B-STP, AAVPHP. B-PQP, AAVPHP. B-SQP, AAVPHP. B-QLP, AAVPHP. B-TMP, AAVPHP. B-TTP, AAVPHP. S / G2A12, AAVG2A15 / G2A3 (G2A3), AAVG2B4 (G2B4), AAVG2B5 (G2B5), AAVPHP. N (PHP.N), PHP. S, AAV1, AAV2, AAV2 variant, AAV2 / 3 variant, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9.47, AAV9(hu14), AAV9, AAV9 K449R, AAV10, AAV11, AAV12, AAVrh8, AAVrhlO, AAVDJ, AAVDJ8, or AAV2G9 capsid protein, or a functional variant thereof (optionally, the capsid protein comprises a VOY101 capsid protein), and / or (ii) any of the capsid proteins listed in Table 1, or a functional variant thereof The AAV particle of any one of claims 38 to 41, comprising:

43. 42. A host cell comprising a nucleic acid according to any one of claims 16 to 22 and 24 to 28, a viral genome according to any one of claims 29 to 36, or an AAV particle according to any one of claims 38 to 42, said host cell optionally being an insect cell, a bacterial cell, or a mammalian cell.

44. 44. A method for producing an antibody, comprising culturing the host cell of claim 43 under conditions suitable for gene expression.

45. A pharmaceutical composition comprising an antibody according to any one of claims 1 to 15 and 23, an isolated nucleic acid according to any one of claims 16 to 22 and 24 to 28, an AAV particle comprising the viral genome according to any one of claims 29 to 36, or an AAV particle according to any one of claims 38 to 42, and a pharmaceutically acceptable excipient.

46. 1. A method for delivering an exogenous antibody that binds to tau to a subject, comprising administering an effective amount of the antibody of any one of claims 1 to 15 and 23, the isolated nucleic acid of any one of claims 16 to 22 and 24 to 28, an AAV particle (e.g., a plurality of AAV particles) comprising the viral genome of any one of claims 29 to 36, an AAV particle (e.g., a plurality of AAV particles) of any one of claims 38 to 42, or the pharmaceutical composition of claim 44; and optionally (i) the subject has, has been diagnosed with, or is at risk of having a disease associated with tau expression; (ii) the subject has, has been diagnosed with, or is at risk of having a neurological disorder, e.g., a neurodegenerative disorder, and / or (iii) the subject has, has been diagnosed with, or is at risk of having a tauopathy; The method.

47. 10. A method of treating a subject having or diagnosed as having a neurological or neurodegenerative disorder, such as a tauopathy, comprising administering to the subject an effective amount of the antibody of any one of claims 1 to 15 and 23, the isolated nucleic acid of any one of claims 16 to 22 and 24 to 28, an AAV particle (e.g., a plurality of AAV particles) comprising the viral genome of any one of claims 29 to 36, the AAV particle (e.g., a plurality of AAV particles) of any one of claims 38 to 42, or the pharmaceutical composition of claim 45.

48. The neurological disorder is (i) a tauopathy, and / or (ii) AD, FTDP-17, FTLD, FTD, CTE, PSP, Down syndrome, Pick's disease, CBD, corticobasal syndrome, ALS, prion disease, CJD, multiple system atrophy, neurofibrillary senile dementia, or progressive subcortical gliosis 48. The method of claim 47, comprising:

49. The method of any one of claims 46 to 48, wherein the subject is a human.

50. 50. The method of any one of claims 46-49, wherein the AAV particles are administered to the subject intravenously, intramuscularly, via intraparenchymal administration, intracerebroventricularly, via intracisternal (ICM) injection, intrathecally, via focused ultrasound (FUS), e.g., in combination with intravenous administration of microbubbles (FUS-MB), or MRI-guided FUS in combination with intravenous administration, and optionally the AAV particles are administered to the subject intravenously or via intracisternal (ICM) injection.

51. The method further comprises administering an additional therapeutic agent and / or therapy suitable for treating or preventing a neurological or neurodegenerative disorder, such as a tauopathy, optionally including administering an additional therapeutic agent and / or therapy suitable for treating or preventing a neurological or neurodegenerative disorder, such as a tauopathy, the additional therapeutic agent and / or therapy being selected from the group consisting of a cholinesterase inhibitor (e.g., donepezil, rivastigmine, and / or galantamine), an N-methyl D-aspartate (NMDA) antagonist (e.g., memantine), an antipsychotic, an anxiolytic, an anticonvulsant, a dopamine agonist (e.g., pramipexole, ropinirole, rotigotine, and / or apomorphine), an MAO 51. The method of any one of claims 46-50, comprising a catechol O-methyltransferase (COMT) inhibitor (e.g., selegiline, rasagiline, and / or safinamide), a catechol O-methyltransferase (COMT) inhibitor (entacapone, opicapone, and / or tolcapone), an anticholinergic (e.g., benztropine and / or trihexyphenidyl), amantadine, carbidopa-levodopa, deep brain stimulation (DBS), or a combination thereof.

52. 27. An antibody according to any one of claims 1 to 15 and 23, an isolated nucleic acid according to any one of claims 16 to 22 and 24 to 28, an AAV particle comprising a viral genome according to any one of claims 29 to 36, an AAV particle according to any one of claims 38 to 42, or a pharmaceutical composition according to claim 45, for use in the manufacture of a medicament.

53. 10. An antibody according to any one of claims 1 to 15 and 23, an isolated nucleic acid according to any one of claims 16 to 22 and 24 to 28, an AAV particle comprising a viral genome according to any one of claims 29 to 36, an AAV particle according to any one of claims 38 to 42, or a pharmaceutical composition according to claim 45, for use in treating a neurological or neurodegenerative disorder such as a tauopathy.

54. 10. Use of an effective amount of an antibody of any one of claims 1 to 15 and 23, an isolated nucleic acid of any one of claims 16 to 22 and 24 to 28, an AAV particle comprising a viral genome of any one of claims 29 to 36, an AAV particle of any one of claims 38 to 42, or a pharmaceutical composition of claim 45 in the manufacture of a medicament for treating a neurological or neurodegenerative disorder, such as a tauopathy, in a subject.

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