Tau binding compounds

Abstract

The present disclosure provides anti-tau antibodies and vectorization thereof (e.g., into AAV particles). Also provided are methods of using anti-tau antibodies and / or AAV particles for prevention, treatment, and / or diagnosis of neurological indications.

Description

TAU BINDING COMPOUNDS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of the filing date of U.S. Provisional Patent Application Nos. 63 / 010261, filed on April 15, 2020, and 63 / 162976, filed on March 18, 2021, the entire contents of the above-referenced applications, including any sequences in the listings and drawings, are incorporated herein by reference. SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been filed electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on April 13, 2021, is named 135333_01920_2057_1308_SL.txt and is 714,773 bytes in size. FIELD OF THE DISCLOSURE

[0003] The present disclosure presents tau binding compounds and adeno-associated virus (AAV) particles comprising the same. BACKGROUND OF THE INVENTION

[0004] Tauopathies are a group of neurodegenerative diseases characterized by the dysfunction and / or aggregation of the microtubule associated protein tau. Tau is normally a very soluble protein known to associate with microtubules based on the extent of its phosphorylation. Tau is considered a critical component of intracellular trafficking processes, particularly in neuronal cells, given their unique and extended structure. Hyperphosphorylation of tan depresses its binding to microtubules and microtubule assembly activity. Further, hyperphosphorylation of tan renders it prone to misfolding and aggregation. In tauopathies, the tau becomes hyperphosphorylated, misfolds and aggregates as neurofibrillary tangles (NFT) of paired helical filaments (PHF), twisted ribbons or straight filaments. These NFT are largely considered indicative of impending neuronal cell death and thought to contribute to widespread neuronal cell loss, leading to a variety of behavioral and cognitive deficits.

[0005] A genetically defined tauopathy was described when mutations in the tau gene were shown to lead to an autosomal dominantly inherited tauopathy known as frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). This provided evidence that changes in tau could lead to neurodegenerative changes in the brain. These molecules are considered to be more amyloidogenic, meaning they are more likely to become hyperphosphorylated and more likely to aggregate into NFT (Hutton, M. er al., 1998, Nature 393(6686):702-5).

[0006] Several approaches have been proposed for therapeutically interfering with progression of tau pathology and preventing the subsequent molecular and cellular consequences. Given that NFT are composed of hyperphosphorylated, misfolded and aggregated forms of tan, interference at each of these stages provides targets that can be pursued. Introducing agents that limit phosphorylation, block misfolding or prevent aggregation are promising strategies. It has also been suggested that introduction of anti-tau antibodies can prevent the trans-neuronal spread of tau pathology.

[0007] There remains a need for anti-tau antibodies for use in tauopathy treatment, diagnostics, and other applications. The present disclosure addresses this need with related compounds and methods described herein. SUMMARY OF THE INVENTION

[0008] The present disclosure pertains at least in part to compositions and methods for modulating the level of tau, e.g., aggregation and or distribution of tau, and / or delivery, e.g., vectorized delivery of an antibody that binds to tau, e.g., an anti-tan antibody, e.g., an anti-tau antibody described herein. In some embodiments, the level of tau, e.g., aggregation or distribution, is reduced or inhibited using an anti-tan antibody described herein or an isolated, e.g., recombinant, AAV particle comprising a viral genome encoding an anti-tau antibody, e.g., an anti-tau antibody described herein. In some embodiments, the degradation of tau 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, e.g., an anti-tau antibody described herein. Such inhibition and / or degradation can be useful in treating disorders related to expression of tau and / or neurological disorders, such as tauopathies.

[0009] Accordingly, in one aspect, the present 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 a heavy chain complementary determining region 1 (HC CDR1), a heavy chain complementary determining region 2 (HC CDR?2), and / or a heavy chain complementary determining region 3 (HC CDR3) of any of the HC CDR sequences of Table 1, 6, 2A-2C, 4, or 5; and / or a light chain variable region (VL) comprising one, two, or three of a light chain complementary determining region 1 (LC CDR1), a light chain complementary determining region 2 (LC CDR2), and / or a light chain complementary determining region 3 (LC CDR3) of any of the LC CDR sequences of Table 1, 6, 2A-2B, 4, ors.

[0010] In another aspect, the present disclosure provides an isolated, e.g., recombinant antibody that binds to human tau, wherein the antibody binds the same or substantially the same epitope as a reference antibody, the reference antibody comprises a VH comprising an HC CDR1, an HC CDR2, and an HC CDR3 and a VL comprising a light LC CDR1, a LC CDR2, and a LC CDR3, wherein: the HC CDR1, HC CDR2, HC CDR3, LC CDR, LC CDR2, and LC CDR3 comprise the amino acid sequence of SEQ ID NO: 315, 341, 410, 474, 529, and 571, respectively; the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequence of SEQ ID NO: 314, 341, 410, 1154, 529, and 571, respectively; or the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequence of SEQ ID NO: 316, 341, 410, 475, 530, and 571, respectively.

[0011] In another aspect, the present disclosure provides an isolated, e.g., recombinant, antibody that binds to human tau, wherein the antibody competes for binding with a reference antibody, wherein the reference antibody comprises a VH comprising an HC CDR1, an HC CDR2, and an HC CDR3 and a VL comprising a light LC CDR1, a LC CDR2, and a LC CDR3, wherein: the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequence of SEQ ID NO: 315, 341, 410, 474, 529, and 571, respectively; the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequence of SEQ ID NO: 314, 341, 410, 1154, 529, and 571, respectively; or the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequence of SEQ ID NO: 316, 341, 410, 475, 530, and 571, respectively.

[0012] In yet another aspect, the present disclosure provides an isolated, e.g., recombinant, antibody that binds to a region of a 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, HC CDR2, HC CDR3 comprise the amino acid sequence of SEQ ID NOs: 1180, 341, and 410, respectively; the HC CDR1, HC CDR2, HC CDR3 comprise the amino acid sequence of SEQ ID NOs: 1183, 1184, and 410, respectively; or the HC CDR1, HC CDR2, HC CDR3 comprise the amino acid sequence 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, LC CDR2, and LC CDR3 comprise the amino acid sequence of SEQ ID NOs: 1181, 1182, and 571, respectively; the LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequence of SEQ ID NOs: 1185, 1182, and 571, respectively; or the LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequence of SEQ ID NOs: 1188, 528, and 571, respectively.

[0013] In yet another aspect, the present disclosure provides an antibody that binds, e.g., directly or indirectly, to a region of a human tau protein comprising residues 32-49, 55-76, 159-194, 185-200, 219-247, 381-426, and / or 409-436, numbered according to SEQ ID NO: 020.

[0014] In yet another aspect, the present disclosure provides an isolated, e.g., recombinant, nucleic acid that encodes an antibody described herein, e.g., an antibody comprising VH comprising one, two, or three of an HC CDR1, an HC CDR2, and / or an HC CDR3 of any of the HC CDR sequences of Table 1, 6, 2A-2C, 4, or 5; and / or a VL comprising one, two, or three of an LC CDR1, an LC CDR2, and / or an LC CDR3 of any of the LC CDR sequences of Table 1, 6, 2A-2C, 4, or 5.

[0015] 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 to 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 poly A signal region (e.g., a poly A signal sequence described herein), and / or an encoded miR binding site.

[0016] In yet another aspect, the present disclosure provides an isolated, e.g., recombinant, AAV particle comprising a capsid protein and a viral genome comprising 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 chosen 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.

[0017] In yet another aspect, the present disclosure provides method of 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, said AAV particle comprising a viral genome described herein.

[0018] In yet another aspect, the present disclosure provides a method of treating a subject having or being diagnosed as having a neurological disorder, a tanopathy, and / or a disease associated with expression of tau. The method comprising administering to the subject an effective amount of an AAV particle or a plurality of AAV particles, described herein, comprising a viral genome described herein.

[0019] In some embodiments, the present disclosure provides an antibody that includes (1) a heavy chain variable domain (VH), wherein the VH includes: a complementarity determining region (CDR)HI that includes an amino acid sequence selected from the group consisting of SEQ ID NOs: 296-339, or a fragment thereof; a CDRH2 that includes an amino acid sequence selected from the group consisting of SEQ ID NOs: 340-391, or a fragment thereof; and a CDRH3 that includes 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), wherein the VL includes: a CDRLI that includes an amino acid sequence selected from the group consisting of SEQ ID NOs: 457-514, or a fragment thereof; a CDRL2 that includes an amino acid sequence selected from the group consisting of SEQ ID NOs: 515-553, or a fragment thereof; and a CDRL3 that includes an amino acid sequence selected from the group consisting of SEQ ID NOs: 554-600, or a fragment thereof. The antibody may include a set of variable domain CDR amino acid sequences, wherein the variable domain CDR amino acid sequence set is selected from Table 6.

[0020] The VH may include: a framework region (FR)H1 that includes an amino acid sequence selected from the group consisting of SEQ ID NOs: 601-643, or a fragment thereof; a FRH2 that includes an amino acid sequence selected from the group consisting of SEQ ID NOs: 644-696, or a fragment thereof; a FRH3 that includes an amino acid sequence selected from the group consisting of SEQ ID NOs: 697-766, or a fragment thereof; and a FRH4 that includes an amino acid sequence selected from the group consisting of SEQ ID NOs: 767- 775, or a fragment thereof.

[0021] The VL may include: a FRL1 that includes an amino acid sequence selected from the group consisting of SEQ ID NOs: 776-822, or a fragment thereof; a FRL2 that includes an amino acid sequence selected from the group consisting of SEQ ID NOs: 823-857, or a fragment thereof; a FRL3 that includes an amino acid sequence selected from the group consisting of SEQ ID NOs: 858-904, or a fragment thereof; and a FRL4 that includes an amino acid sequence selected from the group consisting of SEQ ID NOs: 905-919, or a fragment thereof.

[0022] The VH may include an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-74; and / or an amino acid sequence that is encoded by a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 147-220.

[0023] The VL may include an amino acid sequence selected from the group consisting of SEQ ID NOs: 75-146; and / or an amino acid sequence that is encoded by a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 221-295.

[0024] The antibody may include a variable domain pair selected from Table 3.

[0025] The CDRHI may include 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). The CDRH2 may include the amino acid sequence of NPNNGG (SEQ ID NO: 341). The CDRH3 may include the amino acid sequence of GTGTGAMDY (SEQ ID NO: 410).

[0026] The CDRLI may include 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). The CDRL2 may include an amino acid sequence selected from the group consisting of RVSNRFS (SEQ ID NO: 529), and RVSSREFS (SEQ ID NO: 530). The CDRL3 may include the amino acid sequence of FQGTHVPRT (SEQ ID NO: 571).

[0027] The CDRHI may include 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). The CDRH2 may include the amino acid sequence of YWDDD (SEQ ID NO: 362). The CDRH3 may include 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] The CDRLI may include 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). The CDRL2 may include 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). The CDRL3 may include 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] Antibodies of the present disclosure may include a format selected from the group consisting of a monoclonal antibody, a multispecific antibody, a chimeric antibody, an antibody mimetic, a single chain Fv (scFv) format, and an antibody fragment. The antibody may include an antibody class selected from the group consisting of IgA, IgD, IgE, IgG, and IgM. The antibody may include a mouse IgG, wherein the mouse IgG includes an isotype selected from the group consisting of IgG1, IgG2a, IgG2b, IgG2c¢, and IgG3. The antibody may include a human IgG, wherein the human IgG includes an isotype selected from the group consisting of IgG1, IgG2, IgG3, and IgG4. The antibody may include one or more human constant domain. The one or more human constant domain may include a human IgG constant domain. The antibody may include a humanized antibody.

[0030] Antibodies of the present disclosure may bind to a tau protein epitope. The tau protein epitope may include or may be included 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 UCB D. The tau protein epitope may include residues 409- 436 of human tau (SEQ ID NO: 920). The tau protein epitope may include residues 413-430 of human tau (SEQ ID NO: 920). Antibody binding to the tau protein epitope may exhibit a Kp of from about 0.1 nM to about 0.5 nM. 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). Antibody binding to the tau protein epitope may exhibit a Kp of from about 0.5 nM to about 5 nM. The tau protein epitope may include a region formed by a complex of at least two tau proteins. The antibody may bind to enriched paired helical filament tau protein (ePHF) with a half maximal effective concentration (EC50) of from 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 from about 1 nM to about 30 nM as determined by immunodepletion assay. The immunodepletion assay may be carried out with tau RD Biosensor cells.

[0031] In some embodiments, the present disclosure provides an antibody that competes for binding with a second antibody to a tau protein epitope, wherein the tau protein epitope includes 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 include one or more of residues 409-436 and 413-430 of human tau (SEQ ID NO: 920). The second antibody may include a variable domain pair selected from the group consisting of: a VH with the amino acid sequence of SEQ ID NO: 21 anda VL with the amino acid sequence of SEQ ID NO: 93; a VH with the amino acid sequence of SEQ ID NO: 22 and a VL with the amino acid sequence of SEQ ID NO: 94; and a VH with the amino acid sequence of SEQ ID NO: 23 and a VL with the amino acid sequence of SEQ ID NO: 95.

[0032] Antibodies of the present disclosure may include a conjugate. The conjugate may include a therapeutic agent. The conjugate may include a detectable label.

[0033] In some embodiments, the present disclosure provides a construct encoding an antibody disclosed herein.

[0034] In some embodiments, the present disclosure provides a method of treating a therapeutic indication in a subject by administering an antibody disclosed herein to the subject. The therapeutic indication may be a neurological indication. The neurological indication may 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’s syndrome, Pick’s disease, corticobasal degeneration (CBD), corticobasal syndrome, amyotrophic lateral sclerosis (ALS), a prion disease, Creutzfeldt-Jakob disease (CJD), multiple system atrophy, tangle-only dementia, stroke, or progressive subcortical gliosis.

[0035] In some embodiments, the present disclosure provides a method of 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, FID, CTE, PSP, Down’s syndrome, Pick’s disease, CBD, corticobasal syndrome, ALS, a prion disease, CJD, multiple system atrophy, tangle-only dementia, stroke, or progressive subcortical gliosis. The antibody may be used to detect pathological tau in a subject tissue. The subject tissue may include CNS tissue. The subject tissue may be a thin tissue section. The thin tissue section may be a cryopreserved tissue section.

[0036] In some embodiments, the tau binding compounds or antibodies of the present disclosure may be encoded in an adeno-associated virus (AAV) viral genome. In some embodiments, the AAV viral genome may comprise one or more nucleic acid sequences encoding an antibody described herein, or a fragment thereof.

[0037] In some embodiments, the viral genome may comprise a 5’ inverted terminal repeat (ITR) sequence region selected from SEQ ID NO: 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 NO: 1037 and 1038.

[0038] In some embodiments, the viral genome may comprise one or more exon sequence regions selected from SEQ ID NO: 1051-1055, one or more intron sequence regions selected from SEQ ID NO: 1056-1070, one or more signal sequence regions selected from SEQ ID NO: 1071-1089, one or more tag sequence regions selected from SEQ ID NO: 1127-1133, and / or one or more filler sequence regions selected from SEQ ID NO: 1137 and 1138.

[0039] 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 NO: 1-74. In some embodiments, the viral genome encodes a VL having an amino acid sequence selected from SEQ ID NO: 75-146. In some embodiments, the viral genome encodes a VH and VL pair selected from the pairings shown in Table 3.

[0040] In some embodiments, the first and second nucleic acid sequences of the viral genome are separated by one or more linker sequences, wherein the linker sequence(s) may be selected from SEQ ID NO: 1090-1126.

[0041] In some embodiments, the viral genome comprises a VH nucleic acid sequence selected from SEQ ID NO: 147-220. In some embodiments, the viral genome comprises a VL nucleic acid sequence selected from SEQ ID NO: 221-295.

[0042] In some embodiments, the viral genome may encode one or more CDR sequences having an amino acid sequence selected from SEQ ID NO: 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.

[0043] In some embodiments, the viral genome may encode one or more FR amino acid sequence selected from SEQ ID NO: 601-919.

[0044] 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.

[0045] In some embodiments, an AAV viral genome described herein may be incorporated into an AAV particles.

[0046] In some embodiments, the AAV particle comprises an AAV capsid protein chosen from VOY101, VOY201, AAVPHP.B (PHP.B), AAVPHP.A (PHP.A), AAVG2B-26, AAVG2B-13, AAVTH1.1-32, AAVTHI.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), AAVG2BS (G2BS), AAVPHP.N (PHP.N), PHP.S, AAV1, AAV2, AAV2 variant, AAV2 / 3 variant, AAV4, AAVS, AAV6, AAVT, AAVS, AAV9.47, AAVI(huld), AAVY, AAV9I K449R, AAVI10, AAV1I, AAVI2, AAVrh8, AAVrh10, AAVDI, AAVDIJS, AAV2.BRI1, or AAV2G9 capsid protein, or a functional variant thereof.

[0047] In certain embodiments, the AAV particle comprises a VOY 101 capsid. In some embodiments, the VOY 101 capsid amino acid sequence is given by SEQ ID NO: 1023.

[0048] In some embodiments, the viral genome of an AAV particle described herein may further comprise a nucleotide sequence encoding a miR binding site, e.g., a miR binding site that modulates, e.g., reduces, expression of the payload encoded by the viral genome in a cell or tissue where the corresponding miRNA is expressed.

[0049] In some embodiments, the viral genome of an AAV particle may further comprise at least 1-5 copies of an 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 an encoded miR binding site, optionally wherein all three copies are for the same miR binding site or at least one, two, or all of the copies are for different miR binding sites.

[0050] In some embodiments, the viral genome may further comprise a nucleotide sequence encoding a miR122 binding site, a miR183 binding site, a miR-142-3p, or a combination thereof.

[0051] 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 (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto; or a nucleic acid sequence having at least one, two, three, four, five, six, or seven modifications but no more than ten modifications of SEQ ID NO: 1029.

[0052] 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 (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto; or a nucleic acid sequence having at least one, two, three, four, five, six, or seven modifications but no more than ten modifications of SEQ ID NO: 1032.

[0053] 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 (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto; or a nucleic acid sequence having at least one, two, three, four, five, six, or seven modifications but no more than ten modifications of SEQ ID NO: 1031.

[0054] In some embodiments, the viral genome comprises at least 4 copies of an encoded miR binding site, optionally wherein all four copies comprise the same miR binding site or at least one, two, three, or all of the copies comprise a different miR binding site.

[0055] In some embodiments, the AAV particles disclosed herein may be formulated into a pharmaceutical composition.

[0056] The present disclosure provides a method of producing an antibody in a subject by administering a pharmaceutical composition to the subject.

[0057] The present disclosure also provides methods for preventing or treating a tauopathy in a subject by administering a therapeutically effective amount of a pharmaceutical composition described herein to a subject. The pharmaceutical composition may be administered by any route of administration including, but not limited to, intravenous, intramuscular, intraparenchymal, intracerebroventricular, intracisterna magna (ICM), intrathecal, or a combination thereof.

[0058] The tanopathy that may be treated by the methods and / or compositions of the present disclosure include, but are not limited to, AD, FTDP-17, FTLD, FTD, CTE, PSP, Down’s syndrome, Pick’s disease, CBD, Corticobasal syndrome, ALS, Prion diseases, CID, Multiple system atrophy, Tangle-only dementia, and Progressive subcortical gliosis.

[0059] 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. Such equivalents are intended to be encompassed by the following enumerated embodimen. Enumerated Embodiments El. An isolated, e.g., recombinant, antibody that binds to human tau, wherein the antibody binds the same or substantially the same epitope as a reference antibody, the reference antibody comprises a heavy chain variable region (VH) comprising a heavy chain complementary determining region 1 (HC CDR1), a heavy chain complementary determining region 2 (HC CDR2), and a heavy chain complementary determining region 3 (HC CDR3) and a light chain variable region (VL) comprising a light chain complementary determining region 1 (LC CDR1), a light chain complementary determining region 2 (LC CDR2), and a light chain complementary determining region 3 (LC CDR3), wherein: (1) the HC CDRI1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequence of SEQ ID NO: 315, 341, 410, 474, 529, and 571, respectively; (ii) the HC CDRI1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequence of SEQ ID NO: 314, 341, 410, 1154, 529, and 571, respectively; or, (iii) the HC CDRI1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequence of SEQ ID NO: 316, 341, 410, 475, 530, and 571, respectively. E2. An isolated, e.g., recombinant, antibody that binds to human tau, wherein the antibody competes for binding with a reference antibody, wherein the reference antibody comprises a heavy chain variable region (VH) comprising a heavy chain complementary determining region 1 (HC CDR1), a heavy chain complementary determining region 2 (HC CDR2), and a heavy chain complementary determining region 3 (HC CDR3) and a light chain variable region (VL) comprising a light chain complementary determining region 1 (LC CDR1), a light chain complementary determining region 2 (LC CDR2), and a light chain complementary determining region 3 (LC CDR3), wherein: i) the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequence of SEQ ID NO: 315, 341, 410, 474, 529, and 571, respectively; (ii) the HC CDRI1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequence of SEQ ID NO: 314, 341, 410, 1154, 529, and 571, respectively; or, (iii) the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequence of SEQ ID NO: 316, 341, 410, 475, 530, and 571, respectively. The antibody of embodiment E1 or E2, wherein the reference antibody comprises: (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) a VH comprising the amino acid sequence of SEQ ID NO: 23 and a VL comprising the amino acid sequence of SEQ ID NO: 95. prising (1 The antibody of any one of embodiments E1-E3, wherein the antibody binds an epitope that overlaps the epitope recognized by the reference antibody. The antibody of any one of embodiments E1-E4, wherein the antibody binds to a region of a human tau protein comprising residues 409-436, numbered according to SEQ ID NO: 920. The antibody of any one of embodiments E1-ES, wherein the antibody binds to a region of a human tau protein comprising residues 413-430, numbered according to SEQ ID NO: 920. The antibody of any one of embodiments E1-E6, which binds to a tau protein with a dissociation constant (Kp) of about 0.1 to about 10 nM, or about 0.2-5 nM. The antibody of any one of embodiments E1-E7, wherein the antibody comprises a heavy chain variable region comprising at least one, two, or three of an HC CDR1, an HC CDR2, and an HC CDR3 comprising the amino acid sequences of: (i) SEQ ID NOs: 1180, 341, and 410, respectively; (ii) SEQ ID NOs: 1183, 1184, and 410, respectively; or (iii) SEQID NOs: 1186, 1187, and 1167, respectively. The antibody of any one of embodiments E1-E8, wherein the antibody comprises a light chain variable region (VL) comprising one, two, or three of an LC CDR1, an LC CDR2, and / or an LC CDR3 of: 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-E9, wherein the antibody comprises: 1) the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequence of SEQ ID NO: 315, 341, 410, 474, 529, and 571, respectively; (ii) the HC CDRI1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequence of SEQ ID NO: 1147, 1148, 410, 474, 529, and 571, respectively; or (iii) the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequence of SEQ ID NO: 1168, 1169, 1167, 1170, 528, and 571, respectively. The antibody of any one of embodiments E1-E9, wherein the antibody comprises: 1) the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequence of SEQ ID NO: 314, 341, 410, 1154, 529, and 571, respectively; (ii) the HC CDRI1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequence of SEQ ID NO: 1144, 1145, 410, 1146, 529, and 571, respectively; or (iii) the HC CDRI1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequence of SEQ ID NO: 1165, 1166, 1167, 473, 528, and 571, respectively. The antibody of any one of embodiments E1-E9, wherein the antibody comprises: [6)) the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequence of SEQ ID NO: 316, 341, 410, 475, 530, and 571, respectively; (ii) the HC CDRI1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequence of SEQ ID NO: 1149, 1150, 410, 475, 530, and 571, respectively; or (iii) the HC CDRI1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequence of SEQ ID NO: 1171, 1166, 1167, 1172, 528, and 571, respectively. The antibody of any one of embodiments E1-E12, wherein the antibody comprises: (i) a VH comprising the amino acid sequence of SEQ ID NO: 21-23, 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 the amino acid sequence of SEQ ID NO: 93-95, or an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto. An isolated, e.g., recombinant, antibody that binds to a region of a human tau protein comprising residues 409-436, numbered according to SEQ ID NO: 920, and wherein the antibody comprises: (i) a VH comprising an HC CDR1, an HC CDR2, and an HC CDR3 wherein: (a) the HC CDRI1, HC CDR2, HC CDR3 comprise the amino acid sequence of of SEQ ID NOs: 1180, 341, and 410, respectively; (b) the HC CDRI1, HC CDR2, HC CDR3 comprise the amino acid sequence of of SEQ ID NOs: 1183, 1184, and 410, respectively; or (©) the HC CDRI1, HC CDR2, HC CDR3 comprise the amino acid sequence of of SEQ ID NOs: 1186, 1187, and 1167, respectively; and (ii) a VL comprising an LC CDR1, an LC CDR2, and an LC CDR3 wherein: (a) the LC CDRI1, LC CDR2, LC CDR3 comprise the amino acid sequence of SEQ ID NOs: 1181, 1182, and 571, respectively; (b) the LC CDRI1, LC CDR2, LC CDR3 comprise the amino acid sequence of SEQ ID NOs: 1185, 1182, and 571, respectively; or, (c) the LC CDRI1, LC CDR2, LC CDR3 comprise the amino acid sequence of SEQ ID NOs: 1188, 528, and 571, respectively. An antibody that binds, e.g., directly or indirectly, to a region of a human tau protein comprising residues 32-49, 55-76, 159-194, 185-200, 219-247, 381-426, and / or 409- 436, numbered according to SEQ ID NO: 920. The antibody of embodiment E14 or E15, which binds a region of a human tau protein comprising residues 55-76, 159-194, 219-247, and / or 381-426, numbered according to SEQ ID NO: 920. The antibody of embodiment E14 or E15, which binds a region of a human tau protein comprising residues 57-72, 175-191, 223-238, and / or 383-400, numbered according to SEQ ID NO: 920. The antibody of embodiment E14 or E15, which binds a region of a human tau protein comprising residues 223-238, numbered according to SEQ ID NO: 920. The antibody of any one of embodiments E14-E17, which binds a conformational epitope comprising residues 55-76, 159-194, 219-247, and 381-426, numbered according to SEQ ID NO: 920. The antibody of any one of embodiments E15-E19, comprising: (i) a VH comprising an HC CDR1, an HC CDR2, and an HC CDR3 comprising the amino acid sequence of SEQ ID NOs: 3235, 362, and 435, respectively; and / or a VL comprising an LC CDR1, an LC CDR2, and an LC CDR3 comprising the amino acid sequence of SEQ ID NOs: 495, 540, and 587, respectively; (ii) a VH comprising an HC CDR1, an HC CDR2, and an HC CDR3 comprising the amino acid sequence of SEQ ID NOs: 1152, 1153, and 435, respectively; and / or a VL comprising an LC CDR1, an LC CDR2, and an LC CDR3 comprising the amino acid sequence of SEQ ID NOs: 495, 540, and 587, respectively (iii) a VH comprising an HC CDR1, an HC CDR2, and an HC CDR3 comprising the amino acid sequence of SEQ ID NOs: 1173, 1174, and 1175, respectively; and / or a VL comprising an LC CDR1, an LC CDR2, and an LC CDR3 comprising the amino acid sequence of SEQ ID NOs: 1176, 1177, and 587, respectively. The antibody of any one of embodiments E14-E20, which binds to a tau protein with a dissociation constant (Kp) of about 0.1 to about 1 nM. An isolated, e.g., recombinant, antibody that binds to tau, comprising: 1) a heavy chain variable region (VH) comprising one, two, or three of an HC CDRI1, an HC CDR2, and / or an HC CDR3 of any of the HC CDR sequences of Table 1, 6, 2A-2C, 4, or 5; and / or (ii) a light chain variable region (VL) comprising one, two, or three of an LC CDR1, an LC CDR2, and / or an LC CDR3 of any of the LC CDR sequences of Table 1, 6, 2A-2C, 4, or 5. The antibody of embodiment E22, comprising a VH comprising the HC CDR1, the HC CDR2, and the HC CDR3 of any one of the antibodies in Table 1, 6, 2A-2C, 4, or 5. The antibody of embodiment E22 or E23, comprising a VL comprising the LC CDR1, the LC CDR2, and the LC CDR3 of any one of the antibodies in Table 1, 6, 2A-2C, 4, ors. The antibody of any one of embodiments E22-E24, comprising a VH comprising the HC CDR, the HC CDR2, and the HC CDR3 of any one of the antibodies in Table 1, 6,2A-2C, 4, or 5; and a VL comprising the LC CDR1, the LC CDR2, and the LC CDR3 of said any one of the antibodies in Table 1, 6, 2A-2C, 4, or 5. The antibody of any one of embodiments E22-E25, comprising: (i) an HC CDR1, an HC CDR2, and an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 931 or 932, 341, and 410, respectively; and / or (ii) an LC CDRI1, an LC CDR2, and an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 933 or 934, 935 or 936, and 571, respectively. The antibody of any one of embodiments E22-E26, comprising: (1) an HC DR1, an HC CDR2, and an HC CDR3 comprising the amino acid sequence of SEQ ID NOs: 1180, 341, and 410, respectively; and / or an LC CDR1, an LC CDR2, and an LC CDR3 comprising the amino acid sequence of SEQ ID NOs: 1181, 1182, and 571, respectively; (ii) an HC DR1, an HC CDR2, and an HC CDR3 comprising the amino acid sequence of SEQ ID NOs: 1183, 1184, and 410, respectively; and / or an LC CDRI1, an LC CDR2, and an LC CDR3 comprising the amino acid sequence of SEQ ID NOs: 1185, 1182, and 571, respectively; or (iii) an HC DR1, an HC CDR2, and an HC CDR3 comprising the amino acid sequence of SEQ ID NOs: 1186, 1187, and 1167, respectively; and / or an LC CDR1, an LC CDR2, and an LC CDR23 comprising the amino acid sequence of SEQ ID NOs: 1188, 528, and 571, respectively. The antibody of any one of embodiments E22-E27, comprising: i) an HC CDR1, an HC CDR2, and an HC CDR3 comprising the amino acid sequence of SEQ ID NOs: 3135, 341, and 410, respectively; and / or an LC CDR1, an LC CDR2, and an LC CDR3 comprising the amino acid sequence of SEQ ID NOs: 474, 529, and 571, respectively; (ii) an HC CDR1, an HC CDR2, and an HC CDR3 comprising the amino acid sequence of SEQ ID NOs: 1147, 1148, and 410, respectively; and / or an LC CDRI1, an LC CDR2, and an LC CDR3 comprising the amino acid sequence of SEQ ID NOs: 474, 529, and 571, respectively; or (iii) an HC CDRI1, an HC CDR2, and an HC CDR3 comprising the amino acid sequence of SEQ ID NOs: 1168, 1169, and 1167, respectively; and / or an LC CDR1, an LC CDR2, and an LC CDR3 comprising the amino acid sequence of SEQ ID NOs: 1170, 528, and 571, respectively. The antibody of any one of embodiments E22-E27, comprising: (i) an HC CDR1, an HC CDR2, and an HC CDR3 comprising the amino acid sequence of SEQ ID NOs: 314, 341, and 410, respectively; and / or an LC CDR1, an LC CDR2, and an LC CDR3 comprising the amino acid sequence of SEQ ID NOs: 1154, 529, and 571, respectively; (ii) an HC CDR1, an HC CDR2, and an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 1144, 1145, and 410, respectively; and / or an LC CDRI1, an LC CDR2, and an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 1146, 529, and 571, respectively; or (iii) an HC CDRI, an HC CDR2, and an HC CDR3 comprising the amino acid sequence of SEQ ID NOs: 1165, 1166, and 1167, respectively; and / or an LC CDR1, an LC CDR2, and an LC CDR3 comprising the amino acid sequence of SEQ ID NOs: 473, 528, and 571, respectively. The antibody of any one of embodiments E22-E27, comprising: (i) an HC CDR1, an HC CDR2, and an HC CDR3 comprising the amino acid sequence of SEQ ID NOs: 316, 341, and 410, respectively; and / or an LC CDR1, an LC CDR2, and an LC CDR3 comprising the amino acid sequence of SEQ ID NOs: 475, 530, and 571, respectively; (ii) an HC CDR1, an HC CDR2, and an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 1149, 1150, and 410, respectively; and / or an LC CDR1, an LC CDR2, and an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 475, 1151, and 571, respectively; or (iii) an HC CDRI1, an HC CDR2, and an HC CDR3 comprising the amino acid sequence of SEQ ID NOs: 1171, 1166, and 1167, respectively; and / or an LC CDR1, an LC CDR2, and an LC CDR3 comprising the amino acid sequence of SEQ ID NOs: 1172, 528, and 571, respectively. The antibody of any one of embodiments E22-E27, comprising: (i) an HC CDR1, an HC CDR2, and an HC CDR3 comprising the amino acid sequence of SEQ ID NOs: 323, 362, and 435, respectively; and / or an LC CDR1, an LC CDR2, and an LC CDR3 comprising the amino acid sequence of SEQ ID NOs: 495, 540, and 587, respectively; (ii) an HC CDR1, an HC CDR2, and an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 1152, 1153, and 435, respectively; and / or an LC CDRI1, an LC CDR2, and an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 495, 540, and 587, respectively; or (iii) an HC CDRI, an HC CDR2, and an HC CDR3 comprising the amino acid sequence of SEQ ID NOs: 1173, 1174, and 1173, respectively; and / or an LC CDR1, an LC CDR2, and an LC CDR3 comprising the amino acid sequence of SEQ ID NOs: 1176, 1177, and 587, respectively. The antibody of any one of embodiments E22-E27, comprising: (i) an HC CDR1, an HC CDR2, and an HC CDR3 comprising the amino acid sequence of SEQ ID NOs: 304, 347, and 400, respectively; and / or an LC CDRI1, an LC CDR2, and an LC CDR3 comprising the amino acid sequence of SEQ ID NOs: 464, 523, and 562, respectively; (ii) an HC CDR1, an HC CDR2, and an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 1142, 1143, and 400, respectively; and / or an LC CDR1, an LC CDR2, and an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 464, 523, and 562, respectively; or (iii) an HC CDRI, an HC CDR2, and an HC CDR3 comprising the amino acid sequence of SEQ ID NOs: 1160, 1161, and 1162, respectively; and / or an LC CDRI1, an LC CDR2, and an LC CDR3 comprising the amino acid sequence of SEQ ID NOs: 1163, 1164, and 562, respectively. The antibody of any one of embodiments E22-E27, comprising: (1) an HC CDR1, an HC CDR2, and an HC CDR3 comprising the amino acid sequence of SEQ ID NOs: 299, 343, and 395, respectively; and / or an LC CDR1, an LC CDR2, and an LC CDR3 comprising the amino acid sequence of SEQ ID NOs: 460, 518, and 557, respectively; (ii) an HC CDR1, an HC CDR2, and an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 1140, 1141, and 395, respectively; and / or an LC CDRI1, an LC CDR2, and an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 460, 518, and 557, respectively; or (iii) an HC CDRI, an HC CDR2, and an HC CDR3 comprising the amino acid sequence of SEQ ID NOs: 1155, 1156, and 1157, respectively; and / or an LC CDR1, an LC CDR2, and an LC CDR3 comprising the amino acid sequence of SEQ ID NOs: 1158, 1159, and 557, respectively. The antibody of any one of the preceding embodiments, comprising: (1) one, two, three, or all of a heavy chain framework region 1 (FRH1), a heavy chain framework region 2 (FRH2), a heavy chain framework region 3 (FRH3), and / or a heavy chain framework region 4 (FRH4) comprising the amino sequence of any of the heavy chain framework regions of the antibodies provided in Table 7 or 4; or (ii) one, two, three, or all of a heavy chain framework region 1 (FRH1), a heavy chain framework region 2 (FRH2), a heavy chain framework region 3 (FRH3), and / or a heavy chain framework region 4 (FRH4) comprising an amino acid sequence having at least one, two, or three but no more than four modifications, e.g., substitutions, relative to the amino acid sequence of any of the heavy chain framework regions of the antibodies provided in Table 7 or 4. The antibody of any one of the preceding embodiments, comprising: (i) one, two, three, or all of an FRH1 comprising the amino acid sequence of SEQ ID NO: 603, an FRH2 comprising the amino acid sequence of SEQ ID NO: 664, an FRH3 comprising the amino acid sequence of SEQ ID NO: 718, and / or an FRH4 comprising the amino acid sequence of SEQ ID NO: 771; or an amino acid sequence having at least one, two, or three but no more than four modifications, e.g., substitutions, relative to each of the amino acid sequences of SEQ ID NO: 603, 664, 718, and / or 771; (ii) one, two, three, or all of an FRH1 comprising the amino acid sequence of SEQ ID NO: 619, an FRH2 comprising the amino acid sequence of SEQ ID NO: 663, an FRH3 comprising the amino acid sequence of SEQ ID NO: 717, and / or an FRH4 comprising the amino acid sequence of SEQ ID NO: 771; or an amino acid sequence having at least one, two, or three but no more than four modifications, e.g., substitutions, relative to each of the amino acid sequences of SEQ ID NO: 619, 663, 717, and / or 771; one, two, three, or all of an FRH1 comprising the amino acid sequence of SEQ ID NO: 603, an FRH2 comprising the amino acid sequence of SEQ ID NO: 665, an FRH3 comprising the amino acid sequence of SEQ ID NO: 719, and / or an FRH4 comprising the amino acid sequence of SEQ ID NO: 771; or an amino acid sequence having at least one, two, or three but no more than four modifications, e.g., substitutions, relative to each of the amino acid sequences of SEQ ID NO: 603, 665, 719, and / or 771; one, two, three, or all of an FRH1 comprising the amino acid sequence of SEQ ID NO: 633, an FRH2 comprising the amino acid sequence of SEQ ID NO: 682, an FRH3 comprising the amino acid sequence of SEQ ID NO: 745, and / or an FRH4 comprising the amino acid sequence of SEQ ID NO: 771; or an amino acid sequence having at least one, two, or three but no more than four modifications, e.g., substitutions, relative to each of the amino acid sequences of SEQ ID NO: 663, 682, 745, and / or 771. odne, two, three, or all of an FRH1 comprising the amino acid sequence of SEQ ID NO: 608, an FRH2 comprising the amino acid sequence of SEQ ID NO: 652, an FRH3 comprising the amino acid sequence of SEQ ID NO: 705, and / or an FRH4 comprising the amino acid sequence of SEQ ID NO: 767; or an amino acid sequence having at least one, two, or three but no more than four modifications, e.g., substitutions, relative to each of the amino acid sequences of SEQ ID NO: 608, 652, 705, and / or 767; or, one, two, three, or all of an FRH1 comprising the amino acid sequence of SEQ ID NO: 604, an FRH2 comprising the amino acid sequence of SEQ ID NO: 647, an FRH3 comprising the amino acid sequence of SEQ ID NO: 700, and / or an FRH4 comprising the amino acid sequence of SEQ ID NO: 770; or an amino acid sequence having at least one, two, or three but no more than four modifications, e.g., substitutions, relative to each of the amino acid sequences of SEQ ID NO: 604, 647, 700, and / or 770. The antibody of any one of the preceding embodiments, comprising: i) one, two, three, or all of a light chain framework region 1 (FRL1), a light chain framework region 2 (FRL2), a light chain framework region 3 (FRL3), and / or a light chain framework region 4 (FRL4) comprising the amino sequence of any of the light chain framework regions of the antibodies provided in Table 7 or 4; or (ii) one, two, three, or all of a light chain framework region 1 (FRL1), a light chain framework region 2 (FRL2), a light chain framework region 3 (FRL3), and / or a light chain framework region 4 (FRL4) comprising an amino acid sequence having at least one, two, or three but no more than four modifications, e.g., substitutions, relative to the amino acid sequence of any of the light chain framework regions of the antibodies provided in Table 7 or 4. The antibody of any one of the preceding embodiments, comprising: (i) one, two, three, or all of an FRL1 comprising the amino acid sequence of SEQ ID NO: 793, an FRL2 comprising the amino acid sequence of SEQ ID NO: 836, an FRL3 comprising the amino acid sequence of SEQ ID NO: 874, and / or an FRL4 comprising the amino acid sequence of SEQ ID NO: 910; or an amino acid sequence having at least one, two, or three but no more than four modifications, e.g., substitutions, relative to each of the amino acid sequences of SEQ ID NO: 793, 836, 874, and / or 910; (ii) one, two, three, or all of an FRL1 comprising the amino acid sequence of SEQ ID NO: 1178, an FRL2 comprising the amino acid sequence of SEQ ID NO: 831, an FRL3 comprising the amino acid sequence of SEQ ID NO: 1179, and / or an FRL4 comprising the amino acid sequence of SEQ ID NO: 906; or an amino acid sequence having at least one, two, or three but no more than four modifications, e.g., substitutions, relative to each of the amino acid sequences of SEQ ID NO: 1178, 831, 1179, and / or 906; (iii) one, two, three, or all of an FRL1 comprising the amino acid sequence of SEQ ID NO: 787, an FRL2 comprising the amino acid sequence of SEQ ID NO: 831, an FRL3 comprising the amino acid sequence of SEQ ID NO: 870, and / or an FRL4 comprising the amino acid sequence of SEQ ID NO: 906, or an amino acid sequence having at least one, two, or three but no more than four modifications, e.g., substitutions, relative to each of the amino acid sequences of SEQ ID NO: 787, 831, 870, and / or 906; or one, two, three, or all of an FRL1 comprising the amino acid sequence of SEQ ID NO: 807, an FRL2 comprising the amino acid sequence of SEQ ID NO: 830, an FRL3 comprising the amino acid sequence of SEQ ID NO: 888, and / or an FRL4 comprising the amino acid sequence of SEQ ID NO: 908; or an amino acid sequence having at least one, two, or three but no more than four modifications, e.g., substitutions, relative to each of the amino acid sequences of SEQ ID NO: 807, 830, 888, and / or 908. one, two, three, or all of an FRL1 comprising the amino acid sequence of SEQ ID NO: 783, an FRL2 comprising the amino acid sequence of SEQ ID NO: 830, an FRL3 comprising the amino acid sequence of SEQ ID NO: 866, and / or an FRL4 comprising the amino acid sequence of SEQ ID NO: 906; or an amino acid sequence having at least one, two, or three but no more than four modifications, e.g., substitutions, relative to each of the amino acid sequences of SEQ ID NO: 783, 830, 866, and / or 906; or, one, two, three, or all of an FRL1 comprising the amino acid sequence of SEQ ID NO: 779, an FRL2 comprising the amino acid sequence of SEQ ID NO: 825, an FRL3 comprising the amino acid sequence of SEQ ID NO: 861, and / or an FRL4 comprising the amino acid sequence of SEQ ID NO: 908; or an amino acid sequence having at least one, two, or three but no more than four modifications, e.g., substitutions, relative to each of the amino acid sequences of SEQ ID NO: 779, 825, 861, and / or 908. antibody of any one of embodiments E22-E37, comprising a VH comprising: the amino acid sequence of any VH provided 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; an amino acid sequence having at least one, two or three modifications, but not more than 30, 20 or 10 modifications of the amino acid sequence of any VH provided in Table 3 or 4; or an amino acid sequence encoded by a nucleotide sequence of any VH provided 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-E38, comprising a VH comprising: (i) 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; (ii) an amino acid sequence having at least one, two or three modifications, but not more than 30, 20 or 10 modifications of the amino acid sequence of SEQ ID NO: 4,9,21-23, or 51; 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 isolated antibody of any of the preceding embodiments, comprising a VH comprising, from N-terminus to C-terminus: (i) an FRH1 comprising the amino acid sequence of any FRH1 of an antibody in Table 7; (ii) an HC CDR1 comprising the amino acid sequence of the HC CDRI1 of the antibody in Table 6 or 5; (iii) an FRH2 comprising the amino acid sequence of the FRH2 of the antibody in Table 7 or 4: (iv) an HC CDR2 comprising the amino acid sequence of the HC CDR2 of the antibody in Table 6 or 5; wv) an FRH3 comprising the amino acid sequence of the FRH3 of the antibody in Table 7 or 4: (vi) an HC CDR3 comprising the amino acid sequence of the HC CDR3 of the antibody in Table 6, or 5; and (vil) an FRH4 comprising the amino acid sequence of the FRH4 of the antibody in Table 7 or 4. The antibody of any one of the preceding embodiments comprising a VH comprising, from N-terminus to C-terminus, an FRH1, an HC CDR1, an FRH2, an HC CDR2, an FRH3, an HC CDR3, and an FRH4, wherein: (i) the FRH1, HC CDR1, FRH2, HC CDR2, FRH3, HC CDR 3, FRH4 comprise the amino acid sequences of SEQ ID NO: 603, 315, 664, 341, 718, 410, and 771, respectively; (ii) the FRH1, HC CDR1, FRH2, HC CDR2, FRH3, HC CDR3, FRH4 comprise the amino acid sequences of SEQ ID NO: 619, 314, 663, 341, 717, 410, and 771, respectively; (iii) the FRHI1, HC CDR1, FRH2, HC CDR2, FRH3, HC CDR3, FRH4 comprise the amino acid sequences of SEQ ID NO: 603, 316, 665, 341, 719, 410, and 771, respectively; (vi) the FRH1, HC CDR1, FRH2, HC CDR2, FRH3, HC CDR3, FRH4 comprise the amino acid sequences of SEQ ID NO: 663, 325, 682, 362, 745, 435, and 771, respectively. wv) the FRH1, HC CDR1, FRH2, HC CDR2, FRH3, HCDR3, FRH4 comprise the amino acid sequences of SEQ ID NO: 608, 304, 652, 347, 705, 400, and 767, respectively; or, (vi) the FRHI1, HC CDR1, FRH2, HC CDR2, FRH3, HC CDR3, FRH4 comprise the amino acid sequences of SEQ ID NO: 604, 299, 647, 343, 700, 395, and 770, respectively. The antibody of any one of embodiments E22-E41, wherein the nucleotide sequence encoding the VH comprises a nucleotide sequence of any VH provided 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-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. The antibody of any one of embodiments E22-E43, comprising a VL comprising: (i) the amino acid sequence of any VL provided 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, but not more than 30, 20 or 10 modifications of the amino acid sequence of any VL provided in Table 3 or 4; or (iii) an amino acid sequence encoded by a nucleotide sequence of any VL provided 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-E44, comprising a VL comprising: i) 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; (ii) an amino acid sequence having at least one, two or three modifications, but not more than 30, 20 or 10 modifications of the amino acid sequence of SEQ ID NO: 78, 83, 93-95, or 122: 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 of the preceding embodiments, comprising a VL comprising from N-terminus to C-terminus: (i) an FRL1 comprising the amino acid sequence of any FRL1 of an antibody in Table 7 or 4: (ii) an LC CDR1 comprising the amino acid sequence of the LC CDR1 of the antibody in Table 6 or 5; (iii) an FRL2 comprising the amino acid sequence of the FRL2 of the antibody in Table 7 or 4: (iv) an LC CDR2 comprising the amino acid sequence of the LC CDR2 of the antibody in Table 6 or 5; wv) an FRL3 comprising the amino acid sequence of the FRL3 of the antibody in Table 7 or 4: (vi) an LC CDR3 comprising the amino acid sequence of the LC CDR3 of the antibody in Table 6 or 5; and (vil) an FRL4 comprising the amino acid sequence of the FRL4 of the antibody in Table 7 or 4. The antibody of any one of the preceding embodiments comprising a VL comprising, from N-terminus to C-terminus, an FRL1, an LC CDR1, an FRL2, an LC CDR2, an FRL3, an LC CDR3, and an FRL4, wherein; (i) the FRL1, LC CDR1, FRL2, LC CDR2, FRL3, LC CDR3, FRLA4 comprise the amino acid sequences of SEQ ID NO: 793, 474, 836, 529, 874, 571, and 910, respectively; (ii) the FRL1, LC CDR1, FRL2, LC CDR2, FRL3, LC CDR3, FR14 comprise the amino acid sequences of SEQ ID NO: 1178, 1154, 831, 529, 1179, 571, and 906, respectively; (iii) the FRL1, LC CDRI1, FRL2, LC CDR2, FRL3, LC CDR3, FRL4 comprise the amino acid sequences of SEQ ID NO: 787, 475, 831, 530, 870, 571, and 906, respectively; (iv) the FRL1, LC CDR1, FRL2, LC CDR2, FRL3, LC CDR3, FRL4 comprise the amino acid sequences of SEQ ID NO: 807, 495, 830, 540, 888, 587, and 908, respectively. wv) the FRL1, LC CDR1, FRL2, LC CDR2, FRL3, LC CDR3, FRLA4 comprise the amino acid sequences of SEQ ID NO: SEQ ID NO: 783, 464, 830, 523, 866, 562, and 906, respectively; or, (vi) the FRL1, LC CDRI1, FRL2, LC CDR2, FRL3, LC CDR3, FRL4 comprise the amino acid sequences of SEQ ID NO: 779, 460, 825, 518, 861, 557, and 908, respectively. The antibody of any one of embodiments E22-E47, wherein the nucleotide sequence encoding the VL comprises a nucleotide sequence of any VL provided 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-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. The antibody of any one of the preceding embodiments, comprising: @) a VH comprising: (a) the amino acid sequence of any VH provided 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, but not more than 30, 20 or 10 modifications of the amino acid sequence of any VH provided in Table 3 or 4; or (c) an amino acid sequence encoded by a nucleotide sequence of any VH provided 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 (ii) a VL comprising: (a) the amino acid sequence of any VL provided 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, but not more than 30, 20 or 10 modifications of the amino acid sequence of any VL provided in Table 3 or 4; or (c) an amino acid sequence encoded by a nucleotide sequence of any VL provided 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 the preceding embodiments, comprising the amino acid sequence of any VH of an antibody provided in Table 3 and 4, and the amino acid sequence of the VL of the antibody provided in Table 3 or 4. The antibody of any one of embodiments E22-E28 and E34-E51, comprising: (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; and (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-E27, E29, and E34-E51, comprising: (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; and (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-E27, E30, and E34-E51, comprising: (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; and (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-E27, E31, and E44-E51, comprising: (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; and (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-E27, E32, and E44-E51, comprising: (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; and (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-E27, and E33-E51, comprising: (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; and (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 the preceding embodiments, wherein the nucleotide sequence encoding the antibody comprises: (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: 1535, 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; wv) 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. The antibody of any one of the preceding embodiments, which is a full length antibody, a bispecific antibody, an Fab, an F(ab")z, an Fv, or a single chain Fv fragment (scFv). 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 chosen from the light chain constant regions of kappa or lambda. The antibody of any one of the preceding embodiments, comprising a heavy chain constant region comprising an amino acid of a heavy chain constant region provided 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 a light chain constant region comprising the amino acid sequence of a light chain constant region provided 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 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 provided in Table X, 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 encoding the light chain constant region comprises the nucleotide sequence of a light chain constant region provided in Table X, 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 the preceding embodiments, comprising: (i) a VH comprising the amino acid sequence of any VH provided 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 an amino acid of a heavy chain constant region provided 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 provided 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 an amino acid of a light chain constant region provided 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 antibody of any one of the preceding embodiments, comprising: 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 an amino acid of a heavy chain constant region provided 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 an amino acid of a light chain constant region provided 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 antibody of any one of the preceding embodiments, which antibody binds the C- terminus of a tau protein, e.g., residues 409-436 numbered according to SEQ ID NO: 020). The antibody of any one of the preceding embodiments, which antibody binds a microtubule binding domain of a tau protein. The antibody of any one of the preceding embodiments, which antibody binds a proline rich domain of a tau protein. The antibody of any one of the preceding embodiments, which antibody binds to a tau protein with a dissociation constant (Kp) of less than about 120 nM, e.g., measured by Octet, e.g., as described in Example 8. The antibody of any one of the preceding embodiments, which antibody binds to a tau protein with a Kp of about 0.1 nM to about 0.5 nM. The antibody of any one of the preceding embodiments, which antibody is capable of binding to a tau protein with a Kp of about 0.5 nM to about 5 nM. The antibody of any one of the preceding embodiments, which antibody is capable of binding to a tau protein with a Kp of about 5 nM to about 30 nM. The antibody of any one of the preceding embodiments, which antibody binds a tau protein which comprises at least one, two, three or more phosphorylated residues, e.g., residue T212, T217, S396, S404, S409, or combination thereof, numbered according to SEQ ID NO: 920. The antibody of any one of the preceding embodiments, which antibody binds enriched paired helical filament tau protein (ePHF), e.g., at a half maximal effective concentration (EC50) of from about 0.01 nM to about 100 nM. The antibody of any one of the preceding embodiments, which antibody reduces, e.g., inhibits, aggregation of tau. The antibody of any one of the preceding embodiments, which antibody inhibits aggregation of tau at a half maximal inhibitory concentration (IC50) of from about 1 nM to about 30 nM, e.g., as measured by an immunodepletion assay (e.g., with tau RD Biosensor cells), e.g., as described in Example 6. The antibody of any one of the preceding embodiments, which binds an epitope comprising a region formed by a complex of at least two tau proteins, e.g., a tau dimer. An antibody that competes for binding to tau with the antibody of any one of the preceding embodiments. An antibody that binds to the same epitope as, substantially the same epitope as, or an epitope that overlaps with, the epitope of the antibody of any one of the preceding embodiments. An isolated, e.g., recombinant, nucleic acid encoding the antibody of any one of the preceding embodiments. An isolated, e.g., recombinant, nucleic acid encoding an antibody that binds to tau, wherein the antibody comprises: (1) a heavy chain variable region (VH) comprising at least one, two, or three of an HC CDR1, an HC CDR2, and / or an HC CDR3 of an antibody in 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 an LC CDR1, an LC CDR2, and / or an LC CDR3 of the antibody in Table 1, 6, 2A-2C, 4, or 5. The nucleic acid of embodiment ESQ, wherein: 1) the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequence of SEQ ID NO: 315, 341, 410, 474, 529, and 571, respectively; (ii) the HC CDRI1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequence of SEQ ID NO: 314, 341, 410, 1154, 529, and 571, respectively; (iii) the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequence of SEQ ID NO: 316, 341, 410, 475, 530, and 571, respectively; (iv) the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequence of SEQ ID NO: 325, 362, 435, 495, 540, and 587, respectively; wv) the HC CDRI1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequence of SEQ ID NO: 304, 347, 400, 464, 523, and 562, respectively; or, (vi) the HC CDRI1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequence of SEQ ID NO: 299, 343, 395, 460, 518, and 557, respectively. The nucleic acid of embodiment E80, wherein the antibody comprises: (i) a VH comprising the amino acid sequence of any VH provided in Table 3 or 4, an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity to any VH provided in Table 3 or 4, or an amino acid sequence having at least one, two or three modifications, but not more than 30, 20 or 10 modifications of the amino acid sequence of any VH provided in Table 3 or 4; and / or (ii) a VL comprising the amino acid sequence of any VL provided in Table 3 or 4; an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity to any VL provided in Table 3 or 4; or an amino acid sequence having at least one, two or three modifications, but not more than 30, 20 or 10 modifications of the amino acid sequence of any VL provided in Table 3 or 4. The nucleic acid of any one of embodiments E80-E82, wherein the antibody comprises: 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, but not more than 30, 20 or 10 modifications of the amino acid sequence of SEQ ID NO: 4, 9, 21-23, or 51; 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; or an amino acid sequence having at least one, two or three modifications, but not more than 30, 20 or 10 modifications of the amino acid sequence of SEQ ID NO: 78, 83, 93-95, or 122. The nucleic acid of any one embodiments E80-E83, wherein the antibody comprises: (i) a heavy chain constant region comprising an amino acid of a heavy chain constant region provided 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 the amino acid sequence of a light chain constant region provided 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-E84, comprising: (1) the nucleotide sequence of any VH provided 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 provided 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-E85, comprising: (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 isolated nucleic acid sequence of any one of embodiments E79-E86, wherein the nucleic acid sequence encoding the heavy chain variable region and / or the light chain variable region is codon-optimized. An isolated, e.g., recombinant, antibody encoded by the nucleic acid of any one of embodiments E79-ER7. A vector comprising the nucleic acid of any one of embodiments E79-E87, or a nucleic acid encoding the antibody of any one of embodiments E1-E78 and E88. A host cell comprising the nucleic acid of any one of embodiments E79-E87, a nucleic acid encoding the antibody of any one of embodiments E1-E78 and E88, or the vector (e.g., expression vector) of embodiment E89. The host cell of embodiment E90, wherein the host cell is an insect cell, bacterial cell, or a mammalian cell. A method of producing an antibody, the method comprising culturing the host cell of embodiment E90 or E91, under conditions suitable for gene expression. An isolated nucleic acid encoding a payload, wherein the encoded payload comprises the antibody of any one of embodiments E1-E78 and E88. The nucleic acid of embodiment E93, further encoding a signal sequence, optionally wherein the nucleotide sequence encoding the 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. The nucleic acid of any one of embodiments E93-E94, further encoding a second signal sequence, optionally wherein the nucleotide sequence encoding the 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. The nucleic acid of any one of embodiments E93-E95, wherein the: (i) the nucleotide sequence encoding the signal sequence is located 5° relative to the nucleotide sequence encoding the VH; and / or (ii) the nucleotide sequence encoding the signal sequence is located 5° relative to the nucleotide sequence encoding the VL. The nucleic acid of any one of embodiments E93-E96, wherein the sequences of the encoded VH and VL are connected directly, e.g., without a linker. The nucleic acid of any one of embodiments E93-E97, wherein the sequences of the encoded VH and VL are connected via a linker. The nucleic acid of embodiment E98, wherein the linker comprises the nucleotide sequence of any of the linker sequences provided in Table 15, or a nucleotide sequence with at least 95% sequence identity thereto. The nucleic acid of any one of embodiments E93-E99, wherein the encoded payload is a full length antibody, a bispecific antibody, an Fab, an F(ab"), an Fv, a single chain Fv fragment (scFv), single domain antibody, or a camelid antibody. A viral genome comprising a promoter operably linked to the nucleic acid encoding a payload comprising the antibody of any one of embodiments E1-E78 and E88. The viral genome of embodiment E101, wherein the promoter: @) is chosen from human elongation factor 1a-subunit (EFla), cytomegalovirus (CMV) immediate-early enhancer and / or promoter, chicken B-actin (CBA) and its derivative CAG, B glucuronidase (GUSB), or ubiquitin C (UBC), neuron-specific enolase (NSE), platelet-derived growth factor (PDGF), platelet-derived growth factor B-chain (PDGF-p), 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 (mGIuR2), neurofilament light (NFL) or heavy (NFH), B-globin minigene np2, preproenkephalin (PPE), enkephalin (Enk) and excitatory amino acid transporter 2 (EAAT2), glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), or a fragment, e.g., a truncation, or a functional variant thereof; and / or (ii) comprises the nucleotide sequence of any of the promoter sequences provided in Table 11, or a nucleotide sequence at least 95% identical thereto. The viral genome of any one of embodiments E101-E102, which further comprises an enhancer, optionally wherein the enhancer is a CMV immediate-early (CM Vie) enhancer. The viral genome of any one of embodiments E101-E103, which further comprises a polyadenylation (polyA) signal region. The viral genome of embodiment E104, wherein the polyA signal region comprises the nucleotide sequence of any of SEQ ID NO: 1134-1136, or a nucleotide sequence with at least 95% identity thereto. The viral genome of any one of embodiments E101-E105, further comprising an inverted terminal repeat (ITR) sequence. The viral genome of embodiment E106, wherein: @) the ITR sequence is positioned 5’ relative to the encoded payload; and / or (ii) the ITR sequence is positioned 3’ relative to the encoded payload. The viral genome of any one of embodiments E101-E107, which comprises an ITR sequence positioned 5’ relative to the encoded payload and an ITR sequence positioned 3’ relative to the encoded payload. The viral genome of any one of embodiments E101-E108, wherein the ITR sequence comprises a nucleotide sequence of any one of SEQ ID NOs: 1035-1038, or a nucleotide sequence with at least 80%, 85%, 90%, or 95% sequence identity thereto. The viral genome of any one of embodiments E101-E109, further comprising an intron region. The viral genome of embodiment E110, wherein the intron region comprises a nucleotide sequence of any of the intron regions listed in Table 13, or a nucleotide sequence with at least 95% identity thereto. The viral genome of any one of embodiments E101-E111, comprising at least one, two, or three intron regions. The viral genome of any one of embodiments E101-E112, further comprising an exon region. The viral genome of embodiment E113, wherein the exon region comprises the nucleotide sequence of any of the exon sequences in Table 12, or a nucleotide sequence with at least 95% identity thereto. The viral genome of any one of embodiments E101-E114, comprising at least one, two, or three exon regions. The viral genome of any one of embodiments E101-E115, which further comprises a Kozak sequence, optionally wherein the Kozak sequence comprises the nucleotide sequence of GCCGCCACCATG (SEQ ID NO: 1079) or GAGGAGCCACC (SEQ ID NO: 1089). The viral genome of any one of embodiments E101-E116, which further comprises a nucleotide sequence encoding a miR binding site, e.g., a miR binding site that modulates, e.g., reduces, expression of the payload encoded by the viral genome in a cell or tissue where the corresponding miRNA is expressed. The viral genome of embodiment E117, which comprises at least 1-5 copies of an encoded miR binding site, e.g., at least 1, 2, 3, 4, or 5 copies. The viral genome of any one of embodiments E117-E118, which comprises at least 3 copies of an encoded miR binding sites, optionally wherein all three copies comprise the same miR binding site, or at least one, two, or all of the copies comprise a different miR binding site. The viral genome of any one of embodiments E117-E119, which comprises at least 4 copies of an encoded miR binding site, optionally wherein all four copies comprise the same miR binding site, or at least one, two, three, or all of the copies comprise a different miR binding site. The viral genome of any one of embodiments E117-E120, wherein the encoded miR binding site comprises a miR122 binding site, a miR183 binding site, a miR-142-3p, or a combination thereof, optionally wherein: (i) the encoded miR122 binding site comprises the nucleotide sequence of SEQ ID NO: 1029, or a nucleotide sequence substantially identical (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto; or a nucleotide sequence having at least one, two, three, four, five, six, or seven modifications, but no more than ten 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 (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto; or a nucleotide sequence having at least one, two, three, four, five, six, or seven modifications, but no 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 (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto; or a nucleotide sequence having at least one, two, three, four, five, six, or seven modifications, but no more than ten modifications of SEQ ID NO: 1031. The viral genome of any one of embodiments E101-E121, which is single stranded. The viral genome of any one of embodiments E101-E122, which further comprises a nucleotide sequence encoding a Rep protein, e.g., a non-structural protein, wherein the Rep protein comprises a Rep78 protein, a Rep68, Rep52 protein, and / or a Repd0 protein. 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. The viral genome of any one of embodiments E101-E124, which further comprises a nucleic acid sequence encodes a capsid protein, e.g., a structural protein, wherein the capsid protein comprises a VP1 polypeptide, a VP2 polypeptide, and / or a VP3 polypeptide. 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. A vector comprising the viral genome of any one embodiments E101-E126. An isolated, e.g., recombinant AAV particle comprising: (i) a capsid protein, and, (ii) the nucleic acid of any one of embodiments E79-E87 and E93-E100, or the viral genome of any one of embodiments E101-E126. The isolated AAV particle of embodiment E128, wherein: (i) the capsid protein comprises the amino acid sequence of SEQ ID NO: 1003, or an amino acid sequence with 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 but not more than 30, 20 or 10 modifications of the amino acid sequence of SEQ ID NO: 1003; (iii) the capsid protein comprises the amino acid sequence of SEQ ID NO: 1011, or an amino acid sequence with 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 but not more than 30, 20 or 10 modifications of the amino acid sequence of SEQ ID NO: 1011; w) the capsid protein comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 1002, or a sequence with 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 with at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto. The isolated AAV particle of embodiment E128 or E129, wherein the capsid protein comprises: (i) an amino acid substitution at position K449, e.g., a K449R substitution, numbered according to SEQ ID NO:1003; (ii) an insert comprising the amino acid sequence of TLAVPFK (SEQ ID NO: 1151), optionally wherein the insert is present immediately subsequent to position 588, relative to a 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) the amino acid substitution of A587D and / or Q588G, numbered according to SEQ ID NO: 1003. The AAV particle of any one of embodiments E128-E130, wherein the capsid protein comprises (i) the 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 wherein the insert is present immediately subsequent to position 588 of SEQ ID NO: 1003. The AAV particle of any one of embodiments E128-E130, wherein the capsid protein comprises (i) the 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 wherein the insert is present immediately subsequent to position 588, relative to a reference sequence numbered according to SEQ ID NO: 1003; and (iii) the amino acid substitutions of A587D and Q588G, numbered according to SEQ ID NO: 1003. The AAV particle of any one of embodiments E128-E130, wherein the capsid protein comprises (i) an insert comprising the amino acid sequence of TLAVPFK (SEQ ID NO: 1151), optionally wherein the insert is present immediately subsequent to position 588, relative to a reference sequence numbered according to SEQ ID NO: 1003; and (ii) the amino acid substitutions of AS87D and Q588G, numbered according to SEQ ID NO: 1003. The AAV particle of any one of embodiments E128-E133, wherein the capsid protein comprises any of the capsid proteins listed in Table 9 or a functional variant thereof. The AAV particle of any one of embodiments E128-E134, wherein the capsid protein comprises a 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), AAVG2BS5 (G2B5), AAVPHP.N (PHP.N), PHP.S, AAV1, AAV2, AAV2 variant, AAV2 / 3 variant, AAV4, AAVS, AAV6, AAVT, AAV, AAV9.47, AAVI(huld), AAVY, AAVI K449R, AAV10, AAV11, AAV12, AAVrh8, AAVrh10, AAVDI, AAVDIS, or AAV2G9 capsid protein, or a functional variant thereof. The AAV particle of any of embodiments E128-E135, wherein the capsid protein comprises a VOY 101 capsid protein. The AAV particle of embodiment E136, wherein the capsid protein comprises: (i) the amino acid sequence of SEQ ID NO: 1023, or an amino acid sequence substantially identical (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto; (ii) an amino acid sequence comprising at least one, two, or three modifications but no more than 30, 20, or 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 (e.g., having at least 70%, 15%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto. 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 (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto. E139. The AAV particle of any one of embodiments E128-E138, wherein the capsid protein comprises: (i) a VP1 polypeptide, VP2 polypeptide, VP3 polypeptide, or a combination thereof: (ii) the amino acid sequence corresponding to positions 138-743, e.g., a VP2, of SEQ ID NO: 1023, or a sequence with at least 80% (e.g., at least about 85, 90, 92, 95, 96, 97, 98, or 99%) sequence identity thereto; (iii) the amino acid sequence corresponding to positions 203-743, e.g., a VP3, of SEQ ID NO: 1023, or a sequence with at least 80% (e.g., at least about 85, 90, 92,95, 96, 97, 98, or 99%) sequence identity thereto; and / or (iv) the amino acid sequence corresponding to positions 1-743, e.g., a VP1, of SEQ ID NO: 1023, or a sequence with at least 80% (e.g., at least about 85, 90, 92,95, 96, 97, 98, or 99%) sequence identity thereto. E140. A host cell comprising the nucleic acid of any one of embodiments E79-E87 and E93- E100, the viral genome of any one of embodiments E101-E126, or the AAV particle of any one of embodiments E128-E139, optionally wherein the host cell is an insect cell, a bacterial cell or a mammalian cell. E141. A nucleic acid encoding the viral genome of any one of embodiments E101-E126, and a backbone region suitable for replication of the viral genome in a cell, e.g., a bacterial cell (e.g., wherein the backbone region comprises one or both of a bacterial origin of replication and a selectable marker). A method of making a viral genome, the method comprising: i) providing the nucleic acid molecule comprising the viral genome of any one of embodiments E101-E126; and (ii) excising the viral genome from the backbone region, e.g., by cleaving the nucleic acid molecule at upstream and downstream of the viral genome. A method of making an isolated, e.g., recombinant, AAV particle, the method comprising a) providing a host cell comprising the viral genome of embodiment E140; and (ii) incubating the host cell under conditions suitable to enclose the viral genome in a capsid protein, e.g., a VOY 101 capsid protein; thereby making the isolated AAV particle. The method of embodiment E143, further comprising, prior to step (i), introducing a first nucleic acid molecule comprising the viral genome into the host cell. The method of embodiment E143 or E144, wherein the host cell comprises a second nucleic acid encoding a capsid protein, e.g., a VOY 101 capsid protein. The method of any one of embodiments E143-E144, wherein the second nucleic acid molecule is introduced into the host cell prior to, concurrently with, or after the first nucleic acid molecule. A pharmacentical composition comprising the antibody of any one of embodiments E1-E78 and E88, an AAV particle of any one of embodiments E128-E139, or an AAV particle comprising the viral genome of any one of embodiments E101-E126, or the isolated nucleic acid of any one of embodiments E79-E87 and E93-E100, and a pharmaceutically acceptable excipient. A method of delivering an exogenous antibody that binds to tau, to a subject, comprising administering an effective amount of the pharmaceutical composition of embodiment S1, the antibody of any one of embodiments E1-E78 and E88, an AAV particle, e.g., a plurality of AAV particles, of any one of embodiments E128-E139, or an AAV particle, e.g., a plurality of AAV particles, comprising the viral genome of any one of embodiments E101-E126, or the isolated nucleic acid of any one of embodiments E79-E87 and E93-E100. The method of embodiment E148, wherein the subject has, has been diagnosed with having, or is at risk of having a disease associated with expression of tau. The method of embodiment E148 or E149, wherein the subject has, has been diagnosed with having, or is at risk of having a neurological, e.g., neurodegenerative disorder. The method of embodiment E148, E149, or E150, wherein the subject has, has been diagnosed with having, or is at risk of having a tauopathy. A method of treating a subject having or diagnosed with having a disease associated with expression of tan comprising administering to the subject an effective amount of the pharmaceutical composition of embodiment E147, the antibody of any one of embodiments E1-E78 and E88, an AAV particle, e.g., a plurality of AAV particles, of any one of embodiments E128-E139, or an AAV particle, e.g., a plurality of AAV particles, comprising the viral genome of any one of embodiments E101-E126, or the isolated nucleic acid of any one of embodiments E79-E87 and E93-E100. A method of treating a subject having or diagnosed with having a neurological, e.g., 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-E78 and E88, an AAV particle, e.g., a plurality of AAV particles, of any one of embodiments E128-E139, or an AAV particle, e.g., a plurality of AAV particles, comprising the viral genome of any one of embodiments E101- E126, or the isolated nucleic acid of any one of embodiments E79-E87 and E93-E100. A method of treating a subject having or diagnosed with 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-E78 and E88, an AAV particle, e.g., a plurality of AAV particles, of any one of embodiments E128-E139, or an AAV particle, e.g., a plurality of AAV particles, comprising the viral genome of any one of embodiments E101-E126, or the isolated nucleic acid of any one of embodiments E79-E87 and E93-E100. The method of any one of embodiments E152-E154, wherein the disease associated with Tau expression, the neurological disorder, or the tanopathy comprises AD, FTDP-17, FTLD, FID, CTE, PSP, Down’s syndrome, Pick’s disease, CBD, Corticobasal syndrome, ALS, Prion diseases, CID, Multiple system atrophy, Tangle- only dementia, or Progressive subcortical gliosis. The method of any one of embodiments E152-E155, where treating comprises prevention of progression of the disease in the subject. The method of any one of embodiments E152-E156, wherein the subject is a human. The method of any one of embodiments E152-E157, wherein the AAV particle is administered to the subject intravenously, intramuscularly, via intraparenchymal administration, intracerebroventricularly, via intra-cisterna magna (ICM) injection, intrathecally, via focused ultrasound (FUS), e.g., coupled with the intravenous administration of microbubbles (FUS-MB), or MRI-guided FUS coupled with intravenous administration. The method of any one of embodiments E152-E158, wherein the AAV particle is administered to the subject intravenously. The method of any one of embodiments E152-E158, wherein the AAV particle is administered to the subject via intra-cisterna magna injection (ICM). The method of any one of embodiments E152-E160, further comprising evaluating, e.g., measuring, the level of antibodies generated in a subject, e.g., in a cell or tissue of the subject. The method of any one of embodiments E152-E161, wherein the administration results in the generation of 0.001 ug / mL to 100 mg / mL of antibodies in the subject, e.g., in a cell or tissue of the subject. The method of embodiment E162, wherein the cell is a neuronal cell. The method of embodiment E162, wherein the tissue is a central nervous system tissue, e.g., a brain tissue. The method of any one of embodiments E152-E164, further comprising performing a blood test, an imaging test, a CNS biopsy sample, or an aqueous cerebral spinal fluid biopsy. The method of any one of embodiments E161-E165, wherein measuring the level of antibodies is performed prior to, during, or subsequent to treatment with the AAV particle, e.g., plurality of AAV particles. The method of any one of embodiments E152-E166, wherein the subject has a level of antibodies that is a greater than a reference level, e.g., a subject that has not received treatment, e.g., has not been administered the AAV particle or plurality of AAV particles. The method of any one of embodiments E152-E167, wherein the plurality of AAV particles are administered at a dose of about 1x10° VG / mL to about 1x10'® VG / mL or about 0.0001 mg / kg to about 100 mg / kg. The method of any one of embodiments E152-E168, further comprising administration of an additional therapeutic agent and / or therapy suitable for treatment or prevention of a disorder associated with tau expression, a neurological, e.g., neurodegenerative, disorder. 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 drug, an anti-anxiety drug, an anticonvulsant, a dopamine agonist (e.g., pramipexole, ropinirole, rotigotine, and / or apomorphine), an MAO B inhibitor (e.g., selegiline, rasagiline, and / or safinamide), catechol O-methyltransferase (COMT) inhibitors (entacapone, opicapone, and / or tolcapone), anticholinergics (e.g., benztropine and / or trihexyphenidyl), amantadine, carbidopa-levodopa, deep brain simulation (DBS), or a combination thereof. The antibody of any one of embodiments E1-E78 and E88, the nucleic acid of any one of embodiments E79-E87 and E93-E100, the viral genome of any one of embodiments E101-E126, the pharmaceutical composition of embodiment E147, or the AAV particle of any one of embodiments E128-E139, for use in the manufacture of a medicament. The antibody of any one of embodiments E1-E78 and E88, the nucleic acid of any one of embodiments E79-E87 and E93-E100, the viral genome of any one of embodiments E101-E126, the pharmaceutical composition of embodiment E147, or the AAV particle of any one of embodiments E128-E139, for use in the treatment of a disease associated with tau expression. The antibody of any one of embodiments E1-E78 and E88, the nucleic acid of any one of embodiments E79-E87 and E93-E100, the viral genome of any one of embodiments E101-E126, the pharmaceutical composition of embodiment E147, or the AAV particle of any one of embodiments E128-E139, for use in the treatment of a neurological, e.g., neurodegenerative, disorder. The antibody of any one of embodiments E1-E78 and E88, the nucleic acid of any one of embodiments E79-E87 and E93-E100, the viral genome of any one of embodiments E101-E126, the pharmaceutical composition of embodiment E147, or the AAV particle of any one of embodiments E128-E139, for use in the treatment of a tauopathy. Use of an effective amount of the antibody of any one of embodiments E1-E78 and E88, the nucleic acid of any one of embodiments E79-E87 and E93-E100, the viral genome of any one of embodiments E101-E126, the pharmaceutical composition of embodiment E147, or the AAV particle of any one of embodiments E128-E139, in the manufacture of a medicament for the treatment of a disease associated with tau expression, a neurological, e.g., neurodegenerative, disorder, or a tanopathy in a subject. BRIEF DESCRIPTIONS OF THE DRAWINGS

[0060] FIGs. 1A-1B show alignment of variable light chain or VL (FIG. 1A) and variable heavy chain or VH (FIG. 1B) regions of selected antibodies V0004, V0009, V0022, V0023, V0024 and V0052, with trhe CDR sequences highlighted according to the Kabat numbering system. The corresponding framework region sequences under the Kabat numbering system, including FRH1-FRH4 and FRL1-FRL4, are defined by the boundaries of the CDR regions.

[0061] FIGs. 2A-2B show alignment of variable light chain (FIG. 2A) and variable heavy chain (FIG. 2B) regions of selected antibodies V0004, V0009, V0022, V0023, V0024 and 'V0052, with CDR sequences highlighted according to the Chothia numbering system. The corresponding framework region sequences under the Chothia numbering system, including FRH1-FRH4 and FRL1-FRLA, are defined by the boundaries of the CDR regions.

[0062] FIGs. 3A-3B show alignment of variable light chain (FIG. 3A) and variable heavy chain (FIG. 3B) regions of selected antibodies V0004, V0009, V0022, V0023, V0024 and V0052, with CDR sequences highlighted according to IMGT numbering system. The corresponding framework region sequences under the IMGT numbering system, including FRH1-FRH4 and FRL1-FRLA, are defined by the boundaries of the CDR regions. DETAILED DESCRIPTION OF THE INVENTION 1. COMPOSITIONS

[0063] In some embodiments, the present disclosure provides compositions that interact with human microtubule associated protein tau. Such compositions may be antibodies that bind tau protein epitopes, referred to herein as “anti-tau antibodies.” Dysfunction and / or aggregation of tau is found in a class of neurodegenerative diseases referred to as tauopathies. Tau hyperphosphorylation leads to aggregation and depressed tau-dependent microtubule assembly. In tauopathies, the tau aggregates form paired helical filaments (PHF) found in neurofibrillary tangles (NFTs). These aggregates lead to neuronal loss and cognitive decline. Anti-tau antibodies of the present disclosure may be useful for treating and / or diagnosing tauopathies, as well as other applications described herein. Antibodies

[0064] In some embodiments, compounds (e.g., anti-tau antibodies) and compositions of the present disclosure include antibodies or fragments thereof. In some embodiments, the antibody described herein bind tau. For example, the antibody binds to an epitope, e.g., a confirmation epitope, phosphorylated epitope, or a linear epitope, on tau, e.g., as described herein.

[0065] As used herein, the term “antibody” is referred to in the broadest sense and specifically covers various 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 (such as Fab, F(ab’), F(ab’)2, Fv, etc.), so long as they exhibit a desired functional or biological activity. Antibodies are primarily amino acid-based molecules but may also include one or more modifications (including, but not limited to the addition of sugar moieties, fluorescent moieties, chemical tags, etc.).

[0066] Antibodies (including antigen-binding fragments thereof) of the present disclosure may include, but are not limited to, polyclonal, monoclonal antibodies, multispecific antibodies, bispecific antibodies, trispecific antibodies, human antibodies, humanized antibodies, chimeric antibodies, single chain antibodies, diabodies, linear antibodies, Fab fragments, F(ab’) fragments, F(ab’)2 fragments, Fv fragments, fragments produced by a Fab expression library, variable domains, anti-idiotypic (anti-Id) antibodies (including, e.g., anti- 1d antibodies to antibodies of the invention), intracellularly made antibodies (i.e., intrabodies), codon-optimized antibodies, scFv fragments, tandem scFv antibodies, bispecific T-cell engagers, mAb2 antibodies, chimeric antigen receptors (CAR), tetravalent bispecific antibodies, biosynthetic antibodies, native antibodies, miniaturized antibodies, unibodies, maxibodies, and epitope-binding fragments of any of the above.

[0067] In some embodiments, the antibody comprises at least one immunoglobulin variable domain sequence. An antibody may include, for example, full-length, mature antibodies and antigen-binding fragments of an antibody. For example, an antibody can include 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 includes two heavy (H) chain variable domain sequences and two light (L) chain variable domain sequence, thereby forming two antigen binding sites, such as Fab, Fab’, F(ab’),, Fe, Fd, Fd’, Fv, single chain antibodies (scFv for example), single variable domain antibodies, diabodies (Dab) (bivalent and bispecific), and chimeric (e.g., humanized) antibodies, which may be produced by the modification of whole antibodies or those synthesized de novo using recombinant DNA technologies. These functional antibody fragments retain the ability to selectively bind with their respective antigen or receptor. Antibodies and antibody fragments can be from any class of antibodies including, but not limited to, IgG, IgA, IgM, IgD, and IgE, and from any subclass (e.g., human IgG1, IgG2, IgG3, and IgG4, and murine IgG1, IgG2a, IgG2b, IgG2c, and IgG3) of antibodies. The antibodies of the present disclosure can be monoclonal or polyclonal. The antibody can also be a human, humanized, CDR-grafted, or in vitro generated antibody. The antibody can have a heavy chain constant region chosen from, e.g., IgG1, IgG2, IgG3, or IgG4. The antibody can also have a light chain chosen from, e.g., kappa or lambda.

[0068] In some embodiments, an antibody of the present disclosure comprises a functional fragment or variant thereof. Constant regions of the antibodies 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).

[0069] As used herein, the term “antibody fragment” refers to a portion of an intact antibody or fusion-protein thereof, in some cases including at least one antigen binding region. Examples of antigen-binding fragments include: (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CHI domains; (ii) a F(ab’): fragment, 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 CHI domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a diabody (dAb) fragment, which consists of a VH domain; (vi) a camelid or camelized variable domain; (vii) a single chain Fv (scFv), see e.g., Bird ef al. (1988) Science 242:423-426; and Huston ef 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 with skill in the art, and the fragments are screened for utility in the same manner as are intact antibodies. An antibody fragment can also be incorporated into single domain antibodies, maxibodies, minibodies, nanobodies, intrabodies, diabodies, triabodies, tetrabodies, v-NAR and bis-scFv (see, for example, 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. Also produced is a residual “Fc” fragment, whose name reflects its ability to crystallize readily. Pepsin treatment yields an F(ab’)> fragment that has two antigen-binding sites and is still capable of cross-linking antigen. Antibodies of the present disclosure may include one or more of these fragments and may, for example, be generated through enzymatic digestion of whole antibodies or through recombinant expression.

[0070] In some embodiments, the antibody can be single domain antibody. Single domain antibodies can include antibodies whose complementary 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 4-chain antibodies, engineered antibodies and single domain scaffolds other than those derived from antibodies. Single domain antibodies may be any of the art, or any future single domain antibodies. Single domain antibodies may be derived from any species including, but not limited to mouse, human, camel, llama, fish, shark, goat, rabbit, and bovine. According to another aspect of the invention, a single domain antibody is a naturally occurring single domain antibody known as heavy chain antibody devoid of light chains. Such single domain antibodies are disclosed in WO 9404678, for example. For clarity reasons, this variable domain derived from a heavy chain antibody naturally devoid of light chain is known herein as a VHH or nanobody to distinguish it from the conventional VH of four chain immunoglobulins. Such a VHH molecule can be derived from antibodies raised in Camelidae species, for example in camel, llama, dromedary, alpaca and guanaco. Other species besides Camelidae may produce heavy chain antibodies naturally devoid of light chain; such VHHs are within the scope of the invention.

[0071] “Native antibodies” are usually heterotetrameric glycoproteins of about 150,000 Daltons, composed of two identical light (L) chains and two identical heavy (H) chains. Genes encoding antibody heavy and light chains are known and segments making up each have been well characterized and described (Matsuda, F. er al., 1998. The Journal of Experimental Medicine. 188(11); 2151-62 and Li, A. et al., 2004. Blood. 103(12: 4602-9, the content of each of which are herein incorporated 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 has at one end a variable domain (Vu) followed by a number of constant domains. Each light chain has a variable domain at one end (V1) and a constant domain at its other end; 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.

[0072] As used herein, the term “variable domain” refers to specific antibody domains found on both the antibody heavy and light chains that differ extensively in sequence among antibodies and are used in the binding and specificity of each particular antibody for its particular antigen. In some embodiments, the VH and VL regions of the antibody described herein can be subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR).

[0073] As used herein, the term “hypervariable region” refers to a region within a variable domain that includes amino acid residues responsible for antigen binding. The amino acids present within the hypervariable regions determine the structure of the complementarity determining regions (CDRs) that become part of the antigen-binding site of the antibody.

[0074] As used herein, the term “CDR” refers to a region of an antibody that includes a structure that is complimentary to its target antigen or epitope. CDR regions generally confer antigen specificity and binding affinity. Other portions of the variable domain, not interacting with the antigen, are each referred to as a “framework region” (FR). The antigen- binding site (also known as the antigen combining site or paratope) includes the amino acid residues necessary to interact with a particular antigen. The exact residues making up the antigen-binding site may be determined by CDR analysis.

[0075] 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 region and CDRs has been precisely defined by a number of methods (see, Kabat, E. A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242; Chothia, C. er al. (1987) J. Mol. Biol. 196:901-917; and the AbM definition used by Oxford Molecular’s AbM antibody modeling software. See, generally, 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 may be conducted by co- crystallography with bound antigen. In some embodiments, CDR analysis may include computational assessments based on comparisons with other antibodies (Strohl, W.R. Therapeutic Antibody Engineering. Woodhead Publishing, Philadelphia PA. 2012. Ch. 3, p47-54, the contents of which are herein incorporated by reference in their entirety). CDR analysis and / or the precise amino acid sequence boundaries may include the use of numbering schemes including, but not limited to, those taught by Kabat [Wu, T.T. er al., 1970, JEM, 132(2):211-50 and Johnson, G. er al., 2000, Nucleic Acids Res. 28(1): 214-8, the contents of each of which are herein incorporated 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 herein incorporated by reference in their entirety], Lefranc (Lefranc, M.P. 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 herein incorporated by reference in their entirety). In some embodiments, the CDRs defined according the Chothia number scheme are also sometimes referred to as hypervariable loops.

[0076] For example, under Kabat, the CDR amino acid residues in the heavy chain variable domain (VH) are numbered 31-35 (HCDR1), 50-65 (HCDR2), and 95-102 (HCDR3); and the CDR amino acid residues in the light chain variable domain (VL) are numbered 24-34 (LCDR1), 50-56 (LCDR2), and 89-97 (LCDR3).

[0077] Under Chothia the CDR amino acids in the VH are numbered 26-32 (HCDR1), 52- 56 (HCDR2), and 95-102 (HCDR3); and the amino acid residues in VL are numbered 26-32 (LCDR1), 50-52 (LCDR2), and 91-96 (LCDR3).

[0078] By 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 (LCDR?2), and 89-97 (LCDR3) in human VL.

[0079] For certain antibodies of the invention, equivalent CDR sequences and framework region sequences, based on the Kabat, Chothia, and IMGT numbering systems, can be readily obtained based at least on Tables and sequences described herein, which provide SEQ ID NOs: for the equivalent CDR regions based on the Kabat, Chothia, and IMGT numbering systems, respectively. Also see FIGs. 1A-3B.

[0080] In general, the VH and VL domains have three CDRs each. VL CDRs are referred to herein as CDRL1, CDRL2 and CDRL3, in order of occurrence when moving from N- to C- terminus along the variable domain polypeptide. VH CDRs are referred to herein as CDRH1, CDRH2 and CDRH3, in order of occurrence when moving from N- to C- terminus along the variable domain polypeptide. Each of the CDRs have favored canonical structures with the exception of the CDRH3, which includes amino acid sequences that may be highly variable in sequence and length between antibodies resulting in a variety of three-dimensional structures in antigen-binding domains (Nikoloudis, D. et al., 2014. Peer]. 2:e456). In some cases, CDRH3s may be analyzed among a panel of related antibodies to assess antibody diversity. Various methods of determining CDR sequences are known in the art and may be applied to known antibody sequences (Strohl, W.R. Therapeutic Antibody Engineering. Woodhead Publishing, Philadelphia PA. 2012. Ch. 3, p47-54, the contents of which are herein incorporated by reference in their entirety).

[0081] In some embodiments, the VH and VL domains each have four framework regions (FRs) located before, after, and between CDR regions. VH framework regions are referred to herein as FRH1, FRH2, FRH3, and FRH4 and VL framework regions are referred to herein as FRL1, FRL2, FRL3, and FRL4. In some embodiments, on VH domains, FRs and CDRs are in the order of FRH1-CDRH1-FRH2-CDRH2-FRH3-CDRH3-FRH4, from N-terminus to C-terminus. In some embodiments, on VL domains, FRs and CDRs are in the order of FRL1- CDRLI1-FRL2-CDRL2-FRL3-CDRL3-FRL4, from N-terminus to C-terminus.

[0082] In some embodiments, the antigen binding domain of the antibodies of the present disclosure is the part of the antibody that comprises determinants that form an interface that binds to the tau polypeptide or an epitope thereof. With respect to proteins (or protein mimetics), the antigen-binding site typically includes one or more loops (of at least four amino acids or amino acid mimics) 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, or more typically at least three, four, five or six CDRs and / or hypervariable loops.

[0083] In yet other embodiments, the antibody has a heavy chain constant region chosen from, e.g., the heavy chain constant regions of IgGl, IgG2, IgG3, IgG4, IgM, IgAl, IgA2, IgD, and IgE; particularly, chosen from, e.g., the human heavy chain constant regions of 1gG1, 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 (e.g., murine or human) light chain constant regions of kappa or lambda.

[0084] 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 can fix complement. In other embodiments the antibody does not recruit effector cells; or fix complement. In other embodiments, the antibody has reduced or no ability to bind an Fc receptor. For example, it is an isotype or subtype, fragment or other mutant, which does not support binding to an Fc receptor, e.g., it has a mutagenized or deleted Fc receptor binding region.

[0085] Methods for altering an antibody constant region are known in the art. Antibodies with altered function, e.g. altered affinity for an effector ligand, such as FcR on a cell, or the C1 component of complement can be produced by replacing at least one amino acid residue in the constant portion of the antibody with a different residue (see e.g., EP 388,151 Al, U.S. Pat. No. 5,624,821 and U.S. Pat. No. 5,648,260, the contents of all of which are hereby incorporated by reference). Similar type of alterations could be described which if applied to the murine, or other species immunoglobulin would reduce or eliminate these functions.

[0086] As used herein, the term “Fv” refers to an antibody fragment that includes the minimum fragment on an antibody needed to form a complete antigen-binding site. These regions consist of a dimer of one heavy chain and one light chain variable domain in tight, non-covalent association. Fv fragments can be generated by proteolytic cleavage, but are largely unstable. Recombinant methods are known in the art for generating stable Fv fragments, typically through insertion of a flexible linker between the light chain variable domain and the heavy chain variable domain (to form a single chain Fv (scFv)] or through the introduction of a disulfide bridge between heavy and light chain variable domains (Strohl, W.R. Therapeutic Antibody Engineering. Woodhead Publishing, Philadelphia PA. 2012. Ch. 3, p46-47, the contents of which are herein incorporated by reference in their entirety).

[0087] Antibody “light chains” from any vertebrate species can be assigned to one of two clearly distinct types, called kappa and lambda based on amino acid sequences of their constant domains. Depending on the amino acid sequence of the constant domain of their heavy chains, antibodies can be assigned to different classes.

[0088] As used herein, the term “single chain Fv” or “scFv” refers to a fusion protein of VH and VL antibody domains, wherein these domains are linked together into a single polypeptide chain by a flexible peptide linker. In some embodiments, the Fv polypeptide linker enables 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 they may be expressed in association with a surface member (e.g. phage coat protein) and used in the identification of high affinity peptides for a given antigen. In some embodiments, antibodies of the present disclosure are prepared as scFvFc antibodies. The term “scFvFc” refers to an antibody format which includes the fusion of one or more scFv with an antibody Fc domain.

[0089] The term “chimeric antibody” refers to an antibody with portions derived from two or more sources. Chimeric antibodies may include portions derived from different species. For example, chimeric antibodies may include antibodies with mouse variable domains and human constant domains. Further examples of chimeric antibodies and methods for producing them include any of those described in Morrison, S.L., Transfectomas provide novel chimeric antibodies. Science. 1985 Sep 20;229(4719):1202-7, Gillies, S.D. 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. Pat. Nos. 5,807, 715; 4,816,567; and 4,816,397, the contents of each of which are incorporated herein by reference in their entirety.

[0090] The term “diabodies” refers to small antibody fragments with two antigen-binding sites, which fragments include a heavy chain variable domain Vu connected to a light chain variable domain VL in the same polypeptide chain. By using a linker that is too short to allow pairing between the two domains on the same chain, the domains are forced to pair with the complementary domains of another chain and create two antigen-binding sites. Diabodies are described more fully in, for example, EP 404,097; WO 93 / 11161; and Hollinger et al., Proc. Natl. Acad. Sci. USA, 90:6444-6448 (1993), the contents of each of which are incorporated herein by reference in their entirety.

[0091] The term “intrabody” refers to a form of antibody that is not secreted from a cell in which it is produced, but instead targets one or more intracellular protein(s). Intrabodies may be used to affect a multitude of cellular processes including, but not limited to intracellular trafficking, transcription, translation, metabolic processes, proliferative signaling and cell division. In some embodiments, methods of the present invention may include intrabody- based therapies. In some such embodiments, variable domain sequences and / or CDR sequences disclosed herein may be incorporated into one or more constructs for intrabody- based therapy. In some cases, intrabodies of the invention may target one or more glycated intracellular proteins or may modulate the interaction between one or more glycated intracellular protein and an alternative protein.

[0092] The term “chimeric antigen receptor” or “CAR” as used herein, refers to artificial receptors that are engineered to be expressed on the surface of immune effector cells resulting in specific targeting of such immune effector cells to cells expressing entities that bind with high affinity to the artificial receptors. CARs may be designed to include one or more segments of an antibody, antibody variable domain and / or antibody CDR, such that when such CARs are expressed on immune effector cells, the immune effector cells bind and clear any cells that are recognized by the antibody portions of the CARs. In some cases, CARs are designed to specifically bind cancer cells, leading to immune-regulated clearance of the cancer cells.

[0093] The antibody of the invention can be a monoclonal antibody or a polyclonal antibody. The term “monoclonal antibody” as used herein refers to an antibody obtained from a population of substantially homogeneous cells (or clones), i.e.g., the individual antibodies making up the population are identical and / or bind the same epitope, except for possible variants that may arise during production of the monoclonal antibody, such variants generally being present in minor amounts. In contrast to polyclonal antibody preparations that typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen

[0094] 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.

[0095] In some embodiments, the antibody comprises an amino acid sequence of an antibody in which the variable region, or a portion thereof, e.g., the CDRs, are generated in a non-human organism, e.g., a rat or mouse. Antibodies comprising chimeric, CDR-grafted, and humanized antibodies are within the invention. Antibodies comprising the sequences of antibodies generated in a non-human organism, e.g., a rat or mouse, and then modified, e.g., in the variable framework or constant region, to decrease antigenicity in a human are within the invention.

[0096] The monoclonal antibodies herein include “chimeric” antibodies (immunoglobulins) in which a portion of the heavy and / or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies.

[0097] 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 horse origin.

[0098] In some embodiments, antibodies of the present disclosure may be antibody mimetics. The term “antibody mimetic” refers to any molecule which mimics the function or effect of an antibody and which binds specifically and with high affinity to their molecular targets. In some embodiments, antibody mimetics may be monobodies, designed to incorporate the fibronectin type III domain (Fn3) as a protein scaffold (US 6,673,901; US 6,348,584). In some embodiments, antibody mimetics may be those known in the art including, but are not limited to affibody molecules, affilins, affitins, anticalins, avimers, DARPins, Fynomers and Kunitz and domain peptides. In other embodiments, antibody mimetics may include one or more non-peptide region.

[0099] As used herein, the term “antibody variant” refers to a biomolecule resembling an antibody in structure, sequence and / or function, but including some differences in their amino acid sequence, composition or structure as compared to another antibody or a native antibody. Multispecific Antibodies

[0100] In some embodiments, the antibody is a multispecific antibody, e.g., it comprises a plurality of immunoglobulin variable domains 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., the different proteins (or different subunits of a multimeric protein). In some embodiments, a multispecific antibody comprises a third, fourth or fifth immunoglobulin variable domain. In some embodiments, a multispecific antibody is a bispecific antibody, a trispecific antibody, or tetraspecific antibody. In some embodiments, the anti-tau antibody is a multispecific antibody.

[0101] In some embodiments, a multispecific antibody is a bispecific antibody. A bispecific antibody has specificity for no more than two antigens. A bispecific antibody is characterized by a first immunoglobulin variable domain sequence which 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., the different proteins (or different subunits of a multimeric protein). In some embodiments, a bispecific antibody comprises a heavy chain variable domain sequence and a light chain variable domain sequence which have binding specificity for a first epitope and a heavy chain variable domain sequence and a light chain variable domain sequence which have binding specificity for a second epitope. In some embodiments, a 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, a 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, a bispecific antibody comprises a scFv, or fragment thereof, have binding specificity for a first epitope and a scFv, or fragment thereof, have binding specificity for a second epitope. In some embodiment, the anti-tau antibody is a bispecific antibody.

[0102] In some embodiments, the sequences of the antibody of the present disclosure can be generated from bispecific or heterodimeric antibody produced using protocols known in the art; including but not limited to, for example, the “knob in a hole” approach described in, e.g., US5731168; the electrostatic steering Fc pairing as described in, e.g., WO 09 / 089004, WO 06 / 106905 and WO 2010 / 129304; Strand Exchange Engineered Domains (SEED) heterodimer formation as described in, e.g., WO 07 / 110205; Fab arm exchange as described in, e.g., WO 08 / 119353, WO 2011 / 131746, and WO 2013 / 060867; double antibody conjugate, e.g., by antibody cross-linking to generate a bi-specific structure using a heterobifunctional reagent having an amine-reactive group and a sulfhydryl reactive group as described in, e.g., US4433059; bispecific antibody determinants generated by recombining half antibodies (heavy-light chain pairs or Fabs) from different antibodies through cycle of reduction and oxidation of disulfide bonds between the two heavy chains, as described in, e.g., US 4444878; trifunctional antibodies, e.g., three Fab’ fragments cross-linked through sulfhdryl reactive groups, as described in, e.g., US5273743; biosynthetic binding proteins, e.g., pair of scFvs cross-linked through C-terminal tails preferably through disulfide or amine-reactive chemical cross-linking, as described in, e.g., US5534254; bifunctional antibodies, e.g., Fab fragments with different binding specificities dimerized through leucine zippers (e.g., c-fos and c-jun) that have replaced the constant domain, as described in, e.g., US5582996; bispecific and oligospecific mono-and oligovalent receptors, e.g., VH-CH1 regions of two antibodies (two Fab fragments) linked through a polypeptide spacer between the CHI region of one antibody and the VH region of the other antibody typically with associated light chains, as described in, e.g., US5591828; bispecific DNA-antibody conjugates, e.g., crosslinking of antibodies or Fab fragments through a double stranded piece of DNA, as described in, e.g., US5635602; bispecific fusion proteins, e.g., an expression construct containing two scFvs with a hydrophilic helical peptide linker between them and a full constant region, as described in, e.g., US5637481; multivalent and multispecific binding proteins, e.g., dimer of polypeptides having first domain with binding region of Ig heavy chain variable region, and second domain with binding region of Ig light chain variable region, generally termed diabodies (higher order structures are also disclosed creating bispecific, trispecific, or tetraspecific molecules, as described in, e.g., US5837242; minibody constructs with linked VL and VH chains further connected with peptide spacers to an antibody hinge region and CH3 region, which can be dimerized to form bispecific / multivalent molecules, as described in, e.g., US5837821; VH and VL domains linked with a short peptide linker (e.g., 5 or 10 amino acids) or no linker at all in either orientation, which can form dimers to form bispecific diabodies; trimers and tetramers, as described in, e.g., US5844094; String of VH domains (or VL domains in family members) connected by peptide linkages with crosslinkable groups at the C-terminus further associated with VL domains to form a series of FV (or scFvs), as described in, e.g., US5864019; and single chain binding polypeptides with both a VH and a VL domain linked through a peptide linker are combined into multivalent structures through non-covalent or chemical crosslinking to form, e.g., homobivalent, heterobivalent, trivalent, and tetravalent structures using both scFV or diabody type format, as described in, e.g., US5869620. Antibody development

[0103] Antibodies according to the present disclosure may be developed using methods standard in the art. Two primary antibody preparation technologies are immunization and antibody display technology. In either case, desired antibodies are identified from a larger pool of candidates based on affinity for a specific target or epitope. An immune response is characterized by the reaction of the cells, tissues and / or organs of an organism to the presence of a foreign entity. Such an immune response typically leads to the production by the organism of one or more antibodies against the foreign entity, e.g., antigen or a portion of the antigen. Antigens

[0104] Antibodies may be developed (e.g., through immunization) or selected (e.g., from pool of candidates), for example, using any naturally occurring or synthetic antigen. As used herein, an “antigen” is an entity which induces or evokes an immune response in an organism and may also refer to an antibody binding partner. An immune response is characterized by the reaction of the cells, tissues and / or organs of an organism to the presence of a foreign entity. Such an immune response typically leads to the production by the organism of one or more antibodies against the foreign entity. In some embodiments, antigens include tau proteins.

[0105] As used herein, the term “tau protein” refers to proteins or protein complexes that include microtubule-associated protein tau or peptide fragments thereof. Tau proteins may include enriched paired helical filament tan protein (ePHF), also referred to as “sarkosyl insoluble tan,” or fragments thereof. Tau proteins may include one or more phosphorylated residues. Such phosphorylated residues may correspond to tau proteins associated with disease (also referred to herein as “pathological tau”). Immunization

[0106] In some embodiments, antibodies may be prepared by immunizing a host with an antigen of interest. Host animals (e.g., mice, rabbits, goats, or llamas) may be immunized with an antigenic protein to elicit lymphocytes that specifically bind to the antigen. Lymphocytes may be collected and fused with immortalized cell lines to generate hybridomas which can be cultured in a suitable culture medium to promote growth (e.g., see 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 herein incorporated by reference in their entirety). Alternatively, lymphocytes may be immunized in Vitro.

[0107] Lymphocytes may be fused with immortalized cell lines using suitable fusing agents (e.g., polyethylene glycol) to form a hybridoma cell (e.g., see Goding, J. W., Monoclonal Antibodies: Principles and Practice. Academic Press. 1986; 59-1031, the contents of which are herein incorporated by reference in their entirety). Immortalized cell lines 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 employed. Hybridoma cells may be cultured in suitable culture media, typically including one or more substances that inhibit the growth or survival of unfused cells. For example, parental cells lacking the enzyme hypoxanthine guanine phosphoribosyl transferase (HGPRT or HPRT) may be used and culture media for resulting hybridoma cells may be supplemented with hypoxanthine, aminopterin, and thymidine (“HAT medium”) to prevent growth of HGPRT-deficient (unfused) cells.

[0108] Desirable properties for immortalized cell lines may include, but are not limited to, efficient fusing, supportive of high level antibody expression by selected antibody-producing cells, and sensitivity to unfused cell-inhibitory media (e.g., HAT media). In some embodiments, immortalized cell lines are murine myeloma lines. Such cell lines may 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 may also be used for the production of human monoclonal antibodies (e.g., see Kozbor, D. et al., A human hybrid myeloma for production of human monoclonal antibodies. J Immunol. 1984 Dec;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 herein incorporated by reference in their entireties).

[0109] Hybridoma cell culture media may be assayed for the presence of monoclonal antibodies with desired binding specificity. Assays may include, but are not limited to, immunoprecipitation assay, in vitro binding assay, radioimmunoassay (RIA), surface plasmon resonance (SPR) assay, and / or enzyme-linked immunosorbent assay (ELISA). In some embodiments, binding specificity of monoclonal antibodies may be determined by Scatchard analysis (Munson, P.J. 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 herein incorporated by reference in their entirety).

[0110] Antibodies produced by cultured hybridomas may be analyzed to determine binding specificity for target antigens. Once antibodies with desirable characteristics are identified, corresponding hybridomas may be subcloned through 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 serum of immunized hosts.

[0111] In some embodiments, recombinant versions of antibodies generated through immunization may be prepared. Such antibodies may be prepared using genomic antibody sequences from selected hybridomas. Hybridoma genomic antibody sequences 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 cDNA using primers specific for antibody heavy and light chains. PCR products may then be subcloned into plasmids for sequence analysis. Antibodies may be produced by insertion of resulting antibody sequences into expression vectors. Some recombinant antibodies may be prepared using synthetic nucleic acid constructs that encode amino acid sequences corresponding to amino acid sequences obtained from isolated hybridoma antibodies. Antibody display

[0112] In some embodiments, antibodies may be developed using antibody display technologies. “Display technology” refers to systems and methods for expressing amino acid- based candidate compounds in a format where they are linked with nucleic acids encoding them and are accessible to a target or ligand. Candidate compounds are expressed at the surface of a host capsid or cell in most systems, however, some host-free systems (e.g., ribosomal display) exist. Display technologies may be used to generate display “libraries,” which include sets of candidate compound library members. Display libraries with antibodies (or variants or fragments thereof) as library members are referred to herein as “antibody display libraries.” Antibodies may be designed, selected, or optimized by screening target antigens using antibody display libraries. Antibody display libraries may include millions to billions of members, each expressing unique antibody domains. Antibody fragments displayed may be scFv antibody fragments, which are fusion proteins of Vu and Vi antibody domains joined by a flexible linker. Display libraries may include antibody fragments with differing levels of diversity between variable domain framework regions and CDRs. Display library antibody fragment CDRs may include unique variable loop lengths and / or sequences. Antibody variable domains or CDRs obtained from display library selection may be directly incorporated into antibody sequences for recombinant antibody production or mutated and utilized for further optimization through in vitro affinity maturation.

[0113] Antibody display libraries may include antibody phage display libraries. Antibody phage display libraries utilize phage virus particles as hosts with millions to billions of members, each expressing unique antibody domains. Such libraries may provide richly diverse sources that may be used to select potentially hundreds of antibody fragments with diverse levels of affinity for one or more antigens of interest (McCafferty, et al., 1990. Nature. 348:552-4; Edwards, B.M. et al., 2003. IMB. 334: 103-18; Schofield, D. et al., 2007. Genome Biol. 8, R254 and Pershad, K. ez al., 2010. Protein Engineering Design and Selection. 23:279-88; the contents of each of which are herein incorporated by reference in their entirety). Antibody fragments displayed may be scFv antibody fragments. Phage display library members may be expressed as fusion proteins, linked to viral coat proteins (e.g. the N- terminus of the viral pIII coat protein). Vi chains may be expressed separately for assembly with Vy chains in the periplasm prior to complex incorporation into viral coats. Precipitated library members may be sequenced from the bound phage to obtain cDNA encoding desired antibody domains.

[0114] In some embodiments, antibody display libraries may be generated using yeast surface display technology. Antibody yeast display libraries are made up of yeast cells with surface displayed antibodies or antibody fragments. Antibody yeast display libraries may include antibody variable domains expressed on the surface of Saccharomyces cerevisiae cells. Yeast display libraries may be developed 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 specific target may be isolated according to standard methods. Such methods may include, but are not limited to, magnetic separation and flow cytometry. Recombinant synthesis

[0115] Antibodies of the present disclosure may be prepared using recombinant DNA technology and related processes. Constructs (e.g., DNA expression plasmids) encoding antibodies may be prepared and used to synthesize full antibodies or portions thereof. In some embodiments, DNA sequences encoding antibody variable domains of the present disclosure may 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 may be inserted downstream of upstream expression vector regions with promoter / enhancer elements and / or encoding immunoglobulin signal sequences. DNA sequences encoding antibody variable domains may be inserted upstream of downstream expression vector regions encoding immunoglobulin constant domains. Encoded constant domains may be 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, encoded constant domains encode human IgG (e.g., IgG1, IgG2, IgG3, or IgG4) constant domains. In some embodiments, encoded constant domains encode mouse IgG (e.g., 1gG1, IgG2a, IgG2b, IgG2c, or IgG3) constant domains.

[0116] Expression vectors encoding antibodies of the present disclosure may be used to transfect cells for antibody production. Such cells may be mammalian cells. Cell lines with stable transfection of antibody expression vectors may be prepared and used to establish stable cell lines. Cell lines producing antibodies may be expanded for expression of antibodies which may be isolated or purified from cell culture media. Antibody characterization

[0117] In some embodiments, antibodies of the present disclosure may be identified, selected, or excluded based on different characteristics. Such characteristics may include, but are not limited to, physical and functional characteristics. Physical characteristics may include features of antibody structures [e.g., amino acid sequence or residues; secondary, tertiary, or quaternary protein structure; post-translational modifications (e.g., glycosylations); chemical bonds, and stability]. Functional characteristics may include, but are not limited to, antibody affinity (i.e., for specific epitopes and / or antigens) and antibody activity (e.g., antibody ability to activate or inhibit a target, process, or pathway). Antibody binding and affinity

[0118] In some embodiments, antibodies of the present disclosure may be identified, selected, or excluded based on binding and / or level of affinity for specific epitopes and / or antigens. Antibody binding and / or affinity level may be assessed with different antigen formats. In some embodiments, antibody affinity for different antigen formats may be tested in vitro (e.g., by ELISA). Anti-tau antibody in vitro testing may be carried out using brain samples or fractions. Such samples or fractions may be obtained from subjects with AD (e.g., human AD patients). In some embodiments, brain samples or fractions may be obtained from non-human subjects. Such non-human subjects may include non-human animals used in AD disease model studies (e.g., mice, rats, and primates). In some embodiments, brain samples or fractions used for antibody affinity testing may be derived from TG4510 / P301S mouse strains. Antibody affinity may be compared against control samples lacking the particular antigen for which affinity is being analyzed. In some embodiments, control samples used for anti-tau antibody testing may include brain samples or fractions from non-diseased human subjects. In some embodiments, brain samples or fractions from wild type and / or Tau knockout mouse strains may be used as control samples.

[0119] Invitro affinity testing may be carried out (e.g., by ELISA) using recombinant or isolated protein antigens. For example, recombinant or isolated ePHF may be used for anti- tau antibody affinity testing. In some embodiments, anti-tau antibodies of the present disclosure may exhibit a half maximal effective concentration (EC50) of from about 0.01 nM to about 100 nM for binding to ePHF when 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, anti-tau antibodies of the present disclosure may exhibit an EC50 of from about 0.01 nM to about 100 nM for binding to any of the antigens listed in Table 8, or an epitope that includes or is included within any of the antigens (including, but not limited to conformational epitopes), when 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.

[0120] In some embodiments, anti-tau antibodies of the present disclosure bind to pathological tau, but do not bind to non-pathological tau. Such antibodies may be referred to herein as being “selective” for pathological forms of tau. In some embodiments, anti-tau antibodies of the present disclosure bind to tau tangles.

[0121] In some embodiments, antibody affinity analysis may be used to identify, select, or exclude polyspecific antibodies. As used herein, the term “polyspecific antibody” refers to an antibody with affinity for more than one epitope or antigen. In some embodiments, polyspecific antibodies may be identified, selected, or excluded based on relative affinity for each epitope or antigen recognized. For example, a polyspecific antibody may be selected for use or further development based on higher affinity for one epitope or antigen over a second epitope or antigen for which the polyspecific antibody demonstrates affinity.

[0122] In some embodiments, anti-tau antibodies may be tested for competition with other anti-tau antibodies. Such testing may be carried out to provide information on the specific epitope recognized by an antibody and may yield information related to level of epitope affinity in comparison to the competing antibody. In some embodiments, anti-tau antibodies used in antibody binding and / or affinity analysis may include anti-tau antibody PT3, as described in United States Patent Number 9,371,376; anti-tan antibody C10.2, as described in United States Patent Number 10,196,439 (referred to as antibody “C10-2,” therein); anti-tau antibody IPN0O2, as described in US Patent Number 10,040,847; anti-tau antibody AT8 (ThermoFisher, Waltham, MA); anti-tau antibody AT100 (ThermoFisher, Waltham, MA); anti-tau antibody AT120 as described in United States Patent Number 5,843,779; or anti-tau antibody PT76, as described in Vandermeeren, M. et al., J Alzheimers Dis. 2018;65(1):265- 281. Antibody activity

[0123] In some embodiments, antibodies of the present disclosure may be identified, selected, or excluded based on their ability to promote or reduce a certain activity. Antibody activity may be assessed using analytical assays. Such assays may be selected or designed to detect, screen, measure, and / or rank antibodies based on such antibody activity.

[0124] Anti-tau antibodies may be characterized by ability to inhibit tau aggregation. Inhibition may be based on physical disruption of tau aggregation or may be based on anti- tau antibody-dependent depletion (immunodepletion) of tau protein. Characterization based on tau aggregation inhibition may be assessed using one or more assays of tau aggregation. In some embodiments, anti-tau antibodies may be characterized by tau seeding assay. Tau seeding assays typically involve in vitro initiation of tau aggregation and assessment of aggregation inhibition by candidate compounds being tested. Tau seeding assays may be carried out using tau aggregation biosensor cells. Tau aggregation biosensor cells yield a detectable signal (e.g., a fluorescent signal) in response to tau aggregation. Tau aggregation biosensor cells may be cultured with recombinant or isolated tau or with samples from high tau brain tissues or fluids (to promote tau aggregation) and treated with or without candidate compounds to assess tau aggregation inhibition. In some embodiments, anti-tau antibodies may be used to deplete tau from media prior to incubation with biosensor cells. Aggregation levels with depleted media may be compared to aggregation levels with non-depleted media to assess anti-tau antibody inhibitory function. Tau aggregation biosensor cells may include, but are not limited to, tau RD Biosensor cells. In some embodiments, neurons expressing human tau may be used.

[0125] In some embodiments, anti-tau antibodies of the present disclosure may inhibit tau aggregation with a half maximal inhibitory concentration (IC50) of from about 1 nM to about 30 nM as determined by immunodepletion assay (e.g., using tau RD Biosensor cells). Antibody structure and variations

[0126] Antibodies of the present disclosure may exist as a whole polypeptide, a plurality of polypeptides or fragments of polypeptides, which independently may be encoded by one or more nucleic acids, a plurality of nucleic acids, fragments of nucleic acids or variants of any of the aforementioned.

[0127] As used herein, “polypeptide” means 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 may be at least about 2, 3, 4, or at least 5 amino acid residues long. Polypeptides of the present disclosure may include gene products, naturally occurring polypeptides, synthetic polypeptides, homologs, orthologs, paralogs, fragments, or other equivalents, variants, and analogs of the foregoing. Polypeptides may be single molecules or may be multi-molecular complexes such as dimers, trimers, or tetramers. Polypeptides may also include single chain or multichain polypeptides, which may be associated or linked. Polypeptides may include amino acid polymers in which one or more amino acid residues are artificial chemical analogues of corresponding naturally occurring amino acids.

[0128] The term “polypeptide variant” refers to molecules which differ in their amino acid sequence from a native or reference sequence. Amino acid sequence variants may possess substitutions, deletions, and / or insertions at certain positions within the amino acid sequence, as compared to a native or reference sequence. Ordinarily, variants will possess at least about 50% identity (homology) to a native or reference sequence, and preferably, they will be at least about 80%, more preferably at least about 90% identical (homologous) to a native or reference sequence.

[0129] In some embodiments “variant mimics” are provided. As used herein, the term “variant mimic” is one which contains one or more amino acids which would mimic an activated sequence. For example, glutamate may serve as a mimic for phosphorylated threonine and / or phosphorylated serine. Alternatively, variant mimics may result in deactivation or in an inactivated product containing the mimic, e.g., phenylalanine may act as an inactivating substitution for tyrosine; or alanine may act as an inactivating substitution for serine.

[0130] The term “amino acid sequence variant” refers to molecules with some differences in their amino acid sequences as compared to a native or starting sequence. The amino acid sequence variants may possess substitutions, deletions, and / or insertions at certain positions within the amino acid sequence. “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 referring to an original molecule against which a comparison may be made. “Native” or “starting” sequences or molecules may represent the wild-type (that sequence found in nature) but do not have to be the wild-type sequence.

[0131] Ordinarily, variants will possess 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 as compared to a native sequence.

[0132] By “homologs” as it applies to amino acid sequences is meant the corresponding sequence of other species having substantial identity to a second sequence of a second species.

[0133] “Analogs” is meant to include polypeptide variants which differ by one or more amino acid alterations, e.g., substitutions, additions or deletions of amino acid residues that still maintain the properties of the parent polypeptide.

[0134] The present disclosure contemplates variants and derivatives of antibodies presented herein. These include substitutional, insertional, deletion and covalent variants and derivatives. For example, sequence tags or amino acids, such as one or more lysines, may be added to antibody peptide sequences (e.g., at the N-terminal or C-terminal ends). Sequence tags may be used for peptide purification or localization. Lysines may be used to increase peptide solubility or to allow for biotinylation. Alternatively, amino acid residues located at the carboxy and amino terminal regions of the amino acid sequence of a peptide or polypeptide may optionally be deleted providing for truncated sequences. Certain amino acids (e.g., C-terminal or N-terminal residues) may alternatively be deleted depending on the use of the sequence, as for example, expression of the sequence as part of a larger sequence which is soluble, or linked to a solid support.

[0135] “Substitutional variants” when referring to polypeptides are those that have at least one amino acid residue in a native or starting sequence 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 they may be multiple, where two or more amino acids have been substituted in the same molecule.

[0136] As used herein the term “conservative amino acid substitution” refers to the substitution of an amino acid that is normally present in the sequence with a different amino acid of similar size, charge, or polarity. Examples of conservative substitutions include the substitution of a non-polar (hydrophobic) residue such as isoleucine, valine and leucine for another non-polar residue. Likewise, examples of conservative substitutions include the substitution of one polar (hydrophilic) residue for another such as between arginine and lysine, between glutamine and asparagine, and between glycine and serine. Additionally, 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 acidic residue are additional examples of conservative substitutions. Examples of non-conservative substitutions include the substitution of a non-polar (hydrophobic) amino acid residue such as isoleucine, valine, leucine, alanine, methionine for a polar (hydrophilic) residue such as cysteine, glutamine, glutamic acid or lysine and / or a polar residue for a non-polar residue.

[0137] “Insertional variants” when referring to polypeptides are those with one or more amino acids inserted immediately adjacent to an amino acid at a particular position in a 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.

[0138] “Deletional variants” when referring to polypeptides, are those with one or more amino acids in the native or starting amino acid sequence removed. Ordinarily, deletional variants will have one or more amino acids deleted in a particular region of the molecule.

[0139] As used herein, the term “derivative” is used synonymously with the term “variant” and refers to a molecule that has been modified or changed in any way relative to a reference molecule or starting molecule. In some embodiments, derivatives include native or starting polypeptides that have been modified with an organic proteinaceous or non- proteinaceous derivatizing agent, and post-translational modifications. Covalent modifications are traditionally introduced by reacting targeted amino acid residues of a polypeptide with an organic derivatizing agent that is capable of reacting with selected side- chains or terminal residues, or by harnessing mechanisms of post-translational modifications that function in selected recombinant host cells. The resultant covalent derivatives are useful in programs directed at identifying residues important for biological activity, for immunoassays, or for the preparation of antibodies for immunoaffinity purification.

[0140] Certain post-translational modifications are the result of the action of recombinant host cells on the expressed polypeptide. 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.

[0141] Other post-translational modifications include hydroxylation of proline and lysine, phosphorylation of hydroxyl groups of seryl or threonyl residues, methylation of the alpha- amino groups of lysine, arginine, and histidine side chains (T. E. Creighton, Proteins: Structure and Molecular Properties, W.H. Freeman & Co., San Francisco, pp. 79-86 (1983)).

[0142] Covalent derivatives specifically include fusion molecules in which polypeptides are covalently bonded to non-proteinaceous polymers. Non-proteinaceous polymers may include hydrophilic synthetic polymers, i.e., polymers not otherwise found in nature. However, polymers which exist in nature and are produced by recombinant or in vitro methods are useful, as are polymers which are isolated from nature. Hydrophilic polyvinyl polymers may include polyvinylalcohol and / or polyvinylpyrrolidone. Particularly useful are polyvinylalkylene ethers such a polyethylene glycol and polypropylene glycol. Polypeptides may be linked to various non-proteinaceous polymers, such as polyethylene glycol, polypropylene glycol or polyoxyalkylenes, in the manner set forth in U.S. Pat. No. 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 herein incorporated by reference in their entirety.

[0143] As used herein when referring to polypeptides the term “loop” refers to a structural feature of a peptide or polypeptide which reverses the direction of the backbone of a peptide or polypeptide and includes four or more amino acid residues. Oliva er al. have identified at least 5 classes of polypeptide loops (J. Mol Biol 266 (4): 814-830; 1997, the contents of which are herein incorporated by reference in their entirety).

[0144] As used herein when referring to polypeptides the term “half-loop” refers to a portion of an identified loop having at least half the number of amino acid resides as the loop from which it is derived. It is understood that loops may not always contain an even number of amino acid residues. Therefore, in those cases where a loop contains or is identified to include an odd number of amino acids, a half-loop of the odd-numbered loop will include the whole number portion or next whole number portion of the loop (number of amino acids of the loop / 2+ / -0.5 amino acids). For example, a loop identified as a 7 amino acid loop could produce half-loops of 3 amino acids or 4 amino acids (7 / 2=3.5+ / -0.5 being 3 or 4).

[0145] As used herein when referring to polypeptides the term “domain” refers to a motif of a polypeptide having one or more identifiable structural and / or functional characteristics or properties (e.g., binding capacity), e.g., serving as a site for protein-protein interactions.

[0146] As used herein when referring to polypeptides, the term “site” is synonymous with “amino acid residue” and “amino acid side chain.” A site represents a position on a polypeptide that may be modified, manipulated, altered, derivatized or varied within the polypeptide.

[0147] As used herein the terms “termini or terminus” when referring to polypeptides refers to an extremity of a peptide or polypeptide. Such extremity is not limited only to the first or final site of the peptide or polypeptide but may include additional amino acids in the terminal regions. Polypeptide based molecules of the present disclosure may be characterized as having both an N-terminus (terminated by an amino acid with a free amino group) and a C-terminus (terminated by an amino acid with a free carboxyl group). Proteins of the present disclosure are in some cases made up of multiple polypeptide chains brought together by disulfide bonds or by non-covalent forces (multimers, oligomers). These sorts of proteins will have multiple N- and C-termini. Alternatively, the termini of the polypeptides may be modified such that they begin or end, as the case may be, with a non-polypeptide based moiety such as an organic conjugate. Antibody modification

[0148] Antibodies may be modified to obtain variants with one or more altered properties. Such properties may include or relate to antibody structure, function, affinity, specificity, protein folding, stability, manufacturing, expression, and / or immunogenicity (i.e., immune reactions in subjects being treated with such antibodies). In some embodiments, antibody fragments or variants may be used to modify another antibody or may be incorporated into a synthetic antibody.

[0149] Antibody modification may include amino acid sequence modifications. Such modifications may include, but are not limited to, amino acid deletions, additions, and / or substitutions. Modifications may be informed 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. Compared antibodies may include those binding to the same epitope. Compared antibodies may bind to different epitopes (separate or overlapping) of the same protein or target (e.g., to identify residues or regions conferring specificity to specific epitopes). Comparisons may include light and / or heavy chain sequence variation analysis, CDR sequence variation analysis, germline sequence analysis, and / or framework sequence analysis. Information obtained from such analysis may be used to identify amino acid residues, segments of amino acids, amino acid side chains, CDR lengths, and / or other features or properties that are conserved or variable among antibodies binding to the same or different epitopes.

[0150] In some embodiments, modified versions of anti-tan antibodies described above may be prepared by adding, deleting, or substituting one or more CDR amino acid residues.

[0151] In some embodiments, anti-tau antibodies may be modified by amino acid sequence alignment of antibodies binding to similar targets and preparing modified antibodies with one or more amino acid deletions, substitutions, or insertions based on analysis of the aligned sequences.

[0152] The present disclosure includes amino acid consensus sequences for CDR region sequences, showing specific amino acids (shown in square brackets) that may be modified or amino acid residue positions that may be more generally deleted or substituted (shown using variable “X") in antibody amino acid sequences, e.g. as described in Table 1A or Z.

[0153] Related CDR sequences that can appear in the same VH and / or VL sequences of an antibody are grouped together in the same row. For example, an antibody of the invention may comprise one each of CDRH1-CDRH3 and CDRL1-CDRL3, wherein said CDRH1- CDRH3 and CDRL1-CDRLS3 are represented by SEQ ID NOs: 928, 930, 409, 472, 525, and 570, respectively.

[0154] In addition, in Table 5, for example, each odd numbered rows below the table heading, and the even numbered rows immediately therebelow, are related (if not identical) consensus sequences (e.g., SEQ ID NOs: 927 and 928 are related, 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, wherein each of said CDRH1-CDRH3 and CDRL1- CDRL3 can be independently represented by one of the two related consensus sequences. For example, an antibody of the invention may comprise one each of CDRH1-CDRH3 and CDRLI1-CDRL3, wherein said CDRH1-CDRH3 and CDRL1-CDRL3 are represented by SEQ ID NOs: 931, 341, 410, 934, 935, and 571, respectively.

[0155] Furthermore, amino acid at each X position or Xi position (wherei=1,2, 3, ...) may be any naturally occurring amino acids, or may be a selected subset of amino acids as specified in each consensus sequence X / Xi position. It is contemplated that any one or more of the enumerated specific amino acids at each X or Xi positions can be eliminated as a permissible value for the X or Xi position. For example, in SEQ ID NO: 947, X4 may be any residues, suchas T, S, A, V, I, or L. In some embodiments, X4 is T, L, or V;or S, A, or V, etc. 2 8 9 | = = Zz 2 Eke A= EER z 5050 288168 S222 28% [5 £2 £eis 292¢ 23588 gea2e EEoke 8:88 ze I) a =~ Qo z 00 a > oO 3 A =. - Table 1: Consensus CDRs for exemplary anti-tau antibodies V0022, V0023 and SEQ ID NO Description SEQ ID NO: 1180 HCDR1 (Chothia) Sequence GX TFTX,X3, wherein X,isForY; X;is Ror I; and X3isYorF NPNNGG SEQ ID NO: 341 HCDR2 NPNNGG (Chothia) SEQ ID NO: 410 HCDR3 GTGTGAMDY (Chothia) SEQ ID NO: 1181 LCDR1 RSSQSLVHXNGX,TX5LY, wherein (Chothia) XiisNorS; Xz is Tor N; and XsisYorH SEQ ID NO: 1182 LCDR2 RVSXRFS, wherein Chothia) XiisNor§ SEQ ID NO: 571 LCDR3 FQGTHVPRT A SEQ ID NO: 1182 LCDR2 RVSX|RFS, wherein Chothia) XiisNor§ SEQ ID NO: 571 LCDR3 FQGTHVPRT (Chothia) SEQ ID NO: 1183 HCDRI1 XX, WMH, wherein (Kabat) XiisRorI; and XisYorF SEQ ID NO: 1184 HCDR2 XINPNNGGX,DX3NEX,FKXs, wherein (Kabat) Xiis Nor K; X2is Tor G; X3isF, Y, or N; X,is Kor R; and XsisNorS; SEQ ID NO: 410 HCDR3 GTGTGAMDY bis Stiinta. SEQ ID NO: 410 HCDR3 GTGTGAMDY (Kabat) SEQ ID NO: 1185 LCDRI1 RSSQSLVHXNGX,TX5LY, wherein (Kabat) XiisNorS; XzisTorN; and XsisYorH SEQ ID NO: 1182 LCDR2 RVSX|RFS, wherein Kabat XiisNor§ SEQ ID NO: 571 LCDR3 FQGTHVPRT LS SEQ ID NO: 1182 LCDR2 RVSX|RFS, wherein Kabat XiisNor§ SEQ ID NO: 571 LCDR3 FQGTHVPRT (Kabat) SEQ ID NO: 1186 HCDR1 GX TFTX>XsW, wherein (IMGT) XiisForY; XzisRorI; and X3isYorF SEQ ID NO: 1187 HCDR2 INPNNGG Xi, wherein (IMGT) X,1isTor G SEQ ID NO: 1167 HCDR3 ARGTGTGAMDY SEQ ID NO: 1187 HCDR2 INPNNGG Xi, wherein (IMGT) X,1isTor G SEQ ID NO: 1167 HCDR3 ARGTGTGAMDY (IMGT) SEQ ID NO: 1188 LCDR1 QSLVHX;NGX,TX3, wherein (IMGT) XiisNorS; XzisTorN; and XsisYorH SEQ ID NO: 528 LCDR2 RVS SEQ ID NO: 528 LCDR2 IMGT) SEQ ID NO: 571 LCDR3 FQGTHVPRT

[0156] In some embodiments, anti-tau antibodies of the present disclosure may include a CDRH] that includes the amino acid sequence GYTFTS [Y / N] (SEQ ID NO: 927), or a CDRH] that includes the amino acid sequence GYTFTSX (SEQ ID NO: 928), wherein X may be any amino acid, e.g., X is Y / F / N / Q; a CDRH2 that includes the amino acid sequence NPNNS [D / E] (SEQ ID NO: 929), or a CDRH2 that includes the amino acid sequence NPNNSX (SEQ ID NO: 930), wherein X may be any amino acid, e.g., an amino acid with a negatively charged side chain; and a CDRH3 that includes the amino acid sequence ANYYGGSQFAY (SEQ ID NO: 409); a CDRLI that includes the amino acid sequence RSSQSLVHSNGKTYLH (SEQ ID NO: 472); a CDRL2 that includes the amino acid sequence KVSNRFS (SEQ ID NO: 525); and / or a CDRL3 that includes the amino acid sequence SQSTHVPFT (SEQ ID NO: 570).

[0157] In some embodiments, anti-tau antibodies include a CDRH] that includes the amino acid sequence G [F / Y] TFT [R / I] [Y / F] (SEQ ID NO: 931), or a CDRH1 that includes the amino acid sequence G-X1-TFT-X2-X3 (SEQ ID NO: 932), wherein each of X1, X2, and X3 may be any amino acid, e.g., X1 and / or X3 may be an amino acid with a hydrophobic and / or aromatic side chain, such as F or Y, and / or X2 may be a positively charged residue (such as R, K, H) or a residue with aliphatic side chain (such as A, V, I, or L); a CDRH2 that includes the amino acid sequence NPNNGG (SEQ ID NO: 341); a CDRH3 that includes the amino acid sequence GTGTGAMDY (SEQ ID NO: 410); a CDRLI that includes the amino acid sequence RSSQSLVH [N / S] NG [I / N] T [H / Y] LY (SEQ ID NO: 933), or a CDRL1 that includes the amino acid sequence RSSQSLVH-X1-NG-X2-T-X3-LY (SEQ ID NO: 934), where X1, X2, and X3 may be any amino acid, e.g., X1 is Q / N / S / T and / or X2 is A / V / I / LIQ / N and / or X3 is H / R / K / Y / F; a CDRL2 that includes the amino acid sequence RVS [N / S] RFS (SEQ ID NO: 935), or a CDRL2 that includes the amino acid sequence RVSXRFS (SEQ ID NO: 936), where X may be any amino acid, e.g., X is Q / N / S / T; and / or a CDRL3 that includes the amino acid sequence FQGTHVPRT (SEQ ID NO: 571).

[0158] In some embodiments, anti-tau antibodies include a CDRH] that includes the amino acid sequence G [F / Y] TFT [R / I / D] [Y / F] (SEQ ID NO: 937), or a CDRHI that includes the amino acid sequence G-X1-TFT-X2-X3 (SEQ ID NO: 938), where X1, X2 and X3 may be any amino acid, e.g., X1 and X3 are each independently F / Y and / or X2 is any residue (such as R / K / H / D / E / G / A / I / L / V); a CDRH2 that includes the amino acid sequence NPNNG [G / E] (SEQ ID NO: 939), or a CDRH2 that includes the amino acid sequence NPNNGX (SEQ ID NO: 940), where X may be any amino acid, e.g., E / D / G / A / V / I / L; a CDRH3 that includes 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 that includes the amino acid sequence G-X1- G-X2-G-X3-X4-A-X5-DY (SEQ ID NO: 942), where each of X1-X5 may be any amino acid and / or where X3 and / or X4 may 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 CDRLI that includes 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 CDRLI that includes the amino acid sequence X1-X2-S- X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15 (SEQ ID NO: 944), where X1-X15 may be any amino acid and / or where X11, X12, X13, X14, and / or X15 may be absent, e.g., 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 / IL / N / Q and / or X9 is N / Q / A / I / L / V / M / S / T and / or X10 is G / A / N / Q and / or X11 is Q / N / A / V / T / 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 CDRL?2 consensus sequence with from about 3 to about 7 amino acids with an 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 that includes the amino acid sequence X1-X2-X3-X4-X5-X6-X7 (SEQ ID NO: 946), where X1, X2, X3, X4, X5, X6, and X7 may 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 / LIG and / or X7 is S / T / D / E; and / or a CDRL3 that includes the amino acid sequence [F / Q] [G / N] [G / V] [T / L] [H / T] [V / T] P [R / W] T (SEQ ID NO: 947), or a CDRL3 that includes the amino acid sequence X1-X2-X3-X4-X5-X6-P-X7-T (SEQ ID NO: 948), where X1, X2, X3, X4, X5, X6, and X7 may 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 RFZK / H / W / F / Y.

[0159] In some embodiments, anti-tau antibodies include a CDRHI that includes the amino acid sequence GY [S / T] FT [D / E] Y (SEQ ID NO: 949), or a CDRH] that includes the amino acid sequence GY-X1-FT-X2-Y (SEQ ID NO: 950), where X1 and X2 may be any amino acid, e.g., X1 is S / T and / or X2 is D / E / S / T; a CDRH2 that includes the amino acid sequence [F / Y]PG[S / R][D / G][S / N] (SEQ ID NO: 951), or a CDRH2 that includes the amino acid sequence X1-PG-X2-X3-X4 (SEQ ID NO: 952), where X1-X4 may 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 that includes 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 that includes the amino acid sequence P-X1-X2- X3-X4-X5-DYAM-X6-Y (SEQ ID NO: 954), where X1-X6 may be any amino acid, e.g., 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 X35 is R / K / H and / or X6 is D / E; a CDRLI that includes the amino acid sequence RSSQSIV [Y / H] [S / R / T] NGNTYLE (SEQ ID NO: 955), or a CDRLI that includes the amino acid sequence RSSQSIV-X1-X2-NGNTYLE (SEQ ID NO: 956), where X1 and X2 may be any amino acid, e.g., X1 is Y / F / H / R / K and / or X2 is S / T / R / K / H; a CDRL2 that includes the amino acid sequence KVSNRFS (SEQ ID NO: 525); and / or a CDRL3 that includes the amino acid sequence FQGSHVP[Y / F]T (SEQ ID NO: 957), or a CDRL3 that includes the amino acid sequence FQGSHVPXT (SEQ ID NO: 958), wherein X may be any amino acid, e.g., X is Y / F.

[0160] In some embodiments, anti-tau antibodies include a CDRHI that includes the amino acid sequence GY [S / T] FT [D / E / S] Y (SEQ ID NO: 959), or a CDRH]1 that includes the amino acid sequence GY-X1-FT-X2-Y (SEQ ID NO: 950), where X1 and X2 may be any amino acid, e.g., X1 is S / T and / or X2 is E / D / S / T; a CDRH2 that includes the amino acid sequence [F / Y] P [G / S] [S / R / N] [D / G] [S / G / N] (SEQ ID NO: 960), or a CDRH2 that includes the amino acid sequence X1-P-X2-X3-X4-X5 (SEQ ID NO: 961), where X1-X5 may 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 that includes the amino acid sequence [P / S] [T / A / S] [V / I / Y] [V / Y] [A / S / G] [R / K] DYAM [D / E] Y (SEQ ID NO: 962), or a CDRH3 that includes the amino acid sequence X1-X2-X3-X4-X5-X6- DYAM-X7-Y (SEQ ID NO: 963), where X1-X7 may be any amino acid, e.g., X1 is S / T / P / A / VL / V and / or X2 is T / S / A / V / UL 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 R / K / H and / or X7 is E / D; a CDRLI that includes the amino acid sequence RSSQSIV [Y / H] [S / R / T] NGNTYLE (SEQ ID NO: 955), or a CDRLI1 that includes the amino acid sequence RSSQSIV-X1-X2-NGNTYLE (SEQ ID NO: 956), where X1 and X2 may be any amino acid, e.g., X1 is Y / F / H / R / K and / or X2 is S / T / R / K / H; a CDRL2 that includes the amino acid sequence KVSNRFS (SEQ ID NO: 525); and / or a CDRLS3 that includes the amino acid sequence FQGSHVP[Y / F]T (SEQ ID NO: 957), or a CDRLS3 that includes the amino acid sequence FQGSHVPXT (SEQ ID NO: 958), wherein X may be any amino acid, e.g., X is F / Y.

[0161] In some embodiments, anti-tau antibodies include a CDRH] that includes the amino acid sequence GFSL [S / N] T [S / F] [A / G] M (SEQ ID NO: 964), or a CDRH] that includes the amino acid sequence GFSL-X1-T-X2-X3-M (SEQ ID NO: 965), where X1-X3 may 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 that includes the amino acid sequence YWDDD (SEQ ID NO: 362); a CDRH3 that includes the amino acid sequence R [R / V / K] R [G / Y / S] Y [G / A] MDY (SEQ ID NO: 966), or a CDRH3 that includes the amino acid sequence R-X1-R-X2-Y-X3-MDY (SEQ ID NO: 967), where X1-X3 may be any amino acid, e.g., X1 is R / K / H / A / V / I / L and / or X2 is G / A / V / TL / S / T / Y / F and / or X3 is A / V / I / L / G; a CDRLI that includes the amino acid sequence K [A / S] SQS [V / L] [S / L] [N / S] [absent / S] [absent / G] [absent / N] [absent / Q] [absent / K] [absent / N] [D / Y] [V / L] A (SEQ ID NO: 968), or a CDRLI that includes the amino acid sequence K-X1-SQS-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-A (SEQ ID NO: 969), where X1-X12 may be any amino acid and / or where one or more of X5-X10 may be absent, e.g., X1 is S / T / A / V / I / L and / 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 X35 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 that includes the amino acid sequence [Y / G] [A / T] S [N / T] R [C / E] [T / S] (SEQ ID NO: 970), or a CDRL2 that includes the amino acid sequence X1-X2- S-X3-R-X4-X5 (SEQ ID NO: 971), where X1-X5 may be any amino acid, e.g., X1 is Y / F / G / A / V / UL 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 a CDRL3 that includes 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 that includes the amino acid sequence Q- X1-D-X3-X4-X5-P-X6-T (SEQ ID NO: 973), where X1-X6 may 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 / NV / T / L / Y / F.

[0162] In some embodiments, anti-tau antibodies include a CDRH] that includes the amino acid sequence GFSL [S / N] T [S / F] [A / G] M (SEQ ID NO: 964), or a CDRHI that includes the amino acid sequence GFSL-X1-T-X2-X3-M (SEQ ID NO: 965), where X1-X3 may 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 that includes the amino acid sequence YWDDD (SEQ ID NO: 362); a CDRH3 that includes 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 CDRH3 that includes the amino acid sequence R-X1-X2-X3-X4-X5-X6-X7-X8-X9-DY (SEQ ID NO: 975), where each of X1-X9 may be any amino acid and / or where one or more of X3-X5 may 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 CDRLI that includes 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 CDRLI that includes 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-X15 may be any amino acid and / or where one or more of X9-X14 may be absent, e.g., 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 / T / 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 / T / L / D / E / Y / F 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 CDRL2 that includes 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), or a CDRL2 that includes the amino acid sequence X1-X2-8-X3-X4-X5-X6 (SEQ ID NO: 979), where X1-X6 may be any amino acid, e.g., X1 is Y / F / G / A / V / I / L / R / K / H and / or X2 is A / V / UL / 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 / IL and / or X6 is T / S; and / or a CDRL3 that includes the amino acid sequence [W / Q] [Q / N] [G / D] [T / S / Y / H] [H / S / R] [F / IS / H] P [Q / R / L / Y] [absent / Y] T (SEQ ID NO: 980), or a CDRLS3 that includes the amino acid sequence X1-X2-X3-X4-X5-X6-P-X7-X8-T (SEQ ID NO: 981), where each of X1-X8 may be any amino acid and / or where 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 / N / T / L / Y / F and / or X8 is Y / F / absent. Functional modifications

[0163] 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 mobilize or immobilize targets, and ability to activate or inhibit a target, process, or pathway. In some embodiments, functional properties include or relate to ability to modulate protein- protein interactions, protein aggregation, enzyme activity, receptor-ligand interactions, cellular signaling pathways, proteolytic cascades, and / or biological or physiological responses.

[0164] Antibody modifications may optimize antibodies by modulating epitope affinity. Such modifications may be carried out by affinity maturation. Affinity maturation technology is used to identify sequences encoding CDRs with highest affinity for target antigens. In some embodiments, antibody display technologies (e.g., phage or yeast) may be used. Such methods may include mutating nucleotide sequences encoding parental antibodies being optimized. Nucleotide sequences may be mutated randomly as a whole or to vary expression at specific amino acid residues to create millions to billions of variants. Sites or residues may be selected for mutation based on sequences or amino acid frequencies observed in natural human antibody repertoires. Variants may be subjected to repeated rounds of affinity screening [e.g., using display library screening technologies, surface plasmon resonance technologies, fluorescence-associated cell sorting (FACS) analysis, enzyme-linked immunosorbent assay (ELISA), efc.] for target antigen binding. Repeated rounds of selection, mutation, and expression may be carried out to identify antibody fragment sequences with highest affinity for target antigens. Such sequences may 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 as compared to the affinity of an original or starting antibody. In cases where affinity is less than desired, the process may be repeated.

[0165] In some embodiments, antibody affinity may be assessed with different antigen formats. In some embodiments, antibody affinity for different antigen formats may be tested in vitro (e.g., by ELISA). In vitro testing may be carried out using brain samples or fractions. Such samples or fractions may be obtained from subjects with AD (e.g., human AD patients). In some embodiments, brain samples or fractions may be obtained from non-human subjects. Such non-human subjects may include non-human animals used in AD disease model studies (e.g., mice, rats, and primates). In some embodiments, brain samples or fractions used for antibody affinity testing may be derived from TG4510 / P301S mouse strains. Antibody affinity may be compared against control samples lacking the particular antigen for which affinity is being analyzed. In some embodiments, control samples may include brain samples or fraction from non-diseased human subjects. In some embodiments, brain samples or fractions from wild type and / or Tau knockout mouse strains may be used as control samples. In vitro affinity testing may be carried out (e.g., by ELISA) using recombinant or isolated protein antigens. In some embodiments, recombinant or isolated ePHF is used for antibody affinity testing. In some embodiments, antigens listed in Table 8 may be used.

[0166] In some embodiments, antibody affinity analysis may be used to modulate antibody polyspecificity (e.g., to reduce or enhance antibody polyspecificity). Such modulation may include modulating relative affinity for two or more epitopes or antigens. For example, antibodies may be optimized for higher affinity for one epitope or antigen over a second epitope or antigen.

[0167] Antibodies may be modified to optimize antibody functional properties. Such functional properties may be assessed or engineered based on analytical assay results relating to one or more antibody functional properties. Assays may be used to screen multiple antibodies to identify or rank antibodies based on functional criteria. Anti-tau antibodies may be modified to optimize tau aggregation inhibition. Such inhibition may be based on physical disruption of tau aggregation or may be based on the ability of anti-tan antibodies to deplete tau protein from assay samples. Optimization based on tau aggregation inhibition may be assessed using one or more assays of tau aggregation (e.g., by tau seeding assay). Production modifications

[0168] 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 carried out to address one or more antibody features negatively impacting production. Such features 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, conformity with mouse germline sequences; asparagine deamidation sites; aspartate isomerization sites; N-terminal pyroglutamate formation sites; and aggregation-prone amino acid sequence regions (e.g., within CDR sequences).

[0169] In some embodiments, antibodies of the present disclosure may be prepared using recombinant DNA technology (e.g., see United States Patent No. 4,816,567, which is hereby incorporated by reference in its entirety). Antibody-encoding DNA may be isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that are capable of binding specifically to genes encoding the heavy and light chains of murine antibodies). In some embodiments, hybridoma cells may be used as a preferred source of DNA. Once isolated, the DNA can be placed into expression vectors, which are then transfected into host cells. Host cells may include, but are not limited to HEK293 cells, HEK293T cells, simian COS cells, Chinese hamster ovary (CHO) cells, and myeloma cells that do not otherwise produce immunoglobulin protein, to obtain the synthesis of monoclonal antibodies in the recombinant host cells. The DNA also can be modified, for example, by substituting the coding sequence for human heavy and light chain constant domains in place of the homologous murine sequences (U.S. Pat. No. 4,816,567) or by covalently joining to the immunoglobulin coding sequence all or part of the coding sequence for a non- immunoglobulin polypeptide. Antibody humanization

[0170] In some embodiments, anti-tau antibodies of the present disclosure may be prepared as humanized antibodies. “Humanized” antibodies are chimeric antibodies that contain minimal sequences (e.g., variable domains or CDRs) derived from non-human immunoglobulins (e.g., murine immunoglobulins). Humanized antibodies may be prepared from human (recipient) immunoglobulins in which residues from the hypervariable regions are replaced by hypervariable region residues from one or more non-human “donor” antibodies (e.g., mouse, rat, rabbit, or nonhuman primate). Donor antibodies may be selected based on desired specificity, affinity, and / or capacity. Humanized antibodies may include one or more back-mutation that includes the reversion of one or more amino acids back to amino acids found in a donor antibody. Conversely, residues from donor antibodies included in humanized antibodies may be mutated to match residues present in human recipient antibodies. Back-mutations may be introduced to reduce human immune response to the humanized antibodies. In some embodiments, back-mutations are introduced to avoid issues with antibody manufacturing (e.g., protein aggregation or post-translational modification).

[0171] For construction of expression plasmids encoding fully humanized antibodies with human constant regions, DNA sequences encoding antibody variable regions may be inserted into expression vectors (e.g., mammalian expression vectors) between an upstream promoter / enhancer and immunoglobulin signal sequence and a downstream immunoglobulin constant region gene. DNA samples may then be transfected into mammalian cells for antibody production. Constant domains from any class of human antibody may be used. There are five major classes of intact human antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgG1 (human and murine), IgG2 (human), IgG2a (murine), IgG2b (murine), IgG2¢ (murine), IgG3 (human and murine), IgG4 (human), IgA (murine), IgA1 (human), and IgA2 (human).

[0172] Cell lines with stable transfection of DNA encoding humanized antibodies may be prepared and used to establish stable cell lines. Cell lines producing humanized antibodies may be expanded for expression of humanized antibodies that may be harvested and purified from cell culture media.

[0173] In some embodiments, humanized antibodies of the present disclosure may have cross-reactivity with non-human species. Species cross-reactivity may allow antibodies to be used in different animals for various purposes. For example, cross-reactive antibodies may be used in pre-clinical animal studies to provide information about antibody efficacy and / or toxicity. Non-human species may include, but are not limited to, mouse, rat, rabbit, dog, pig, goat, sheep, and nonhuman primates (e.g., Cynomolgus monkeys). Antibody conjugates

[0174] In some embodiments, antibodies of the present disclosure may be or be prepared as antibody conjugates. As used herein, the term “conjugate” refers to any agent, cargo, or chemical moiety that is attached to a recipient entity or the process of attaching such an agent, cargo, or chemical moiety. As used herein, the term “antibody conjugate” refers to any antibody with an attached agent, cargo, or chemical moiety. Conjugates utilized to prepare antibody conjugates may include therapeutic agents. Such therapeutic agents may include drugs. Antibody conjugates that include a conjugated drug are referred to herein as “antibody drug conjugates.” Antibody drug conjugates may be used to direct conjugated drugs to specific targets based on the affinity of associated antibodies for proteins or epitopes associated with such targets. Such antibody drug conjugates may be used to localize biological activity associated with such conjugated drugs to targeted cells, tissues, organs, or other targeted entities. In some embodiments, conjugates utilized to prepare antibody conjugates include detectable labels. Antibodies may be conjugated with detectable labels for purposes of detection. Such detectable labels may include, but are not limited to, radioisotopes, fluorophores, chromophores, chemiluminescent compounds, enzymes, enzyme co-factors, dyes, metal ions, ligands, biotin, avidin, streptavidin, haptens, quantum dots, or any other detectable labels known in the art or described herein.

[0175] Conjugates may be attached to antibodies directly or via a linker. Direct attachment may be by covalent bonding or by non-covalent association (e.g., ionic bonds, hydrostatic bonds, hydrophobic bonds, hydrogen bonds, hybridization, ezc.). Linkers used for conjugate attachment may include any chemical structure capable of connecting an antibody to a conjugate. In some embodiments, linkers include polymeric molecules (e.g., nucleic acids, polypeptides, polyethylene glycols, carbohydrates, lipids, or combinations thereof). Antibody conjugate linkers may be cleavable (e.g., through contact with an enzyme, change in pH, or change in temperature). Exemplary anti-tau antibodies

[0176] 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., antibody chosen from V0001-V0065, V1001-V1005, or V2001- V2005, e.g., 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 aforesaid sequences.

[0177] In some embodiments, the anti-tau antibody comprises a heavy chain variable region from an antibody described herein, e.g., chosen 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 aforesaid 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), but not more than 30, 20, or 10 modifications (e.g., substitutions, e.g., conservative substitutions) of an amino acid sequence of a heavy chain variable region provided in Table 3, 6, or 4.

[0178] 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., chosen from V0001-V0065, V1001-V1005, or V2001-V2005, e.g., as described in Table 3 or 4, 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 aforesaid sequences.

[0179] In some embodiments, the anti-tau antibody comprises a light chain variable region from an antibody described herein, e.g., chosen 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 aforesaid sequences. In some embodiments, the light chain variable region comprises an amino acid sequence having at least one, two, or three modifications (e.g., substitutions, e.g., conservative substitutions), but not more than 30, 20, or 10 modifications (e.g., substitutions, e.g., conservative substitutions) of an amino acid sequence of a light chain variable region provided in Table 3, 6, or 4.

[0180] 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., chosen from V0001-V0065, V1001-V1005, or V2001-V2005, e.g., as described in Table 3 or 4, 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 aforesaid sequences.

[0181] 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., chosen 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 aforesaid sequences. In some embodiments, the 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), but not more than 30, 20, or 10 modifications (e.g., substitutions, e.g., conservative substitutions) of an amino acid sequence of a heavy chain variable region provided in Table 3, 6, or 4; 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), but not more than 30, 20, or 10 modifications (e.g., substitutions, e.g., conservative substitutions) of an amino acid sequence of a light chain variable region provided in Table 3, 6, or 4.

[0182] In some embodiments, the anti-tau antibody comprises a heavy chain constant region, e.g., a human IgG1, IgG2, IgG3, or IgG4 constant regions, or a murine IgG1, IgG2A, IgG2B, IgG2C, or IgG3 constant regions. 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 aforesaid sequences. In some embodiments, a 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 aforesaid sequences.

[0183] 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 murine 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 aforesaid sequences. In some embodiments, 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 aforesaid sequences.

[0184] 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 (e.g., having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto. In some embodiments, the nucleotide sequence encoding the anti-tau antibody comprises the nucleotide sequence of a heavy chain constant region and the nucleotide sequence of a kappa or lambda light chain constant region. In some embodiments, the nucleotide sequence encoding the heavy chain constant region and light chain constant region comprise a nucleotide sequence set forth in Table X, or a nucleotide sequence substantially identical (e.g., having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto.

[0185] In some embodiments, the anti-tau antibody comprises a heavy chain variable region and a constant region, a light chain variable region and a constant region, or both, comprising an amino acid sequence of Table 3, 6, or 4 for variable region, and an amino acid sequence of Table X for constant region; or is 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 aforesaid sequences.

[0186] In some embodiments, the anti-tau antibody comprises at least one, two, three, or four framework regions from a heavy chain variable region of an antibody described herein, e.g., chosen from V0001-V0065, V1001-V1005, or V2001-V2005, e.g., 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 aforesaid 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 shown in Table 7 or 4. In some embodiments, the anti-tau antibody includes a substitution in a heavy chain framework region, e.g., one or more substitutions in a FRH1, FRH2, FRH3, and / or FRH4 of the heavy chain.

[0187] In some embodiments, the anti-tau antibody comprises at least one, two, three, or four framework regions from a light chain variable region of an antibody described herein, e.g., chosen from V0001-V0065, V1001-V1005, or V2001-V2005, e.g., 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 aforesaid 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 shown in Table 7 or 4. In some embodiments, the anti-tau antibody includes a substitution in a light chain framework region, e.g., one or more substitutions in a FRL1, FRL2, FRL3, and / or FRL4 of the light chain.

[0188] 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 in Table 2A-2C, 3, 6, 4, or 5, or is encoded by a nucleic acid sequence in Table 4; or a sequence substantially identical (e.g., having at least about 70%, 15%, 80%, 85%, 90%, 92%, 95%, 971%, 98%, or 99% sequence identity) to any of the aforesaid 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 shown in Table 2A-2C, 6, 4, or 5, or encoded by a nucleotide sequence shown in Table 4. In some embodiments, the encoded anti-tau antibody includes a substitution in a heavy chain CDR, e.g., one or more substitutions in a CDR1, CDR2 and / or CDR3 of the heavy chain.

[0189] 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 in Table 2A-2C, 6, 4, or 5, or is encoded by a nucleic acid sequence in 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 aforesaid 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 shown in Table 2A-2C, 6, 4, or 5, or encoded by a nucleotide sequence shown in Table 4. In some embodiments, the anti-tau antibody includes a substitution in a light chain CDR, e.g., one or more substitutions in a CDR1, CDR2 and / or CDR3 of the light chain.

[0190] 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 a heavy and light chain variable region comprising an amino acid sequence shown in Table 2A-2C, 6, 4, or 5, or is encoded by a nucleotide sequence 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 changes, e.g., amino acid substitutions, insertions, or deletions, relative to the CDRs shown in Table 2A- 2C, 6, 4, or 5, or encoded by a nucleotide sequence shown in Table 4.

[0191] In some embodiments, the anti-tau antibody comprises all three CDRs from a heavy chain variable region, all three CDRs from light chain variable region, or both (e.g., all six CDRs from a heavy chain variable region and a light chain variable region) comprising an amino acid sequence shown in Table 2A-2C, 6, 4, or 5, or is encoded by a nucleotide sequence shown in Table 4.

[0192] In some embodiments, an anti-tau antibody of the present disclosure may include CDRs identified through CDR analysis of variable domain sequences presented herein via co- crystallography with bound antigen; by computational assessments based on comparisons with other antibodies (e.g., see Strohl, W.R. Therapeutic Antibody Engineering. Woodhead Publishing, Philadelphia PA. 2012. Ch. 3, p47-54); or Kabat, Chothia, Al-Lazikani, Lefranc, or Honegger numbering schemes, as described previously. Table 2A: CDR sequences of selected antibodies based on Kabat numbering system V000S | DYYMS (SEQ ID NO: 1142) RIDPNSGGTR | DEDV YNEKFKN _ ) | (sEQ ID NO: 395) No: 1141) LIRNKAKGET |DINY TEYSASVKG | oo op ) | (sEQ 1D NO: 400) NO: 1143) V0022 | RYWMH (SEQ ID NO: 1144) V0023 | IFWMH (SEQ ID NO: 1147) Ab ID HC CDR1 HC CDR2 HC CDR3 LC CDR1 LC CDR2 LC CDR3 v0004 NYWMH RIDPNSGGTR DFDV RASGNIHN NAKTLPD QHFWSTPLT (SEQ ID INTHERI {SEQ ID uw (SEQ ID (SEQ ID NO: 1140) | (SEQ ID NO: 395) | (SEQ ID |NO: 518) |NO: 557) NO: 1141) NO: 460) v0009 DYYMS LIRNKAKGEFT DINY KSSQSLLY WASSRES QQYYSYPRT (smo 1p | TEYSRSVKG | (gpg 1p | STNOENYL | (gpg 1p (SEQ ID NO: 1142) (SEQ ID NO: 400) NO: 523) NO: 562) NO: 1143) (sEQ ID NO: 464) vo022 RYWMH NINPNNGGTD GTGTGAMD RSSQSLVH RVSNRFS FQGTHVPRT (seg 1p | FNEKFEN ¥ NNGITYLY | (spo 10 (SEQ ID NO: 1144) (SEQ ID {SEQ ID {SEQ ID NO: 529) NO: 571) NO: 1145) NO: 410) NO: 1146) v0023 IFWMH KINPNNGGGD GTGTGAMD RSSQSLVH RVSNRFS FQGTHVPRT (smQ 1p | YNEKFKS ¥ SNGITHLY | (srg 1p (SEQ ID NO: 1147) | (SEQ ID (SEQ ID (SEQ ID |NO: 529) |No: 571) NO: 1148) NO: 410) NO: 474) v0024 RFWMH NINPNNGGTD GTGTGAMD RSSQSLVH RVSSRFS FQGTHVPRT (SEQ ID NNERFKS Y SNGNTHLY (SEQ ID (SEQ ID NO: 1149) | (SEQ ID (SEQ ID (SEQ ID |NO: 530) |NO: 571) NO: 1150) NO: 410) |NO: 475) V0052 TSAMGVS HIYWDDDKRY RRRGYGMD KASQSVSN YASNRCT QODYRSPLT (SEQ ID FPFIRS ¥ ova (SEQ ID (SEQ ID NO: 1152) (SEQ ID {SEQ ID (SEQ ID NO: 540) NO: 587) NO: 1153) NO: 435) |NO: 495) Table 2B: CDR sequences of selected antibodies based on Chothia numbering system Ab ID | HC CDRL HC CDR2 HC CDR3 | LC CDRL LC CDR2 LC CDR3 v0004 DYTFTNY DPNSGG DFDV RASGNIHN NAKTLPD QHFWSTPLT (SEQ ID (SEQ ID (SEQ ID YLA (SEQ ID (SEQ ID NO: 299) | NO: 343) NO: 395) | (SEQ ID |NO: 518) |NO: 557) Ae Tele DEDV (SEQ ID NO: 395) Vv0009 GFTFIDY RNKAKGFT DINY i (SEQ ID (SEQ ID (SEQ ID NO: 304) NO: 347) NO: 400) v0022 GFTFTRY NPNNGG (SEQ ID (SEQ ID NO: 314) | NO: 341) v0023 GYTFTIF NPNNGG (SEQ ID (SEQ ID No: 315) | NO: 341) v0024 GYTFTRF NPNNGG (SEQ ID (SEQ ID NO: 316) NO: 341) QHFWSTPLT (SEQ ID 3) | NO: 557) QQYYSYPRT Ab ID | HC CDRL HC CDR2 HC CDR3 | LC CDR1 | LC CDR2 LC CDR3 V0004 | DYTFTNY DPNSGG DEDV RASGNIHN | NAKTLPD QHFWSTPLT (SEQ ID (SEQ ID (seg 10 | MA (SEQ ID (SEQ ID NO: 299) | NO: 343) NO: 395) | (SEQ ID |NO: 518) |NO: 557) NO: 460) V0009 | GFTFTIDY RNKAKGET DINY KSSQSLLY | WASSRES QQYYSYPRT (SEQ ID (SEQ ID smo 10 [TOPE | (gpg 1p | (sme 10 NO: 304) |NO: 347) NO: 400) No: 523) |[No: 562) (SEQ ID NO: 464) V0022 | GFTFTRY NPNNGG GIGIGAMD | RSSQSLVE | RVSNRES FQGTHVPRT (SEQ ID (SEQ ID ¥ NNGTTYLY | (smo 1p | (sEQ 1D NO: 314) | NO: 341) (SEQ ID (SEQ ID | NO: 529) |No: 571) NO: 410) | NO: 1154) V0023 | GYTFTIF NPNNGG GIGIGAMD | RSSQSLVE | RVSNRES FQGTHVPRT (SEQ ID (SEQ ID ¥ SNGTTHLY | (smo 1p | (sEQ 1D NO: 315) | NO: 341) (SEQ ID (SEQ ID |NO: 529) |NO: 571) NO: 410) | NO: 474) V0024 | GYTFTRE NPNNGG GIGIGAMD | RSSQSLVH | RVSSRES FQGTHVPRT (SEQ ID (SEQ ID ¥ SNGNTHLY | spo 1p (SEQ ID NO: 316) | NO: 341) (SEQ ID (SEQ ID |NO: 530) |NO: 571) NO: 410) | NO: 475) V0052 | GFSLSTSAM | YWDDD RRRGYGMD | KASQSVSN | YASNRCT QQDYRSPLT (SEQ ID (SEQ ID ¥ vA (sEQ 10 | (sEQ ID NO: 325) |NO: 362) (SEQ ID (SEQ ID |NO: 540) |NO: 587) NO: 435) | NO: 495) Table 2C: CDR sequences of selected antibodies based on IMGT numbering system Ab ID | HC CDRL HC CDR2 HC CDR3 LC CDR1 | LC CDR2 LC CDR3 V0004 | DYTFTNYW | IDENSGGT AGDFDV GNIHNY NAK QHFWSTPLT (SEQ ID (SEQ ID (SEQ ID (SEQ ID (SEQ ID (SEQ ID NO: 1155) |NO: 1156) |NO: 1157) |NO: NO: 1159) [No: 557) 1158) V0009 | GFTFTDYY | IRNKAKGFTT | VRDINY QSLLYSTN | WAS QQYYSYPRT QENY FQGTHVPRT (SEQ ID ) NO: 571) FQGTHVPRT (SEQ ID ) NO: 571) (SEQ ID (SEQ ID (SEQ ID {SEQ ID (SEQ ID (SEQ ID NO: 1160) NO: 1161) NO: 1162) NO: NC: 1164) NO: 562) 1163) v0022 GFTFTRYW INPNNGGT ARGTGTGAM | QSLVHNNG RVS FQGTHVPRT (SEQ ID (SEQ ID Bx Laid (SEQ ID (SEQ ID NO: 1165) NC: 1166) (SEQ ID (SEQ ID NO: 528 ) NO: 571) NC: 1167) NO: 473) v0023 GYTFTIFW INPNNGGG ARGIGIGAM | QSLVHSNG RVS FQGTHVPRT (SEQ ID (SEQ ID p¥ ITH (sEQ ID (SEQ ID NO: 1168) NO: 1169) (SEQ ID (SEQ ID NO: 528 ) NO: 571) NO: 1167) NO: 1170) v0024 GYTFTRFW INPNNGGT ARGIGIGAM | QSLVHSNG RVS FQGTHVPRT (SEQ ID (SEQ ID p¥ NTH (sEQ ID (SEQ ID NO: 1171) |NO: 1166) | (SEQ ID (SEQ ID | NO: 528 ) |No: 571) NO: 1167) NO: 1172} v0052 GFSLSTSAM IYWDDDK ARRRRGYGM | QSVSND YAS QQDYRSPLT é (SEQ ID p¥ (SEQ ID | (SEQ ID (SEQ ID (SEQ ID NO: 1174) (SEQ ID NO: NO: 1177) NO: 587) NO: 1173) NO: 1175) | 1176) v0052 | GFSLSTSAM | IYWDDDK ARRRRGYGM | QSVSND YAS QQDYRSPLT é (SEQ ID p¥ (SEQ ID (SEQ ID (SEQ ID (SEQ ID NO: 1174) (SEQ ID NO: No: 1177) |No: 587) NO: 1173) NO: 1175) | 1176) Table 3. Amino acid and nucleotide sequences of the heavy and light chain variable regions of exemplary anti-Tau antibodies ID# |VH SEQ ID NO|VH SEQ ID NO| VL SEQ ID NO| VL SEQ ID NO aminoacid ' nucleotide ' aminoacid ' nucleotide 147 75 21 2 148 76 333 3 149 77 223 4 150 78 224 5 151 79 225 6 152 R00 226 7 153 R1 237 8 154 82 228 9 155 R]3 229 10 156 R84 230 11 157 85 231 12 158 86 232 13 159 R7 233 14 160 R7 234 15 161 88 235 16 162 8]8 236 17 163 R]90 237 18 164 90 238 19 165 91 239 s = — s —_— V0001 : 147 75 21 0002 a T8 “6 ag V0003 EE 149 77 223 0004 4 “150 8 Th 0003 5 “Isr 9 5 V0006 “6 152 80 226 V0007 7 “153 rT “27 V0008 8 “154 8 28 0009 To 155 83 229 10 “156 “Rd “230 1 157 8 “231 12 “158 “86 232 13 159 T&T “233 “1a “160 87 “23 15 Tier 8 “235 “16 “162 “88 “236 17 “163 8 “237 18 Ties To “238 V0020 19 165 Tor 239 V0021 20 166 To “240 65 211 135 284 66 212 136 285 67 213 137 286 68 214 138 287 69 215 139 288 69 215 140 289 69 215 141 200 70 216 142 201 71 217 143 292 72 218 144 203 73 219 145 204 74 220 146 205 Table 4. Exemplary anti-tau antibodies Ae 343 HC CDR2 DPNSGG Ae 395 HC CDR3 DEDV dle 1140 HC CDR1 NYWMH ARC 1141 HC CDR2 RIDPNSGGTRYNEKFKN ARC 395 HC CDR3 DFDV ARC 1155 HC CDR1 DYTFINYW —t ri 1156 HC CDR2 IDPNSGGT 7 1157 HC CDR3 AGDFDV 604 QVQLOQPGAELVKPGASVKLSCKAS 647 700 770 i 150 DNA VH SEQ Description Sequence ID NO 299 HC CDR1 DYTIFINY (Chothia) 343 HC CDR2 DENSGG (Chothia) 395 HC CDR3 DEFDV (Chothia 1140 HC CDR1 NYWMH (Kabat) 1141 HC CDR2 RIDPNSGGTRYNEKFKN (Kabat) 395 HC CDR3 DEDV (Kabat 1155 HC CDR1 DYTFINYW (IMGT; 1156 HC CDR2 IDPNSGGT (IMGT) 1157 HC CDR3 AGDFDV (IMGT) 604 FR H1 QVQLQOPGAELVKPGASVKLSCKAS (corresponding to the Chothia CDR definition) 647 FR H2 WMHWVKQRPGRGLEWIGRI (corresponding to the Chothia CDR definition) 700 FR H3 TRYNEKFKNKATLTVDKPSSTAYMHLSSLTSEDSAVYYCAG (corresponding to the Chothia CDR definition’ 770 FR H4 WGIGITVIVSS (corresponding to the ___| Chothia CDR definition 4 VH QVQLQQPGAELVKPGASVKLSCKASDY TF TNYWMHWVKQRPGR GLEWIGRIDPNSGGTRYNEKFKNKATLTVDKPSSTAYMHLSSL TSEDSAVYYCAGDFDVWGTGTTVTIVSS 150 DNA VH CAGGTCCAACTGCAGCAGCCTIGGGGCTGAGCTIGTGAAGCCTG GGGCTTCAGTGAAGCTGTCCTGCAAGGCTICTGACTACACCTT CACCAACTACTGGATGCACTGGGTGAAGCAGAGGCCTGGACGA GGCCTTIGAGTGGATAGGAAGGATTIGATCCTAATAGTGGTGGTA CTAGGTACAATGAGAAGTTCAAGAACAAGGCCACACTGACTGT TGACAAACCCTCCAGCACAGCCTACATGCATCTCAGCAGCCTG ACATCTGAGGACTCTGCGGTCTATTATTGTGCAGGGGACTTCG ATGTCTGGGGCACAGGGACCACGGTCACCGTCTCCTCA RASGNIHNYLA NAKTLPD QHFWSTPLT RASGNIHNYLA NAKTLPD QHFWSTPLT GNIHNY NAK QHFWSTPLT DIQMTQSPASLSASVGETVTITC DNA VL RNKAKGFT DINY DYYMS LIRNKAKGFTTEYSASVKG DINY GFIFIDYY IRNKAKGFTT DNA VH (IMGT HC CDR3 VRDINY (IMGT FR H1 (corresponding to the Chothia CDR definition) | EVQLVESGGALVQPGGSLSLSCAAS FR H2 (corresponding to the Chothia CDR definition) | YMSWVRQPPGKALEWLALI FR H3 (corresponding to the Chothia CDR definition) | TEYSASVKGRFTISRDNSQSILLFQMNDLRADDSATYYCVR FR H4 (corresponding to the Chothia CDR definition) | WGQGITLTVSS VH EVQLVESGGALVQPGGSLSLSCAASGFTFTDYYMSWVRQPPGK ALEWLALIRNKAKGFTTEYSASVKGRFTISRDNSQSILLFQMN DLRADDSATYYCVRDINYWGQGTILTIVSS DNA VH GAGGTGCAGCTGGTGGAGTCTGGAGGAGCCTTGGTACAGCCTG GGGGTICICTGAGTICICTCCTGTGCAGCTICTGGATTCACCTT CACTGATTACTACATGAGCIGGGICCGCCAGCCTCCAGGGAAG GCACTTGAGTGGCTGGCTTTGATTAGAAACAAAGCTAAAGGTT TCACARCAGAATACAGTGCATCTGTGARGGGTCGGTTCACCAT CTCCAGAGATAATTCCCAAAGCATCCTCCTTTTTCAAATGAAT GACCTGAGAGCTIGACGACAGTGCCACTTATTACTGTGTAAGAG ATATARACTACTGGGGCCAAGGCACCACTCTCACAGTCTCCTIC A J Ct WASSRES QQYYSYPRT KSSQSLLYSTNQENYLA WASSRES QOYYSYPRT QSLLYSTINQENY WAS QQYYSYPRT LC CDR1 (Chothia) KSSQSLLYSTNQENYLA LC CDR2 (Chothia) WASSRES LC CDR3 (Chothia) QQYYSYPRT LC CDRI KSSQSLLYSTNQENYLA (Kabat) LC CDR2 WASSRES (Kabat) LC CDR3 QQYYSYPRT (Kabat) LC CDRI QSLLYSINQENY (IMGT, LC CDR2 WAS (IMGT; LC CDR3 QQYYSYPRT (IMGT; FRLI1 (corresponding to the Chothia CDR definition DIVMSQSPSSLAVSVGEKVTIMSC FR L2 (corresponding to the Chothia CDR definition) | WYQQKPGQSPKLLIY FR L3 (corresponding to the Chothia CDR definition) | GVPDRFTGSGSGTDFTLTISSVKAEDLAVYYC FR L4 (corresponding to the Chothia CDR definition) | FGGGTKLEIK 83 VL DIVMSQSPSSLAVSVGEKVIMSCKSSQSLLYSTNQENYLAWYQ QKPGQSPKLLIYWASSRESGVPDRFTGSGSGTDFTLTISSVKA EDLAVYYCQQYYSYPRTFGGGTKLEIK 229 DNA VL GACATTGTGATGICACAGTCTCCATCCTCCCTAGCTGTGTCAG TTGGAGAGAAGGTTACTATGAGCTGCAAGTCCAGTCAGAGCCT TITATATAGTACCAATCAAGAGAACTACTTGGCCTGGTACCAG CAGAAACCAGGGCAGTCTCCTAAACTGCTGATTTACTGGGCAT CCTCTAGGGAATCTGGGGTCCCTGATCGCTTTACAGGCAGTGG ATCIGGGACAGATITCACTCTCACCATCAGCAGTIGIGAAGGCT GAAGACCTGGCAGTTTATTACTGTCAGCAATATTATAGCTATC CTCGGACGTTCGGTGGAGGCACCAAGCTGGAAATCAAA —_— GETFIRY NPNNGG GTGTGAMDY RYWMH NINPNNGGIDFNEKFKN GTGTGAMDY GETEIRYW INPNNGGT ARGTGTGAMDY 167 DNA VH RSSQSLVHNNGITYLY RVSNRF'S LC CDRI 1154 (Chothia) LC CDR2 529 (Chothia; LC CDR3 571 (Chothia] FQGTHVPRT RVSNRF'S FQGTHVPRT QSLVHNNGITY RVS FQGTHVPRT LC CDRI 1146 (Kabat RSSQSLVHNNGITYLY LC CDR2 529 (Kabat RVSNRF'S LC CDR3 571 (Kabat) FQGTHVPRT LC CDRI 473 (IMGT) QSLVHNNGITY LC CDR2 528 (IMGT) RVS LC CDR3 571 (IMGT) FQGTHVPRT FRLI1 (corresponding to the Chothia CDR definition) 1178 DVVMIQIPLSLPVSLGDQASISC NPNNGG GTGTGAMDY IFWMH KINPNNGGGDYNEKFKS GTGTGAMDY GYTFTIFW INPNNGGG ARGTGTGAMDY | Lhothia LUK definition) 1178 DVVMIQIPLSLPVSLGDQASISC FR L2 (corresponding to the 831 Chothia CDR definition) | WYLOKPGQSPKLLIY FRL3 (corresponding to the 1179 Chothia CDR definition; GVPDREGGSGSGIDFTLKISRVEAEDLGVYFC FRL4 (corresponding to the 906 Chothia CDR definition) | FGGGTKLEIK 93 VL DVVMIQTPLSLPVSLGDQASISCRSSQSLVHNNGITYLYWYLQ KPGQSPKLLIYRVSNRESGVPDRFGGSGSGTDFTLKISRVEAE DLGVYFCFQGTHVPRTFGGGTKLEIK 241 DNA VL GATGTTGTGATGACCCAAACTCCACTCTCCCTGCCTGTCAGTC TIGGAGATCAAGCTTCCATCTCTIGCAGATCTAGTCAGAGCCT TGTACACAACAATGGAATCACCTATTTATATTGGTACCTGCAG AAGCCAGGCCAGTCTCCAAAGCTCCTGATCTACAGGGTTICCA ACCGATTTTCTGGGGTCCCAGACAGGTTCGGTGGCAGTGGATC AGGGACAGATTTCACACTCAAGATCAGCAGAGTGGAGGCTGAG GATCTGGGAGTITATITCTGCTTICAAGGTACACATGTITCCIC GGACGTTCGGTGGAGGCACCAAGCTGGAAATCAAA V0023 HC CDR1 315 (Chothia’ GYIFTIF HC CDR2 341 (Chothia’ NPNNGG HC CDR3 410 (Chothia) GTGTGAMDY HC CDR1 1147 (Kabat) IFWMH HC CDR2 1148 (Kabat) KINPNNGGGDYNEKFKS HC CDR3 410 (Kabat) GTGTGAMDY HC CDR1 1168 (IMGT) GYTETIFW HC CDR2 1169 (IMGT) INPNNGGG HC CDR3 1167 (IMGT; ARGTGTGAMDY FR H1 (corresponding to the 603 Chothia CDR definition QVQLOQPGTELVKPGASVKLSCKAS FR H2 WMHWVKQRPGHGLEWIGKI (corresponding to the Chothia CDR definition FR H3 (corresponding to the Chothia CDR definition) | GDYNEKFKSKATLTVDKSSTTAYLQLSSLTSEDSAVYYCAR FR H4 (corresponding to the Chothia CDR definition) | WGQGTSVTVSS VH QVOLQQPGTELVKPGASVKLSCKASGYTFTIFWMHWVKQRPGH GLEWIGKINPNNGGGDYNEKFKSKATLTVDKSSTTAYLQLSSL TSEDSAVYYCARGTGTGAMDYWGQGTSVIVSS DNA VH CAGGTCCAACTGCAGCAGCCTIGGGACTGAACTGGTGAAGCCTG GGGCTTCAGTGAAGCTGTCCTGCAAGGCTTCTGGCTACACCTT CACCATCITCTGGATGCACTIGGGTGAAGCAGAGGCCTGGACAT GGCCTTGAGTGGATTGGAAAGATTAATCCTAACAATGGAGGTG GIGACTACAATGAGARATTCAAGAGTARGGCCACATTGACTGT AGACARATCCTCCACCACAGCCTACTTGCAGCTCAGCAGCCTG ACATCTGAGGACTCTGCGGTCTATTATTGTGCAAGAGGAACTG GGACGGGAGCTATGGACTACTGGGGTCAAGGARCCTCAGTCAC CGTCTCCICA Er — RSSQSLVHSNGITHLY RVSNRFS FOQGTHVPRT RSSQSLVHSNGITHLY RVSNRFS FOQGTHVPRT QSLVHSNGITH RVS FQGTHVPRT DNA VL GATCTGGGAGTITATITCTGCTTTCAAGGTACACATGTTCCIC GGACGTTCGGTGGAGGCACCAAGCTGGARATCGAA GYTFTRF NPNNGG GTGTGAMDY REWMH NINPNNGGTDNNERFKS GTGTGAMDY GYTFTRFW INPNNGGT ARGTGTGAMDY DNA VH RSSQSLVHSNGNTHLY RVSSRES FQGTHVPRT RSSQSLVHSNGNTHLY RVSSRES FQGTHVPRT QSLVHSNGNTH RVS 243 DNA VL (IMGT: LC CDR3 571 (IMGT FQGTHVPRT FRLI1 (corresponding to the 787 Chothia CDR definition) | DVVMTQTPLSLPVSLGDQASISC FR L2 (corresponding to the 831 Chothia CDR definition) | WYLOKPGQSPKLLIY FRL3 (corresponding to the 870 Chothia CDR definition) | GVPDRFSGSGSGTDFTLKISRVEAEDLGVYFC FRL4 (corresponding to the 906 Chothia CDR definition) | FGGGTKLEIK 95 VL DVVMIQTPLSLPVSLGDQASISCRSSQSLVHSNGNTHLYWYLQ KPGQSPKLLIYRVSSRFSGVPDRFSGSGSGTDFTLKISRVEAE DLGVYFCFQGTHVPRIFGGGTKLEIK 243 DNA VL GATGTGGTGATGACCCARACTCCACTCTCCCTGCCTGTCAGTIC TIGGAGATCAGGCTTCCATCTCTIGCAGATCTAGTCAGAGCCT TGTACACAGCAATGGAAACACCCATTITATATIGGTACCTGCAG AAGCCAGGCCAGTCTCCARAGCTCCTGATCTACAGGGTTICCA GCCGATTITCTGGGGTICCCAGACAGGTICAGTGGCAGTGGATC AGGGACAGATTTCACACTCAAGATCAGCAGAGTGGAGGCTGAG GATCTGGGAGTITATITCTGCTTICAGGGTACACATGTITCCIC GGACGTTCGGTGGAGGCACCAAGCTGGARATCARA J Ct YWDDD RRRGYGMDY TSAMGVS HIYWDDDKRYNPSLKS RRRGYGMDY GFSLSTSAMG IYWDDDK ARRRRGYGMDY I TT TAT TA AT rs TR V0052 HC CDR1 325 (Chothia) GESLSTSAM HC CDR2 362 (Chothia) YWDDD HC CDR3 435 (Chothia) RRRGYGMDY HC CDR1 1152 (Kabat TSAMGVS HC CDR2 1153 (Kabat HIYWDDDKRYNPSLKS HC CDR3 435 (Kabat RRRGYGMDY HC CDR1 1173 (IMGT GFSLSTSAMG HC CDR2 1174 (IMGT IYWDDDK HC CDR3 1175 (IMGT) ARRRRGYGMDY FR H1 (corresponding to the 633 Chothia CDR definition) | QITLKESGPGILQSSQTLSLTCSFS FR H2 (corresponding to the 682 Chothia CDR definition) | GVSWIRQPSGEGLEWLAHI FR H3 (corresponding to the 745 Chothia CDR definition; KRYNPSLKSRLTISKDTSRNQVFLKITSVDTADTATYYCAR FR H4 (corresponding to the 771 Chothia CDR definition) | WGQGTISVIVSS 51 VH QITLKESGPGILQSSQTLSLTCSFSGFSLSTSAMGVSWIRQPS GEGLEWLAHIYWDDDKRYNPSLKSRLTISKDTSRNQVFLKITS VDTADTATYYCARRRRGYGMDYWGQGTSVIVSS 197 DNA VH CAGATTACTCTGAARGAGTCTGGCCCTGGGATATTGCAGTCCT CCCAGACCCTCAGICTGACTTGTTCTTICTCTGGGTTTTCACT GAGCACTTCTGCTATGGGTGTGAGTTGGATTCGTCAGCCTTCA GGAGAGGGTCTGGAGTGGCTGGCACACATTTACTGGGATGATG ACAAGCGCTATAACCCATCCCTGAAGAGCCGGCTCACAATCTC CAAGGATACCTCCAGAAACCAGGTATTCCTCAAGATCACCAGT GIGGACACTGCAGATACTGCCACATACTACTGTGCTCGAAGAA GGAGGGGGTATGGTATGGACTACTGGGGTCAAGGAACCTCAGT CACCGTICTICCTCA re oo KASQSVSNDVA YASNRCT QODYRSPLT KASQSVSNDVA YASNRCT QQDYRSPLT QSVSND YAS QQDYRSPLT 270 DNA VL Table 6. Exemplary heavy and light chain CDR amino acid sequences of anti-tau antibodies ID# | CDRH1 SEQ | CDRH2 SEQ | CDRH3 SEQ | CDRL1 SEQ | CDRL2 SEQ | CDRL3 SEQ ID NO ID NO ID NO ID NO ID NO ID NO V0001 296 340] 392] 457 515 554 'V0002 297 341 393 458 516 555 Table 7. Exemplary FR amino acid sequences of anti-tau antibodies FRHI _ FRH2 | FRH3 , FRH4 | FRL1 ,_ FRL2 | FRL3 | FRL4 SEQ ID | sEQ ID | SEQID | SEQID | SEQ ID | SEQ ID | SEQ ID SEQ ID NO NO NO NO NO NO NO NO 601 644 697 767 776 823 858 905 602 645 698 768 777 823 859 906 603 646 699 769 778 824 860 907 604 647 700 770 770. 825 861 908 605 648 701 768 780 826 862 908 606 649 702 768 781 827 863 906 607 650 703 771 782 828 864 908 606 651 704 771 777 829 865 909 608 652 705 767 783 830 866 906 631 673 745 771 808 R33 871 906 631 673 T48 771 809 R33 871 906 631 673 749 771 808 R33 871 906 631 673 730 771 808 R33 871 906 609 653 750 767 780 R47 889 906 609 653 751 767 810 R47 889 906 634 684 7152 767 811 R48 890 906 610 685 753 770 792 R49 891 906 635 686 754 767 812 R50 892 906 604 687 755 771 792 R51 893 908 626 688 7156 T68 813 R52 894 906 636 689 757 768 814 R53 8905 917 637 690 758 771 815 R54 806 906 638 691 759 774 816 R53 897 908 636 689 760 768 817 R53 808 908 639 692 761 771 818 R55 899 908 639 692 761 771 819 R55 899 908 639 692 761 771 819 R56 900 908 640 679 762 771 794 R31 R68 906 640 693 763 771 820 R31 901 906 641 694 764 768 821 R309 902 906 642 695 765 767 797 R57 903 918 643 696 766 775 822 R30 904 919 Table X. Constant Regions of Heavy Chains and Light Chains SEQ Description | Sequence 1189 1190 1191 SEQ Description | Sequence ID NO 1189 Constant AKTTPPSVYPLAPGSAAQTINSMVTLGCLVKGYFPEPVTVIWNSGSLSSGVHTFPAVLQ Region of SDLYTLSSSVTVPSSPRPSETVTCNVAHPASSTKVDKKIVPRDCGCKPCICTVPEVSS Heavy VEIFPPKPKDVLTITLTPKVICVVVDISKDDPEVQF SWEVDDVEVHTAQTQPREEQFN Chain, STFRSVSELP IMHQDWLNGKEFKCRVNSAAFPAPTEKTISKTKGRPKAPQVYTIPPPK secreted EQMAKDKVSLTCMITDEFPEDITVEWQWNGQPAENYKNTQP IMNTNGSYFVYSKLNVQ form & KSNWEAGNTFTCSVLHEGLHNHHTEKSLSHSPGK membrane- 1190 bound form AKTTPPSVYPLAPGSARQINSMVILGCLVKGYFPEPVIVIWNSGSLSSGVHTFPAVLO (mIgGl) SDLYTLSSSVTVPSSPRPSETVTCNVAHPASSTKVDKKIVPRDCGCKPCICTVPEVSS VEFIFPPKPKDVLTITLTPKVICVVVDISKDDPEVQF SWEVDDVEVHTAQTQPREEQFN STFRSVSELP IMHQDWLNGKEFKCRVNSAAFPAPIEKTISKTKGRPKAPQVYTIPPPK EQMAKDKVSLTCMITDFFPEDITVEWQWNGQPAENYKNTQP IMNTNGSYFVYSKLNVQ KSNWEAGNTFTCSVLHEGLHNHHTEKSLSHSPGLQLDETCAEAQDGELDGLWTITITIF ISLFLLSVCYSAAVTLFKVKWIFSSVVELKQTLVPEYKNMIGQAP 1191 Constant AKTTAPSVYPLAPVCGDTIGSSVILGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLO Region of SDLYTLSSSVIVISSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPCPPCKCPAPN murine LLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQT Heavy HREDYNSTLRVVSALP IQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVY Chain, VLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMY (mIgG2A) SKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSF SRTPGK 1192 DNA GCTAAAACAACAGCCCCATCGGICTATCCACTGGCCCCTGTGTGTGGAGATACAACTG Constant GCTCCTCGGTGACTCTAGGATGCCTGGTCAAGGGTTATTTCCCTGAGCCAGTGACCTT Region of GACCTGGAACTCTGGATCCCTGTCCAGIGGTGTGCACACCTTICCCAGCTGTCCTGCAG Heav TCTGACCTCTACACCCTCAGCAGCTCAGTGACTGTAACCTCGAGCACCTGGCCCAGCT Chain AGTCCATCACCTGCAATGTGGCCCACCCGGCAAGCAGCACCAAGGTGGACARGAARAT (mIgG2A) TGAGCCCAGAGGGCCCACAATCAAGCCCTGTCCTCCATGCAAATGCCCAGCACCTAAC CTCTTGGGTGGACCATCCGTICTTCATCTTCCCTCCAAAGATCAAGGATGTACTCATGA TCTCCCTGAGCCCCATAGTCACATGTIGTIGGTGGTGGATGTGAGCGAGGATGACCCAGA TGTCCAGATCAGCTGGTTTGTGAACAACGTGGAAGTACACACAGCTCAGACACAAACC CATAGAGAGGATTACAACAGTACTCTCCGGGTGGTCAGTGCCCTCCCCATCCAGCACC AGGACTGGATGAGIGGCAAGGAGTITCAAATGCARGGTCAACAACAAAGACCTCCCAGC GCCCATCGAGAGAACCATCTCAAAACCCAAAGGGTCAGTAAGAGCTCCACAGGTATAT GTCITGCCTCCACCAGAAGAAGAGATGACTARGAAACAGGTCACTCTGACCTGCATGG TCACAGACTTCATGCCTGAAGACATTTACGTGGAGTGGACCAACAACGGGAAAACAGA GCTAAACTACARGAACACTGAACCAGTCCTIGGACTCTGATGGTTICTTACTTCATGTAC AGCAAGCTGAGAGIGGARAAGAAGARCTGGGTGGARAGARATAGCTACTCCTGTITCAG TGGTCCACGAGGGTCTGCACAATCACCACACGACTAAGAGCTTCTCCCGGACTCCGGG TAAR Constant AKTTAPSVYPLVPVCGGTIGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPALLQ Region of SGLYTLSSSVIVTSNIWPSQTITCNVAHPASSTKVDKKIEPRVP ITONPCPPHQRVPP Heavy CARPDLLGGP SVE IFPPKIKDVLMISLSPMVICVVVDVSEDDPDVQISWFVNNVEVHET Chain, AQTQTHREDYNSTLRVVSALP IQHQDWMSGKEFKCKVNNRALPSPIEKTISKPRGPVR secreted APQVYVLPPPAEEMTKKEFSLICMITGFLPAEIAVDWISNGRTEQNYKNTATVLDSDG form SYFMYSKLRVQKSTWERGSLFACSVVHEVLENHLTTKTISRSLGK (mIgG2A) Constant KTTPPSVYPLAPGCGDTTGSSVTLGCLVKGYFPESVTIVIWNSGSLSSSVHTFPALLQS Region of GLYTMSSSVIVPSSTWPSQIVICSVAHPASSTTVDKKLEP SGP ISTINPCPPCKECHK murine CPAPNLEGGPSVFIFPPNIKDVLMISLTPKVTICVVVDVSEDDPDVQISWFVNNVEVHT Heavy AQTQTHREDYNSTIRVVSTLP IQHODWMSGKEFKCKVNNKDLP SPIERTISKIKGLVR Chain, APQVYILPPPAEQLSRKDVSLTCLVVGFNPGDISVEWTSNGHTEENYKDTAPVLDSDG secreted SYFIYSKLNMKTSKWEKTDSFSCNVRHEGLKNYYLKKTISRSPGLDLDDICAEAKDGE form LDGLWITITIFISLFLLSVCYSASVILFKVKWIFSSVVELKQKISPDYRNMIGQGA (mIgG2B) Constant KITAPSVYPLAPVCGGITGSSVILGCLVKGYFPEPVILTWNSGSLSSGVHTFPALLQS Region of GLYTLSSSVTIVTSNTWPSQTITCNVAHPASSTKVDKKIEPRVP ITQNPCPPLKECPPC murine AAPDLLGGPSVFIFPPKIKDVLMISLSPMVTCVVVDVSEDDPDVQISWEVNNVEVHTA Heavy QTQTHREDYNSTLRVVSALP IQHQDWMSGKEFKCKVNNRALP SPIEKTISKPRGPVRA Chain, PQVYVLPPPAEEMTKKEFSLTCMITGFLPAEIAVDWTSNGRTEQNYKNTATVLDSDGS (mIgG2B) YFMYSKLRVQKSTWERGSLFACSVVHEGLHNHLITKTISRSLGLDLDDVCTEAQDGEL DGLWTTITIFISLFLLSVCYSASVTLFKVKWIFSSVVELKQKI SPDYRNMIGQGA Constant TTTAPSVYPLVPGCSDTSGSSVTILGCLVKGYFPEPVTVKWNYGALSSGVRTVSSVLQS Region of GFYSLSSLVIVPSSTWPSQIVICNVAHPASKIELIKRIEPRIPKPSTPPGSSCPPGNI murine LGGPSVFIFPPKPKDALMISLTPKVTICVVVDVSEDDPDVHVSWFVDNKEVHTAWTQPR Heavy EAQYNSTFRVVSALP IQHODWMRGKEFKCKVNNKALPAP IERT I SKPKGRAQTPQVYT Chain, IPPPREQMSKKKVSLTCLVINFFSEAISVEWERNGELEQDYKNTPPILDSDGTYFLYS secreted KLTVDTDSWLQGEIFTCSVVHEALHNHHTQKNLSRSPELELNETCAEAQDGELDGLWT form TITIFISLFLLSVCYSASVILFKVKWIFSSVVQVKQTAIPDYRNMIGQGA (mlgG3) Constant ADAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWIDQ Region of DSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC Murine Kappa Light | Chain DNA GCAGATGCTGCACCAACTGTATCCATCTICCCACCATCCAGTGAGCAGTITAACATCIG Constant GAGGTGCCTCAGTCGTGTGCTTCTTGAACAACTTCTACCCCAAAGACATCAATGTCAA Region of GTGGAAGATTGATGGCAGTGAACGACARAATGGCGTCCTGAACAGTTGGACTGATCAG Murine GACAGCAAAGACAGCACCTACAGCATGAGCAGCACCCTCACGTTGACCAAGGACGAGT Kappa Light | ATGAACGACATAACAGCTATACCTGTGRGGCCACTCACAAGRCATCARCTTCACCCAT Chain TGTCAAGAGCTTCAACAGGAATGAGIGT Constant QPKSSPSVTLFPPSSEELETNKATLVCTITDFYPGVVTIVDWKVDGTPVTQGMETTQPS Region of KQSNNKYMASSYLTLTARAWERHSSYSCQVTHEGHTVEKSLSRADCS murine Lambda QPKSTPTLTVFPPSSEELKENKATLVCLISNFSPSGVIVAWKANGTPITQGVDTSNPT Light Chain KEGNKFMASSFLHLTSDQWRSHNSETCQVTHEGDTVEKSLSPAECL (subclasses 1,2, and 3) QPKSTPTLTMFPPSPEELQENKATLVCLISNFSPSGVIVAWKANGTP ITQGVDTSNPT KEDNKYMASSFLHLTSDQWRSHNSFTCQVTHEGDTVEKSLSPAECL Constant ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ Region of SSGLYSLSSVVIVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPE human LLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKP Heavy REEQYNSTYRVVSVLIVLHQDWLNGKEYKCKVSNKALPAP IEKTISKAKGQPREPQVY Chain TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY (higG1 SKLTVDKSRWQQGNVF SCSVMHEALHNHYTQKSLSLSPG DNA GCCAGCACAARAGGGCCCAGTIGIGITCCCGCTCGCACCAAGCAGCAAATCAACGTCAG Constant GCGGCACAGCCGCGTTIGGGTTGCCTTGTAAAAGACTACTTCCCAGAACCAGTTACGGT Region of GTCATGGAACAGTGGIGCACTCACGAGCGGCGTICATACCTICCCCGCCGTACTTCAG human AGTTCAGGTCTTTACTCACTTTCCAGCGTGGTCACAGTACCGTCAAGCTCTCTTGGAA Heavy CACAGACATATATCTGTAACGTARATCATAAGCCTAGCAATACCARAGTCGATARACG Chain AGTGGAACCCAAGAGTTGTGATAAARCCCACACCTGTCCCCCTIGCCCGGCACCGGAA (hIgG1) CTGCTGGGTGGTCCATCAGTATTCTTGTTTCCGCCTAAGCCAAAGGACACACTGATGA TATCCAGAACTCCAGAGGTTACGTIGCGTAGTCGTGGACGTCAGTCATGAAGACCCCGA AGTTAAGTTCAACTGGTACGTGGATGGTGTGGAAGTACATAATGCGAAGACGAAACCC AGGGAAGAACAATATAACTCARCTITATAGGGTAGTCAGCGTCTIGACTGTACTTICACC ARGATTGGTIGAATGGCAAAGAGTACAAATGCARGGTAAGCAACAAAGCATTIGCCIGE GCCAATCGAAAAGACTATCTCAAAAGCARAGGGCCAGCCACGCGAACCACAAGTGTAT ACATTGCCGCCCAGTCGGGAAGARATGACGARARATCAAGTCAGTCTCACATGCCTICG TGAAAGGATTTTATCCCTCTGACATAGCTGTGGAGTGGGAAAGTAATGGCCAACCCGA ARATAATTACARAACGACGCCICCCGTITIGGACTCAGATGGGAGTTITITCCTTTAC AGTAAGCTGACGGITGACAAARGCAGGTGGCAACARGGGAACGICTTITCTIGTAGTIG TGATGCATGAGGCGCTCCACAATCATTACACTCAAAAATCCTTGAGCCTGTCTCCAGG Cc Constant ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ Region of SSGLYSLSSVVIVPSSNFGIQTYTCNVDHKP SNTKVDKTVERKCCVECPPCPAPPVAG Heavy PSVFLFPPKPKDTLMISRTPEVICVVVDVSHEDPEVQFNWYVDGVEVHENAKTKPREEQ Chain FNSTFRVVSVLTVVHQODWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPP (hIgG2) SREEMTKNQVSLTCLVKGEYPSDISVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLT VDKSRWQQGNVF SCSVMHEALHNHYTQKSLSLSPGK Constant ASTKGPSVFPLAPCSRSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ Region of SSGLYSLSSVVIVPSSSLGIQTYTCNVNHKP SNTKVDKRVELKTPLGDTTHICPRCPE Heavy PKSCDTPPPCPRCPEPKSCDTPPPCPRCPEPKSCDTPPPCPRCPAPELLGGPSVFLFP Chain PKPKDTLMISRIPEVICVVVDVSHEDPEVQFKWYVDGVEVENAKTKPREEQYNSTFRV (hIgG3) VSVLTVLHQDWLNGKEYKCKVSNKALPAP IEKTISKTKGQPREPQVYTLPPSREEMTK NQVSLTCLVKGFYPSDIAVEWESSGQPENNYNTTPPMLDSDGSFFLY SKLTVDKSRWQ QGNIFSCSVMHEALHENRFTQKSLSLSPGK Constant ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ Region of SSGLYSLSSVVIVPSSSLGTKIYTCNVDHKP SNTKVDKRVESKYGPPCPSCPAPEFLG human GPSVFLFPPKPKDTLMISRTPEVICVVVDVSQEDPEVQFNWYVDGVEVENAKTKPREE Heavy QFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLP SSIEKTISKAKGQPREPQVYTLP Chain PSQEEMTKNQVSLTICLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SRL (hIgG4) TVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK Constant GQPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADGSPVKAGVETTKP Region of SKQSNNKYAASSYLSLTPEQWKSHRSYSCQVIHEGSTVEKTVAPTECS human Light Chain (hIgG | GOQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGRVIVAWKADSSPVKAGVETTTP Lambda, SKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS subclasses 12.3.6 GQPKAAPSVTLEPPSSEELQANKATLVCLISDFYPGAVIVAWKADS SPVKAGVETTTP and 7) | SKQSNNKYAASSYLSLTPEQWKSHKSYSCQVTHEGSTVEKTVAPTECS GQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVKVAWKADGSPVNTGVETTTP SKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPAECS GQPKAAPSVTLFPPSSEELQANKATLVCLVSDFNPGAVIVAWKADGSPVKVGVETTKP SKQSNNKYAASSYLSLTPEQWKSHRSYSCRVTHEGSTVEKTVAPAECS 1212 Constant TVAAPSVFIFPPSDEQLKSGTASVVCLLNNF YPREAKVQWKVDNALQSGNSQESVTEQ Region of DSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVIKSFNRGEC human Light Chain (hIgG Kappa) 1213 DNA ACTGTCGCAGCACCTTCTGTCTICATCTITCCGCCAAGCGATGAACAGTTGAAATCTG Constant GAACAGCGTCCGTGGTIGTGCCTGCTCAACAACTICTATCCTCGGGAAGCGAAGGTGCA Region of ATGGAAGGTAGATAATGCTCTICAGAGTGGCAATTCCCAAGAGTCAGTTACGGAGCAA human Light | GATAGCARGGACAGCACGTATTICCCTGICTAGTACGTTGACTCTTTCCARGGCTGACT Chain (hIgG | ATGAARAGCACAAGGTGTATGCCTGTGAAGTAACCCACCAAGGTCTCTCAAGTCCTGT kappa) AARCTAAGAGCTTTAATCGAGGAGAATGC

[0193] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of a heavy chain complementary determining region 1 (HC CDR1), a HC CDR2, and / or a HC CDR3, wherein the HC CDR1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NO: 299, 343, and 395, respectively. In some embodiments, the anti- tau antibody comprises at least one, two, three, or all of a LC CDR1, a LC CDR2 and / or an LC CDR3, wherein the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NO: 460, 518, and 557, respectively. In some embodiments, the anti- tau antibody comprises a HC CDR1, a HC CDR2, a HC CDR3, a LC CDR1, a LC CDR2 and an LC CDR3, wherein the HC CDR1, HC CDR2, HC CDR3, LC CDRI1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NO: 299, 343, 395, 460, 518, and 557, 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 NO: 299, 343, 395, 460, 518, or 557.

[0194] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of a heavy chain complementary determining region 1 (HC CDR1), a HC CDR2, and / or a HC CDR3, wherein the HC CDR 1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NO: 1140, 1141, and 395, respectively. In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of a LC CDR1, a LC CDR2 and / or an LC CDR3, wherein the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NO: 460, 518, and 557, respectively. In some embodiments, the anti- tau antibody comprises a HC CDR1, a HC CDR2, a HC CDR3, a LC CDR1, a LC CDR2 and an LC CDR3, wherein the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NO: 1140, 1141, 395, 460, 518, and 557, 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 NO: 1140, 1141, 395, 460, 518, and 557.

[0195] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of a heavy chain complementary determining region 1 (HC CDR1), a HC CDR2, and / or a HC CDR3, wherein the HC CDR1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NO: 1155, 1156, and 1157, respectively. In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of a LC CDR1, a LC CDR2 and / or an LC CDR3, wherein the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NO: 1158, 1159, and 557, respectively. In some embodiments, the anti-tau antibody comprises a HC CDR1, a HC CDR2, a HC CDR3, a LC CDR1, a LC CDR2 and an LC CDR3, wherein the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NO: 1155, 1156, 1157, 1158, 1159, and 557, 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 NO: 1155, 1156, 1157, 1158, 1159, and 557.

[0196] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of a heavy chain complementary determining region 1 (HC CDR1), a HC CDR2, and / or a HC CDR3, wherein the HC CDR1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NO: 304, 347, and 400, respectively. In some embodiments, the anti- tau antibody comprises at least one, two, three, or all of a LC CDR1, a LC CDR2 and / or an LC CDR3, wherein the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NO: 464, 523, and 562, respectively. In some embodiments, the anti- tau antibody comprises a HC CDR1, a HC CDR2, a HC CDR3, a LC CDR1, a LC CDR2 and an LC CDR3, wherein the HC CDR1, HC CDR2, HC CDR3, LC CDRI1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NO: 304, 347, 400, 464, 523, 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 NO: 304, 347, 400, 464, 523, and 562.

[0197] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of a heavy chain complementary determining region 1 (HC CDR1), a HC CDR2, and / or a HC CDR3, wherein the HC CDR1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NO: 1142, 1143, and 400, respectively. In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of a LC CDR1, a LC CDR2 and / or an LC CDR3, wherein the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NO: 464, 523, and 562, respectively. In some embodiments, the anti- tau antibody comprises a HC CDR1, a HC CDR2, a HC CDR3, a LC CDR1, a LC CDR2 and an LC CDR3, wherein the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NO: 1142, 1143, 400, 464, 523, 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 NO: 1142, 1143, 400, 464, 523, and 562.

[0198] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of a heavy chain complementary determining region 1 (HC CDR1), a HC CDR2, and / or a HC CDR3, wherein the HC CDR1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NO: 1160, 1161, and 1162, respectively. In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of a LC CDR1, a LC CDR2 and / or an LC CDR3, wherein the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NO: 1163, 1164, and 562, respectively. In some embodiments, the anti-tau antibody comprises a HC CDR1, a HC CDR2, a HC CDR3, a LC CDR1, a LC CDR2 and an LC CDR3, wherein the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NO: 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 NO: 1160, 1161, 1162, 1163, 1164, and 562.

[0199] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of a heavy chain complementary determining region 1 (HC CDR1), a HC CDR2, and / or a HC CDR3, wherein the HC CDR1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NO: 314, 341, and 410, respectively. In some embodiments, the anti- tan antibody comprises at least one, two, three, or all of a LC CDR1, a LC CDR2 and / or an LC CDR3, wherein the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NO: 1154, 529, and 571, respectively. In some embodiments, the anti- tau antibody comprises a HC CDR1, a HC CDR2, a HC CDR3, a LC CDR1, a LC CDR2 and an LC CDR3, wherein the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NO: 314, 341, 410, 1154, 529, and 571, 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 NO: 314, 341, 410, 1154, 529, and 571.

[0200] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of a heavy chain complementary determining region 1 (HC CDR1), a HC CDR2, and / or a HC CDR3, wherein the HC CDR1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NO: 1144, 1145, and 410, respectively. In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of a LC CDR1, a LC CDR2 and / or an LC CDR3, wherein the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NO: 1146, 529, and 571, respectively. In some embodiments, the anti- tau antibody comprises a HC CDR 1, a HC CDR2, a HC CDR3, a LC CDR1, a LC CDR2 and an LC CDR3, wherein the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NO: 1144, 1145, 410, 1146, 529, and 571, 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 NO: 1144, 1145, 410, 1146, 529, and 571.

[0201] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of a heavy chain complementary determining region 1 (HC CDR1), a HC CDR2, and / or a HC CDR3, wherein the HC CDR1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NO: 1165, 1166, and 1167, respectively. In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of a LC CDR1, a LC CDR2 and / or an LC CDR3, wherein the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NO: 473, 528, and 571, respectively. In some embodiments, the anti- tau antibody comprises a HC CDR1, a HC CDR2, a HC CDR3, a LC CDR1, a LC CDR2 and an LC CDR3, wherein the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NO: 1165, 1166, 1167, 473, 528, and 571, 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 NO: 1165, 1166, 1167, 473, 528, and 571.

[0202] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of a heavy chain complementary determining region 1 (HC CDR1), a HC CDR2, and / or a HC CDR3, wherein the HC CDR1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NO: 315, 341, and 410, respectively. In some embodiments, the anti- tau antibody comprises at least one, two, three, or all of a LC CDR1, a LC CDR2 and / or an LC CDR3, wherein the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NO: 474, 529, and 571, respectively. In some embodiments, the anti- tau antibody comprises a HC CDR1, a HC CDR2, a HC CDR3, a LC CDR1, a LC CDR2 and an LC CDR3, wherein the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NO: 315, 341, 410, 474, 529, and 571, 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 NO: 315, 341, 410, 474, 529, and 571.

[0203] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of a heavy chain complementary determining region 1 (HC CDR1), a HC CDR2, and / or a HC CDR3, wherein the HC CDR1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NO: 1147, 1148, and 410, respectively. In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of a LC CDR1, a LC CDR2 and / or an LC CDR3, wherein the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NO: 474, 529, and 571, respectively. In some embodiments, the anti- tau antibody comprises a HC CDR 1, a HC CDR2, a HC CDR3, a LC CDR1, a LC CDR2 and an LC CDR3, wherein the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NO: 1147, 1148, 410, 474, 529, and 571, 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 NO: 1147, 1148, 410, 474, 529, and 571.

[0204] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of a heavy chain complementary determining region 1 (HC CDR1), a HC CDR2, and / or a HC CDR3, wherein the HC CDR1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NO: 1168, 1169, and 1167, respectively. In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of a LC CDR1, a LC CDR2 and / or an LC CDR3, wherein the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NO: 1170, 528, and 571, respectively. In some embodiments, the anti- tau antibody comprises a HC CDR1, a HC CDR2, a HC CDR3, a LC CDR1, a LC CDR2 and an LC CDR3, wherein the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NO: 1168, 1169, 1167, 1170, 528, and 571, 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 NO: 1168, 1169, 1167, 1170, 528, and 571.

[0205] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of a heavy chain complementary determining region 1 (HC CDR1), a HC CDR2, and / or a HC CDR3, wherein the HC CDR1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NO: 316, 341, and 410, respectively. In some embodiments, the anti- tau antibody comprises at least one, two, three, or all of a LC CDR1, a LC CDR2 and / or an LC CDR3, wherein the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NO: 475, 530, and 571, respectively. In some embodiments, the anti- tau antibody comprises a HC CDR 1, a HC CDR2, a HC CDR3, a LC CDR1, a LC CDR2 and an LC CDR3, wherein the HC CDR1, HC CDR2, HC CDR3, LC CDRI1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NO: 316, 341, 410, 475, 530, and 571, 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 NO: 316, 341, 410, 475, 530, and 571.

[0206] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of a heavy chain complementary determining region 1 (HC CDR1), a HC CDR2, and / or a HC CDR3, wherein the HC CDR 1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NO: 1149, 1150, and 410, respectively. In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of a LC CDR1, a LC CDR2 and / or an LC CDR3, wherein the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NO: 475, 530, and 571, respectively. In some embodiments, the anti- tan antibody comprises a HC CDR1, a HC CDR2, a HC CDR3, a LC CDRI1, a LC CDR2 and an LC CDR3, wherein the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NO: 1149, 1150, 410, 475, 530, and 571, 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 NO: 1149, 1150, 410, 475, 530, and 571.

[0207] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of a heavy chain complementary determining region 1 (HC CDR1), a HC CDR2, and / or a HC CDR3, wherein the HC CDR1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NO: 1171, 1166, and 1167, respectively. In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of a LC CDR1, a LC CDR2 and / or an LC CDR3, wherein the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NO: 1172, 528, and 571, respectively. In some embodiments, the anti- tau antibody comprises a HC CDR1, a HC CDR2, a HC CDR3, a LC CDR1, a LC CDR2 and an LC CDR3, wherein the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NO: 1171, 1166, 1167, 1172, 528, and 571, 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 NO: 1171, 1166, 1167, 1172, 528, and 571.

[0208] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of a heavy chain complementary determining region 1 (HC CDR1), a HC CDR2, and / or a HC CDR3, wherein the HC CDR1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NO: 325, 362, and 435, respectively. In some embodiments, the anti- tau antibody comprises at least one, two, three, or all of a LC CDR1, a LC CDR2 and / or an LC CDR3, wherein the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NO: 495, 540, and 587, respectively. In some embodiments, the anti- tau antibody comprises a HC CDR 1, a HC CDR2, a HC CDR3, a LC CDR1, a LC CDR2 and an LC CDR3, wherein the HC CDR1, HC CDR2, HC CDR3, LC CDRI1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NO: 325, 362, 435, 495, 540, and 587, 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 NO: 325, 362, 435, 495, 540, and 587.

[0209] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of a heavy chain complementary determining region 1 (HC CDR1), a HC CDR2, and / or a HC CDR3, wherein the HC CDR1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NO: 1152, 1153, and 4335, respectively. In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of a LC CDR1, a LC CDR2 and / or an LC CDR3, wherein the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NO: 495, 540, and 587, respectively. In some embodiments, the anti- tau antibody comprises a HC CDR1, a HC CDR2, a HC CDR3, a LC CDRI1, a LC CDR2 and an LC CDR3, wherein the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NO: 1152, 1153, 435, 495, 540, and 587, 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 NO: 1152, 1153, 435, 495, 540, and 587.

[0210] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of a heavy chain complementary determining region 1 (HC CDR1), a HC CDR2, and / or a HC CDR3, wherein the HC CDR1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NO: 1173, 1174, and 1175, respectively. In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of a LC CDR1, a LC CDR2 and / or an LC CDR3, wherein the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NO: 1176, 1177, and 587, respectively. In some embodiments, the anti-tau antibody comprises a HC CDR1, a HC CDR2, a HC CDR3, a LC CDR1, a LC CDR2 and an LC CDR3, wherein the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NO: 1173, 1174, 1175, 1176, 1177, and 587, 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 NO: 1173, 1174, 1175, 1176, 1177, and 587.

[0211] 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 aforesaid 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 aforesaid sequences. In some embodiments, the anti-tau antibody comprises a heavy chain variable region and a light chain variable region comprising the amino acid sequences of SEQ ID NO: 4 and 78, respectively; or encoded by the nucleotide sequences of SEQ ID NO: 150 and 224, respectively; 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 aforesaid 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 (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 (e.g., having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity).

[0212] 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 aforesaid 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 aforesaid sequences. In some embodiments, the anti-tau antibody comprises a heavy chain variable region and a light chain variable region comprising the amino acid sequences of SEQ ID NO: 9 and 83, respectively; or encoded by the nucleotide sequences of SEQ ID NO: 155 and 229, respectively; 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 aforesaid 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 (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 (e.g., having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity).

[0213] 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 aforesaid 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 aforesaid sequences. In some embodiments, the anti-tau antibody comprises a heavy chain variable region and a light chain variable region comprising the amino acid sequences of SEQ ID NO: 21 and 93, respectively; or encoded by the nucleotide sequences of SEQ ID NO: 167 and 241, respectively; 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 aforesaid 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 (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 (e.g., having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity).

[0214] 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 aforesaid 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 aforesaid sequences. In some embodiments, the anti-tau antibody comprises a heavy chain variable region and a light chain variable region comprising the amino acid sequences of SEQ ID NO: 22 and 94, respectively; or encoded by the nucleotide sequences of SEQ ID NO: 168 and 242, respectively; 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 aforesaid 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 (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 (e.g., having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity).

[0215] 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 aforesaid 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 aforesaid sequences. In some embodiments, the anti-tau antibody comprises a heavy chain variable region and a light chain variable region comprising the amino acid sequences of SEQ ID NO: 23 and 95, respectively; or encoded by the nucleotide sequences of SEQ ID NO: 169 and 243, respectively; 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 aforesaid 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 (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 (e.g., having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity).

[0216] 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 aforesaid 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 aforesaid sequences. In some embodiments, the anti-tau antibody comprises a heavy chain variable region and a light chain variable region comprising the amino acid sequences of SEQ ID NO: 51 and 122, respectively; or encoded by the nucleotide sequences of SEQ ID NO: 197 and 270, respectively; 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 aforesaid 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 (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 (e.g., having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity).

[0217] In some embodiments, the anti-tau antibody comprises a VH and / or VL encoded by a codon-optimized nucleic acid sequence. Codon-optimization may be achieved by any method known to one with skill in the art such as, but not limited to, by a method according to Genescript, EMBOSS, Bioinformatics, NUS, NUS2, Geneinfinity, IDT, NUS3, GregThatcher, Insilico, Molbio, N2P, Snapgene, and / or VectorNTL

[0218] Anti-tau antibodies according to the present disclosure may be prepared using any of the antibody sequences (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) presented herein, any may be prepared, for example, as monoclonal antibodies, multispecific antibodies, chimeric antibodies, antibody mimetics, scFvs, or antibody fragments.

[0219] 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 mouse IgG antibodies, anti-tau antibodies may be prepared as IgG1, IgG2a, IgG2b, IgG2c, or IgG3 isotypes. When prepared as human IgG antibodies, anti-tau antibodies may be prepared as IgG1, IgG2, IgG3, or IgG4 isotypes. Anti-tau antibodies prepared as human or humanized antibodies may include one or more human constant domains.

[0220] This present disclosure provides in some embodiments, a nucleic acid (e.g., an isolated nucleic acid) encoding any of the above described antibodies, and viral genomes, vectors, AAV particles, and cells comprising the same. Tau protein antigens

[0221] In some embodiments, anti-tau antibodies bind to tau protein antigens, e.g., an epitope on a tau protein. Tau protein antigens may include human microtubule-associated protein tau, isoform 2 (SEQ ID NO: 920) or fragments thereof. Tau protein antigens may include ePHF or fragments thereof. Tau protein antigens may include one or more phosphorylated residues. Such phosphorylated residues may correspond to those found with pathological tau. In some embodiments tau protein antigens include any of those listed in Table 8. In the Table, phosphorylated residues associated with each antigen are double- underlined. In some embodiments, tau proteins may include variants (e.g., phosphorylated or unphosphorylated variants) or fragments of the sequences listed. Table 8. Tau protein antigen sequences 922 om | 923 Tfozd | 924 926 Antigen Sequence SEQ ID NO human microtubule- |[MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQ [920 associated protein tau, |TPTEDGSEEPGSETSDAKSTP TAEDVTAPLVDEGAPGKQAAAQPHTEIP isoform 2 EGTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADG KTKIATPRGAAPPGQKGOANATRIPAKTPPAPKTPPSSGEPPKSGDRSG YSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSSAKSRLQT APVPMPDLKNVKSKIGSTENLKHOPGGGKVQIINKKLDLSNVOSKCGSK DNIKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEK LDFKDRVQSKIGSLDNITHVP GGGNKKIETHKLTFRENAKAKTDHGAET VYKSPVVSGDTSPRHLSNVSSTGSIDMVDSPQLATLADEVSASLAKQGL PT3 epitope peptide ~~ |TPGSRSRIPSLPIPPTREPK 921 pT212 / pT217) Peptide 5 GTPGSRSRIPSLPIPPTRE 922 pT212 / pS214 / pT217) RENAKAKTDHGAE TVYKSPVVSGDTSPRHLENVSSTG 923 pS396 / pS404 / pS409 Peptide 1 (AT120 PTREPKKV 924 epitope) [6CS epitope peptide [RRMVSKS UCB D & PT76 SPSSAKSRLQTAPVPMPDLKNVKS 926 epitope peptide

[0222] In some embodiments, anti-tau antibodies of the present disclosure bind to tau protein epitopes on tau protein antigens described herein. Such tau protein epitopes may include or be included within a tau protein antigen amino acid sequence listed in Table 8. In some embodiments, anti-tau antibodies of the present disclosure bind to tan protein epitopes that include a region formed by a complex of at least two tau proteins.

[0223] In some embodiments, disclosed herein is an encoded an antibody that competes for binding to tau with the aforesaid antibodies. In some embodiments, disclosed herein is an antibody that binds 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 aforesaid anti- tau antibody.

[0224] In some embodiment, compete or cross-compete refers to the ability of an antibody to interfere with binding of an anti-tau antibody, e.g., an anti-tau antibody provided herein, to a target, e.g., tau protein. The interference with binding can be direct or indirect (e.g., through an allosteric modulation of the antibody or the target). The extent to which an antibody is able to interfere with the binding of another antibody to the target, and therefore whether it can be said to compete, can be determined using a competition binding assay, for example, a FACS assay, an ELISA or BIACORE assay. In some embodiments, a competition binding assay is a quantitative competition assay. In some embodiments, a first anti-tau antibody is said to compete for binding to the target with a second anti-tau antibody when the binding of the first antibody to the target is reduced 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 competition binding assay (e.g., a competition assay described herein).

[0225] In some embodiments, an epitope comprises the moieties of an antigen (e.g., a tau protein antigen) that specifically interact with an antibody. Such moieties, referred to herein as epitopic determinants, typically comprise, or are part of, elements such as amino acid side chains or sugar side chains. An epitopic determinate can be defined by methods known in the art or disclosed herein, e.g., by crystallography or by hydrogen-deuterium exchange. At least one or some of the moieties on the antibody, that specifically interact with an epitopic determinant, are typically located in a CDR(s). Typically, an epitope has a specific three dimensional structural characteristics. Typically, an epitope has specific charge characteristics. Some epitopes are linear epitopes while others are conformational epitopes.

[0226] In an embodiment, an epitopic determinant is a moiety on the antigen, e.g., such as amino acid side chain or sugar side chain, or part thereof, which, when the antigen and antibody are co-crystallized, is within a predetermined distance, e.g., within 5 Angstroms, of a moiety on the antibody, 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.

[0227] A first antibody binds the same epitope as a second antibody (e.g., a reference antibody, e.g., an antibody disclosed herein) if the first antibody specifically interacts with the same epitopic determinants on the antigen as does the second or reference antibody, e.g., when interaction is measured in the same way for both the antibody and the second or reference antibody. Epitopes that overlap share at least one epitopic determinant. A first antibody binds 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 and a second antibody (e.g., a reference antibody, e.g., an antibody disclosed herein) bind substantially overlapping epitopes if at least half of the epitopic determinants of the second or reference antibody are found as epitopic determinants in the epitope of the first antibody. A first and a second antibody (e.g., a reference antibody, e.g., an antibody disclosed herein) bind substantially the same epitope if the first antibody binds at least half of the core epitopic determinants of the epitope of the second or reference antibody, wherein the core epitopic determinants are defined by crystallography. Epitope specificity

[0228] Antibodies of the present disclosure may bind to tau protein epitopes, which may include or be included within the residues of SEQ ID NOs: 920-926. Antibodies may compete for binding to tau protein epitopes with other anti-tau antibodies, including, but not limited to, AT100, AT120, PT3, C10.2, PT76, IPN002, 6C5, and UCB D. Tau protein epitopes may include C-terminal residues 409-436 of human tau (SEQ ID NO: 920). Such epitopes may include residues 413-430 of human tau (SEQ ID NO: 920). Antibody binding to such residues may exhibit a Kp of from about 0.1 nM to about 0.5 nM. In some embodiments, tan 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 binding to such residues may exhibit a Kp of from about (0.5 nM to about 5 nM.

[0229] In some embodiments, the present disclosure provides antibodies that compete for binding with second antibodies to tau protein epitopes. Such epitopes 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).

[0230] Tau protein epitopes may include one or more of residues 409-436 and 413-430 of human tau (SEQ ID NO: 920). Second antibodies competing for binding to such epitopes may include variable domain pairs selected from the group consisting of: a VH with the amino acid sequence of SEQ ID NO: 21 and a VL with the amino acid sequence of SEQ ID NO: 93; a VH with the amino acid sequence of SEQ ID NO: 22 and a VL with the amino acid sequence of SEQ ID NO: 94; and a VH with the amino acid sequence of SEQ ID NO: 23 and a VL with the amino acid sequence of SEQ ID NO: 95.

[0231] Antibodies competing for tau epitope binding with such second antibodies may include a CDRHI that includes the amino acid sequence of G [F / Y] TFT [R / I] [Y / F] (SEQ ID NO: 931), or more generally G-X1-TFT-X2-X3 (SEQ ID NO: 932), where X1, X2, and X3 may be any amino acid, e.g., X1 and / or X3 may be an amino acid with a hydrophobic and / or aromatic side chain, such as F or Y, and / or X2 may be a positively charged residue (such as R, K, H) or a residue with aliphatic side chain (such as A, V, I, or L); a CDRH2 that includes the amino acid sequence NPNNGG (SEQ ID NO: 341); a CDRH3 that includes the amino acid sequence GTGTGAMDY (SEQ ID NO: 410); a CDRLI that includes the amino acid sequence RSSQSLVH [N / S] NG [IN] T [H / Y] LY (SEQ ID NO: 933), or more generally RSSQSLVH-X1-NG-X2-T-X3-LY (SEQ ID NO: 934), where X1, X2, and X3 may 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 that includes the amino acid sequence RVS [N / S] RFS (SEQ ID NO: 935), or more generally RVSXRFS (SEQ ID NO: 936), where X may be any amino acid, e.g., X1 is Q / N / S / T; and / or a CDRL3 that includes the amino acid sequence FQGTHVPRT (SEQ ID NO: 571).

[0232] In some embodiments, the CDRH1 may include the amino acid sequence G[F / YITFT[R / I][Y / F] (SEQ ID NO: 931). The CDRH2 may include the amino acid sequence NPNNGG (SEQ ID NO: 341). The CDRH3 may include the amino acid sequence GTGTGAMDY (SEQ ID NO: 410). The CDRLI1 may include the amino acid sequence RSSQSLVH [N / S] NG [IN] T [H / Y] LY (SEQ ID NO: 933). The CDRL2 may include the amino acid sequence RVS [N / S] RFS (SEQ ID NO: 935). The CDRL3 may include the amino acid sequence FQGTHVPRT (SEQ ID NO: 571).

[0233] In some embodiments, tau protein epitopes may include one or more of residues 57-72, 175-191, 223-238, and 383-400 of human tau (SEQ ID NO: 920). Second antibodies competing for binding to such epitopes may include variable domain pairs selected from the group consisting of: a VH with the amino acid sequence of SEQ ID NO: 51 and a VL with the amino acid sequence of SEQ ID NO: 122; a VH with the amino acid sequence of SEQ ID NO: 53 and a VL with the amino acid sequence of SEQ ID NO: 124; a VH with the amino acid sequence of SEQ ID NO: 54 and a VL with the amino acid sequence of SEQ ID NO: 125; a VH with the amino acid sequence of SEQ ID NO: 56 and a VL with the amino acid sequence of SEQ ID NO: 125; a VH with the amino acid sequence of SEQ ID NO: 57 and a VL with the amino acid sequence of SEQ ID NO: 126; a VH with the amino acid sequence of SEQ ID NO: 35 and a VL with the amino acid sequence of SEQ ID NO: 107; and a VH with the amino acid sequence of SEQ ID NO: 48 and a VL with the amino acid sequence of SEQ ID NO: 120.

[0234] Antibodies competing for tau epitope binding with such second antibodies may include a CDRH1 that includes the amino acid sequence of GFSL [S / N] T [S / F] [A / G] M (SEQ ID NO: 964), or more generally GFSL-X1-T-X2-X3-M (SEQ ID NO: 965), where X1- X3 may 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 / T / L / V; a CDRH?2 that includes the amino acid sequence YWDDD (SEQ ID NO: 362); a CDRH3 that includes 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 more generally R-X1-X2-X3-X4-X5-X6-X7-X8-X9-DY (SEQ ID NO: 975), where each of X1-X9 may be any amino acid and / or where one or more of X3-X5 may be absent, e.g., X1 is R / K / H / A / V / VLIG / 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 / TL and / or X8 is G / A / V / I / L / Y / F / N / Q and / or X9 is M / F / Y; a CDRL1 that includes 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 generally 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-X15 may be any amino acid and / or where one or more of X9-X14 may be absent, e.g., X1 is K / R / H / S / T and / or X2 is S / T / A / V / UL 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 / 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 / LH / K / R / N / Q; a CDRL2 that includes 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), or more generally X1-X2-S-X3-X4-X5- X6 (SEQ ID NO: 979), where X1-X6 may 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 / TL and / or X5 is C / S / E / D / A / V / T / L and / or X6 is T / S; and / or a CDRL3 that includes the amino acid sequence [W / Q] [Q / N] [G / D] [T / S / Y / H] [H / S / R] [F / V / 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-X8 may be any amino acid and / or where 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 / N / T / L / Y / F and / or X8 is Y / F / absent.

[0235] The CDRHI may include the amino acid sequence GFSL [S / N] T [S / F] [A / G] M (SEQ ID NO: 964). The CDRH2 may include the amino acid sequence YWDDD (SEQ ID NO: 362). The CDRH3 may include 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). The CDRL1 may include 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). The CDRL2 may include 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). The CDRL3 may include 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). 11. VECTORIZATION

[0236] According to the present disclosure, compositions for delivering anti-tau antibodies or functional variants thereof by adeno-associated virus particles (AAVs) are provided. In some embodiments, an AAV particle, e.g., an AAV particle as described herein, or plurality of particles, may be provided, e.g., delivered, via any of several routes of administration, to a cell, tissue, organ, or organism, ir vivo, ex vivo, or in vitro.

[0237] As used herein, an “AAV particle” is a virus which comprises a capsid and a viral genome with at least one payload region and at least one inverted terminal repeat (ITR) region.

[0238] As used herein, “viral genome” or “vector genome” refers to the nucleic acid sequence(s) encapsulated in an AAV particle. Viral genomes comprise at least one payload region encoding polypeptides, e.g., antibodies, antibody-based compositions or fragments thereof.

[0239] As used herein, a “payload” or “payload region” is any nucleic acid molecule which encodes one or more polypeptides. At a minimum, a payload region comprises nucleic acid sequences that encode an antibody, an antibody-based composition, or a fragment thereof, but may also optionally comprise one or more functional or regulatory elements to facilitate transcriptional expression and / or polypeptide translation.

[0240] In some embodiments, AAV particles, viral genomes and / or payloads, and the methods of their use may be as described in W02017189963 or W02020223276, the contents of each of which are herein incorporated by reference in their entirety.

[0241] 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 CDRs (e.g., heavy chain and / or light chain CDRs) of an antibody, a variable heavy (VH) chain region and / or variable light (VL) chain region, a heavy and / or light chain constant region, or a combination thereof. In some embodiments, the nucleic acid sequence encoding the antibody may also encode a linker, e.g., such that the VH / heavy chain and the ‘VL / light chain 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 concatemer count (e.g., the VH, VL, heavy chain, light chain, and / or linker) may be different within or among different payload regions. The identity, position and number of linkers expressed by payload regions may 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.

[0242] In some embodiments, the present disclosure provides methods for delivering an antibody (e.g., an anti-tau antibody described herein) and / or a nucleic acid sequence encoding an antibody (e.g., an anti-tan antibody described herein) comprised within the viral genome comprised within a recombinant, AAV particle (e.g., an AAV particle described herein) to a cell, tissue, organ, or subject. Adeno-associated viruses (AAVs) and AAV particles

[0243] In some embodiments, adeno-associated viruses (AAV) are small non-enveloped icosahedral capsid viruses of the Parvoviridae family characterized by a single stranded DNA viral genome. Parvoviridae family viruses consist of two subfamilies: Parvovirinae, which infect vertebrates, and Densovirinae, which infect invertebrates. The Parvoviridae family comprises the Dependovirus genus which includes AAV. In some embodiments, the AAV is capable of replication in vertebrate hosts including, but not limited to, human, primate, bovine, canine, equine, and ovine species.

[0244] The parvoviruses and other members of the Parvoviridae family are generally described 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.

[0245] AAV have proven to be useful as a biological tool due to their relatively simple structure, their ability to infect a wide range of cells (including quiescent and dividing cells) without integration into the host genome and without replicating, and their relatively benign immunogenic profile. The genome of the virus may be manipulated to contain a minimum of components for the assembly of a functional recombinant virus, or viral particle, which is loaded with or engineered to target a particular tissue and express or deliver a desired payload.

[0246] The wild-type AAV vector genome is a linear, single-stranded DNA (ssDNA) molecule approximately 5,000 nucleotides (nt) in length. Inverted terminal repeats (ITRs) traditionally cap the viral genome at both the 5’ and the 3’ end, providing origins of replication for the viral genome. While not wishing to be bound by theory, an AAV viral genome typically comprises two ITR sequences. These ITRs have a characteristic T-shaped hairpin structure defined by a self-complementary region (145nt 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 structures comprise multiple functions including, but not limited to, acting as an origin for DNA replication by functioning as primers for the endogenous DNA polymerase complex of the host viral replication cell.

[0247] The wild-type AAV viral genome further comprises nucleotide sequences for two open reading frames, one for the four non-structural Rep proteins (Rep78, Rep68, Rep52, Rep40, encoded by Rep genes) and one for the three capsid, or structural, proteins (VPI, 'VP2, VP3, encoded by capsid genes or Cap genes). The Rep proteins are important for replication and packaging, while the capsid proteins are assembled to create the protein shell of the AAV, or AAV capsid. Alternative splicing and alternate initiation codons and promoters result in the generation of four different Rep proteins from a single open reading frame and the generation of three capsid proteins from a single open reading frame. Though it varies by AAV serotype, as a non-limiting example, for AAV9 / hu.14 (SEQ ID NO: 123 of US 7,906,111, the contents of which are herein incorporated by reference in their entirety) ‘VPI 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 of the whole. As a result, changes in the sequence in the VP3 region, are also changes to VP1 and VP2, however, the percent difference as compared to the parent sequence will be greatest for VP3 since it is the shortest sequence of the three. Though described here in relation to the amino acid sequence, the nucleic acid sequence encoding these proteins can be similarly described. Together, the three capsid proteins assemble to create the AAV capsid protein. While not wishing to be bound by theory, the AAV capsid protein typically comprises a molar ratio of 1:1:10 of VP1:VP2:VP3. As used herein, an “AAV serotype” is defined primarily by the AAV capsid. In some instances, the ITRs are also specifically described by the AAV serotype (e.g., AAV2 / 9).

[0248] For use as a biological tool, the wild-type AAV viral genome can be modified to replace the rep / cap sequences with a nucleic acid sequence comprising a payload region with at least one ITR region. Typically, in recombinant AAV viral genomes there are two ITR regions. The rep / cap sequences can be provided in trans during production to generate AAV particles.

[0249] In addition to the encoded heterologous payload, AAV vectors may comprise the viral genome, in whole or in part, of any naturally occurring and / or recombinant AAV serotype nucleotide sequence or variant. AAV variants may have sequences of significant homology at the nucleic acid (genome or capsid) and amino acid levels (capsids), to produce constructs which are generally physical and functional equivalents, replicate by similar mechanisms, and assemble by similar mechanisms. Chiorini ez al., J. Vir. 71: 6823-33(1997); Srivastava ef al., J. Vir. 45:555-64 (1983); Chiorini ez al., J. Vir. 73:1309-1319 (1999); Rutledge er al., J. Vir. 72:309-319 (1998); and Wu er al., I. Vir. 74: 8635-47 (2000), the contents of each of which are incorporated herein by reference in their entirety.

[0250] In some embodiments, AAV particles of the present disclosure are recombinant AAV viral vectors which are replication defective and lacking sequences encoding functional Rep and Cap proteins within their viral genome. These defective AAV vectors may lack most or all parental coding sequences and essentially carry only one or two AAV ITR sequences and the nucleic acid of interest for delivery to a cell, a tissue, an organ, or an organism.

[0251] In some embodiments, the viral genome of the AAV particles of the present disclosure comprise at least one control element which provides for the replication, transcription, and translation of a coding sequence encoded therein. Not all of the control elements need always be present as long as the coding sequence is capable of being replicated, transcribed, and / or translated 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 efficacy (e.g., Kozak consensus sequence), sequences that enhance protein stability, and / or sequences that enhance protein processing and / or secretion.

[0252] According to the present disclosure, AAV particles for use in therapeutics and / or diagnostics comprise a virus that has been distilled or reduced to the minimum components necessary for transduction of a nucleic acid payload or cargo of interest. In this manner, AAV particles are engineered as vehicles for specific delivery while lacking the deleterious replication and / or integration features found in wild-type viruses.

[0253] AAV vectors of the present disclosure may be produced recombinantly and may be based on adeno-associated virus (AAV) parent or reference sequences. As used herein, a “vector” is any molecule or moiety which transports, transduces, or otherwise acts as a carrier of a heterologous molecule such as the nucleic acids described herein.

[0254] In addition to single stranded AAV viral genomes (e.g., sSSAAVs), the present disclosure also provides for self-complementary AAV (scAAVs) viral genomes. sScAAV vector genomes contain DNA strands which anneal together to form double stranded DNA. By skipping second strand synthesis, scAAVs allow for rapid expression in the transduced cell.

[0255] In some embodiments, the AAV particle of the present disclosure is an scCAAV.

[0256] In some embodiments, the AAV particle of the present disclosure is an sSAAV.

[0257] Methods for producing and / or modifying AAV particles are disclosed in the art such as pseudotyped AAV vectors (PCT Patent Publication Nos. W0200028004; W0200123001; W0O2004112727; W02005005610; and WO2005072364, the content of each of which is incorporated herein by reference in its entirety).

[0258] AAV particles may be modified to enhance the efficiency of delivery. Such modified AAV particles can be packaged efficiently and be used to successfully infect the target cells at high frequency and with minimal toxicity. In some embodiments, the capsids of the AAV particles are engineered according to the methods described in US Publication Number US20130195801, the contents of which are incorporated herein by reference in their entirety.

[0259] In some embodiments, the AAV particles comprising a payload region encoding the polypeptides may be introduced into mammalian cells. AAV serotypes

[0260] In some embodiments, the AAV particle, e.g., an AAV particle for the vectorized delivery of an antibody described herein (e.g., an anti-tan antibody), may comprise or be derived from any natural or recombinant AAV serotype. AAV particles of the present disclosure may comprise or be derived from any natural or recombinant AAV serotype. According to the present disclosure, the AAV particles may utilize or be based on a serotype or include a peptide selected from any of the following VOY101, VOY201, AAVPHP.B (PHP.B), AAVPHP.A (PHP.A), AAVG2B-26, AAVG2B-13, AAVTHI1.1-32, AAVTHL1.1- 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), AAVG2BS (G2BS5), PHP.S, AAV1, AAV2, AAV2GY, AAV3, AAV3a, AAV3b, AAV3-3, AAV4, AAV4-4, AAVS, AAVE, AAV6.1, AAV6.2, AAV6.1.2, AAVT, AAV 2, AAVS, AAV9, AAVI K449R, AAVI.11, AAVO.13, AAV9.16, AAVO.24, AAVI 45, AAV9.47, AAVI.61, AAVI.68, AAVI.84, AAVO.9, AAV10, AAV1], AAVI12, 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, AAV42-15, AAV42-aa, AAV43-1, AAV43-12, AAV43-20, AAVA43-21, AAV43-23, AAV43-25, AAV43-5, AAV44.1, AAV4A4.2, AAV44.5, AAV223.1, AAV223.2, AAV223.4, AAV223.5, AAV223.6, AAV223.7, AAV1-7 / rh.48, AAV1-8 / rth.49, AAV2- 15 / rh.62, AAV2-3 / th.61, AAV2-4 / rh.50, AAV2-5 / th.51, AAV3.1 / hu.6, AAV3.1 / hu.9, AAV3-9 / th.52, AAV3-11 / th.53, AAV4-8 / r11.64, AAV4-9 / th.54, AAV4-19 / rh.55, AAVS- 3 / rh.57, AAV5-22 / rh.58, AAV7.3 / hu.7, AAV16.8 / hu.10, AAV16.12 / 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, AAV52 / hu.19, AAV52.1 / hu.20, AAV58.2 / hu.25, AAVA3.3, AAVA3.4, AAVA3S, AAVA3.7, AAVCI, AAVC2, AAVCS, AAV-DJ, AAV-DJ8, AAVF3, AAVF35, AAVH2, AAV1h.72, AAVhu.8, AAVrh.68, AAVrh.70, AAVpi.1, AAVpi...

Claims

CLAIMS ‘What is claimed is: 1; An isolated, e.g., recombinant, antibody that binds to tau comprising a heavy chain variable region (VH) comprising an HC CDR1, an HC CDR2, and an HC CDR3, and a light chain variable region (VL) comprising an LC CDR1, an LC CDR2, and an LC CDR3, wherein: (i) the HC CDRI1, HC CDR2, and HC CDR3 comprise the amino acid sequence of SEQ ID NOs: 315, 341, and 410, respectively; and the LC CDR1, LC CDR2, LC CDR3 comprise the amino acid sequence of SEQ ID NOs: 474, 529, and 571, respectively; (ii) the HC CDRI1, HC CDR2, and HC CDR3 comprise the amino acid sequence of SEQ ID NOs: 314, 341, and 410, respectively; and the LC CDR1, LC CDR2, LC CDR3 comprise the amino acid sequence of SEQ ID NOs: 1154, 529, and 571, respectively; (iii) the HC CDR1, HC CDR2, and HC CDR3 comprise the amino acid sequence of SEQ ID NOs: 316, 341, and 410, respectively; and the LC CDR1, LC CDR2, LC CDR3 comprise the amino acid sequence of SEQ ID NOs: 475, 530, and 571, respectively; (iv) the HC CDRI1, HC CDR2, and HC CDR3 comprise the amino acid sequence of SEQ ID NOs: 325, 362, and 435, respectively; and the LC CDR1, LC CDR2, LC CDR3 comprise the amino acid sequence of SEQ ID NOs: 495, 540, and 587, respectively; wv) the HC CDRI1, HC CDR2, and HC CDR3 comprise the amino acid sequence of SEQ ID NOs: 304, 347, and 400, respectively; and the LC CDR1, LC CDR2, LC CDR3 comprise the amino acid sequence of SEQ ID NOs: 464, 523, and 562, respectively; (vi) the HC CDRI1, HC CDR2, and HC CDR3 comprise the amino acid sequence of SEQ ID NOs: 299, 343, and 395, respectively; and the LC CDR1, LC CDR2, LC CDR3 comprise the amino acid sequence of SEQ ID NOs: 460, 518, and 557, respectively; or (vii) the HC CDRI1, HC CDR2, and HC CDR3 comprise the amino acid sequence of any of the HC CDR sequences of Tables 1, 6, 2A-2C, 4, or 5; and the LC CDRI1, LC CDR2, LC CDR3 comprise the amino acid sequence of any of the LC CDR sequences of Tables 1, 6, 2A-2C, 4, or 5.

2. An isolated, e.g., recombinant, antibody that binds to tau comprising a heavy chain variable region (VH) comprising an HC CDR1, an HC CDR2, and an HC CDR3, and a light chain variable region (VL) comprising an LC CDR1, an LC CDR2, and an LC CDR3, wherein: 1) the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequence of SEQ ID NOs: 1180, 341, 410, 1181, 1182, and 571, respectively; (ii) the HC CDRI1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequence of SEQ ID NOs: 1183, 1184, 410, 1185, 1182, and 571, respectively; or (iii) the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequence of SEQ ID NOs: 1186, 1187, 1167, 1188, 528, and 571, respectively; optionally wherein the antibody binds to a region of a human tau protein comprising residues 409-436, numbered according to SEQ ID NO:

920. 3: The antibody of claim 2, wherein the antibody binds to the region of the human tau protein comprising residues 409-436, numbered according to SEQ ID NO: 920, and wherein: (i) the HC CDRI1, HC CDR2, and HC CDR3 comprise the amino acid sequence of SEQ ID NOs: 1180, 341, and 410, respectively; and (ii) the LC CDRI1, LC CDR2, and LC CDR3 comprise the amino acid sequence of SEQ ID NOs: 1181, 1182 and 571, respectively.

4. The antibody of any one of claims 1-3, wherein: (i) the VH comprises the 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; (ii) the VH comprises an amino acid sequence having at least one, two or three modifications, but not more than 30, 20 or 10 modifications of the amino acid sequence of SEQ ID NO: 22, 21, 23, 51, 9, or 4; (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 provided in Table 3 or 4, or an amino acid sequence having at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; or an amino acid sequence having at least one, two or three modifications, but not more than 30, 20 or 10 modifications of the amino acid sequence of any VH provided in Table 3 or 4.

5. The antibody of any one of claims 1-4, wherein: (i) the VL comprises the 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; (ii) the VL comprises an amino acid sequence having at least one, two or three modifications, but not more than 30, 20 or 10 modifications of the amino acid sequence of SEQ ID NO: 94, 93, 95, 122, 83, or 78; (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 the amino acid sequence of any VL provided in Table 3 or 4, or an amino acid sequence having at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto; or an amino acid sequence having at least one, two or three modifications, but not more than 30, 20 or 10 modifications of the amino acid sequence of any VL provided in Table 3 or 4.

6. The antibody of any one of claims 1-5, wherein: (i) the VH comprises the amino acid sequence of SEQ ID NO: 22 or an amino acid sequence either having at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto or having at least one, two or three modifications, but not more than 10 modifications thereof, and the VL comprises the amino acid sequence of SEQ ID NO: 94 or an amino acid sequence either having at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto or having at least one, two or three modifications, but not more than 10 modifications thereof’: (ii) the VH comprises the amino acid sequence of SEQ ID NO: 21 or an amino acid sequence either having at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto or having at least one, two or three modifications, but not more than 10 modifications thereof, and the VL comprises the amino acid sequence of SEQ ID NO: 93 or an amino acid sequence either having at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto or having at least one, two or three modifications, but not more than 10 modifications thereof; the VH comprises the amino acid sequence of SEQ ID NO: 23 or an amino acid sequence either having at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto or having at least one, two or three modifications, but not more than 10 modifications thereof, and the VL comprises the amino acid sequence of SEQ ID NO: 95 or an amino acid sequence either having at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto or having at least one, two or three modifications, but not more than 10 modifications thereof’ the VH comprises the amino acid sequence of SEQ ID NO: 51 or an amino acid sequence either having at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto or having at least one, two or three modifications, but not more than 10 modifications thereof, and the VL comprises the amino acid sequence of SEQ ID NO: 122 or an amino acid sequence either having at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto or having at least one, two or three modifications, but not more than 10 modifications thereof; the VH comprises the amino acid sequence of SEQ ID NO: 9 or an amino acid sequence either having at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto or having at least one, two or three modifications, but not more than 10 modifications thereof, and the VL comprises the amino acid sequence of SEQ ID NO: 83 or an amino acid sequence either having at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto or having at least one, two or three modifications, but not more than 10 modifications thereof; or, the VH comprises the amino acid sequence of SEQ ID NO: 4 or an amino acid sequence either having at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto or having at least one, two or three modifications, but not more than 10 modifications thereof, and the VL comprises the amino acid sequence of SEQ ID NO: 78 or an amino acid sequence either having at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto or having at least one, two or three modifications, but not more than 10 modifications thereof.

7. The antibody of any one of claims 1-6, wherein: 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.

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

9. The antibody of any one of claims 1-8, comprising a heavy chain constant region selected from human IgG1, human IgG2, human IgG3, and human IgG4, murine IgG1, murine IgG2a, murine IgG2b, murine IgG2¢, and murine IgG3; and / or a light chain constant region chosen from the light chain constant regions of kappa or lambda, e.g., human or mouse kappa, or human or mouse lambda.

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

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

12. The antibody of any one of claims 1-11, which binds to a tau protein with a dissociation constant (Kp) of less than about 120 nM (e.g., as measured by Octet, e.g., as described in Example 8).

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

14. Anisolated, e.g., recombinant, antibody that competes for binding to tau with the antibody of any one of the preceding claims. 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 the antibody of any one of the preceding claims.

16. An isolated, e.g., recombinant, nucleic acid encoding the antibody of any one of the preceding claims.

17. Anisolated, e.g., recombinant, nucleic acid encoding an antibody comprising a VH comprising an HC CDR1, an HC CDR2, and an HC CDR3, and a VL comprising an LC CDR1, an LC CDR2, and an LC CDR3, wherein: (i) the HC CDRI1, HC CDR2, and HC CDR3 comprise the amino acid sequence of SEQ ID NOs: 315, 341, and 410, respectively; and the LC CDR1, LC CDR2, LC CDR3 comprise the amino acid sequence of SEQ ID NOs: 474, 529, and 571, respectively; (ii) the HC CDRI1, HC CDR2, and HC CDR3 comprise the amino acid sequence of SEQ ID NOs: 314, 341, and 410, respectively; and the LC CDR1, LC CDR2, LC CDR3 comprise the amino acid sequence of SEQ ID NOs: 1154, 529, and 571, respectively; (iii) the HC CDR1, HC CDR2, and HC CDR3 comprise the amino acid sequence of SEQ ID NOs: 316, 341, and 410, respectively; and the LC CDR1, LC CDR2, LC CDR3 comprise the amino acid sequence of SEQ ID NOs: 475, 530, and 571, respectively; (iv) the HC CDRI1, HC CDR2, and HC CDR3 comprise the amino acid sequence of SEQ ID NOs: 325, 362, and 435, respectively; and the LC CDR1, LC CDR2, LC CDR3 comprise the amino acid sequence of SEQ ID NOs: 495, 540, and 587, respectively; w) the HC CDRI1, HC CDR2, and HC CDR3 comprise the amino acid sequence of SEQ ID NOs: 304, 347, and 400, respectively; and the LC CDR1, LC CDR2, LC CDR3 comprise the amino acid sequence of SEQ ID NOs: 464, 523, and 562, respectively; (vi) the HC CDRI1, HC CDR2, and HC CDR3 comprise the amino acid sequence of SEQ ID NOs: 299, 343, and 395, respectively; and the LC CDR1, LC CDR2, LC CDR3 comprise the amino acid sequence of SEQ ID NOs: 460, 518, and 557, respectively; or (vii) the HC CDRI1, HC CDR2, and HC CDR3 comprise the amino acid sequence of any of the HC CDR sequences of Tables 1, 6, 2A-2C, 4, or 5; and the LC CDRI1, LC CDR2, LC CDR3 comprise the amino acid sequence of any LC CDR sequence of Tables 1, 6, 2A-2C, 4, or 5.

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

19. The nucleic acid of claims 17 or 18, comprising: (i) the nucleotide sequence of any VH provided 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 provided in Table 3 or 4, or a nucleotide sequence having at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

20. The nucleic acid of any one of claims 17-19, comprising: 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.

21. The nucleic acid of any one of claims 17-20, wherein the antibody comprises: (i) a heavy chain constant region comprising an amino acid of a heavy chain constant region provided 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 the amino acid sequence of a light chain constant region provided in Table X, or an amino acid sequence having at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto.

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

23. An isolated, e.g., recombinant antibody, encoded by the nucleic acid of any one of claims 17-22.

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

25. The nucleic acid of claim 24, further encoding a signal sequence and optionally a second signal sequence, optionally wherein 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 with at least 95% sequence identity thereto.

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

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

28. The nucleic acid of any one of claims 24-27, wherein the encoded payload is a full length antibody, a bispecific antibody, an Fab, an F(ab'),, an Fv, a single chain Fv fragment (scFv), single domain antibody, or a camelid antibody.

29. A viral genome comprising a promoter operably linked to the nucleic acid encoding a payload comprising the antibody of any one of claims 1-15 and 23, optionally, wherein the promoter: @) is chosen from human elongation factor 1a-subunit (EFla), cytomegalovirus (CMV) immediate-early enhancer and / or promoter, chicken p-actin (CBA) and its derivative CAG, PB glucuronidase (GUSB), or ubiquitin C (UBC), neuron-specific enolase (NSE), platelet-derived growth factor (PDGF), platelet-derived growth factor B-chain (PDGF-p), 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 (mGIluR?2), neurofilament light (NFL) or heavy (NFH), B-globin minigene np2, preproenkephalin (PPE), enkephalin (Enk) and excitatory amino acid transporter 2 (EAAT2), glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), or a fragment, e.g., a truncation, or a functional variant thereof; and / or (ii) comprises the nucleotide sequence of any of the promoter sequences provided in Table 11, or a nucleotide sequence at least 95% identical thereto.

30. The viral genome of claim 29, which further comprises an enhancer, optionally wherein the enhancer is a CMV immediate-early (CM Vie) enhancer.

31. The viral genome of claim 29 or 30, which further comprises: (1) a polyadenylation (polyA) signal region, optionally, wherein the polyA signal region comprises the nucleotide sequence of any of SEQ ID NO: 1134-1136, or a nucleotide sequence with at least 95% identity thereto; (ii) an ITR sequence, optionally wherein: (a) the ITR sequence is positioned 5° relative to the encoded payload and / or the ITR sequence is positioned 3’ relative to the encoded; and / or (b) the ITR sequence comprises a nucleotide sequence of any one of SEQ ID NOs: 1035-1038, or a nucleotide sequence with at least 80%, 85%, 90%, or 95% sequence identity thereto; (iii) atleast 1, 2, or 3 intron regions, optionally, wherein each intron region independently comprises a nucleotide sequence of any of the intron regions listed in Table 13, or a nucleotide sequence with at least 95% identity thereto; (iv) at least 1, 2, or 3 exon regions; optionally, wherein each exon region independently comprises a nucleotide sequence of any of the exon sequences in Table 12, or a nucleotide sequence with at least 95% identity thereto; and / or wv) a Kozak sequence, optionally wherein the Kozak sequence comprises the nucleotide sequence of GCCGCCACCATG (SEQ ID NO: 1079) or GAGGAGCCACC (SEQ ID NO: 1089).

32. The viral genome of any one of claims 29-31, which further comprises a nucleotide sequence encoding a miR binding site, e.g., a miR binding site that modulates, e.g., reduces, expression of the payload encoded by the viral genome in a cell or tissue where the corresponding miRNA is expressed.

33. The viral genome of claim 32, which comprises at least 1-5 copies of an encoded miR binding site, e.g., at least 1, 2, 3, 4, or 5 copies.

34. The viral genome of claim 32 or 33, which comprises at least 3 or 4 copies of the encoded miR binding site, optionally wherein all copies comprise the same miR binding site, or at least one, two, three or all of the copies comprise a different miR binding site.

35. The viral genome of any one of claims 32-34, wherein the encoded miR binding site comprises a miR 122 binding site, a miR 183 binding site, a miR-142-3p, or a combination thereof, optionally wherein: i) the encoded miR122 binding site comprises the nucleotide sequence of SEQ ID NO: 1029, or a nucleotide sequence substantially identical (e.g., having at least 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto; or a nucleotide sequence having at least one, two, three, four, five, six, or seven modifications, but no more than ten 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 (e.g., having at least 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto; or a nucleotide sequence having at least one, two, three, four, five, six, or seven modifications, but no 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 (e.g., having at least 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) thereto; or a nucleotide sequence having at least one, two, three, four, five, six, or seven modifications, but no more than ten modifications of SEQ ID NO: 1031.

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

37. A vector comprising the viral genome of any one claims 29-36, optionally wherein the vector further comprises: (i) a nucleotide sequence encoding a Rep protein, e.g., a non-structural protein, wherein the Rep protein comprises a Rep78 protein, a Rep68, Rep52 protein, and / or a Rep4( protein, optionally wherein 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, e.g., a structural protein, wherein the capsid protein comprises a VP1 polypeptide, a VP2 polypeptide, and / or a VP3 polypeptide, optionally wherein the VP1 polypeptide, the VP2 polypeptide, and / or the VP3 polypeptide are encoded by at least one Cap gene.

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

39. The isolated AAV particle of claim 38, wherein: (1) the capsid protein comprises the amino acid sequence of SEQ ID NO: 1003, or an amino acid sequence with 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 but not more than 30, 20 or 10 modifications of the amino acid sequence of SEQ ID NO: 1003; (iii) the capsid protein comprises the amino acid sequence of SEQ ID NO: 1011, or an amino acid sequence with 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 but not more than 30, 20 or 10 modifications of the amino acid sequence of SEQ ID NO: 1011; w) the capsid protein comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 1002, or a sequence with 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 with at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto.

40. The isolated AAV particle of claim 38 or 39, wherein the capsid protein comprises: (i) an amino acid substitution at position K449, e.g., a K449R substitution, numbered according to SEQ ID NO:1003; (ii) an insert comprising the amino acid sequence of TLAVPFK (SEQ ID NO: 1151), optionally wherein the insert is present immediately subsequent to position 588, relative to a 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) the amino acid substitution of A587D and / or Q588G, numbered according to SEQ ID NO: 1003.

41. The isolated AAV particle of any one of claims 38-40, wherein the capsid protein comprises: i) (a) the 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 wherein the insert is present immediately subsequent to position 588 of SEQ ID NO: 1003; (ii) (a) the 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 wherein the insert is present immediately subsequent to position 588, relative to a reference sequence numbered according to SEQ ID NO: 1003; and (c) the 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 wherein the insert is present immediately subsequent to position 588, relative to a reference sequence numbered according to SEQ ID NO: 1003; and (b) the amino acid substitutions of A587D and Q588G, numbered according to SEQ ID NO: 1003.

42. The AAV particle of any one of claims 38-41, wherein the capsid protein comprises: 1) aVOY101, 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), AAVG2BS (G2B5), AAVPHP.N (PHP.N), PHP.S, AAV1, AAV2, AAV2 variant, AAV2 / 3 variant, AAV4, AAVS, AAV6, AAV7, AAVS, AAV9.47, AAV9(huld), AAV9, AAV9 K449R, AAV 10, AAV11, AAV12, AAVrhS, AAVrhl10, AAVDJ], AAVDIS, or AAV2G9 capsid protein, or a functional variant thereof; optionally, the capsid protein comprises a VOY 101 capsid protein; and / or (ii) any of the capsid proteins listed in Table 1 or a functional variant thereof.

43. A host cell comprising the nucleic acid of any one of claims 16-22 and 24-28, the viral genome of any one of claims 29-36, or the AAV particle of any one of claims 38-42, optionally wherein the host cell is an insect cell, a bacterial cell or a mammalian cell. 44, A method of producing an antibody, the method comprising culturing the host cell of claim 43 under conditions suitable for gene expression.

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

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

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

48. The method of claim 47, wherein the neurological disorder comprises: i) a tauopathy; and / or (ii) AD, FTDP-17, FTLD, FID, CTE, PSP, Down’s syndrome, Pick’s disease, CBD, Corticobasal syndrome, ALS, Prion diseases, CJD, Multiple system atrophy, Tangle-only dementia, or Progressive subcortical gliosis.

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

50. The method of any one of claims 46-49, wherein the AAV particle is administered to the subject intravenously, intramuscularly, via intraparenchymal administration, intracerebroventricularly, via intra-cisterna magna (ICM) injection, intrathecally, via focused ultrasound (FUS), e.g., coupled with the intravenous administration of microbubbles (FUS-MB), or MRI-guided FUS coupled with intravenous administration; optionally, the AAV particle is administered to the subject intravenously; or via intra-cisterna magna injection (ICM).

51. The method of any one of claims 46-50, further comprising administration of an additional therapeutic agent and / or therapy suitable for treatment or prevention of a neurological or neurodegenerative disorder, e.g., a tauopathy, optionally, 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 drug, an anti-anxiety drug, an anticonvulsant, a dopamine agonist (e.g., pramipexole, ropinirole, rotigotine, and / or apomorphine), an MAO B inhibitor (e.g., selegiline, rasagiline, and / or safinamide), catechol O-methyltransferase (COMT) inhibitors (entacapone, opicapone, and / or tolcapone), anticholinergics (e.g., benztropine and / or trihexyphenidyl), amantadine, carbidopa-levodopa, deep brain simulation (DBS), or a combination thereof.

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

53. The antibody of any one of claims 1-15 and 23, the isolated nucleic acid of any one of claims 16-22 and 24-28, the AAV particle comprising the viral genome of any one of claims 29-36, the AAV particle of any one of claims 38-42, or the pharmaceutical composition of claim 45, for use in treating a neurological or neurodegenerative disorder, e.g., a tauopathy.

54. Use of an effective amount of the antibody of any one of claims 1-15 and 23, the isolated nucleic acid of any one of claims 16-22 and 24-28, the AAV particle comprising the viral genome of any one of claims 29-36, the AAV particle of any one of claims 38-42, or the pharmaceutical composition of claim 435, in the manufacture of a medicament for the treatment of a neurological or neurodegenerative disorder, e.g., a tauopathy in a subject.