Tau-binding compound

Abstract

The present disclosure provides anti-tau antibodies and their vectorization (e.g., into AAV particles), as well as methods of using the anti-tau antibodies and / or AAV particles for the prevention, treatment, and / or diagnosis of neurological indications.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of the filing dates of U.S. Provisional Patent Application No. 63 / 010,261, filed Apr. 15, 2020, and U.S. Provisional Patent Application No. 63 / 162,976, filed Mar. 18, 2021, and the entire contents of the applications referenced above are incorporated herein by reference, including all arrangements in the tables and drawings.

[0002] Sequence Listing This application includes a sequence listing submitted electronically in ASCII format, which is incorporated herein by reference in its entirety.

[0003] The present disclosure presents tau - binding compounds and adeno - associated virus (AAV) particles containing the same.

Background Art

[0004] Tauopathies are a group of neurodegenerative diseases characterized by the dysfunction and / or aggregation of the microtubule - associated protein tau. Tau is a protein that is normally highly soluble and is known to associate with microtubules based on its degree of phosphorylation. Given its unique and extended structure, tau is considered an important component of the intracellular transport process, particularly in neurons. Hyperphosphorylation of tau inhibits its binding to microtubules and microtubule assembly activity. Furthermore, when tau becomes hyperphosphorylated, it is prone to misfolding and aggregation. In tauopathies, tau is hyperphosphorylated, misfolds, and aggregates as paired helical filaments (PHF), twisted ribbons, or straight filaments of neurofibrillary tangles (NFT). These NFTs are widely considered to indicate impending neuronal death and are thought to contribute to widespread neuronal loss, leading to various behavioral and cognitive impairments.

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

[0006] Several approaches have been proposed to therapeutically interfere with the progression of tau lesions and prevent subsequent molecular and cellular consequences. Given that NFTs are composed of hyperphosphorylated, misfolded, and aggregated forms of tau, interference at each of these stages presents tractable targets. The introduction of agents that limit phosphorylation, block misfolding, or prevent aggregation is a promising strategy. It has also been suggested that the introduction of anti-tau antibodies can prevent the transneuronal spread of tau lesions.

[0007] There remains a need for anti-tau antibodies for use in the treatment, diagnosis, and other uses of tauopathies. The present disclosure addresses this need by the related compounds and methods described herein.

Prior Art Documents

Non-Patent Documents

[0008]

Non-Patent Document 1

Summary of the Invention

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

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

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

[0012] 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, the reference antibody comprising a VH comprising HC CDR1, HC CDR2, and HC CDR3 and a VL comprising light chain LC CDR1, LC CDR2, and LC CDR3, wherein HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 each comprise the amino acid sequences of SEQ ID NOs: 315, 341, 410, 474, 529, and 571, or HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 each comprise the amino acid sequences of SEQ ID NOs: 314, 341, 410, 1154, 529, and 571, or HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 each comprise the amino acid sequences of SEQ ID NOs: 316, 341, 410, 475, 530, and 571.

[0013] 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 HC CDR1, HC CDR2, and HC CDR3, wherein HC CDR1, HC CDR2, and HC CDR3 comprise the amino acid sequences of SEQ ID NOs: 1180, 341, and 410, respectively, or HC CDR1, HC CDR2, and HC CDR3 comprise the amino acid sequences of SEQ ID NOs: 1183, 1184, and 410, respectively, or HC CDR1, HC CDR2, and HC CDR3 comprise the amino acid sequences of SEQ ID NOs: 1186, 1187, and 1167, respectively. In some embodiments, the antibody comprises a VL comprising LC CDR1, LC CDR2, and LC CDR3, wherein LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 1181, 1182, and 571, respectively, or LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 1185, 1182, and 571, respectively, or LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 1188, 528, and 571, respectively.

[0014] 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: 920.

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

[0016] In yet another aspect, the 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 as described herein). In some embodiments, the viral genome further comprises an internal terminal repeat (ITR) sequence (e.g., an ITR region as described herein), an enhancer (e.g., an enhancer as described herein), an intron region (e.g., an intron region as described herein) and / or an exon region (e.g., an exon region as described herein), a polyA signal region (e.g., a polyA signal sequence as described herein), and / or a coded miR - binding site.

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

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

[0019] In yet another aspect, the present disclosure provides a method for treating a subject having or diagnosed with a neuropathy, tauopathy, and / or a disease associated with tau expression. The method includes administering to the subject an effective amount of an AAV particle or a plurality of AAV particles described herein, wherein the AAV particle includes a viral genome described herein.

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

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

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

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

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

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

[0026] CDRL1 may 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). CDRL2 may include an amino acid sequence selected from the group consisting of RVSNRFS (SEQ ID NO: 529) and RVSSRFS (SEQ ID NO: 530). CDRL3 may include the amino acid sequence of FQGTHVPRT (SEQ ID NO: 571).

[0027] CDRH1 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). CDRH2 may include the amino acid sequence of YWDDD (SEQ ID NO: 362). 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] CDRL1 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). 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). 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] The antibodies of the present disclosure may include formats selected from the group consisting of monoclonal antibodies, multispecific antibodies, chimeric antibodies, antibody mimetics, single-chain Fv (scFv) formats, and antibody fragments. The antibodies may include antibody classes selected from the group consisting of IgA, IgD, IgE, IgG, and IgM. The antibodies may include mouse IgG, and mouse IgG includes isotypes selected from the group consisting of IgG1, IgG2a, IgG2b, IgG2c, and IgG3. The antibodies may include human IgG, and human IgG includes isotypes selected from the group consisting of IgG1, IgG2, IgG3, and IgG4. The antibodies may include one or more human constant domains. The one or more human constant domains may include human IgG constant domains. The antibodies may include humanized antibodies.

[0030] The antibodies of the present disclosure may bind to tau protein epitopes. The tau protein epitope may include or may be contained within an amino acid sequence selected from the group consisting of SEQ ID NOs: 920-926. The antibodies may compete for binding to the tau protein epitope with one or more selected from 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). The antibody that binds to the tau protein epitope may exhibit a K D of 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). The antibody that binds to the tau protein epitope may exhibit a K Dcan be presented. The tau protein epitope may include a region formed by a complex of at least two tau proteins. The antibody can bind to enriched paired helical filament tau protein (ePHF) with a maximum half-maximal effective concentration (EC50) of about 0.01 nM to about 100 nM. The antibody may not bind to non-pathological tau. The antibody can bind to pathological tau. The antibody can inhibit tau aggregation with a maximum half-maximal inhibitory concentration (IC50) of about 1 nM to about 30 nM as determined by an immunodepletion assay. The immunodepletion assay can be performed using tau RD biosensor cells.

[0031] In some embodiments, the disclosure provides an antibody that competes with a second antibody for binding to a tau protein epitope, the tau protein epitope including 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 VH having the amino acid sequence of SEQ ID NO: 21 and VL having the amino acid sequence of SEQ ID NO: 93, VH having the amino acid sequence of SEQ ID NO: 22 and VL having the amino acid sequence of SEQ ID NO: 94, and VH having the amino acid sequence of SEQ ID NO: 23 and VL having the amino acid sequence of SEQ ID NO: 95.

[0032] The antibodies of the disclosure may include a conjugate. The conjugate may include a therapeutic agent. The conjugate may include a detectable label. In some embodiments, the disclosure provides a construct encoding an antibody disclosed herein.

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

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

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

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

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

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

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

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

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

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

[0043] In some embodiments, the AAV viral genomes described herein may be incorporated into AAV particles. In some embodiments, the AAV particle comprises an AAV capsid protein selected from VOY101, VOY201, AAVPHP.B (PHP.B), AAVPHP.A (PHP.A), AAVG2B-26, AAVG2B-13, AAVTH1.1-32, AAVTH1.1-35, AAVPHP.B2 (PHP.B2), AAVPHP.B3 (PHP.B3), AAVPHP.N / PHP.B-DGT, AAVPHP.B-EST, AAVPHP.B-GGT, AAVPHP.B-ATP, AAVPHP.B-ATT-T, AAVPHP.B-DGT-T, AAVPHP.B-GGT-T, AAVPHP.B-SGS, AAVPHP.B-AQP, AAVPHP.B-QQP, AAVPHP.B-SNP(3), AAVPHP.B-SNP, AAVPHP.B-QGT, AAVPHP.B-NQT, AAVPHP.B-EGS, AAVPHP.B-SGN, AAVPHP.B-EGT, AAVPHP.B-DST, AAVPHP.B-DST, AAVPHP.B-STP, AAVPHP.B-PQP, AAVPHP.B-SQP, AAVPHP.B-QLP, AAVPHP.B-TMP, AAVPHP.B-TTP, AAVPHP.S / G2A12, AAVG2A15 / G2A3 (G2A3), AAVG2B4 (G2B4), AAVG2B5 (G2B5), AAVPHP.N (PHP.N), PHP.S, AAV1, AAV2, AAV2 variant, AAV2 / 3 variant, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9.47, AAV9 (hu14), AAV9, AAV9 K449R, AAV10, AAV11, AAV12, AAVrh8, AAVrh10, AAVDJ, AAVDJ8, AAV2.BR1, or AAV2G9 capsid protein, or a functional variant thereof.

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

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

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

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

[0048] In some embodiments, the viral genome includes an encoded miR122 binding site having the nucleotide sequence of SEQ ID NO: 1029, or a nucleotide sequence that is substantially identical thereto (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity), or having at least 1, 2, 3, 4, 5, 6, or 7 modifications of SEQ ID NO: 1029, provided that the number of modifications is 10 or less.

[0049] In some embodiments, the viral genome has a nucleotide sequence of SEQ ID NO: 1032, or a nucleotide sequence that is substantially identical thereto (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity), or has at least 1, 2, 3, 4, 5, 6, or 7 modifications of SEQ ID NO: 1032, but has 10 or fewer modifications, and has a coded miR183 binding site.

[0050] In some embodiments, the viral genome has a nucleotide sequence of SEQ ID NO: 1031, or a nucleotide sequence that is substantially identical thereto (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity), or has at least 1, 2, 3, 4, 5, 6, or 7 modifications of SEQ ID NO: 1031, but has 10 or fewer modifications, and has a coded miR-142-3p binding site.

[0051] In some embodiments, the viral genome contains at least 4 copies of the coded miR binding site, and optionally, all 4 copies contain the same miR binding site, or at least 1, 2, or 3 copies contain different miR binding sites.

[0052] In some embodiments, the AAV particles disclosed herein can be formulated into a pharmaceutical composition. The present disclosure provides a method for producing an antibody in a subject by administering a pharmaceutical composition to the subject.

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

[0054] Tauopathies that can 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 syndrome, Pick's disease, CBD, corticobasal syndrome, ALS, prion disease, CJD, multiple system atrophy, neurofibrillary type senile dementia, and progressive subcortical gliosis.

[0055] One of ordinary skill 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 embodiments.

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

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

[0058] E3. Said reference antibody is (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 and is the antibody according to embodiment E1 or E2.

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

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

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

[0062] E7. An antibody according to any one of embodiments E1 to E6, which binds to tau protein with a dissociation constant (K D ) of about 0.1 to about 10 nM, or about 0.2 to 5 nM.

[0063] E8. (i) SEQ ID NOs: 1180, 341, and 410, respectively, (ii) SEQ ID NOs: 1183, 1184, and 410, respectively, or (iii) SEQ ID NOs: 1186, 1187, and 1167 An antibody according to any one of embodiments E1 to E7, which comprises a heavy chain variable region comprising at least 1, 2, or 3 of HC CDR1, HC CDR2, and HC CDR3, which comprise the amino acid sequences of (i), (ii), or (iii) above.

[0064] E9. (i) SEQ ID NOs: 1181, 1182, and 571, respectively, (ii) SEQ ID NOs: 1185, 1182, and 571, respectively, or, (iii) SEQ ID NOs: 1188, 528, and 571 An antibody according to any one of embodiments E1 to E8, which comprises a light chain variable region (VL) comprising 1, 2, or 3 of LC CDR1, LC CDR2, and / or LC CDR3, which comprise the sequences of (i), (ii), or (iii) above.

[0065] E10. (i) The HC CDR1, the HC CDR2, the HC CDR3, the LC CDR1, the LC CDR2, and the LC CDR3 each contain the amino acid sequence of SEQ ID NO: 315, 341, 410, 474, 529, and 571, or (ii) The HC CDR1, the HC CDR2, the HC CDR3, the LC CDR1, the LC CDR2, and the LC CDR3 each contain the amino acid sequence of SEQ ID NO: 1147, 1148, 410, 474, 529, and 571, or (iii) The HC CDR1, the HC CDR2, the HC CDR3, the LC CDR1, the LC CDR2, and the LC CDR3 each contain the amino acid sequence of SEQ ID NO: 1168, 1169, 1167, 1170, 528, and 571. The antibody according to any one of Embodiments E1 to E9.

[0066] E11. (i) The HC CDR1, the HC CDR2, the HC CDR3, the LC CDR1, the LC CDR2, and the LC CDR3 each contain the amino acid sequence of SEQ ID NO: 314, 341, 410, 1154, 529, and 571, or (ii) The HC CDR1, the HC CDR2, the HC CDR3, the LC CDR1, the LC CDR2, and the LC CDR3 each contain the amino acid sequence of SEQ ID NO: 1144, 1145, 410, 1146, 529, and 571, or (iii) The HC CDR1, the HC CDR2, the HC CDR3, the LC CDR1, the LC CDR2, and the LC CDR3 each contain the amino acid sequence of SEQ ID NO: 1165, 1166, 1167, 473, 528, and 571. The antibody according to any one of Embodiments E1 to E9.

[0067] E12. (i) The HC CDR1, the HC CDR2, the HC CDR3, the LC CDR1, the LC CDR2, and the LC CDR3 each contain the amino acid sequence of SEQ ID NO: 316, 341, 410, 475, 530, and 571, or (ii) The HC CDR1, the HC CDR2, the HC CDR3, the LC CDR1, the LC CDR2, and the LC CDR3 each contain the amino acid sequence of SEQ ID NO: 1149, 1150, 410, 475, 530, and 571, or (iii) The HC CDR1, the HC CDR2, the HC CDR3, the LC CDR1, the LC CDR2, and the LC CDR3 each contain the amino acid sequence of SEQ ID NO: 1171, 1166, 1167, 1172, 528, and 571, An antibody according to any one of Embodiments E1 to E9.

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

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

[0070] E15. An antibody that binds, for example, 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.

[0071] E16. The antibody according to embodiment E14 or E15, which binds to 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.

[0072] E17. The antibody according to embodiment E14 or E15, which binds to 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.

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

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

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

[0076] E21. The antibody according to any one of embodiments E14-E20, which binds to tau protein with a dissociation constant (K D ) of about 0.1 to about 1 nM.

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

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

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

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

[0081] E26. (i) HC CDR1, HC CDR2, and HC CDR3 each containing the amino acid sequences of SEQ ID NO: 931 or 932, 341, and 410, and / or (ii) LC CDR1, LC CDR2, and LC CDR3 each containing the amino acid sequences of SEQ ID NO: 933 or 934, 935 or 936, and 571 The antibody according to any one of embodiments E22 - E25, containing the above.

[0082] E27. (i) HC DR1, HC CDR2, and HC CDR3 each containing the amino acid sequences of SEQ ID NOs: 1180, 341, and 410, respectively, and / or LC CDR1, LC CDR2, and LC CDR3 each containing the amino acid sequences of SEQ ID NOs: 1181, 1182, and 571, respectively, (ii) HC DR1, HC CDR2, and HC CDR3 each containing the amino acid sequences of SEQ ID NOs: 1183, 1184, and 410, respectively, and / or LC CDR1, LC CDR2, and LC CDR3 each containing the amino acid sequences of SEQ ID NOs: 1185, 1182, and 571, respectively, or (iii) HC DR1, HC CDR2, and HC CDR3 each containing the amino acid sequences of SEQ ID NOs: 1186, 1187, and 1167, respectively, and / or LC CDR1, LC CDR2, and LC CDR3 each containing the amino acid sequences of SEQ ID NOs: 1188, 528, and 571, respectively The antibody according to any one of Embodiments E22 to E26, comprising

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

[0084] E29. (i) HC CDR1, HC CDR2, and HC CDR3 each comprising the amino acid sequence of SEQ ID NO: 314, 341, and 410, respectively, and / or LC CDR1, LC CDR2, and LC CDR3 each comprising the amino acid sequence of SEQ ID NO: 1154, 529, and 571, respectively, (ii) HC CDR1, HC CDR2, and HC CDR3 each comprising the amino acid sequence of SEQ ID NO: 1144, 1145, and 410, respectively, and / or LC CDR1, LC CDR2, and LC CDR3 each comprising the amino acid sequence of SEQ ID NO: 1146, 529, and 571, respectively, or (iii) HC CDR1, HC CDR2, and HC CDR3 each comprising the amino acid sequence of SEQ ID NO: 1165, 1166, and 1167, respectively, and / or LC CDR1, LC CDR2, and LC CDR3 each comprising the amino acid sequence of SEQ ID NO: 473, 528, and 571, respectively The antibody according to any one of Embodiments E22 to E27, comprising

[0085] E30. (i) HC CDR1, HC CDR2, and HC CDR3 each comprising the amino acid sequence of SEQ ID NO: 316, 341, and 410, respectively, and / or LC CDR1, LC CDR2, and LC CDR3 each comprising the amino acid sequence of SEQ ID NO: 475, 530, and 571, respectively, (ii) HC CDR1, HC CDR2, and HC CDR3 each comprising the amino acid sequence of SEQ ID NO: 1149, 1150, and 410, respectively, and / or LC CDR1, LC CDR2, and LC CDR3 each comprising the amino acid sequence of SEQ ID NO: 475, 1151, and 571, respectively, or (iii) HC CDR1, HC CDR2, and HC CDR3 each containing the amino acid sequences of SEQ ID NO: 1171, 1166, and 1167, respectively, and / or LC CDR1, LC CDR2, and LC CDR3 each containing the amino acid sequences of SEQ ID NO: 1172, 528, and 571, respectively The antibody according to any one of Embodiments E22 to E27, comprising

[0086] E31. (i) HC CDR1, HC CDR2, and HC CDR3 each containing the amino acid sequences of SEQ ID NO: 325, 362, and 435, respectively, and / or LC CDR1, LC CDR2, and LC CDR3 each containing the amino acid sequences of SEQ ID NO: 495, 540, and 587, respectively (ii) HC CDR1, HC CDR2, and HC CDR3 each containing the amino acid sequences of SEQ ID NO: 1152, 1153, and 435, respectively, and / or LC CDR1, LC CDR2, and LC CDR3 each containing the amino acid sequences of SEQ ID NO: 495, 540, and 587, respectively, or (iii) HC CDR1, HC CDR2, and HC CDR3 each containing the amino acid sequences of SEQ ID NO: 1173, 1174, and 1175, respectively, and / or LC CDR1, LC CDR2, and LC CDR3 each containing the amino acid sequences of SEQ ID NO: 1176, 1177, and 587, respectively The antibody according to any one of Embodiments E22 to E27, comprising

[0087] E32. (i) HC CDR1, HC CDR2, and HC CDR3 each containing the amino acid sequences of SEQ ID NO: 304, 347, and 400, respectively, and / or LC CDR1, LC CDR2, and LC CDR3 each containing the amino acid sequences of SEQ ID NO: 464, 523, and 562, respectively (ii) HC CDR1, HC CDR2, and HC CDR3 each containing the amino acid sequences of SEQ ID NOs: 1142, 1143, and 400, respectively, and / or LC CDR1, LC CDR2, and LC CDR3 each containing the amino acid sequences of SEQ ID NOs: 464, 523, and 562, respectively, or (iii) HC CDR1, HC CDR2, and HC CDR3 each containing the amino acid sequences of SEQ ID NOs: 1160, 1161, and 1162, respectively, and / or LC CDR1, LC CDR2, and LC CDR3 each containing the amino acid sequences of SEQ ID NOs: 1163, 1164, and 562, respectively The antibody according to any one of Embodiments E22 to E27, comprising

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

[0089] E34. (i) A heavy chain framework region 1 (FRH1), heavy chain framework region 2 (FRH2), heavy chain framework region 3 (FRH3), and / or heavy chain framework region 4 (FRH4) that includes any of the amino acid sequences of the heavy chain framework regions presented in Table 7 or 4, one, two, three, or all of them, or (ii) A heavy chain framework region 1 (FRH1), heavy chain framework region 2 (FRH2), heavy chain framework region 3 (FRH3), and / or heavy chain framework region 4 (FRH4) that includes an amino acid sequence having at least 1, 2, or 3 but 4 or fewer modifications, such as substitutions, with respect to any of the amino acid sequences of the heavy chain framework regions presented in Table 7 or 4, one, two, three, or all of them An antibody according to any one of the preceding embodiments, comprising

[0090] E35. (i) One, two, three, or all of FRH1 that includes the amino acid sequence of SEQ ID NO: 603, FRH2 that includes the amino acid sequence of SEQ ID NO: 664, FRH3 that includes the amino acid sequence of SEQ ID NO: 718, and / or FRH4 that includes the amino acid sequence of SEQ ID NO: 771, or an amino acid sequence having at least 1, 2, or 3 but 4 or fewer modifications, such as substitutions, with respect to each of the amino acid sequences of SEQ ID NO: 603, 664, 718, and / or 771, (ii) One, two, three, or all of FRH1 that includes the amino acid sequence of SEQ ID NO: 619, FRH2 that includes the amino acid sequence of SEQ ID NO: 663, FRH3 that includes the amino acid sequence of SEQ ID NO: 717, and / or FRH4 that includes the amino acid sequence of SEQ ID NO: 771, or an amino acid sequence having at least 1, 2, or 3 but 4 or fewer modifications, such as substitutions, with respect to each of the amino acid sequences of SEQ ID NO: 619, 663, 717, and / or 771, (iii) One, two, three, or all of FRH1 comprising the amino acid sequence of SEQ ID NO: 603, FRH2 comprising the amino acid sequence of SEQ ID NO: 665, FRH3 comprising the amino acid sequence of SEQ ID NO: 719, and / or FRH4 comprising the amino acid sequence of SEQ ID NO: 771, or an amino acid sequence having at least 1, 2, or 3 but 4 or less modifications, such as substitutions, for each of the amino acid sequences of SEQ ID NO: 603, 665, 719, and / or 771, (iv) One, two, three, or all of FRH1 comprising the amino acid sequence of SEQ ID NO: 633, FRH2 comprising the amino acid sequence of SEQ ID NO: 682, FRH3 comprising the amino acid sequence of SEQ ID NO: 745, and / or FRH4 comprising the amino acid sequence of SEQ ID NO: 771, or an amino acid sequence having at least 1, 2, or 3 but 4 or less modifications, such as substitutions, for each of the amino acid sequences of SEQ ID NO: 663, 682, 745, and / or 771, (v) One, two, three, or all of FRH1 comprising the amino acid sequence of SEQ ID NO: 608, FRH2 comprising the amino acid sequence of SEQ ID NO: 652, FRH3 comprising the amino acid sequence of SEQ ID NO: 705, and / or FRH4 comprising the amino acid sequence of SEQ ID NO: 767, or an amino acid sequence having at least 1, 2, or 3 but 4 or less modifications, such as substitutions, for each of the amino acid sequences of SEQ ID NO: 608, 652, 705, and / or 767, or, (vi) One, two, three, or all of FRH1 comprising the amino acid sequence of SEQ ID NO: 604, FRH2 comprising the amino acid sequence of SEQ ID NO: 647, FRH3 comprising the amino acid sequence of SEQ ID NO: 700, and / or FRH4 comprising the amino acid sequence of SEQ ID NO: 770, or an amino acid sequence having at least 1, 2, or 3 but 4 or less modifications, such as substitutions, for each of the amino acid sequences of SEQ ID NO: 604, 647, 700, and / or 770 An antibody according to any one of the preceding embodiments, comprising

[0091] E36. (i) A light chain framework region 1 (FRL1), light chain framework region 2 (FRL2), light chain framework region 3 (FRL3), and / or light chain framework region 4 (FRL4) that contains any of the amino acid sequences of the light chain framework regions of the antibodies presented in Table 7 or 4, one, two, three, or all of them, or (ii) A light chain framework region 1 (FRL1), light chain framework region 2 (FRL2), light chain framework region 3 (FRL3), and / or light chain framework region 4 (FRL4) that contains an amino acid sequence having at least 1, 2, or 3 but 4 or fewer modifications, such as substitutions, with respect to any of the amino acid sequences of the light chain framework regions of the antibodies presented in Table 7 or 4, one, two, three, or all of them An antibody according to any one of the preceding embodiments, comprising

[0092] E37. (i) One, two, three, or all of FRL1 containing the amino acid sequence of SEQ ID NO: 793, FRL2 containing the amino acid sequence of SEQ ID NO: 836, FRL3 containing the amino acid sequence of SEQ ID NO: 874, and / or FRL4 containing the amino acid sequence of SEQ ID NO: 910, or an amino acid sequence having at least 1, 2, or 3 but 4 or fewer modifications, such as substitutions, with respect to each of the amino acid sequences of SEQ ID NO: 793, 836, 874, and / or 910, (ii) One, two, three, or all of FRL1 containing the amino acid sequence of SEQ ID NO: 1178, FRL2 containing the amino acid sequence of SEQ ID NO: 831, FRL3 containing the amino acid sequence of SEQ ID NO: 1179, and / or FRL4 containing the amino acid sequence of SEQ ID NO: 906, or an amino acid sequence having at least 1, 2, or 3 but 4 or fewer modifications, such as substitutions, with respect to each of the amino acid sequences of SEQ ID NO: 1178, 831, 1179, and / or 906, (iii) One, two, three, or all of FRL1 comprising the amino acid sequence of SEQ ID NO: 787, FRL2 comprising the amino acid sequence of SEQ ID NO: 831, FRL3 comprising the amino acid sequence of SEQ ID NO: 870, and / or FRL4 comprising the amino acid sequence of SEQ ID NO: 906, or an amino acid sequence having at least 1, 2, or 3 but 4 or less modifications, such as substitutions, for each of the amino acid sequences of SEQ ID NO: 787, 831, 870, and / or 906, or (iv) One, two, three, or all of FRL1 comprising the amino acid sequence of SEQ ID NO: 807, FRL2 comprising the amino acid sequence of SEQ ID NO: 830, FRL3 comprising the amino acid sequence of SEQ ID NO: 888, and / or FRL4 comprising the amino acid sequence of SEQ ID NO: 908, or an amino acid sequence having at least 1, 2, or 3 but 4 or less modifications, such as substitutions, for each of the amino acid sequences of SEQ ID NO: 807, 830, 888, and / or 908, (v) One, two, three, or all of FRL1 comprising the amino acid sequence of SEQ ID NO: 783, FRL2 comprising the amino acid sequence of SEQ ID NO: 830, FRL3 comprising the amino acid sequence of SEQ ID NO: 866, and / or FRL4 comprising the amino acid sequence of SEQ ID NO: 906, or an amino acid sequence having at least 1, 2, or 3 but 4 or less modifications, such as substitutions, for each of the amino acid sequences of SEQ ID NO: 783, 830, 866, and / or 906, or, (vi) One, two, three, or all of FRL1 comprising the amino acid sequence of SEQ ID NO: 779, FRL2 comprising the amino acid sequence of SEQ ID NO: 825, FRL3 comprising the amino acid sequence of SEQ ID NO: 861, and / or FRL4 comprising the amino acid sequence of SEQ ID NO: 908, or an amino acid sequence having at least 1, 2, or 3 but 4 or less modifications, such as substitutions, for each of the amino acid sequences of SEQ ID NO: 779, 825, 861, and / or 908 An antibody according to any one of the preceding embodiments, comprising

[0093] E38. (i) Any VH amino acid sequence presented 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 1, 2, or 3 modifications of any VH amino acid sequence presented in Table 3 or 4, provided that the number of modifications is 30 or less, 20 or less, or 10 or less, or (iii) An amino acid sequence encoded by any VH nucleotide sequence presented in Table 3 or 4, or a nucleotide sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto An antibody according to any one of Embodiments E22 to E37, comprising a VH comprising any of the above.

[0094] E39. (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 1, 2, or 3 modifications of the amino acid sequence of SEQ ID NO: 4, 9, 21 - 23, or 51, provided that the number of modifications is 30 or less, 20 or less, or 10 or less, 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 An antibody according to any one of Embodiments E22 to E38, comprising a VH comprising any of the above.

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

[0096] E41. Comprising a VH comprising, from N-terminus to C-terminus, FRH1, HC CDR1, FRH2, HC CDR2, FRH3, HC CDR3, and FRH4, (i) wherein the FRH1, the HC CDR1, the FRH2, the HC CDR2, the FRH3, the HC CDR3, the FRH4 each comprise the amino acid sequence of SEQ ID NO: 603, 315, 664, 341, 718, 410, and 771, or (ii) wherein the FRH1, the HC CDR1, the FRH2, the HC CDR2, the FRH3, the HC CDR3, the FRH4 each comprise the amino acid sequence of SEQ ID NO: 619, 314, 663, 341, 717, 410, and 771, or (iii) wherein the FRH1, the HC CDR1, the FRH2, the HC CDR2, the FRH3, the HC CDR3, the FRH4 each comprise the amino acid sequence of SEQ ID NO: 603, 316, 665, 341, 719, 410, and 771, or (vi) wherein the FRH1, the HC CDR1, the FRH2, the HC CDR2, the FRH3, the HC CDR3, the FRH4 each comprise the amino acid sequence of SEQ ID NO: 663, 325, 682, 362, 745, 435, and 771, or (v) The FRH1, the HC CDR1, the FRH2, the HC CDR2, the FRH3, the HCDR3, and the FRH4 each contain the amino acid sequences of SEQ ID NO: 608, 304, 652, 347, 705, 400, and 767, respectively, or (vi) The FRH1, the HC CDR1, the FRH2, the HC CDR2, the FRH3, the HC CDR3, and the FRH4 each contain the amino acid sequences of SEQ ID NO: 604, 299, 647, 343, 700, 395, and 770, respectively. The antibody according to any one of the preceding embodiments.

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

[0098] E43. The nucleotide sequence encoding the VH contains 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 according to any one of Embodiments E22 to E42.

[0099] E44. (i) The amino acid sequence of any VL presented 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 1, 2, or 3 modifications of the amino acid sequence of any VL presented in Table 3 or 4, provided that the number of modifications is 30 or less, 20 or less, or 10 or less, or (iii) The amino acid sequence encoded by any VL nucleotide sequence presented in Table 3 or 4, or a nucleotide sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto An antibody according to any one of Embodiments E22 to E43, comprising a VL comprising

[0100] E45. (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 1, 2, or 3 modifications of the amino acid sequence of SEQ ID NO: 78, 83, 93-95, or 122, provided that the number of modifications is 30 or less, 20 or less, or 10 or less, or (iii) The 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 An antibody according to any one of Embodiments E22 to E44, comprising a VL comprising

[0101] E46. From the N-terminus to the C-terminus, (i) FRL1 comprising the amino acid sequence of FRL1 of any of the antibodies in Table 7 or 4, (ii) LC CDR1 comprising the amino acid sequence of LC CDR1 of the antibodies in Table 6 or 5, (iii) FRL2 comprising the amino acid sequence of FRL2 of any of the antibodies in Table 7 or 4, (iv) LC CDR2 comprising the amino acid sequence of LC CDR2 of the antibodies in Table 6 or 5, (v) FRL3 comprising the amino acid sequence of FRL3 of any of the antibodies 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 (vii) An FRL4 comprising the amino acid sequence of the FRL4 of the antibody in Table 7 or 4 An antibody according to any of the preceding embodiments, comprising a VL comprising the same.

[0102] E47. A VL comprising, from the N-terminus to the C-terminus, FRL1, LC CDR1, FRL2, LC CDR2, FRL3, LC CDR3, and FRL4, (i) wherein the FRL1, the LC CDR1, the FRL2, the LC CDR2, the FRL3, the LC CDR3, the FRL4 each comprise the amino acid sequence of SEQ ID NO: 793, 474, 836, 529, 874, 571, and 910, or (ii) wherein the FRL1, the LC CDR1, the FRL2, the LC CDR2, the FRL3, the LC CDR3, the FRL4 each comprise the amino acid sequence of SEQ ID NO: 1178, 1154, 831, 529, 1179, 571, and 906, or (iii) wherein the FRL1, the LC CDR1, the FRL2, the LC CDR2, the FRL3, the LC CDR3, the FRL4 each comprise the amino acid sequence of SEQ ID NO: 787, 475, 831, 530, 870, 571, and 906, or (iv) wherein the FRL1, the LC CDR1, the FRL2, the LC CDR2, the FRL3, the LC CDR3, the FRL4 each comprise the amino acid sequence of SEQ ID NO: 807, 495, 830, 540, 888, 587, and 908, or (v) wherein the FRL1, the LC CDR1, the FRL2, the LC CDR2, the FRL3, the LC CDR3, the FRL4 each comprise the amino acid sequence of SEQ ID NO: 783, 464, 830, 523, 866, 562, and 906, or, (vi) The FRL1, the LC CDR1, the FRL2, the LC CDR2, the FRL3, the LC CDR3, and the FRL4 each contain the amino acid sequences of SEQ ID NO: 779, 460, 825, 518, 861, 557, and 908, An antibody according to any one of the preceding embodiments.

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

[0104] E49. The nucleotide sequence encoding the VL contains 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, and is an antibody according to any one of Embodiments E22 to E48.

[0105] E50. (i) VH, wherein (a) the amino acid sequence of any VH presented 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 1, 2, or 3 modifications of the amino acid sequence of any VH presented in Table 3 or 4, provided that the number of modifications is 30 or less, 20 or less, or 10 or less, or (c) The VH amino acid sequence presented in Table 3 or 4, or an amino acid sequence encoded by a nucleotide sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto, and (ii) A VL, (a) Any VL amino acid sequence presented 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 1, 2, or 3 modifications of any VL amino acid sequence presented in Table 3 or 4, provided that the number of modifications is 30 or less, 20 or less, or 10 or less, or (c) The VL amino acid sequence encoded by any VL nucleotide sequence presented in Table 3 or 4, or an amino acid sequence encoded by a nucleotide sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto The antibody according to any one of the preceding embodiments, comprising

[0106] E51. The antibody according to any one of the preceding embodiments, comprising the amino acid sequence of any VH of the antibodies presented in Tables 3 and 4 and the amino acid sequence of the VL of the antibodies presented in Table 3 or 4.

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

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

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

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

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

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

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

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

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

[0116] E61. The antibody according to any one of the preceding embodiments, comprising the amino acids of the heavy chain constant region presented 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 the amino acid sequence of the light chain constant region presented 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.

[0117] E62. The nucleotide sequence encoding the heavy chain constant region includes the nucleotide sequence of the heavy chain constant region presented 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 includes the nucleotide sequence of the light chain constant region presented 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, an antibody according to any one of the preceding embodiments.

[0118] E63. (i) A VH comprising the amino acid sequence of any VH presented 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 the amino acids of the heavy chain constant region presented 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 presented 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 the amino acids of the light chain constant region presented 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 An antibody according to any one of the preceding embodiments, comprising.

[0119] E64. (i) The 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 the amino acid sequence of the heavy chain constant region presented in Table X, or a heavy chain constant region comprising 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) The 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 the amino acid sequence of the light chain constant region presented in Table X, or a light chain constant region comprising an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity thereto An antibody according to any one of the preceding embodiments, comprising

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

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

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

[0123] E68. For example, as described in Example 8, when measured by, for example, Octet, a dissociation constant (K DThe antibody according to any one of the preceding embodiments, which binds to the tau protein.

[0124] E69. A K of about 0.1 nM to about 0.5 nM D The antibody according to any one of the preceding embodiments, which binds to the tau protein.

[0125] E70. A K of about 0.5 nM to about 5 nM D The antibody according to any one of the preceding embodiments, which can bind to the tau protein.

[0126] E71. A K of about 5 nM to about 30 nM D The antibody according to any one of the preceding embodiments, which can bind to the tau protein.

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

[0128] E73. The antibody according to any one of the preceding embodiments, which binds to paired helical filament tau protein (ePHF) with a maximum half-maximal effective concentration (EC50) of, for example, about 0.01 nM to about 100 nM.

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

[0130] E76. An antibody according to any one of the preceding embodiments, which binds to an epitope comprising a region formed by a complex of at least two tau proteins, such as a tau dimer.

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

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

[0133] E80. An isolated, e.g., recombinant, nucleic acid encoding an antibody that binds to tau, wherein the antibody (i) comprises a heavy chain variable region (VH) comprising at least 1, 2, or 3 of the HC CDR1, HC CDR2, and / or HC CDR3 of the antibodies of Table 1, 6, 2A - 2C, 4, or 5, and / or (ii) comprises a light chain variable region (VL) comprising at least 1, 2, or 3 of the LC CDR1, LC CDR2, and / or LC CDR3 of the antibodies of Table 1, 6, 2A - 2C, 4, or 5 and the nucleic acid.

[0134] E81. (i) The HC CDR1, the HC CDR2, the HC CDR3, the LC CDR1, the LC CDR2, and the LC CDR3 each comprise the amino acid sequences of SEQ ID NOs: 315, 341, 410, 474, 529, and 571, or (ii) The HC CDR1, the HC CDR2, the HC CDR3, the LC CDR1, the LC CDR2, and the LC CDR3 each contain the amino acid sequence of SEQ ID NO: 314, 341, 410, 1154, 529, and 571, or (iii) The HC CDR1, the HC CDR2, the HC CDR3, the LC CDR1, the LC CDR2, and the LC CDR3 each contain the amino acid sequence of SEQ ID NO: 316, 341, 410, 475, 530, and 571, or (iv) The HC CDR1, the HC CDR2, the HC CDR3, the LC CDR1, the LC CDR2, and the LC CDR3 each contain the amino acid sequence of SEQ ID NO: 325, 362, 435, 495, 540, and 587, or (v) The HC CDR1, the HC CDR2, the HC CDR3, the LC CDR1, the LC CDR2, and the LC CDR3 each contain the amino acid sequence of SEQ ID NO: 304, 347, 400, 464, 523, and 562, or (vi) The HC CDR1, the HC CDR2, the HC CDR3, the LC CDR1, the LC CDR2, and the LC CDR3 each contain the amino acid sequence of SEQ ID NO: 299, 343, 395, 460, 518, and 557, The nucleic acid according to Embodiment E80.

[0135] E82. The antibody is (i) The amino acid sequence of any VH presented 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 presented in Table 3 or 4, or an amino acid sequence having at least 1, 2, or 3 modifications of the amino acid sequence of any VH presented in Table 3 or 4, provided that the number of modifications is 30 or less, 20 or less, or 10 or less, and / or (ii) An amino acid sequence of any VL presented 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 presented in Table 3 or 4, or an amino acid sequence having at least 1, 2, or 3 modifications of the amino acid sequence of any VL presented in Table 3 or 4, provided that the number of modifications is 30 or less, 20 or less, or 10 or less, and containing VL The nucleic acid according to Embodiment E80, comprising

[0136] E83. The antibody is (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, or an amino acid sequence having at least 1, 2, or 3 modifications of the amino acid sequence of SEQ ID NO: 4, 9, 21-23, or 51, provided that the number of modifications is 30 or less, 20 or less, or 10 or less, and containing VH, and / or (ii) 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 1, 2, or 3 modifications of the amino acid sequence of SEQ ID NO: 78, 83, 93-95, or 122, provided that the number of modifications is 30 or less, 20 or less, or 10 or less, and containing VL The nucleic acid according to any one of Embodiments E80 to E82, comprising

[0137] E84. The antibody is (i) The amino acids of the heavy chain constant region presented in Table X, or a heavy chain constant region containing 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) the amino acid sequence of the light chain constant region presented in Table X, or a light chain constant region comprising 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 according to any one of Embodiments E80 to E83, comprising:

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

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

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

[0141] E88. An isolated, e.g., recombinant, antibody encoded by the nucleic acid according to any one of Embodiments E79 to E87.

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

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

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

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

[0146] E94. The nucleic acid according to Embodiment E93, further encoding a signal sequence, and optionally, the nucleotide sequence encoding the signal sequence comprises the nucleotide sequence of any one of the signal sequences listed in Table 14, or a nucleotide sequence having at least 95% sequence identity thereto.

[0147] E95. Further encoding a second signal sequence, optionally, the nucleotide sequence encoding the signal sequence comprises a nucleotide sequence of any of the signal sequences listed in Table 14, or a nucleotide sequence having at least 95% sequence identity thereto, the nucleic acid according to any one of Embodiments E93 to E94.

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

[0149] E97. The sequences of the encoded VH and VL are directly connected, for example, without a linker, the nucleic acid according to any one of Embodiments E93 to E96.

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

[0151] E99. The linker comprises a nucleotide sequence of any of the linker sequences presented in Table 15, or a nucleotide sequence having at least 95% sequence identity thereto, the nucleic acid according to Embodiment E98.

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

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

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

[0155] E103. The viral genome according to any one of Embodiments E101 to E102, further comprising an enhancer, and optionally, the enhancer is a CMV major immediate-early (CMVie) enhancer.

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

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

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

[0159] E107. (i) 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 according to Embodiment E106.

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

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

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

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

[0164] E112. The viral genome according to any one of Embodiments E101 to E111, comprising at least 1, 2, or 3 intron regions.

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

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

[0167] E115. The viral genome according to any one of Embodiments E101 to E114, comprising at least 1, 2, or 3 exon regions.

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

[0169] E117. The viral genome according to any one of Embodiments E101 to E116, further comprising a nucleotide sequence encoding an miR binding site, such as an miR binding site that regulates, for example, reduces the expression of the payload encoded by the viral genome in cells or tissues where the corresponding miRNA is expressed.

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

[0171] E119. The viral genome according to any one of embodiments E117 - E118, comprising at least 3 copies of the encoded miR binding site, wherein optionally all 3 copies contain the same miR binding site, or at least 1, 2, or all of the copies contain different miR binding sites.

[0172] E120. The viral genome according to any one of embodiments E117 - E119, comprising at least 4 copies of the encoded miR binding site, wherein optionally all 4 copies contain the same miR binding site, or at least 1, 2, 3, or all of the copies contain different miR binding sites.

[0173] E121. The encoded miR binding site comprises a miR122 binding site, a miR183 binding site, miR - 142 - 3p, or a combination thereof, and optionally, (i) the encoded miR122 binding site comprises the nucleotide sequence of SEQ ID NO: 1029, or a nucleotide sequence substantially identical thereto (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity), or a nucleotide sequence having at least 1, 2, 3, 4, 5, 6, or 7 modifications of SEQ ID NO: 1029, provided that the number of modifications is 10 or less. (ii) The encoded miR183 binding site comprises the nucleotide sequence of SEQ ID NO: 1032, or a nucleotide sequence substantially identical thereto (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity), or a nucleotide sequence having at least 1, 2, 3, 4, 5, 6, or 7 modifications of SEQ ID NO: 1032, provided that the number of modifications is 10 or less, and / or (iii) The encoded miR-142-3p binding site comprises the nucleotide sequence of SEQ ID NO: 1031, or a nucleotide sequence substantially identical thereto (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity), or a nucleotide sequence having at least 1, 2, 3, 4, 5, 6, or 7 modifications of SEQ ID NO: 1031, provided that the number of modifications is 10 or less. The viral genome according to any one of Embodiments E117 to E120.

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

[0175] E124. The viral genome according to Embodiment E123, wherein the Rep78 protein, the Rep68 protein, the Rep52 protein, and / or the Rep40 protein is encoded by at least one Rep gene.

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

[0177] E126. The viral genome according to Embodiment E125, wherein the VP1 polypeptide, the VP2 polypeptide, and / or the VP3 polypeptide is encoded by at least one Cap gene.

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

[0179] E129. (i) The capsid protein includes the amino acid sequence of SEQ ID NO: 1003, or an amino acid sequence having at least 80% (for example, at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto. (ii) The capsid protein includes an amino acid sequence having at least 1, 2, or 3 modifications of the amino acid sequence of SEQ ID NO: 1003, but the number of modifications is 30 or less, 20 or less, or 10 or less. (iii) The capsid protein includes the amino acid sequence of SEQ ID NO: 1011, or an amino acid sequence having at least 80% (for example, at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto. (iv) The capsid protein includes an amino acid sequence having at least 1, 2, or 3 modifications of the amino acid sequence of SEQ ID NO: 1011, provided that the number of modifications is 30 or less, 20 or less, or 10 or less. (v) The capsid protein includes an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 1002 or a sequence having at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto, and / or (vi) The nucleotide sequence encoding the capsid protein includes the nucleotide sequence of SEQ ID NO: 1002 or a sequence having at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto. An isolated AAV particle according to Embodiment E128.

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

[0181] E131. The capsid protein is an insert containing (i) an amino acid substitution of K449R numbered according to SEQ ID NO: 1003, and (ii) an amino acid sequence of TLAVPFK (SEQ ID NO: 1151), optionally containing the insert present immediately after position 588 of SEQ ID NO: 1003, and is an AAV particle according to any one of Embodiments E128 to E130.

[0182] E132. The capsid protein is an insert containing (i) an amino acid substitution of K449R numbered according to SEQ ID NO: 1003, (ii) an amino acid sequence of TLAVPFK (SEQ ID NO: 1151), optionally containing the insert present immediately after position 588 relative to the reference sequence numbered according to SEQ ID NO: 1003, and (iii) amino acid substitutions of A587D and Q588G numbered according to SEQ ID NO: 1003, and is an AAV particle according to any one of Embodiments E128 to E130.

[0183] E133. The capsid protein is an insert containing (i) an amino acid sequence of TLAVPFK (SEQ ID NO: 1151), optionally containing the insert present immediately after position 588 relative to the reference sequence numbered according to SEQ ID NO: 1003, and (ii) amino acid substitutions of A587D and Q588G numbered according to SEQ ID NO: 1003, and is an AAV particle according to any one of Embodiments E128 to E130.

[0184] E134. The capsid protein contains any of the capsid proteins listed in Table 9, or a functional variant thereof, and is an AAV particle according to any one of Embodiments E128 to E133.

[0185] E135. The capsid protein is the AAV particle according to any one of Embodiments E128 to E134, including VOY101, VOY201, AAVPHP.B (PHP.B), AAVPHP.A (PHP.A), AAVG2B-26, AAVG2B-13, AAVTH1.1-32, AAVTH1.1-35, AAVPHP.B2 (PHP.B2), AAVPHP.B3 (PHP.B3), AAVPHP.N / PHP.B-DGT, AAVPHP.B-EST, AAVPHP.B-GGT, AAVPHP.B-ATP, AAVPHP.B-ATT-T, AAVPHP.B-DGT-T, AAVPHP.B-GGT-T, AAVPHP.B-SGS, AAVPHP.B-AQP, AAVPHP.B-QQP, AAVPHP.B-SNP(3), AAVPHP.B-SNP, AAVPHP.B-QGT, AAVPHP.B-NQT, AAVPHP.B-EGS, AAVPHP.B-SGN, AAVPHP.B-EGT, AAVPHP.B-DST, AAVPHP.B-DST, AAVPHP.B-STP, AAVPHP.B-PQP, AAVPHP.B-SQP, AAVPHP.B-QLP, AAVPHP.B-TMP, AAVPHP.B-TTP, AAVPHP.S / G2A12, AAVG2A15 / G2A3 (G2A3), AAVG2B4 (G2B4), AAVG2B5 (G2B5), AAVPHP.N (PHP.N), PHP.S, AAV1, AAV2, AAV2 variant, AAV2 / 3 variant, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9.47, AAV9 (hu14), AAV9, AAV9 K449R, AAV10, AAV11, AAV12, AAVrh8, AAVrh10, AAVDJ, AAVDJ8, or AAV2G9 capsid protein, or a functional variant thereof.

[0186] E136. The capsid protein is the AAV particle according to any one of Embodiments E128 to E135, including the VOY101 capsid protein.

[0187] E137. The capsid protein is (i) The amino acid sequence of SEQ ID NO: 1023, or an amino acid sequence that is substantially identical thereto (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity), (ii) An amino acid sequence having at least 1, 2, or 3 modifications but 30 or fewer, 20 or fewer, or 10 or fewer modifications, such as substitutions, 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 that is substantially identical thereto (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) The AAV particle according to embodiment E136, comprising

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

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

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

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

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

[0193] E143. A method for producing an isolated, for example, recombinant AAV particle, comprising: (i) preparing a host cell comprising a viral genome according to Embodiment E140; and (ii) incubating the host cell under conditions suitable for encapsulating the viral genome in a capsid protein such as the VOY101 capsid protein. Thereby, the method for producing the isolated AAV particles.

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

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

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

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

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

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

[0200] E150. The method according to embodiment E148 or E149, wherein the subject has, is diagnosed as having, or is at risk of having a neuropathy, such as a neurodegenerative disorder.

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

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

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

[0204] E154. A method of treating a subject having or diagnosed with tauopathy, comprising administering to the subject an effective amount of the pharmaceutical composition according to Embodiment E147, an antibody according to any one of Embodiments E1 to E78 and E88, AAV particles according to any one of Embodiments E128 to E139, for example, a plurality of AAV particles, or AAV particles containing a viral genome according to any one of Embodiments E101 to E126, for example, a plurality of AAV particles, or an isolated nucleic acid according to any one of Embodiments E79 to E87 and E93 to E100.

[0205] E155. The disease, the neuropathy, or the tauopathy related to tau expression includes AD, FTDP-17, FTLD, FTD, CTE, PSP, Down syndrome, Pick's disease, CBD, corticobasal syndrome, ALS, prion disease, CJD, multiple system atrophy, neurofibrillary type senile dementia, or progressive subcortical gliosis, according to any one of Embodiments E152 to E154.

[0206] E156. The treatment includes preventing the progression of the disease in the subject, according to any one of Embodiments E152 to E155.

[0207] E157. The subject is a human, according to any one of Embodiments E152 to E156. E158. The AAV particles are administered to the subject intravenously, intramuscularly, via parenchymal administration, intraventricularly, via intracisternal (ICM) injection, intrathecally, focused ultrasound (FUS), for example, in combination with intravenous administration of microbubbles (FUS-MB), or via MRI-guided FUS in combination with intravenous administration, according to any one of Embodiments E152 to E157.

[0208] E159. The AAV particles are administered intravenously to the subject by the method according to any one of Embodiments E152 to E158.

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

[0210] E161. The method according to any one of Embodiments E152 to E160, further comprising evaluating, for example, measuring the level of an antibody produced in a subject, for example, in the cells or tissues of the subject.

[0211] E162. The administration results in the production of an antibody at 0.001 μg / mL to 100 mg / mL in the subject, for example, in the cells or tissues of the subject, by the method according to any one of Embodiments E152 to E161.

[0212] E163. The method according to Embodiment E162, wherein the cells are nerve cells. E164. The method according to Embodiment E162, wherein the tissue is a central nervous system tissue, for example, a brain tissue.

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

[0214] E166. The method according to any one of Embodiments E161 to E165, wherein the measurement of the level of the antibody is performed before, during, or after treatment with the AAV particles, for example, a plurality of AAV particles.

[0215] E167. The subject is the method according to any one of embodiments E152 to E166, having a higher level of antibody than a reference level, for example, a subject not undergoing treatment, for example, a subject not administered the AAV particle or plurality of AAV particles.

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

[0217] E169. The method according to any one of embodiments E152 to E168, further comprising administering a further therapeutic agent and / or therapy suitable for treating or preventing a disorder associated with tau expression, a neuropathy, for example, a neurodegenerative disorder.

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

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

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

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

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

[0223] E175. Use of an effective amount of an antibody according to any one of embodiments E1 to E78 and E88, a nucleic acid according to any one of embodiments E79 to E87 and E93 to E100, a viral genome according to any one of embodiments E101 to E126, a pharmaceutical composition according to embodiment E147, or an AAV particle according to any one of embodiments E128 to E139 in the manufacture of a medicament for treating a disease, neuropathy, such as a neurodegenerative disorder, or tauopathy related to tau expression in a subject. BRIEF DESCRIPTION OF THE DRAWINGS

[0224]

Figure 1

Figure 2

Figure 3

[0225] I. Composition In some embodiments, the present disclosure provides a composition that interacts with human microtubule-associated protein tau. Such a composition can be an antibody that binds to a tau protein epitope, referred to herein as an "anti-tau antibody." Dysfunction and / or aggregation of tau are seen in a class of neurodegenerative diseases called tauopathies. Hyperphosphorylation of tau leads to aggregation and suppression of microtubule assembly that is dependent on tau. In tauopathies, tau aggregates form paired helical filaments (PHFs) seen in neurofibrillary tangles (NFTs). These aggregates lead to neuronal loss and cognitive decline. The anti-tau antibodies of the present disclosure can be useful for the treatment and / or diagnosis of tauopathies, as well as other uses described herein.

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

[0227] As used herein, the term "antibody" is used in its broadest sense and specifically encompasses 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 (e.g., Fab, F(ab’), F(ab’)2, Fv, etc.), provided that they exhibit the desired functional or biological activity. Antibodies are primarily amino acid-based molecules, but may include one or more modifications (including, but not limited to, addition of sugar moieties, fluorescent moieties, chemical tags, etc.).

[0228] The antibodies (including antigen-binding fragments thereof) of the present disclosure are 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-idiotype (anti-Id) antibodies (including, e.g., anti-Id antibodies to the antibodies of the present invention), antibodies made intracellularly (i.e., intrabodies), codon-optimized antibodies, scFv fragments, tandem scFv antibodies, bispecific T cell engagers, mAb2 antibodies, chimeric antigen receptors (CARs), tetravalent bispecific antibodies, biosynthetic antibodies, natural antibodies, miniaturized antibodies, uni-bodies, maxibodies, and epitope-binding fragments of any of the foregoing, and may include, but are not limited to, these.

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

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

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

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

[0233] "Natural antibodies" are typically heterotetrameric glycoproteins of approximately 150,000 daltons composed of two identical light (L) chains and two identical heavy (H) chains. The genes encoding the heavy and light chains of antibodies are known, and the segments that make up each have been well characterized and described (Matsuda, F. et al., 1998. The Journal of Experimental Medicine. 188(11);2151-62 and Li, A. et al., 2004. Blood. 103(12:4602-9, the contents of each reference are hereby incorporated by reference in their entirety). Each light chain is linked to the heavy chain by one disulfide covalent bond, although the number of disulfide bonds varies between the heavy chains of different immunoglobulin isotypes. Also, each heavy and light chain has regularly spaced intrachain disulfide bridges. Each heavy chain has a variable domain (V H ) at one end, followed by several constant domains. Each light chain has a variable domain (V L ) at one end and a constant domain at the 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.

[0234] As used herein, the term "variable domain" is found in both the heavy and light chains of an antibody and refers to a specific antibody domain that has highly variable sequences within the antibody and is used for the binding and specificity of each particular antibody to a particular antigen. In some embodiments, the VH and VL regions of the antibodies described herein can be subdivided into hypervariable regions called complementarity determining regions (CDRs) interspersed with highly conserved regions called framework regions (FR).

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

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

[0237] As used herein, the term "CDR analysis" refers to any process used to determine which antibody variable domain residues constitute the CDRs. The framework regions and the CDR ranges are precisely defined by several 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. et al. (1987) J. Mol. Biol. 196:901-917, and the AbM definition used by Oxford Molecular's AbM antibody modeling software. Generally, for example, see Protein Sequence and Structure Analysis of Antibody Variable Domains. In: Antibody Engineering Lab Manual (Eds.: Duebel, S. and Kontermann, R., Springer-Verlag, Heidelberg). CDR analysis can be performed by co-crystallographic analysis with the bound antigen. In some embodiments, CDR analysis can include computer-based evaluation based on comparison with other antibodies (Strohl, W.R. Therapeutic Antibody Engineering. Woodhead Publishing, Philadelphia PA. 2012. Ch. 3, p47-54, the contents of which are hereby incorporated by reference in their entirety).For CDR analysis and / or the boundaries of the exact amino acid sequences, the use of numbering schemes including, but not limited to, those taught by Kabat [Wu, T.T. et al., 1970, JEM, 132(2):211 - 50 and Johnson, G. et al., 2000, Nucleic Acids Res. 28(1):214 - 8, the contents of each reference are hereby 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 reference are hereby 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 content of the same reference is hereby incorporated by reference in its entirety) may be included. In some embodiments, the CDRs defined according to the Chothia numbering scheme may also be called hypervariable loops.

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

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

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

[0241] For certain antibodies of the present invention, equivalent CDR sequences and framework region sequences based on the Kabat, Chothia, and IMGT numbering systems can be readily obtained, at least based on the tables and sequences described herein that present the sequence numbers of equivalent CDR regions based on the Kabat, Chothia, and IMGT numbering systems, respectively. See also Figures 1A - 3B.

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

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

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

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

[0246] The constant region can be varied, 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, 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 neither recruits effector cells nor fixes complement. In other embodiments, the ability of the antibody to bind to Fc receptors is reduced or absent. For example, the antibody is an isotype or subtype, fragment or other variant that does not support binding to Fc receptors, e.g., its Fc receptor binding region has a mutation or is deleted.

[0247] Methods for varying the antibody constant region are known in the art. Antibodies with altered function, e.g., altered affinity for effector ligands such as FcR on cells or the C1 component of complement, can be produced by substituting at least one amino acid residue in the constant portion of the antibody with a different residue (see, e.g., EP388,151A1, U.S. Patent No. 5,624,821, and U.S. Patent No. 5,648,260, all of which are incorporated herein by reference). Similar types of changes that reduce or eliminate these functions when applied to mouse or other species immunoglobulins have also been described.

[0248] As used herein, the term "Fv" refers to an antibody fragment that includes the minimal fragment of an antibody necessary to form a complete antigen-binding site. These regions consist of a dimer of one heavy chain variable domain and one light chain variable domain in a close non-covalent association state. Fv fragments can be generated by proteolytic cleavage, but most are unstable. Recombinant methods for generating stable Fv fragments are known in the art and typically involve inserting a flexible linker between the light chain variable domain and the heavy chain variable domain [thereby forming a single-chain Fv (scFv)], or introducing a disulfide bridge between the heavy chain variable domain and the light chain variable domain (Strohl, W.R. Therapeutic Antibody Engineering. Woodhead Publishing, Philadelphia PA. 2012. Ch. 3, p46-47, the contents of which are hereby incorporated by reference in their entirety).

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

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

[0251] The term "chimeric antibody" refers to an antibody having portions derived from two or more sources. A chimeric antibody can include portions derived from different species. For example, a chimeric antibody can include an antibody having murine variable domains and human constant domains. Further examples of chimeric antibodies and methods for producing them include 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 all those described in U.S. Patent 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.

[0252] The term "diabody" refers to a small antibody fragment having two antigen binding sites, which are light chain variable domains V L connected to the heavy chain variable domain V H in the same polypeptide chain. By using a linker that is too short to allow pairing between the two domains on the same chain, these domains are paired with the complementary domains of another chain to create two antigen binding sites. Diabodies are described in more detail, for example, in EP404,097, WO93 / 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.

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

[0254] As used herein, the term "chimeric antigen receptor" or "CAR" refers to an artificial receptor that is expressed on the surface of an immune effector cell and is engineered such that the immune effector cell specifically targets cells that express an entity that binds with high affinity to the artificial receptor. A CAR can be designed to include one or more segments of an antibody, an antibody variable domain, and / or an antibody CDR such that when the CAR is expressed on an immune effector cell, the immune effector cell binds to cells recognized by the antibody portion of the CAR and eliminates them. Optionally, a CAR can be designed to specifically bind to cancer cells and effect clearance of the cancer cells through immune modulation.

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

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

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

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

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

[0260] In some embodiments, the antibodies of the present disclosure can be antibody mimetics. The term "antibody mimetic" refers to any molecule that mimics the function or effect of an antibody and binds specifically and with high affinity to its molecular target. In some embodiments, the antibody mimetic can be a monobody designed to incorporate a fibronectin type III domain (Fn3) as a protein scaffold (US6,673,901, US6,348,584). In some embodiments, the antibody mimetic can be one known in the art, including but not limited to affibody molecules, affilins, affitins, anticalins, avimers, DARPins, Fynomers, and Kunitz, as well as domain peptides. In other embodiments, the antibody mimetic can include one or more non-peptide regions.

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

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

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

[0264] In some embodiments, the sequences of the antibodies of the present disclosure can be generated from bispecific or heterodimeric antibodies produced using protocols known in the art, such as the "knob-in-hole" technique described in, for example, US5731168; electrostatic steering Fc pairing described in WO09 / 089004, WO06 / 106905, and WO2010 / 129304; SEED (Strand Exchange Engineered Domain) heterodimer formation described in WO07 / 110205; Fab arm exchange described in WO08 / 119353, WO2011 / 131746, and WO2013 / 060867; bispecific constructs by cross-linking antibodies using heterobifunctional reagents having, for example, amine-reactive and sulfhydryl-reactive groups, as described in US4433059; bispecific antibody determinants generated by recombining half-antibodies (heavy-chain-light-chain pairs or Fabs) from different antibodies via cycles of reduction and oxidation of disulfide bonds between two heavy chains, as described in US4444878; trifunctional antibodies, such as three Fab' fragments cross-linked via sulfhydryl-reactive groups, as described in US5273743; biosynthetic binding proteins, such as pairs of scFvs cross-linked through C-terminal tails via preferably disulfide or amine-reactive chemical cross-linking, as described in US5534254; bifunctional antibodies, such as Fab fragments with different binding specificities dimerized via leucine zippers with substituted constant domains (e.g., c-fos and c-jun), as described in US5591828; bispecific and oligomeric monovalent and oligovalent receptors, such as the VH-CH1 regions of two antibodies (two Fab fragments) linked via a polypeptide spacer between the CH1 region of one antibody and the VH region of the other antibody, typically associated with a light chain, as described in US5635602; bispecific DNA-antibody conjugates, such as cross-linking of antibodies or Fab fragments via double-stranded portions of DNA, as described in US5635602;Bispecific fusion proteins as described in, for example, US5637481, such as expression constructs containing two scFvs with a hydrophilic helical peptide linker in between and a complete constant region; multivalent and multispecific binding proteins as described in, for example, US5837242, such as dimers of polypeptides having a first domain with a binding region of an Ig heavy chain variable region and a second domain with a binding region of an Ig light chain variable region, generally referred to as diabodies (higher order structures that create bispecific, trispecific, or tetravalent molecules are also disclosed); minibody constructs having linked VL and VH chains, further connected by a peptide spacer to an antibody hinge region and CH3 region, capable of dimerizing to form a bispecific / polyvalent molecule; VH and VL domains linked by a short peptide linker (e.g., 5 or 10 amino acids) or without any linker in either orientation, capable of forming a dimer to form a bispecific diabody; trimers and tetramers as described in, for example, US5844094; a series of VH domains (or VL domains of a family member) connected at the C-terminus by a peptide bond to a crosslinkable group and further associated with VL domains to form a series of Fv (or scFv); and single-chain binding polypeptides in which both the VH domain and the VL domain linked via a peptide linker are integrated into a polyvalent structure via non-covalent or chemical crosslinking to form, for example, homo- and hetero-bivalent, trivalent, and tetravalent structures using both scFV and diabody type formats, including but not limited to these.;

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

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

[0267] As used herein, the term "tau protein" refers to a protein or protein complex that includes microtubule-associated protein tau or a peptide fragment thereof. Tau proteins can include paired helical filament tau protein (ePHF), also referred to as "sarkosyl-insoluble tau," or a fragment thereof. Tau proteins can include one or more phosphorylated residues. Such phosphorylated residues can correspond to tau proteins associated with disease (also referred to herein as "pathological tau").

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

[0269] A suitable fusogen (e.g., polyethylene glycol) can be used to fuse the lymphocytes with an immortalized cell line to form hybridoma cells (see, e.g., Goding, J.W., Monoclonal Antibodies: Principles and Practice. Academic Press. 1986;59-1031. The content of this reference is incorporated herein by reference in its entirety). The immortalized cell line can be a transformed mammalian cell, particularly a myeloma cell of rodent, rabbit, bovine, or human origin. In some embodiments, a rat or mouse myeloma cell line is used. The hybridoma cells can be cultured in a suitable culture medium typically containing one or more substances that inhibit the growth or survival of unfused cells. For example, parent cells lacking the enzyme hypoxanthine-guanine phosphoribosyl transferase (HGPRT or HPRT) can be used, and the culture medium for the resulting hybridoma cells can be supplemented with hypoxanthine, aminopterin, and thymidine (''HAT medium'') to prevent the growth of HGPRT-deficient (unfused) cells.

[0270] Desirable properties of immortalized cell lines can include, but are not limited to, efficient fusion, support of high-level antibody expression by selected antibody-producing cells, and sensitivity to unfused cell-inhibiting media (e.g., HAT medium). In some embodiments, the immortalized cell line is a mouse myeloma cell line. Such cell lines can be obtained, for example, from the Salk Institute Cell Distribution Center (San Diego, CA) or the American Type Culture Collection (Manassas, VA). Human myeloma and mouse-human heteromyeloma cell lines can also be used for the production of human monoclonal antibodies (see, for example, 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 content of each document is hereby incorporated by reference in its entirety).

[0271] Hybridoma cell culture media can be assayed for the presence of monoclonal antibodies having the desired binding specificity. Assays can include, but are not limited to, immunoprecipitation assays, in vitro binding assays, radioimmunoassays (RIAs), surface plasmon resonance (SPR) assays, and / or enzyme-linked immunosorbent assays (ELISAs). In some embodiments, the binding specificity of the monoclonal antibody can 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 content of which is hereby incorporated by reference in its entirety).

[0272] The antibodies produced by the cultured hybridomas may be analyzed to determine their binding specificity for the target antigen. Once antibodies with desirable characteristics are identified, the corresponding hybridomas can be subcloned by limiting dilution procedures and grown by standard methods. Antibodies produced by hybridomas can 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, the antibodies may be isolated directly from the serum of the immunized host.

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

[0274] Antibody Display In some embodiments, the antibody can be developed using antibody display technology. “Display technology” refers to systems and methods for expressing an amino acid-based candidate compound, where the nucleic acid encoding the compound is linked to the compound and the compound is expressed in a format accessible to a target or ligand. The candidate compound is expressed on the surface of a host capsid or cell in most systems, although there are some cell-free systems (e.g., ribosome display). Using display technology, a display “library” can be generated that includes a set of display library members, which are candidate compound library members. A display library that includes an antibody (or a variant or fragment thereof) as a library member is referred to herein as an “antibody display library”. Antibodies can be designed, selected, or optimized by screening a target antigen using an antibody display library. An antibody display library can include millions to billions of members, each expressing a unique antibody domain. The presented antibody fragment can be an scFv antibody fragment that is a fusion protein in which the V H and V L antibody domains of the antibody are joined by a flexible linker. The display library can include antibody fragments with different levels of diversity between the variable domain framework region and the CDRs. The CDRs of the display library antibody fragments can include unique variable loop lengths and / or sequences. The antibody variable domains or CDRs obtained from display library selection can be incorporated directly into the antibody sequence for the production of recombinant antibodies or can be mutated and utilized for further optimization via in vitro affinity maturation.

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

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

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

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

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

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

[0281] In vitro affinity assays may be performed (e.g., by ELISA) using recombinant or isolated protein antigens. For example, recombinant or isolated ePHF may be used for anti-tau antibody affinity assays. In some embodiments, the anti-tau antibodies of the present disclosure may exhibit a maximum half-maximal effective concentration (EC50) of about 0.01 nM to about 100 nM for binding to ePHF when evaluated by ELISA. In some embodiments, the EC50 presented 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, the anti-tau antibodies of the present disclosure may exhibit an EC50 of about 0.01 nM to about 100 nM for binding to any of the antigens listed in Table 8, or to an epitope (including but not limited to conformational epitopes) that includes or is included within any of the antigens, when evaluated by ELISA. In some embodiments, the EC50 presented may be less than about 50 nM, less than about 20 nM, less than about 10 nM, or less than about 1 nM.

[0282] In some embodiments, the anti-tau antibodies of the present disclosure bind to pathological tau but not to non-pathological tau. Such antibodies may be referred to herein as "selective" for the pathological form of tau. In some embodiments, the anti-tau antibodies of the present disclosure bind to tau condensates.

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

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

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

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

[0287] In some embodiments, the anti-tau antibodies of the disclosure can inhibit tau aggregation with a maximum half-inhibitory concentration (IC50) of from about 1 nM to about 30 nM as determined by an immunodepletion assay (e.g., using tau RD biosensor cells).

[0288] Antibody Structure and Variations The antibodies of the disclosure may exist as an entire polypeptide, multiple polypeptides, or fragments of a polypeptide, each of which may independently be encoded by one or more nucleic acids, multiple nucleic acids, fragments of nucleic acids, or variants of any of the foregoing.

[0289] As used herein, "polypeptide" generally means a polymer of amino acid residues (natural or non-natural), covalently linked together most commonly by peptide bonds. This term, as used herein, refers to proteins, polypeptides, and peptides of any size, structure, or function. Polypeptides smaller than about 50 amino acids may sometimes be referred to using the term "peptide". Peptides can be at least about 2, 3, 4, or at least 5 amino acid residues in length. The polypeptides of the present disclosure can include gene products, polypeptides of natural origin, synthetic polypeptides, homologs, orthologs, paralogs, fragments, or other equivalents, variants, and analogs of the foregoing. A polypeptide can be a single molecule or a multimolecular complex such as a dimer, trimer, or tetramer. A polypeptide can include single-chain or multichain polypeptides, which may be associated or linked. A polypeptide can include an amino acid polymer in which one or more amino acid residues are artificial chemical analogs of the corresponding naturally-occurring amino acids.

[0290] The term "polypeptide variant" refers to a molecule in which the amino acid sequence differs from a native sequence or a reference sequence. An amino acid sequence variant can have substitutions, deletions, and / or insertions at certain positions within the amino acid sequence when compared to the native sequence or reference sequence. Typically, a variant has at least about 50% identity (homology) to the native sequence or reference sequence, preferably at least about 80%, more preferably at least about 90% identical (homologous) to the native sequence or reference sequence.

[0291] In some embodiments, "variant mimics" are provided. As used herein, the term "variant mimic" refers to something that contains one or more amino acids that mimic an activated sequence. For example, glutamic acid can function as a mimic of phosphorylated threonine and / or phosphorylated serine. Alternatively, a variant mimic can result in deactivation, or a deactivated product containing a mimic; for example, phenylalanine can act as a deactivating substitution for tyrosine, or alanine can act as a deactivating substitution for serine.

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

[0293] Typically, a variant has 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 the native sequence.

[0294] A "homolog" as applied to an amino acid sequence means a corresponding sequence of another species that has substantial identity to a second sequence of a second species. An "analog" is intended to include polypeptide variants that differ by one or more amino acid changes, such as substitutions, additions, or deletions of amino acid residues, but still maintain the properties of the parent polypeptide.

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

[0296] As used herein with reference to a polypeptide, a "substitution variant" is one in which at least one amino acid residue has been removed from the native or starting sequence and a different amino acid has been inserted in its place at the same position. The substitution may be a single substitution in which only one amino acid in the molecule is replaced, or a multiple substitution in which two or more amino acids are replaced in the same molecule.

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

[0298] As used in reference to a polypeptide, an "insertion variant" has one or more amino acids inserted immediately adjacent to an amino acid at a particular position within the native or starting sequence. "Immediately adjacent" to an amino acid means connected to either the alpha-carboxy or alpha-amino functional group of the amino acid.

[0299] As used in reference to a polypeptide, a "deletion variant" has one or more amino acids removed from the native or starting amino acid sequence. Typically, deletion variants have one or more amino acids deleted within a particular region of the molecule.

[0300] As used herein, the term "derivative" is used synonymously with the term "variant" and refers to a molecule that has been modified or altered in some way with respect to a reference or starting molecule. In some embodiments, derivatives include proteinaceous or non-proteinaceous organic derivatizing agents and native or starting polypeptides that have been modified by post-translational modifications. Covalent modifications have conventionally been introduced by reacting a target amino acid residue of a polypeptide with an organic derivatizing agent capable of reacting with a selected side chain or terminal residue, or by utilizing the mechanisms of post-translational modification that function in selected recombinant host cells. The resulting covalent derivatives are useful in programs designed to identify important residues for biological activity, immunoassays, or the preparation of antibodies for immunoaffinity purification.

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

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

[0303] A conjugate derivative specifically includes a fusion molecule in which a polypeptide is covalently bound to a non-proteinaceous polymer. The non-proteinaceous polymer can include a hydrophilic synthetic polymer, i.e., a polymer that would not otherwise be found in nature. However, polymers that occur naturally and are produced by recombinant or in vitro methods are as useful as polymers isolated from nature. The hydrophilic polyvinyl polymer can include polyvinyl alcohol and / or polyvinylpyrrolidone. Particularly useful are polyvinyl alkylene ethers such as polyethylene glycol and polypropylene glycol. The polypeptide can be linked to various non-proteinaceous polymers such as polyethylene glycol, polypropylene glycol, or polyoxyalkylene in the manner described in U.S. Patent Nos. 4,640,835, 4,496,689, 4,301,144, 4,670,417, 4,791,192, or 4,179,337, the content of each of which is incorporated herein by reference in its entirety.

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

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

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

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

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

[0309] Modification of Antibodies Antibodies can be modified to obtain variants having one or more altered properties. Such properties can include, or be related to, the structure, function, affinity, specificity, protein folding, stability, manufacture, expression, and / or immunogenicity of the antibody (i.e., the immune response in a subject treated with such an antibody). In some embodiments, antibody fragments or variants may be used for the modification of another antibody or incorporated into a synthetic antibody.

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

[0311] In some embodiments, a modified version of the anti-tau antibody described above can be prepared by adding, deleting, or substituting one or more CDR amino acid residues. In some embodiments, the anti-tau antibody can be modified by preparing a modified antibody having one or more amino acid deletions, substitutions, or insertions based on an amino acid sequence alignment of antibodies that bind to a similar target and analysis of the aligned sequences.

[0312] The present disclosure includes the amino acid consensus sequence of the CDR region sequences and indicates specific amino acids (shown within brackets) that can be modified, or more generally the positions of amino acid residues that can be deleted or substituted, in antibody amino acid sequences such as those described in Table 1A or Z.

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

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

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

[0316]

Table 1-1

[0317]

Table 1-2

[0318]

Table 1-3

[0319]

Table 1-4

[0320]

Table 1-5

[0321]

Table 1-6

[0322]

Table 1-7

[0323]

Table 1-8

[0324]

Table 2-1

[0325]

Table 2-2

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

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

[0328] In some embodiments, the anti-tau antibody has a CDRH1 comprising the amino acid sequence G[F / Y]TFT[R / I / D][Y / F] (SEQ ID NO: 937), or a CDRH1 comprising the amino acid sequence G-X1-TFT-X2-X3 (SEQ ID NO: 938), where X1, X2, and X3 may be any amino acid, for example, X1 and X3 are each independently F / Y, and / or X2 is any residue (e.g., R / K / H / D / E / G / A / I / L / V); a CDRH2 comprising the amino acid sequence NPNNG[G / E] (SEQ ID NO: 939), or a CDRH2 comprising the amino acid sequence NPNNGX (SEQ ID NO: 940), where X may be any amino acid, for example, E / D / G / A / V / I / L; a CDRH3 comprising the amino acid sequence G[T / R]G[T / M]G[absent / Y][absent / Y]A[M / L]DY (SEQ ID NO: 941), or a CDRH3 comprising the amino acid sequence G-X1-G-X2-G-X3-X4-A-X5-DY (SEQ ID NO: 942), where each of X1 to X5 may be any amino acid, and / or X3 and / or X4 may be absent, for example, 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;CDRL1 containing 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 CDRL1 containing 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 to X15 may be any amino acid and / or X11, X12, X13, X14, and / or X15 may be absent; for example, X1 is R / K / H / G / A / V / I / L, and / or X2 is S / T / A / V / I / L, and / or X3 is Q / N / E / D, and / or X4 is S / T / N / Q, and / or X5 is L / V / A / I, and / or X6 is A / V / I / L / Y / F, and / or X7 is H / R / K / G / A, and / or X8 is S / T / A / V / I / L / N / Q, and / or X9 is N / Q / A / I / L / V / M / S / T, and / or X10 is G / A / N / Q, and / or X11 is Q / N / A / V / I / L / absent, and / or X12 is T / S / absent, and / or X13 is H / R / K / Y / F / absent, and / or X14 is A / V / I / L / absent, and / or X15 is Y / F / absent); a CDRL2 consensus sequence having about 3 to about 7 amino acids of the amino acid sequence [R / G][V / A][S / T][N / T / S][R / L][F / A][S / D] (SEQ ID NO: 945), or CDRL2 containing 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; for example, X1 is R / K / H / G / A, and / or X2 is V / A / I / L, and / or X3 is S / T, and / or X4 is N / Q / T / S, and / or X5 is R / K / H / A / V / I / L, and / or X6 is F / Y / A / V / I / L / G, and / or X7 is S / T / D / E);and / or a CDRL3 comprising the amino acid sequence [F / Q][G / N][G / V][T / L][H / T][V / I]P[R / W]T (SEQ ID NO: 947), or a CDRL3 comprising the amino acid sequence X1-X2-X3-X4-X5-X6-P-X7-T (SEQ ID NO: 948) (wherein X1, X2, X3, X4, X5, X6, and X7 may be any amino acid, for example, X1 is F / Y / Q / N, and / or X2 is G / A / Q / N, and / or X3 is G / A / V / I / L, and / or X4 is T / S / A / V / I / L, and / or X5 is H / R / K / T / S, and / or X6 is V / I / A / L, and / or X7 is R / K / H / W / F / Y).;

[0329] In some embodiments, the anti-tau antibody comprises a CDRH1 comprising the amino acid sequence GY[S / T]FT[D / E]Y (SEQ ID NO: 949), or a CDRH1 comprising the amino acid sequence GY-X1-FT-X2-Y (SEQ ID NO: 950), where X1 and X2 may be any amino acid, for example, X1 is S / T, and / or X2 is D / E / S / T; a CDRH2 comprising the amino acid sequence [F / Y]PG[S / R][D / G][S / N] (SEQ ID NO: 951), or a CDRH2 comprising the amino acid sequence X1-PG-X2-X3-X4 (SEQ ID NO: 952), where X1 to X4 may be any amino acid, for example, X1 is F / Y, and / or X2 is S / T / R / K / H, and / or X3 is D / E / G / A, and / or X4 is S / T / N / Q; a CDRH3 comprising the amino acid sequence P[T / A][V / I / Y][V / Y][A / S][R / K]DYAM[D / E]Y (SEQ ID NO: 953), or a CDRH3 comprising the amino acid sequence P-X1-X2-X3-X4-X5-DYAM-X6-Y (SEQ ID NO: 954), where X1 to X6 may be any amino acid, for example, X1 is T / S / A / V / I / L, and / or X2 is V / I / A / L / Y / F, and / or X3 is V / I / A / L / Y / F, and / or X4 is A / V / I / L / S / T, and / or X5 is R / K / H, and / or X6 is D / E; a CDRL1 comprising the amino acid sequence RSSQSIV[Y / H][S / R / T]NGNTYLE (SEQ ID NO: 955), or a CDRL1 comprising the amino acid sequence RSSQSIV-X1-X2-NGNTYLE (SEQ ID NO: 956), where X1 and X2 may be any amino acid, for example, X1 is Y / F / H / R / K, and / or X2 is S / T / R / K / H; a CDRL2 comprising the amino acid sequence KVSNRFS (SEQ ID NO: 525); and / or a CDRL3 comprising the amino acid sequence FQGSHVP[Y / F]T (SEQ ID NO: 957), or a CDRL3 comprising the amino acid sequence FQGSHVPXT (SEQ ID NO: 958), where X may be any amino acid, for example, X is Y / F.

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

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

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

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

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

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

[0336] In some embodiments, antibody affinity analysis can be used to modulate the multispecificity of an antibody (e.g., to reduce or enhance the multispecificity of an antibody). Such modulation can include modulating the relative affinity for two or more epitopes or antigens. For example, an antibody can be optimized such that its affinity for one epitope or antigen is higher compared to a second epitope or antigen.

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

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

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

[0340] Humanization of Antibodies In some embodiments, the anti-tau antibodies of the present disclosure can be prepared as humanized antibodies. A "humanized" antibody is a chimeric antibody that contains minimal sequences (e.g., variable domains or CDRs) derived from non-human immunoglobulins (e.g., murine immunoglobulins). A humanized antibody can be prepared from a human (recipient) immunoglobulin in which the residues of the hypervariable regions are replaced by hypervariable region residues from one or more non-human "donor" antibodies (e.g., mouse, rat, rabbit, or non-human primate). The donor antibody can be selected based on the desired specificity, affinity, and / or potency. A humanized antibody can contain one or more revertant mutations, including the return of one or more amino acids to the amino acids found in the donor antibody. Conversely, the residues derived from the donor antibody contained in the humanized antibody can be mutated to match the residues present in the human recipient antibody. Revertant mutations can be introduced to reduce the human immune response to the humanized antibody. In some embodiments, revertant mutations are introduced to avoid problems related to the production of the antibody (e.g., protein aggregation or post-translational modification).

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

[0342] A cell line stably transfected with DNA encoding a humanized antibody may be prepared and used to establish a stable cell line. The cell line producing the humanized antibody may be expanded to express the humanized antibody, which may be collected and purified from the cell culture medium.

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

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

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

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

[0347] In some embodiments, the anti-tau antibody comprises a heavy chain variable region derived from an antibody selected from, for example, V0001-V0065, V1001-V1005, or V2001-V2005, such as those described in Table 3, 6, or 4 as described herein, or a sequence that is substantially identical (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences. In some embodiments, the heavy chain variable region comprises an amino acid sequence having at least 1, 2, or 3 modifications (e.g., substitutions, such as conservative substitutions) of the amino acid sequence of the heavy chain variable region presented in Table 3, 6, or 4, but the modifications (e.g., substitutions, such as conservative substitutions) are 30 or fewer, 20 or fewer, or 10 or fewer amino acids.

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

[0349] In some embodiments, the anti-tau antibody comprises a light chain variable region derived from an antibody selected from, for example, V0001-V0065, V1001-V1005, or V2001-V2005, such as those described in Table 3, 6, or 4 as described herein, or a sequence that is substantially identical (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences. In some embodiments, the light chain variable region comprises an amino acid sequence having at least 1, 2, or 3 modifications (e.g., substitutions, such as conservative substitutions) of the amino acid sequence of the light chain variable region presented in Table 3, 6, or 4, but having 30 or fewer, 20 or fewer, or 10 or fewer modifications (e.g., substitutions, such as conservative substitutions).

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

[0351] In some embodiments, the anti-tau antibody comprises a heavy chain variable region and a light chain variable region derived from an antibody selected from, for example, V0001-V0065, V1001-V1005, or V2001-V2005, such as those described in Table 3, 6, or 4 as described herein, or a sequence that is substantially identical (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences. In some embodiments, the anti-tau antibody comprises a heavy chain variable region having at least 1, 2, or 3 modifications (e.g., substitutions, such as conservative substitutions) of the amino acid sequence presented in Table 3, 6, or 4, but where the modifications (e.g., substitutions, such as conservative substitutions) are 30 or fewer, 20 or fewer, or 10 or fewer, and a light chain variable region having at least 1, 2, or 3 modifications (e.g., substitutions, such as conservative substitutions) of the amino acid sequence presented in Table 3, 6, or 4, but where the modifications (e.g., substitutions, such as conservative substitutions) are 30 or fewer, 20 or fewer, or 10 or fewer.

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

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

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

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

[0356] In some embodiments, the anti-tau antibody comprises at least 1, 2, 3, or 4 framework regions derived from the heavy chain variable region of an antibody selected from, for example, V0001-V0065, V1001-V1005, or V2001-V2005, as described herein, for example, as described in Table 7 or 4, or a sequence substantially identical (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences. In some embodiments, one or more (or collectively all) of the framework regions have 1, 2, 3, 4, 5, or more changes, such as 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 comprises substitutions in the heavy chain framework region, such as one or more substitutions in FRH1, FRH2, FRH3, and / or FRH4 of the heavy chain.

[0357] In some embodiments, the anti-tau antibody comprises at least 1, 2, 3, or 4 framework regions derived from the light chain variable region of an antibody selected from, for example, V0001-V0065, V1001-V1005, or V2001-V2005, such as those described in Table 7 or 4 herein, or a sequence that is substantially identical (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences. In some embodiments, one or more (or collectively all) of the framework regions have 1, 2, 3, 4, 5, or more changes, such as amino acid substitutions, insertions, or deletions, relative to the amino acid sequences shown in Table 7 or 4. In some embodiments, the anti-tau antibody comprises substitutions in the light chain framework region, such as one or more substitutions in FRL1, FRL2, FRL3, and / or FRL4 of the light chain.

[0358] In some embodiments, the anti-tau antibody comprises at least 1, 2, or 3 complementarity determining regions (CDRs) derived from the heavy chain variable region, which comprises the amino acid sequences of Tables 2A-2C, 3, 6, 4, or 5, or a sequence that is substantially identical (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences or is encoded by the nucleic acid sequences of Table 4. In some embodiments, one or more (or collectively all) of the CDRs have 1, 2, 3, 4, 5, or more changes, such as amino acid substitutions, insertions, or deletions, relative to the amino acid sequences shown in Tables 2A-2C, 6, 4, or 5, or encoded by the nucleotide sequences shown in Table 4. In some embodiments, the encoded anti-tau antibody comprises substitutions in the heavy chain CDRs, such as one or more substitutions in CDR1, CDR2, and / or CDR3 of the heavy chain.

[0359] In some embodiments, the anti-tau antibody comprises at least 1, 2, or 3 complementarity determining regions (CDRs) derived from the variable region of the light chain that comprise the amino acid sequence of Table 2A-2C, 6, 4, or 5, or are encoded by a nucleic acid sequence of Table 4, or a sequence that is substantially identical to any of the foregoing sequences (e.g., having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity). In some embodiments, one or more (or collectively all) of the CDRs have one, two, three, four, five, or more changes, such as amino acid substitutions, insertions, or deletions, relative to the amino acid sequence encoded by the nucleotide sequence shown in Table 2A-2C, 6, 4, or 5, or shown in Table 4. In some embodiments, the anti-tau antibody comprises substitutions in the light chain CDRs, e.g., one or more substitutions in CDR1, CDR2, and / or CDR3 of the light chain.

[0360] In some embodiments, the anti-tau antibody comprises at least 1, 2, 3, 4, 5, or 6 CDRs (or collectively all CDRs) derived from the variable regions of the heavy and light chains that comprise the amino acid sequence shown in Table 2A-2C, 6, 4, or 5, or encoded by the nucleotide sequence shown in Table 4. In some embodiments, one or more (or collectively all) of the CDRs have one, two, three, four, five, six, or more changes, such as amino acid substitutions, insertions, or deletions, relative to the CDRs encoded by the nucleotide sequence shown in Table 2A-2C, 6, 4, or 5, or shown in Table 4.

[0361] In some embodiments, the anti-tau antibody comprises all 3 CDRs derived from the variable region of the heavy chain, all 3 CDRs derived from the variable region of the light chain, or both (e.g., all 6 CDRs derived from the variable regions of the heavy and light chains) that comprise the amino acid sequence shown in Table 2A-2C, 6, 4, or 5, or encoded by the nucleotide sequence shown in Table 4.

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

[0363]

Table 3

[0364]

Table 4

[0365]

Table 5

[0366]

Table 6-1

[0367]

Table 6-2

[0368]

Table 6-3

[0369]

Table 7-1

[0370]

Table 7-2

[0371]

Table 7-3

[0372]

Table 7-4

[0373]

Table 7-5

[0374]

Table 7-6

[0375]

Table 7-7

[0376]

Table 7-8

[0377]

Table 7-9

[0378]

Table 7-10

[0379]

Table 7-11

[0380]

Table 7-12

[0381]

Table 7-13

[0382]

Table 7-14

[0383]

Table 8-1

[0384]

Table 8-2

[0385]

Table 8-3

[0386]

Table 9-1

[0387]

Table 9-2

[0388]

Table 10-1

[0389]

Table 10-2

[0390]

Table 10-3

[0391]

Table 10-4

[0392]

Table 10-5

[0393]

Table 10-6

[0394] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of heavy chain complementarity determining region 1 (HC CDR1), HC CDR2, and / or HC CDR3, and the HC CDR1, HC CDR2, and HC CDR3 sequences each 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 light chain complementarity determining region 1 (LC CDR1), LC CDR2, and / or LC CDR3, and the LC CDR1, LC CDR2, and LC CDR3 sequences each comprise the sequences of SEQ ID NO: 460, 518, and 557, respectively. In some embodiments, the anti-tau antibody comprises HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3, and the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences each comprise the sequences of SEQ ID NO: 299, 343, 395, 460, 518, and 557, respectively. In some embodiments, one or more (or collectively all) of the CDRs have one, two, three, four, five, or more changes, such as amino acid substitutions, insertions, or deletions, relative to any of the amino acid sequences of SEQ ID NO: 299, 343, 395, 460, 518, or 557.

[0395] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of heavy chain complementarity determining region 1 (HC CDR1), HC CDR2, and / or HC CDR3, and the HC CDR1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NOs: 1140, 1141, and 395, respectively. In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of light chain complementarity determining region 1 (LC CDR1), LC CDR2, and / or LC CDR3, and the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NOs: 460, 518, and 557, respectively. In some embodiments, the anti-tau antibody comprises HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3, and the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NOs: 1140, 1141, 395, 460, 518, and 557, respectively. In some embodiments, one or more (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 any of the amino acid sequences of SEQ ID NOs: 1140, 1141, 395, 460, 518, and 557.

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

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

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

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

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

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

[0402] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of heavy chain complementarity determining region 1 (HC CDR1), HC CDR2, and / or HC CDR3, and the HC CDR1, HC CDR2, and HC CDR3 sequences each comprise the sequences of SEQ ID NOs: 1165, 1166, and 1167, respectively. In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of light chain complementarity determining region 1 (LC CDR1), LC CDR2, and / or LC CDR3, and the LC CDR1, LC CDR2, and LC CDR3 sequences each comprise the sequences of SEQ ID NOs: 473, 528, and 571, respectively. In some embodiments, the anti-tau antibody comprises HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3, and the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences each comprise the sequences of SEQ ID NOs: 1165, 1166, 1167, 473, 528, and 571, respectively. In some embodiments, one or more (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 any of the amino acid sequences of SEQ ID NOs: 1165, 1166, 1167, 473, 528, and 571.

[0403] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of heavy chain complementarity determining region 1 (HC CDR1), HC CDR2, and / or HC CDR3, and the HC CDR1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NOs: 315, 341, and 410, respectively. In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of light chain complementarity determining region 1 (LC CDR1), LC CDR2, and / or LC CDR3, and the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NOs: 474, 529, and 571, respectively. In some embodiments, the anti-tau antibody comprises HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3, and the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NOs: 315, 341, 410, 474, 529, and 571, respectively. In some embodiments, one or more (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 any of the amino acid sequences of SEQ ID NOs: 315, 341, 410, 474, 529, and 571.

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

[0405] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of heavy chain complementarity determining region 1 (HC CDR1), HC CDR2, and / or HC CDR3, and the HC CDR1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NOs: 1168, 1169, and 1167, respectively. In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of light chain complementarity determining region 1 (LC CDR1), LC CDR2, and / or LC CDR3, and the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NOs: 1170, 528, and 571, respectively. In some embodiments, the anti-tau antibody comprises HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3, and the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NOs: 1168, 1169, 1167, 1170, 528, and 571, respectively. In some embodiments, one or more (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 any of the amino acid sequences of SEQ ID NOs: 1168, 1169, 1167, 1170, 528, and 571.

[0406] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of heavy chain complementarity determining region 1 (HC CDR1), HC CDR2, and / or HC CDR3, and the HC CDR1, HC CDR2, and HC CDR3 sequences each 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 light chain complementarity determining region 1 (LC CDR1), LC CDR2, and / or LC CDR3, and the LC CDR1, LC CDR2, and LC CDR3 sequences each comprise the sequences of SEQ ID NO: 475, 530, and 571, respectively. In some embodiments, the anti-tau antibody comprises HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3, and the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences each comprise the sequences of SEQ ID NO: 316, 341, 410, 475, 530, and 571, respectively. In some embodiments, one or more (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 any of the amino acid sequences of SEQ ID NO: 316, 341, 410, 475, 530, and 571.

[0407] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of heavy chain complementarity determining region 1 (HC CDR1), HC CDR2, and / or HC CDR3, and the HC CDR1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NOs: 1149, 1150, and 410, respectively. In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of light chain complementarity determining region 1 (LC CDR1), LC CDR2, and / or LC CDR3, and the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NOs: 475, 530, and 571, respectively. In some embodiments, the anti-tau antibody comprises HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3, and the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NOs: 1149, 1150, 410, 475, 530, and 571, respectively. In some embodiments, one or more (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 any of the amino acid sequences of SEQ ID NOs: 1149, 1150, 410, 475, 530, and 571.

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

[0409] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of heavy chain complementarity determining region 1 (HC CDR1), HC CDR2, and / or HC CDR3, and the HC CDR1, HC CDR2, and HC CDR3 sequences each 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 light chain complementarity determining region 1 (LC CDR1), LC CDR2, and / or LC CDR3, and the LC CDR1, LC CDR2, and LC CDR3 sequences each comprise the sequences of SEQ ID NO: 495, 540, and 587, respectively. In some embodiments, the anti-tau antibody comprises HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3, and the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences each comprise the sequences of SEQ ID NO: 325, 362, 435, 495, 540, and 587, respectively. In some embodiments, one or more (or collectively all) of the CDRs have one, two, three, four, five, or more changes, such as amino acid substitutions, insertions, or deletions, relative to any of the amino acid sequences of SEQ ID NO: 325, 362, 435, 495, 540, and 587.

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

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

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

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

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

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

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

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

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

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

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

[0421] The present disclosure provides, in some embodiments, a nucleic acid (e.g., an isolated nucleic acid) encoding any of the above-described antibodies, as well as a viral genome, a vector, an AAV particle, and a cell containing the same.

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

[0423]

Table 11

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

[0425] In some embodiments, disclosed herein is a coded antibody that competes with the aforementioned antibodies for binding to tau. In some embodiments, disclosed herein is an antibody that binds to the same epitope, a substantially the same epitope, an overlapping epitope, or a substantially overlapping epitope as the epitope of the aforementioned anti-tau antibody.

[0426] In some embodiments, competition or cross-competition refers to the ability of an antibody to interfere with the binding of an anti-tau antibody, such as the anti-tau antibodies provided herein, to a target, such as a tau protein. The interference with binding may be direct or indirect (e.g., via allosteric modulation of the antibody or target). The extent to which one antibody can interfere with the binding of another antibody to a target, and thus whether it can be said to compete, can be determined using a competition binding assay, such as a FACS assay, ELISA, or BIACORE assay. In some embodiments, the competition binding assay is a quantitative competition assay. In some embodiments, a first anti-tau antibody is said to compete with a second anti-tau antibody for binding to a target when, in a competition binding assay (e.g., a competition assay described herein), 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.

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

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

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

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

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

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

[0433] Antibodies that compete with such a second antibody for tau epitope binding include CDRH1 containing the amino acid sequence 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, for example, X1 and / or X3 may be an amino acid having a hydrophobic and / or aromatic side chain such as F or Y, and / or X2 may be a positively charged residue (e.g., R, K, H) or a residue having an aliphatic side chain (e.g., A, V, I, or L)); CDRH2 containing the amino acid sequence NPNNGG (SEQ ID NO: 341); CDRH3 containing the amino acid sequence GTGTGAMDY (SEQ ID NO: 410); CDRL1 containing the amino acid sequence RSSQSLVH[N / S]NG[I / N]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, for example, 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); CDRL2 containing 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, for example, X1 is Q / N / S / T); and / or CDRL3 containing the amino acid sequence FQGTHVPRT (SEQ ID NO: 571).

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

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

[0436] An antibody that competes with such a second antibody for tau epitope binding comprises a CDRH1 having the amino acid sequence 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 to X3 may be any amino acid, for example, 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 having the amino acid sequence YWDDD (SEQ ID NO: 362); a CDRH3 having 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 to X9 may be any amino acid, and / or one or more of X3 to X5 may be absent, for example, 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;The CDRL1 containing 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 to X15 may be any amino acid, and / or one or more of X9 to X14 may be absent, for example, X1 is K / R / H / S / T, and / or X2 is S / T / A / V / I / L, and / or X3 is Q / N / S / T, and / or X4 is L / I / V / A, and / or X5 is A / V / I / L / S / T, and / or X6 is N / Q / S / T / D / E, and / or X7 is D / E / S / T, and / or X8 is G / A / V / I / L / D / E / Y / F, and / or X9 is N / Q / G / A / absent, and / or X10 is Q / N / absent, and / or X11 is K / R / H / absent, and / or X12 is N / Q / T / S / absent, and / or X13 is Y / F / absent, and / or X14 is A / V / I / L / absent, and / or X15 is A / V / I / L / H / K / R / N / Q); the CDRL2 containing 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 to X6 may be any amino acid, for example, X1 is Y / F / G / A / V / I / L / R / K / H, and / or X2 is A / V / I / L / T / S, and / or X3 is N / Q / T / S / K / R / H, and / or X4 is R / K / H / A / V / I / L, and / or X5 is C / S / E / D / A / V / I / L, and / or X6 is T / S);and / or an amino acid sequence [W / Q][Q / N][G / D][T / S / Y / H][H / S / R][F / I / S / H]P[Q / R / L / Y][absent / Y]T (SEQ ID NO: 980), or more generally X1-X2-X3-X4-X5-X6-P-X7-X8-T (SEQ ID NO: 981), may be included in CDRL3 (where each of X1 to X8 may be any amino acid and / or X8 may be absent; for example, X1 is Q / N / W / F / Y and / or X2 is Q / N and / or X3 is G / A / V / I / L / D / E and / or X4 is T / S / Y / F / H / K / R and / or X5 is H / K / R / S / T and / or X6 is F / Y / A / V / I / L / S / T / H / K / R and / or X7 is Q / N / R / K / H / A / V / I / L / Y / F and / or X8 is Y / F / absent).;

[0437] CDRH1 may include the amino acid sequence GFSL[S / N]T[S / F][A / G]M (SEQ ID NO: 964). CDRH2 may include the amino acid sequence YWDDD (SEQ ID NO: 362). 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). 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). 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). 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).

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

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

[0440] As used herein, a "viral genome" or "vector genome" refers to the nucleic acid sequence(s) encapsulated within an AAV particle. The viral genome includes at least one payload region encoding a polypeptide, e.g., an antibody, an antibody-based composition, or a fragment thereof.

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

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

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

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

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

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

[0447] AAV has proven useful as a biological tool because of its relatively simple structure, its ability to infect a wide range of cells (including quiescent and dividing cells) without integrating into or replicating in the host genome, and its relatively mild immunogenic profile. The viral genome can be engineered to contain the minimal components for the assembly of a functional recombinant virus or viral particle that carries a desired payload or is engineered to express or deliver a desired payload to a specific tissue target.

[0448] 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) conventionally cap the viral genome at both the 5' and 3' ends and provide the origin of replication for the viral genome. Without wishing to be bound by theory, the AAV viral genome typically contains two ITR sequences. These ITRs have a characteristic T-shaped hairpin structure defined by self-complementary regions (145 nt in wild-type AAV) at the 5' and 3' ends of the ssDNA that form an energetically stable double-stranded region. The double-stranded hairpin structure serves multiple functions including, but not limited to, acting as an origin of DNA replication by functioning as a primer for the host cell's endogenous DNA polymerase complex involved in viral replication.

[0449] The wild-type AAV viral genome further contains the nucleotide sequences of two open reading frames, one for four non-structural Rep proteins (Rep78, Rep68, Rep52, Rep40 encoded by the Rep gene) and one for three capsid or structural proteins (VP1, VP2, VP3 encoded by the capsid gene or Cap gene). The Rep proteins are important for replication and packaging, and the capsid proteins are assembled to create the protein shell of AAV, i.e., the AAV capsid. Alternative splicing and alternative start codons and promoters result in the production of four different Rep proteins from a single open reading frame and three capsid proteins from a single open reading frame. Although it varies depending on the AAV serotype, as a non-limiting example, for AAV9 / hu.14 (SEQ ID NO: 123 of US7,906,111, the entire content of which is incorporated herein by reference), VP1 refers to amino acids 1 to 736, VP2 refers to amino acids 138 to 736, and VP3 refers to amino acids 203 to 736. In other words, VP1 is the full-length capsid sequence, and VP2 and VP3 are shorter components overall. As a result, a change in the sequence within the VP3 region is also a change to VP1 and VP2, but since VP3 is the shortest of the three sequences, the percent difference compared to the parental sequence is greatest for VP3. Although described here in relation to the amino acid sequence, the same can be said for the nucleic acid sequences encoding these proteins. The three capsid proteins assemble together to create the AAV capsid protein. Without wishing to be bound by theory, the AAV capsid protein typically contains VP1:VP2:VP3 in a molar ratio of 1:1:10. As used herein, "AAV serotype" is primarily defined by the AAV capsid. In some cases, the ITR is also specifically described by the AAV serotype (e.g., AAV2 / 9).

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

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

[0452] In some embodiments, the AAV particles of the disclosure are recombinant AAV viral vectors that are replication-deficient and lack the sequences encoding functional Rep and Cap proteins within their viral genomes. These defective AAV vectors lack most or all of the parental coding sequences and can essentially carry only one or two AAV ITR sequences and the nucleic acid of interest for delivery to cells, tissues, organs, or organisms.

[0453] In some embodiments, the viral genome of the AAV particles of the present disclosure includes at least one control element that results in the replication, transcription, and translation of the coding sequences encoded therein. Not all of the control elements need to be present at all times, as long as the coding sequences are replicable, transcribable, and / or translatable in a suitable 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 signals and polyadenylation signals, sequences that stabilize cytoplasmic mRNA, sequences that enhance translational efficiency (e.g., Kozak consensus sequences), sequences that enhance protein stability, and / or sequences that enhance protein processing and / or secretion.

[0454] According to the present disclosure, AAV particles for use in therapeutic and / or diagnostic agents include a virus distilled or reduced to the minimal components necessary for the transduction of the nucleic acid payload or cargo of interest. In this way, the AAV particles are engineered as vehicles for specific delivery, without the harmful replication and / or integration properties found in wild-type viruses.

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

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

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

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

[0459] In some embodiments, AAV particles comprising a payload region encoding a polypeptide can be introduced into mammalian cells. AAV serotype In some embodiments, AAV particles, e.g., AAV particles for vectorized delivery of an antibody (e.g., an anti-tau antibody) described herein, can include or be derived from any natural or recombinant AAV serotype. The AAV particles of the present disclosure can include or be derived from any natural or recombinant AAV serotype. According to the present disclosure, the AAV particles are VOY101, VOY201, AAVPHP.B (PHP.B), AAVPHP.A (PHP.A), AAVG2B-26, AAVG2B-13, AAVTH1.1-32, AAVTH1.1-35, AAVPHP.B2 (PHP.B2), AAVPHP.B3 (PHP.B3), AAVPHP.N / PHP.B-DGT, AAVPHP.B-EST, AAVPHP.B-GGT, AAVPHP.B-ATP, AAVPHP.B-ATT-T, AAVPHP.B-DGT-T, AAVPHP.B-GGT-T, AAVPHP.B-SGS, AAVPHP.B-AQP, AAVPHP.B-QQP, AAVPHP.B-SNP(3), AAVPHP.B-SNP, AAVPHP.B-QGT, AAVPHP.B-NQT, AAVPHP.B-EGS, AAVPHP.B-SGN, AAVPHP.B-EGT, AAVPHP.B-DST, AAVPHP.B-DST, AAVPHP.B-STP, AAVPHP.B-PQP, AAVPHP.B-SQP, AAVPHP.B-QLP, AAVPHP.B-TMP, AAVPHP.B-TTP, AAVPHP.S / G2A12, AAVG2A15 / G2A3 (G2A3), AAVG2B4 (G2B4), AAVG2B5 (G2B5), PHP.S, AAV1, AAV2, AAV2G9, AAV3, AAV3a, AAV3b, AAV3-3, AAV4, AAV4-4, AAV5, AAV6, AAV6.1, AAV6.2, AAV6.1.2, AAV7, AAV7.2, AAV8, AAV9, AAV9 K449R, AAV9.11, AAV9.13, AAV9.16, AAV9.24, AAV9.45, AAV9.47, AAV9.61, AAV9.68, AAV9.84, AAV9.9, AAV10, AAV11, AAV12, AAV16.3, AAV24.1, AAV27.3, AAV42.12, AAV42-1b, AAV42-2, AAV42-3a, AAV42-3b, AAV42-4, AAV42-5a, AAV42-5b, AAV42-6b, AAV42-8, AAV42-10, AAV42-11, AAV42-12, AAV42-13, AAV42-15, AAV42-aa, AAV43-1, AAV43-12, AAV43-20, AAV43-21, AAV43-23, AAV43-25, AAV43-5, AAV44.1, AAV44.2, AAV44.5, AAV223.1, AAV223.2, AAV223.4, AAV223.5, AAV223.6, AAV223.7, AAV1-7 / rh.48, AAV1-8 / rh.49, AAV2-15 / rh.62, AAV2-3 / rh.61, AAV2-4 / rh.50, AAV2-5 / rh.51, AAV3.1 / hu.6, AAV3.1 / hu.9, AAV3-9 / rh.52, AAV3-11 / rh.53, AAV4-8 / r11.64, AAV4-9 / rh.54, AAV4-19 / rh.55, AAV5-3 / rh.57, AAV5-22 / rh.58, AAV7.3 / hu.7, AAV16.8 / hu.10, 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, AAV A3.3, AAV A3.4, AAV A3.5, AAV A3.7, AAV C1, AAV C2, AAV C5, AAV-DJ, AAV-DJ8, AAV F3, AAV F5, AAV H2, AAV rh.72, AAV hu.8, AAV rh.68, AAV rh.70, AAV pi.1, AAV pi.3, AAV pi.2, AAV rh.60, AAV rh.44, AAV rh.65, AAV rh.55, AAV rh.47, AAV rh.69, AAV rh.45, AAV rh.59, AAVhu.12, AAVH6, AAVLK03, AAVH-1 / hu.1, AAVH-5 / hu.3, AAVLG-10 / rh.40, AAVLG-4 / rh.38, AAVLG-9 / hu.39, AAVN721-8 / rh.43, AAVCh.5, AAVCh.5R1, AAVcy.2, AAVcy.3, AAVcy.4, AAVcy.5, AVCy.5R1, AVCy.5R2, AVCy.5R3, AVCy.5R4, AAVcy.6, AAVhu.1, AAVhu.2, AAVhu.3, AAVhu.4, AAVhu.5, AAVhu.6, AAVhu.7, AAVhu.9, AAVhu.10, AAVhu.11, AAVhu.13, AAVhu.15, AAVhu.16, AAVhu.17, AAVhu.18, AAVhu.20, AAVhu.21, AAVhu.22, AAVhu.23.2, AAVhu.24, AAVhu.25, AAVhu.27, AAVhu.28, AAVhu.29, AAVhu.29R, AAVhu.31, AAVhu.32, AAVhu.34, AAVhu.35, AAVhu.37, AAVhu.39, AAVhu.40, AAVhu.41, AAVhu.42, AAVhu.43, AAVhu.44, AAVhu.44R1, AAVhu.44R2, AAVhu.44R3, AAVhu.45, AAVhu.46, AAVhu.47, AAVhu.48, AAVhu.48R1, AAVhu.48R2, AAVhu.48R3, AAVhu.49, AAVhu.51, AAVhu.52, AAVhu.54, AAVhu.55, AAVhu.56, AAVhu.57, AAVhu.58, AAVhu.60, AAVhu.61, AAVhu.63, AAVhu.64, AAVhu.66, AAVhu.67, AAVhu.14 / 9, AAVhu.t 19, AAVrh.2, AAVrh.2R, AAVrh.8, AAVrh.8R, AAVrh.10, AAVrh.12, AAVrh.13, AAVrh.13R, AAVrh.14, AAVrh.17, AAVrh.18, AAVrh.19, AAVrh.20, AAVrh.21, AAVrh.22, AAVrh.23, AAVrh.24, AAVrh.25, AAVrh.31, AAVrh.32, AAVrh.33, AAVrh.34, AAVrh.35, AAVrh.36, AAVrh.37, AAVrh.37R2, AAVrh.38, AAVrh.39, AAVrh.40, AAVrh.46, AAVrh.48, AAVrh.48.1, AAVrh.48.1.2, AAVrh.48.2, AAVrh.49, AAVrh.51, AAVrh.52, AAVrh.53, AAVrh.54, AAVrh.56, AAVrh.57, AAVrh.58, AAVrh.61, AAVrh.64, AAVrh.64R1, AAVrh.64R2, AAVrh.67, AAVrh.73, AAVrh.74, AAVrh8R, AAVrh8R A586R variant, AAVrh8R R533A variant, AAAV, BAAV, Caprine AAV, Bovine AAV, AAVhE1.1, AAVhEr1.5, AAVhER1.14, AAVhEr1.8, AAVhEr1.16, AAVhEr1.18, AAVhEr1.35, AAVhEr1.7, AAVhEr1.36, AAVhEr2.29, AAVhEr2.4, AAVhEr2.16, AAVhEr2.30, AAVhEr2.31, AAVhEr2.36, AAVhER1.23, AAVhEr3.1, AAV2.5T, AAV-PAEC, AAV-LK01, AAV-LK02, AAV-LK03, AAV-LK04, AAV-LK05, AAV-LK06, AAV-LK07, AAV-LK08, AAV-LK09, AAV-LK10, AAV-LK11, AAV-LK12, AAV-LK13, AAV-LK14, AAV-LK15, AAV-LK16, AAV-LK17, AAV-LK18, AAV-LK19, AAV-PAEC2, AAV-PAEC4, AAV-PAEC6, AAV-PAEC7, AAV-PAEC8, AAV-PAEC11, AAV-PAEC12, AAV-2-pre-miRNA-101, AAV-8h, AAV-8b, AAV-h, AAV-b, AAV SM 10-2, AAV Shuffle 100-1, AAV Shuffle 100-3, AAV Shuffle 100-7, AAV Shuffle 10-2, AAV Shuffle 10-6, AAV Shuffle 10-8, AAV Shuffle 100-2, AAV SM 10-1, AAV SM 10-8, AAV SM 100-3, AAV SM 100-10, BNP61 AAV, BNP62 AAV, BNP63 AAV, AAVrh.50, AAVrh.43, AAVrh.62, AAVrh.48, AAVhu.19, AAVhu.11, AAVhu.53, AAV4-8 / rh.64, AAVLG-9 / hu.39, AAV54.5 / hu.23, AAV54.2 / hu.22, AAV54.7 / hu.24, AAV54.1 / hu.21, AAV54.4R / hu.27, AAV46.2 / hu.28, AAV46.6 / hu.29, AAV128.1 / hu.43, true-type AAV (ttAAV), UPENN AAV 10, Japanese AAV 10 serotype, AAV CBr-7.1, AAV CBr-7.10, AAV CBr-7.2, AAV CBr-7.3, AAV CBr-7.4, AAV CBr-7.5, AAV CBr-7.7, AAV CBr-7.8, AAV CBr-B7.3, AAV CBr-B7.4, AAV CBr-E1, AAV CBr-E2, AAV CBr-E3, AAV CBr-E4, AAV CBr-E5, AAV CBr-e5, AAV CBr-E6, AAV CBr-E7, AAV CBr-E8, AAV CHt-1, AAV CHt-2, AAV CHt-3, AAV CHt-6.1, AAV CHt-6.10, AAV CHt-6.5, AAV CHt-6.6, AAV CHt-6.7, AAV CHt-6.8, AAV CHt-P1, AAV CHt-P2, AAV CHt-P5, AAV CHt-P6, AAV CHt-P8, AAV CHt-P9, AAV CKd-1, AAV CKd-10, AAV CKd-2, AAV CKd-3, AAV CKd-4, AAV CKd-6, AAV CKd-7, AAV CKd-8, AAV CKd-B1, AAV CKd-B2, AAV CKd-B3, AAV CKd-B4, AAV CKd-B5, AAV CKd-B6, AAV CKd-B7, AAV CKd-B8, AAV CKd-H1, AAV CKd-H2, AAV CKd-H3, AAV CKd-H4, AAV CKd-H5, AAV CKd-H6, AAV CKd-N3, AAV CKd-N4, AAV CKd-N9, AAV CLg-F1, AAV CLg-F2, AAV CLg-F3, AAV CLg-F4, AAV CLg-F5, AAV CLg-F6, AAV CLg-F7, AAV CLg-F8, AAV CLv-1, AAV CLv1-1, AAV Clv1-10, AAV CLv1-2, AAV CLv-12, AAV CLv1-3, AAV CLv-13, AAV CLv1-4, AAV Clv1-7, AAV Clv1-8, AAV Clv1-9, AAV CLv-2, AAV CLv-3, AAV CLv-4, AAV CLv-6, AAV CLv-8, AAV CLv-D1, AAV CLv-D2, AAV CLv-D3, AAV CLv-D4, AAV CL. Use a serotype selected from any of v-D5, AAV CLv-D6, AAV CLv-D7, AAV CLv-D8, AAV CLv-E1, AAV CLv-K1, AAV CLv-K3, AAV CLv-K6, AAV CLv-L4, AAV CLv-L5, AAV CLv-L6, AAV CLv-M1, AAV CLv-M11, AAV CLv-M2, AAV CLv-M5, AAV CLv-M6, AAV CLv-M7, AAV CLv-M8, AAV CLv-M9, AAV CLv-R1, AAV CLv-R2, AAV CLv-R3, AAV CLv-R4, AAV CLv-R5, AAV CLv-R6, AAV CLv-R7, AAV CLv-R8, AAV CLv-R9, AAV CSp-1, AAV CSp-10, AAV CSp-11, AAV CSp-2, AAV CSp-3, AAV CSp-4, AAV CSp-6, AAV CSp-7, AAV CSp-8, AAV CSp-8.10, AAV CSp-8.2, AAV CSp-8.4, AAV CSp-8.5, AAV CSp-8.6, AAV CSp-8.7, AAV CSp-8.8, AAV CSp-8.9, AAV CSp-9, AAV.hu.48R3, AAV.VR-355, AAV3B, AAV4, AAV5, AAVF1 / HSC1, AAVF11 / HSC11, AAVF12 / HSC12, AAVF13 / HSC13, AAVF14 / HSC14, AAVF15 / HSC15, AAVF16 / HSC16, AAVF17 / HSC17, AAVF2 / HSC2, AAVF3 / HSC3, AAVF4 / HSC4, AAVF5 / HSC5, AAVF6 / HSC6, AAVF7 / HSC7, AAVF8 / HSC8, and / or AAVF9 / HSC9, or be based on them, or can contain a peptide selected from any of these.

[0460] In some embodiments, the AAV serotype is a sequence described in U.S. Publication No. US20030138772, the entire content of which is incorporated herein by reference, for example, but not limited to, AAV1 (SEQ ID NOs: 6 and 64 of US20030138772), AAV2 (SEQ ID NOs: 7 and 70 of US20030138772), AAV3 (SEQ ID NOs: 8 and 71 of US20030138772), AAV4 (SEQ ID NO: 63 of US20030138772), AAV5 (SEQ ID NO: 114 of US20030138772), AAV6 (SEQ ID NO: 65 of US20030138772), AAV7 (SEQ ID NOs: 1-3 of US20030138772), AAV8 (SEQ ID NOs: 4 and 95 of US20030138772), AAV9 (SEQ ID NOs: 5 and 100 of US20030138772), AAV10 (SEQ ID NO: 117 of US20030138772), AAV11 (SEQ ID NO: 118 of US20030138772), AAV12 (SEQ ID NO: 119 of US20030138772), AAVrh10 (amino acids 1-738 of SEQ ID NO: 81 of US20030138772), AAV16.3 (SEQ ID NO: 10 of US20030138772), AAV29.3 / bb.1 (SEQ ID NO: 11 of US20030138772), AAV29.4 (SEQ ID NO: 12 of US20030138772), AAV29.5 / bb.2 (SEQ ID NO: 13 of US20030138772), AAV1.3 (SEQ ID NO: 14 of US20030138772), AAV13.3 (SEQ ID NO: 15 of US20030138772), AAV24.1 (SEQ ID NO: 16 of US20030138772), AAV27.3 (SEQ ID NO: 17 of US20030138772), AAV7.2 (SEQ ID NO: 18 of US20030138772), AAVC1 (SEQ ID NO: 19 of US20030138772), AAVC3 (SEQ ID NO: 20 of US20030138772), AAVC5 (SEQ ID NO: 21 of US20030138772), AAVF1 (SEQ ID NO: 22 of US20030138772), AAVF3 (SEQ ID NO: 23 of US20030138772), AAVF5 (SEQ ID NO: 24 of US20030138772), AAVH6 (SEQ ID NO: 25 of US20030138772), AAVH2 (SEQ ID NO: 26 of US20030138772), AAV42-8 (SEQ ID NO: 27 of US20030138772), AAV42-15 (SEQ ID NO: 28 of US20030138772), AAV42-5b (SEQ ID NO: 29 of US20030138772), AAV42-1b (SEQ ID NO: 30 of US20030138772), AAV42-13 (SEQ ID NO: 31 of US20030138772), AAV42-3a (SEQ ID NO: 32 of US20030138772), AAV42-4 (SEQ ID NO: 33 of US20030138772), AAV42-5a (SEQ ID NO: 34 of US20030138772), AAV42-10 (SEQ ID NO: 35 of US20030138772), AAV42-3b (SEQ ID NO: 36 of US20030138772), AAV42-11 (SEQ ID NO: 37 of US20030138772), AAV42-6b (SEQ ID NO: 38 of US20030138772), AAV43-1 (SEQ ID NO: 39 of US20030138772), AAV43-5 (SEQ ID NO: 40 of US20030138772), AAV43-12 (SEQ ID NO: 41 of US20030138772), AAV43-20 (SEQ ID NO: 42 of US20030138772), AAV43-21 (SEQ ID NO: 43 of US20030138772), AAV43-23 (SEQ ID NO: 44 of US20030138772), AAV43-25 (SEQ ID NO: 45 of US20030138772), AAV44.1 (SEQ ID NO: 46 of US20030138772), AAV44.5 (SEQ ID NO: 47 of US20030138772), AAV223.1 (SEQ ID NO: 48 of US20030138772), AAV223.2 (SEQ ID NO: 49 of US20030138772), AAV223.4 (SEQ ID NO: 50 of US20030138772), AAV223.5 (SEQ ID NO: 51 of US20030138772), AAV223.6 (SEQ ID NO: 52 of US20030138772), AAV223.7 (SEQ ID NO: 53 of US20030138772), AAVA3.4 (SEQ ID NO: 54 of US20030138772), AAVA3.5 (SEQ ID NO: 55 of US20030138772), AAVA3.7 (SEQ ID NO: 56 of US20030138772), AAVA3.3 (SEQ ID NO: 57 of US20030138772), AAV42.12 (SEQ ID NO: 58 of US20030138772), AAV44.2 (SEQ ID NO: 59 of US20030138772), AAV42-2 (SEQ ID NO: 9 of US20030138772), or a variant thereof, or may have it.

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

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

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

[0464] In some embodiments, the AAV serotype is the sequence described in U.S. Patent No. US6156303, the entire content of which is incorporated herein by reference, such as, but not limited to, AAV3B (SEQ ID NOs: 1 and 10 of US6156303), AAV6 (SEQ ID NOs: 2, 7 and 11 of US6156303), AAV2 (SEQ ID NOs: 3 and 8 of US6156303), AAV3A (SEQ ID NOs: 4 and 9 of US6156303), or derivatives thereof, or may have them.

[0465] In some embodiments, the AAV serotype is the sequence described in U.S. Publication No. US20140359799, the entire content of which is incorporated herein by reference, such as, but not limited to, AAV8 (SEQ ID NO: 1 of US20140359799), AAVDJ (SEQ ID NOs: 2 and 3 of US20140359799), or variants thereof, or may have them.

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

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

[0468] In some embodiments, the AAV serotype is as described in International Publication No. WO2014144229, incorporated herein by reference in its entirety, or can have mutations in the AAV2 sequence that generate AAV2G9.

[0469] In some embodiments, the AAV serotype is a sequence described in International Publication No. WO2005033321, the entire content of which is incorporated herein by reference, such as, but not limited to, AAV3-3 (SEQ ID NO: 217 of WO2005033321), AAV1 (SEQ ID NO: 219 and 202 of WO2005033321), AAV106.1 / hu.37 (SEQ ID NO: 10 of WO2005033321), AAV114.3 / hu.40 (SEQ ID NO: 11 of WO2005033321), AAV127.2 / hu.41 (SEQ ID NO: 6 and 8 of WO2005033321), AAV128.3 / hu.44 (SEQ ID NO: 81 of WO2005033321), AAV130.4 / hu.48 (SEQ ID NO: 78 of WO2005033321), AAV145.1 / hu.53 (SEQ ID NO: 176 and 177 of WO2005033321), AAV145.6 / hu.56 (SEQ ID NO: 168 and 192 of WO2005033321), AAV16.12 / hu.11 (SEQ ID NO: 153 and 57 of WO2005033321), AAV16.8 / hu.10 (SEQ ID NO: 156 and 56 of WO2005033321), AAV161.10 / hu.60 (SEQ ID NO: 170 of WO2005033321), AAV161.6 / hu.61 (SEQ ID NO: 174 of WO2005033321), AAV1-7 / rh.48 (SEQ ID NO: 32 of WO2005033321), AAV1-8 / rh.49 (SEQ ID NO: 103 and 25 of WO2005033321), AAV2 (SEQ ID NO: 211 and 221 of WO2005033321), AAV2-15 / rh.62 (SEQ ID NO: 33 and 114 of WO2005033321), AAV2-3 / rh.61 (SEQ ID NO: 21 of WO2005033321), AAV2-4 / rh.50 (SEQ ID NO: 23 and 108 of WO2005033321), AAV2-5 / rh.51 (SEQ ID NO: 104 and 22 of WO2005033321), AAV3.1 / hu.6 (SEQ ID NO: 5 and 84 of WO2005033321), AAV3.1 / hu.9 (SEQ ID NO: 155 and 58 of WO2005033321), AAV3-11 / rh.53 (SEQ ID NO: 186 and 176 of WO2005033321), AAV3-3 (SEQ ID NO: 200 of WO2005033321), AAV33.12 / hu.17 (SEQ ID NO: 4 of WO2005033321), AAV33.4 / hu.15 (SEQ ID NO: 50 of WO2005033321), AAV33.8 / hu.16 (SEQ ID NO: 51 of WO2005033321), AAV3-9 / rh.52 (SEQ ID NOs: 96 and 18 of WO2005033321), AAV4-19 / rh.55 (SEQ ID NO: 117 of WO2005033321), AAV4-4 (SEQ ID NOs: 201 and 218 of WO2005033321), AAV4-9 / rh.54 (SEQ ID NO: 116 of WO2005033321), AAV5 (SEQ ID NOs: 199 and 216 of WO2005033321), AAV52.1 / hu.20 (SEQ ID NO: 63 of WO2005033321), AAV52 / hu.19 (SEQ ID NO: 133 of WO2005033321), AAV5-22 / rh.58 (SEQ ID NO: 27 of WO2005033321), AAV5-3 / rh.57 (SEQ ID NO: 105 of WO2005033321), AAV5-3 / rh.57 (SEQ ID NO: 26 of WO2005033321), AAV58.2 / hu.25 (SEQ ID NO: 49 of WO2005033321), AAV6 (SEQ ID NOs: 203 and 220 of WO2005033321), AAV7 (SEQ ID NOs: 222 and 213 of WO2005033321), AAV7.3 / hu.7 (SEQ ID NO: 55 of WO2005033321), AAV8 (SEQ ID NOs: 223 and 214 of WO2005033321), AAVH-1 / hu.1 (SEQ ID NO: 46 of WO2005033321), AAVH-5 / hu.3 (SEQ ID NO: 44 of WO2005033321), AAVhu.1 (SEQ ID NO: 144 of WO2005033321), AAVhu.10 (SEQ ID NO: 156 of WO2005033321), AAVhu.11 (SEQ ID NO: 153 of WO2005033321), AAVhu.12 (SEQ ID NO: 59 of WO2005033321), AAVhu.13 (SEQ ID NO: 129 of WO2005033321), AAVhu.14 / AAV9 (SEQ ID NOs: 123 and 3 of WO2005033321), AAVhu.15 (SEQ ID NO: 147 of WO2005033321), AAVhu.16 (SEQ ID NO: 148 of WO2005033321), AAVhu.17 (SEQ ID NO: 83 of WO2005033321), AAVhu.18 (SEQ ID NO: 149 of WO2005033321), AAVhu.19 (SEQ ID NO: 133 of WO2005033321), AAVhu.2 (SEQ ID NO: 143 of WO2005033321), AAVhu.20 (SEQ ID NO: 134 of WO2005033321), AAVhu.21 (SEQ ID NO: 135 of WO2005033321), AAVhu.22 (SEQ ID NO: 138 of WO2005033321), AAVhu.23.2 (SEQ ID NO: 137 of WO2005033321), AAVhu.24 (SEQ ID NO: 136 of WO2005033321), AAVhu.25 (SEQ ID NO: 146 of WO2005033321), AAVhu.27 (SEQ ID NO: 140 of WO2005033321), AAVhu.29 (SEQ ID NO: 132 of WO2005033321), AAVhu.3 (SEQ ID NO: 145 of WO2005033321), AAVhu.31 (SEQ ID NO: 121 of WO2005033321), AAVhu.32 (SEQ ID NO: 122 of WO2005033321), AAVhu.34 (SEQ ID NO: 125 of WO2005033321), AAVhu.35 (SEQ ID NO: 164 of WO2005033321), AAVhu.37 (SEQ ID NO: 88 of WO2005033321), AAVhu.39 (SEQ ID NO: 102 of WO2005033321), AAVhu.4 (SEQ ID NO: 141 of WO2005033321), AAVhu.40 (SEQ ID NO: 87 of WO2005033321), AAVhu.41 (SEQ ID NO: 91 of WO2005033321), AAVhu.42 (SEQ ID NO: 85 of WO2005033321), AAVhu.43 (SEQ ID NO: 160 of WO2005033321), AAVhu.44 (SEQ ID NO: 144 of WO2005033321), AAVhu.45 (SEQ ID NO: 127 of WO2005033321), AAVhu.46 (SEQ ID NO: 159 of WO2005033321), AAVhu.47 (SEQ ID NO: 128 of WO2005033321), AAVhu.48 (SEQ ID NO: 157 of WO2005033321), AAVhu.49 (SEQ ID NO: 189 of WO2005033321), AAVhu.51 (SEQ ID NO: 190 of WO2005033321), AAVhu.52 (SEQ ID NO: 191 of WO2005033321), AAVhu.53 (SEQ ID NO: 186 of WO2005033321), AAVhu.54 (SEQ ID NO: 188 of WO2005033321), AAVhu.55 (SEQ ID NO: 187 of WO2005033321), AAVhu.56 (SEQ ID NO: 192 of WO2005033321), AAVhu.57 (SEQ ID NO: 193 of WO2005033321), AAVhu.58 (SEQ ID NO: 194 of WO2005033321), AAVhu.6 (SEQ ID NO: 84 of WO2005033321), AAVhu.60 (SEQ ID NO: 184 of WO2005033321), AAVhu.61 (SEQ ID NO: 185 of WO2005033321), AAVhu.63 (SEQ ID NO: 195 of WO2005033321), AAVhu.64 (SEQ ID NO: 196 of WO2005033321), AAVhu.66 (SEQ ID NO: 197 of WO2005033321), AAVhu.67 (SEQ ID NO: 198 of WO2005033321), AAVhu.7 (SEQ ID NO: 150 of WO2005033321), AAVhu....

Claims

**Claim 1**: An antibody that binds to tau and comprises a heavy-chain variable region (VH) containing heavy-chain complementarity-determining regions 1 (HC CDR1), HC CDR2, and HC CDR3, and a light-chain variable region (VL) containing light-chain complementarity-determining regions 1 (LC CDR1), LC CDR2, and LC CDR3, wherein (i) the HC CDR1, the HC CDR2, and the HC CDR3 each comprise the amino acid sequences of SEQ ID NOs: 1144, 1145, and 410, and the LC CDR1, the LC CDR2, and the LC CDR3 each comprise the amino acid sequences of SEQ ID NOs: 1146, 529, and 571, or (ii) the HC CDR1, the HC CDR2, and the HC CDR3 each comprise the amino acid sequences of SEQ ID NOs: 1165, 1166, and 1167, and the LC CDR1, the LC CDR2, and the LC CDR3 each comprise the amino acid sequences of SEQ ID NOs: 473, 528, and 571, or (iii) the HC CDR1, the HC CDR2, and the HC CDR3 each comprise the amino acid sequences of SEQ ID NOs: 314, 341, and 410, and the LC CDR1, the LC CDR2, and the LC CDR3 each comprise the amino acid sequences of SEQ ID NOs: 1154, 529, and 571. **Claim 2**: The antibody according to claim 1, wherein the VH comprises the amino acid sequence of SEQ ID NO: 21 or an amino acid sequence having at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO:

21. **Claim 3**: The antibody according to claim 1 or 2, wherein the VH comprises an amino acid sequence having at least 1, 2, or 3 modifications of the amino acid sequence of SEQ ID NO: 21, provided that the number of modifications is 30 or less, 20 or less, or 10 or less. The antibody according to claim 1 or 2. **Claim 4**: The antibody according to any one of claims 1 to 3, wherein the VL comprises the amino acid sequence of SEQ ID NO: 93 or an amino acid sequence having at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO:

93. **Claim 5**: The antibody according to any one of claims 1 to 4, wherein the VL comprises an amino acid sequence having at least 1, 2, or 3 modifications of the amino acid sequence of SEQ ID NO: 93, with the number of modifications being 30 or less, 20 or less, or 10 or less. **Claim 6**: The antibody according to any one of claims 1 to 5, wherein the VH comprises the amino acid sequence of SEQ ID NO: 21 or an amino acid sequence having at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO: 21, and the VL comprises the amino acid sequence of SEQ ID NO: 93 or an amino acid sequence having at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity to the amino acid sequence of SEQ ID NO:

93. **Claim 7** Full-length antibody, bispecific antibody, Fab, F(ab'), ２ , Fv, or single-chain Fv fragment (scFv), the antibody according to any one of claims 1 to 6. **Claim 8** The antibody according to any one of claims 1 to 7, which is a humanized antibody. **Claim 9** The antibody according to any one of claims 1 to 8, comprising a heavy chain constant region selected from human IgG1, human IgG2, human IgG3, human IgG4, mouse IgG1, mouse IgG2a, mouse IgG2b, mouse IgG2c, or mouse IgG3. **Claim 10**: The antibody according to any one of claims 1 to 9, comprising a light chain constant region selected from a kappa or lambda light chain constant region. **Claim 11** The antibody according to any one of claims 1 to 10, comprising a human IgG4 heavy chain constant region and a human kappa light chain constant region. **Claim 12** (i) binds to the C-terminus of the tau protein, (ii) binds to a tau protein containing at least one, two, three, or more phosphorylated residues, and / or (iii) binds to paired helical filament tau protein (ePHF), (iv) binds to an epitope comprising a region formed by a complex of at least two tau proteins, (v) having a dissociation constant (K Ｄ ) that binds to the tau protein and / or (v) reduces or inhibits tau aggregation. The antibody according to any one of claims 1 to 11. **Claim 13** A nucleic acid encoding the antibody according to any one of claims 1 to 12. **Claim 14** The nucleotide sequence encoding VH comprises the nucleotide sequence of SEQ ID NO: 167, or a nucleotide sequence having at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity to the nucleotide sequence of SEQ ID NO: 167, the nucleic acid according to claim 13.

15. The nucleotide sequence encoding VL comprises the nucleotide sequence of SEQ ID NO: 241, or a nucleotide sequence having at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity to the nucleotide sequence of SEQ ID NO: 241, the nucleic acid according to claim 13 or 14.

16. The nucleotide sequence encoding VH comprises the nucleotide sequence of SEQ ID NO: 167, or a nucleotide sequence having at least 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity to the nucleotide sequence of SEQ ID NO: 167, and the nucleotide sequence encoding VL comprises the nucleotide sequence of SEQ ID NO: 241, or a nucleotide sequence having 80%, 85%, 90%, 92%, 95%, 96%, 97%, 98%, or 99% sequence identity to the nucleotide sequence of SEQ ID NO: 241, the nucleic acid according to any one of claims 13 to 15.

17. A viral genome comprising a promoter operably linked to a nucleic acid encoding an antibody according to any one of claims 1 to 12.

18. The promoter is Human elongation factor 1α-subunit (EF1α), cytomegalovirus (CMV) major immediate-early enhancer and / or promoter, chicken β-actin (CBA) and its derivative CAG, β-glucuronidase (GUS B), or ubiquitin C (UBC), neuron-specific enolase (NSE), platelet-derived growth factor (PDGF), platelet-derived growth factor B chain (PDGF-β), intercellular adhesion molecule 2 (ICAM-2), synapsin (Syn), methyl CpG-binding protein 2 (MeCP2), Ca2+ / calmodulin-dependent protein kinase II (CaMKII), metabotropic glutamate receptor 2 (mGluR2), neurofilament light chain (NFL) or neurofilament heavy chain (NFH), β-globin mini-gene nβ2, preproenkephalin (PPE), enkephalin (Enk) and excitatory amino acid transporter 2 (EAAT2), glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), or a functional variant thereof, selected from The viral genome according to claim 17.

19. (i) an enhancer, (ii) a polyadenylation (polyA) signal region, (iii) an ITR sequence located 5' to the nucleic acid encoding the antibody and / or an ITR sequence located 3' to the nucleic acid encoding the antibody, (iv) an intron region, (v) an exon region, and / or (vi) a nucleotide sequence encoding a microRNA (miRNA) binding site The viral genome according to claim 17 or 18, further comprising

20. A vector comprising the nucleic acid according to any one of claims 13 to 16, the viral genome according to any one of claims 17 to 19, or the nucleotide sequence encoding the antibody according to any one of claims 1 to 12.

21. (i) a capsid protein, and (ii) the viral genome according to any one of claims 17 to 19 An AAV particle comprising

22. The AAV particle according to claim 21, wherein the capsid protein comprises an AAV5 capsid protein or a variant thereof, or an AAV9 capsid protein or a variant thereof.

23. A host cell comprising the antibody according to any one of claims 1 to 12, the nucleic acid according to any one of claims 13 to 16, the viral genome according to any one of claims 17 to 19, the vector according to claim 20, or the AAV particle according to claim 21 or 22.

24. The host cell according to claim 23, which is an insect cell, a bacterial cell, or a mammalian cell.

25. A method for producing an antibody, the method comprising culturing the host cell according to claim 23 or 24 under conditions suitable for gene expression.

26. A pharmaceutical composition comprising the antibody according to any one of claims 1 to 12, an AAV particle comprising the viral genome according to any one of claims 17 to 19, or the AAV particle according to claim 21 or 22, and a pharmaceutically acceptable excipient.

27. The antibody according to any one of claims 1 to 12, an AAV particle comprising the viral genome according to any one of claims 17 to 19, the AAV particle according to claim 21 or 22, or the pharmaceutical composition according to claim 26, for use in delivering an exogenous antibody that binds to tau to a subject.

28. (i) The subject has, is diagnosed as having, or is at risk of having a disease associated with tau expression, (ii) The subject has, is diagnosed as having, or is at risk of having a neuropathy or neurodegenerative disorder, and / or (iii) The subject has, is diagnosed as having, or is at risk of having a tauopathy, The antibody, AAV particle, or pharmaceutical composition according to claim 27.

29. The antibody according to any one of claims 1 to 12, an AAV particle having the viral genome according to any one of claims 17 to 19, the AAV particle according to claim 21 or 22, or the pharmaceutical composition according to claim 26, for use in treating a neuropathy or neurodegenerative disorder in a subject.

30. The neuropathy or neurodegenerative disorder is (i) tauopathy, or The antibody, AAV particle, or pharmaceutical composition according to claim 28 or 29, wherein the disease is Alzheimer's disease (AD), frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), frontotemporal lobar degeneration (FTLD), frontotemporal dementia (FTD), chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), Down syndrome, Pick's disease, corticobasal degeneration (CBD), corticobasal syndrome, amyotrophic lateral sclerosis (ALS), prion disease, Creutzfeldt-Jakob disease (CJD), multiple system atrophy, neurofibrillary type senile dementia, stroke, or progressive subcortical gliosis.

31. The antibody, AAV particle, or pharmaceutical composition according to any one of claims 27 to 30, which is formulated for intravenous administration, intramuscular administration, intraparenchymal administration, intracerebroventricular administration, intracisternal (ICM) injection, or intrathecal administration.

32. Use of the antibody according to any one of claims 1 to 12, the AAV particle containing the viral genome according to any one of claims 17 to 19, the AAV particle according to claim 21 or 22, or the pharmaceutical composition according to claim 26, in the manufacture of a medicament for delivering an exogenous antibody that binds to tau.

33. (i) The subject has, is diagnosed as having, or is at risk of having a disease associated with tau expression. (ii) The subject has, is diagnosed as having, or is at risk of having a neuropathy or neurodegenerative disorder, and / or (iii) The subject has, is diagnosed as having, or is at risk of having tauopathy. The use according to claim 32.

34. Use of the antibody according to any one of claims 1 to 12, the AAV particle containing the viral genome according to any one of claims 17 to 19, the AAV particle according to claim 21 or 22, or the pharmaceutical composition according to claim 26, in the manufacture of a medicament for treating a neuropathy or neurodegenerative disorder in a subject.

35. The neuropathy or neurodegenerative disorder is (i) tauopathy, or (ii) Alzheimer's disease (AD), frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), frontotemporal lobar degeneration (FTLD), frontotemporal dementia (FTD), chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), Down syndrome, Pick's disease, corticobasal degeneration (CBD), corticobasal syndrome, amyotrophic lateral sclerosis (ALS), prion disease, Creutzfeldt-Jakob disease (CJD), multiple system atrophy, neurofibrillary type senile dementia, or progressive subcortical gliosis The use according to claim 33 or 34, wherein it is as described above.

36. The use according to any one of claims 32 to 35, wherein the antibody, the AAV particle, or the pharmaceutical composition is formulated for intravenous administration, intramuscular administration, parenchymal administration, intraventricular administration, intracisternal (ICM) injection, or intrathecal administration.

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