Tau-binding compounds

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] Related Applications This application claims priority to U.S. Provisional Application No. 63 / 406,924, filed September 15, 2022, and U.S. Provisional Application No. 63 / 448,913, filed February 28, 2023, the entire contents of each of which are incorporated herein by reference.

[0002] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in XML format and is incorporated herein by reference in its entirety. The XML copy created on August 23, 2023 is named V2071-3005PCT_SL.xml and is 1,438,459 bytes in size.

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

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

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

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

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

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

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

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

[0011] In yet another aspect, the disclosure provides an antibody that binds to human tau, comprising a heavy chain variable region (VH) comprising heavy chain complementarity determining region 1 (HC CDR1), heavy chain complementarity determining region 2 (HC CDR2), and heavy chain complementarity determining region 3 (HC CDR3), and / or 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), wherein (a) HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 64, 1145, 1167, 1146, 529, and 571, respectively; or (b) HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 64, 1145, 1167, 1146, 529, and 571, respectively. (c) the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 1165, 1166, 1167, 473, RVS, and 571, respectively; or (d) the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 314, 341, 410, 1154, 529, and 571, respectively. In some embodiments, the antibody is a humanized antibody.

[0012] In yet another aspect, the disclosure provides an antibody that binds to human tau, comprising a heavy chain variable region (VH) comprising heavy chain complementarity determining region 1 (HC CDR1), heavy chain complementarity determining region 2 (HC CDR2), and heavy chain complementarity determining region 3 (HC CDR3), and / or 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), wherein (a) HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 64, 1145, 1167, 1146, 529, and 571, respectively; or (b) HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 64, 1145, 1167, 1146, 529, and 571, respectively. (c) HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 1165, 1166, 1167, 473, RVS, and 571, respectively; or (d) HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 1165, 1166, 1167, 473, RVS, and 571, respectively. The antibodies provided herein have CDR3s comprising the amino acid sequences of SEQ ID NOs: 314, 341, 410, 1154, 529, and 571, respectively, and (i) VH comprises an amino acid sequence that includes one, two, three, four, five, six, seven, eight, nine, or all of the following amino acids, other than Q at position 5, P at position 7, T at position 9, L at position 11, V at position 12, N at position 19, L at position 20, K at position 67, A at position 68, and / or S at position 76, as numbered according to SEQ ID NO: 21; and / or (ii) VL comprises an amino acid sequence that includes one, two, or all of the following amino acids, other than D at position 17, Q at position 18, and / or G at position 68, as numbered according to SEQ ID NO: 93.

[0013] In yet another aspect, the disclosure provides an antibody that binds to human tau, comprising a heavy chain variable region (VH) comprising heavy chain complementarity determining region 1 (HC CDR1), heavy chain complementarity determining region 2 (HC CDR2), and heavy chain complementarity determining region 3 (HC CDR3), and / or 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), wherein (a) HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 64, 1145, 1167, 1146, 529, and 571, respectively; or (b) HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 64, 1145, 1167, 1146, 529, and 571, respectively. (c) HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 1165, 1166, 1167, 473, RVS, and 571, respectively; or (d) HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 1165, 1166, 1167, 473, RVS, and 571, respectively. The antibodies provided herein have CDR3s comprising the amino acid sequences of SEQ ID NOs: 314, 341, 410, 1154, 529, and 571, respectively, and (i) VH comprises an amino acid sequence that includes one, two, three, four, five, six, seven, eight, or all of V at position 5, S at position 7, A at position 9, V at position 11, K at position 12, K at position 19, V at position 20, R at position 67, and / or V at position 68, as numbered according to SEQ ID NO: 21; and / or (ii) VL comprises an amino acid sequence that includes one, two, or all of Q or E at position 17, P or R at position 18, and / or S at position 68, as numbered according to SEQ ID NO: 93.

[0014] In yet another aspect, the disclosure provides an antibody that binds to human tau, comprising a heavy chain variable region (VH) comprising heavy chain complementarity determining region 1 (HC CDR1), heavy chain complementarity determining region 2 (HC CDR2), and heavy chain complementarity determining region 3 (HC CDR3), and / or 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), wherein (a) HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 64, 1145, 1167, 1146, 529, and 571, respectively; or (b) HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 64, 1145, 1167, 1146, 529, and 571, respectively. (c) HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 1165, 1166, 1167, 473, RVS, and 571, respectively; or (d) HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 1165, 1166, 1167, 473, RVS, and 571, respectively. The present invention provides antibodies in which CDR3 comprises the amino acid sequences of SEQ ID NOs: 314, 341, 410, 1154, 529, and 571, respectively, and (i) VH comprises an amino acid sequence that is at least 86% (e.g., at least 90, 92, 95, 96, 97, 98, or 99%) identical to the amino acid sequence of any one of SEQ ID NOs: 67 to 71, and / or (ii) VL comprises an amino acid sequence that is at least 91% (e.g., at least 92, 95, 96, 97, 98, or 99%) identical to the amino acid sequence of any one of SEQ ID NOs: 72 to 76.

[0015] In yet another aspect, the disclosure provides an antibody that binds to human tau, comprising a heavy chain variable region (VH) comprising heavy chain complementarity determining region 1 (HC CDR1), heavy chain complementarity determining region 2 (HC CDR2), and heavy chain complementarity determining region 3 (HC CDR3), and a light chain variable region (VL) comprising light chain complementarity determining region 1 (LC CDR1), light chain complementarity determining region 2 (LC CDR2), and light chain complementarity determining region 3 (LC CDR3), wherein (a) HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 64, 1145, 1167, 1146, 529, and 571, respectively; or (b) HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 64, 1145, 1167, 1146, 529, and 571, respectively. (c) HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 1165, 1166, 1167, 473, RVS, and 571, respectively; or (d) HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 1165, 1166, 1167, 473, RVS, and 571, respectively. CDR3 comprises the amino acid sequences of SEQ ID NOs: 314, 341, 410, 1154, 529, and 571, respectively, and (i) VH contains one of the following residues in the numbering order according to SEQ ID NO: 21: V at position 5, S at position 7, A at position 9, V at position 11, K at position 12, S at position 14, A at position 16, K at position 19, V at position 20, R at position 38, Q at position 39, A at position 40, Q at position 43, R at position 67, V at position 68, I at position 71, R at position 72, D at position 73, T at position 74, T at position 76, T at position 84, and / or L at position 113; and (ii) the VL comprises one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, or all of: I at position 2, S at position 7, S at position 12, T at position 14, P at position 15, Q at position 17, P at position 18, Q at position 50, S at position 68, V at position 88, Y at position 92, Q at position 105, and / or V at position 109, numbered according to SEQ ID NO: 93.

[0016] In yet another aspect, the disclosure provides an antibody that binds to human tau, comprising a heavy chain variable region (VH) comprising heavy chain complementarity determining region 1 (HC CDR1), heavy chain complementarity determining region 2 (HC CDR2), and heavy chain complementarity determining region 3 (HC CDR3), and / or 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), wherein (a) HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 64, 1145, 1167, 1146, 529, and 571, respectively; or (b) HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 64, 1145, 1167, 1146, 529, and 571, respectively. (c) HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 1165, 1166, 1167, 473, RVS, and 571, respectively; or (d) HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 comprise the amino acid sequences of SEQ ID NOs: 1165, 1166, 1167, 473, RVS, and 571, respectively. The antibodies provided herein include antibodies in which the CDR3 comprises the amino acid sequence of SEQ ID NO: 314, 341, 410, 1154, 529, and 571, respectively, and (i) the VH comprises the amino acid sequence of SEQ ID NO: 69 or an amino acid sequence at least 86% (e.g., at least 90, 92, 95, 96, 97, 98, or 99%) identical to the amino acid sequence of SEQ ID NO: 69, and / or (ii) the VL comprises the amino acid sequence of SEQ ID NO: 73 or an amino acid sequence at least 91% (e.g., at least 92, 95, 96, 97, 98, or 99%) identical to the amino acid sequence of SEQ ID NO: 73.

[0017] In yet another aspect, the disclosure provides an antibody that binds to human tau, comprising a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 69 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 73.

[0018] In yet another aspect, the disclosure provides an antibody that binds to human tau, comprising a heavy chain (HC) comprising the amino acid sequence of SEQ ID NO: 172 and a light chain (LC) comprising the amino acid sequence of SEQ ID NO: 176.

[0019] In yet another aspect, the disclosure provides nucleic acids encoding antibodies that bind to tau (e.g., anti-tau antibodies described herein). In yet another aspect, the disclosure provides vectors encoding antibodies that bind to tau (e.g., anti-tau antibodies described herein).

[0020] In yet another aspect, the disclosure provides a host cell comprising an antibody that binds tau (e.g., an anti-tau antibody described herein) or a nucleic acid encoding an antibody that binds tau (e.g., an anti-tau antibody described herein). In some embodiments, the host cell is a mammalian cell, an insect cell, or a bacterial cell.

[0021] In yet another aspect, the disclosure provides methods for producing an antibody that binds to tau (e.g., an anti-tau antibody described herein). In some embodiments, the method comprises culturing a host cell comprising an anti-tau antibody described herein under conditions suitable for gene expression.

[0022] In yet another aspect, the present disclosure provides a viral genome comprising a promoter operably linked to a nucleic acid encoding an antibody that binds tau (e.g., an anti-tau antibody described herein). In some embodiments, the viral genome further comprises an internal terminal repeat (ITR) sequence (e.g., an ITR region described herein), an enhancer (e.g., an enhancer described herein), an intron region (e.g., an intron region described herein) and / or an exon region (e.g., an exon region described herein), a polyA signal region (e.g., a polyA signal sequence described herein), and / or an encoded miR binding site.

[0023] In yet another aspect, the present disclosure provides an isolated, e.g., recombinant, AAV particle comprising a capsid protein and a viral genome comprising a nucleic acid encoding an antibody that binds to tau (e.g., an anti-tau antibody described herein). In some embodiments, the capsid protein comprises an AAV capsid protein, e.g., a wild-type AAV capsid protein or a functional variant thereof. In some embodiments, the capsid protein comprises or is selected from an AAV9 capsid protein, an AAV5 capsid protein, a VOY101 capsid protein, a PHP.N capsid protein, or a PHP.B capsid protein, or a functional variant thereof.

[0024] In yet another aspect, the present disclosure provides a method of delivering an exogenous antibody that binds to tau (e.g., an anti-tau antibody described herein) to a subject. In some embodiments, the subject has or has been diagnosed with a neurological disorder, tauopathy, and / or a disease associated with tau expression. In some embodiments, the disease, neurological disorder, or tauopathy associated with tau expression comprises AD, FTDP-17, FTLD, FTD, CTE, PSP, Down syndrome, Pick's disease, CBD, corticobasal syndrome, ALS, prion disease, CJD, multiple system atrophy, mild cognitive impairment, neurofibrillary senile dementia, or progressive subcortical gliosis.

[0025] In yet another aspect, the present disclosure provides a method of treating a subject having or diagnosed with a neurological disorder, tauopathy, and / or a disease associated with tau expression. In some embodiments, the capsid protein comprises an AAV9 capsid protein or a variant thereof. In some embodiments, the capsid protein comprises an AAV5 capsid protein or a variant thereof. In some embodiments, the disease, neurological disorder, or tauopathy associated with tau expression comprises AD, FTDP-17, FTLD, FTD, CTE, PSP, Down syndrome, Pick's disease, CBD, corticobasal syndrome, ALS, prion disease, CJD, multiple system atrophy, mild cognitive impairment, neurofibrillary senile dementia, or progressive subcortical gliosis.

[0026] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein which equivalents are intended to be encompassed by the following recited embodiments.

[0027] Enumeration of Embodiments 1. An antibody that binds to human tau, (a) a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (HC CDR1) comprising the amino acid sequence of SEQ ID NO: 64, a heavy chain complementarity determining region 2 (HC CDR2) comprising the amino acid sequence of SEQ ID NO: 1145, and a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of SEQ ID NO: 1167; and a light chain variable region (VL) comprising a light chain complementarity determining region 1 (LC CDR1) comprising the amino acid sequence of SEQ ID NO: 1146, a light chain complementarity determining region 2 (LC CDR2) comprising the amino acid sequence of SEQ ID NO: 529, and a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of SEQ ID NO: 571; (b) a VH comprising an HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1144, an HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1145, and an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410; and a VL comprising an LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1146, an LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; (c) a VH comprising an HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1165, an HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1166, and an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 1167, and a VL comprising an LC CDR1 comprising the amino acid sequence of SEQ ID NO: 473, an LC CDR2 comprising the amino acid sequence of RVS, and an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; or (d) a VH comprising an HC CDR1 comprising the amino acid sequence of SEQ ID NO: 314, an HC CDR2 comprising the amino acid sequence of SEQ ID NO: 341, and an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410, and a VL comprising an LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1154, an LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; Optionally, the antibody is a humanized antibody.

[0028] 2. An antibody that binds to human tau, (a) a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (HC CDR1) comprising the amino acid sequence of SEQ ID NO: 64, a heavy chain complementarity determining region 2 (HC CDR2) comprising the amino acid sequence of SEQ ID NO: 1145, and a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of SEQ ID NO: 1167; and a light chain variable region (VL) comprising a light chain complementarity determining region 1 (LC CDR1) comprising the amino acid sequence of SEQ ID NO: 1146, a light chain complementarity determining region 2 (LC CDR2) comprising the amino acid sequence of SEQ ID NO: 529, and a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of SEQ ID NO: 571; (b) a VH comprising an HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1144, an HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1145, and an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410; and a VL comprising an LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1146, an LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; (c) a VH comprising an HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1165, an HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1166, and an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 1167, and a VL comprising an LC CDR1 comprising the amino acid sequence of SEQ ID NO: 473, an LC CDR2 comprising the amino acid sequence of RVS, and an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; or (d) a VH comprising an HC CDR1 comprising the amino acid sequence of SEQ ID NO: 314, an HC CDR2 comprising the amino acid sequence of SEQ ID NO: 341, and an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410, and a VL comprising an LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1154, an LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; and (i) the VH comprises an amino acid sequence including one, two, three, four, five, six, seven, eight, nine, or all of the following amino acids, numbered according to SEQ ID NO: 21, other than Q at position 5, P at position 7, T at position 9, L at position 11, V at position 12, N at position 19, L at position 20, K at position 67, A at position 68, and / or S at position 76; and / or (ii) the VL comprises an amino acid sequence numbered according to SEQ ID NO: 93, including one, two, or all of the amino acids other than D at position 17, Q at position 18, and / or G at position 68; The antibody.

[0029] 3. An antibody that binds to human tau, (a) a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (HC CDR1) comprising the amino acid sequence of SEQ ID NO: 64, a heavy chain complementarity determining region 2 (HC CDR2) comprising the amino acid sequence of SEQ ID NO: 1145, and a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of SEQ ID NO: 1167; and a light chain variable region (VL) comprising a light chain complementarity determining region 1 (LC CDR1) comprising the amino acid sequence of SEQ ID NO: 1146, a light chain complementarity determining region 2 (LC CDR2) comprising the amino acid sequence of SEQ ID NO: 529, and a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of SEQ ID NO: 571; (b) a VH comprising an HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1144, an HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1145, and an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410; and a VL comprising an LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1146, an LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; (c) a VH comprising an HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1165, an HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1166, and an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 1167, and a VL comprising an LC CDR1 comprising the amino acid sequence of SEQ ID NO: 473, an LC CDR2 comprising the amino acid sequence of RVS, and an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; or (d) a VH comprising an HC CDR1 comprising the amino acid sequence of SEQ ID NO: 314, an HC CDR2 comprising the amino acid sequence of SEQ ID NO: 341, and an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410, and a VL comprising an LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1154, an LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; and (i) the VH comprises an amino acid sequence containing one, two, three, four, five, six, seven, eight, or all of: V at position 5, S at position 7, A at position 9, V at position 11, K at position 12, K at position 19, V at position 20, R at position 67, and / or V at position 68, numbered according to SEQ ID NO: 21; and / or (ii) the VL comprises an amino acid sequence numbered according to SEQ ID NO: 93, including one, two, or all of Q or E at position 17, P or R at position 18, and / or S at position 68; The antibody.

[0030] 4. An antibody that binds to human tau, (a) a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (HC CDR1) comprising the amino acid sequence of SEQ ID NO: 64, a heavy chain complementarity determining region 2 (HC CDR2) comprising the amino acid sequence of SEQ ID NO: 1145, and a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of SEQ ID NO: 1167; and a light chain variable region (VL) comprising a light chain complementarity determining region 1 (LC CDR1) comprising the amino acid sequence of SEQ ID NO: 1146, a light chain complementarity determining region 2 (LC CDR2) comprising the amino acid sequence of SEQ ID NO: 529, and a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of SEQ ID NO: 571; (b) a VH comprising an HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1144, an HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1145, and an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410; and a VL comprising an LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1146, an LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; (c) a VH comprising an HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1165, an HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1166, and an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 1167, and a VL comprising an LC CDR1 comprising the amino acid sequence of SEQ ID NO: 473, an LC CDR2 comprising the amino acid sequence of RVS, and an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; or (d) a VH comprising an HC CDR1 comprising the amino acid sequence of SEQ ID NO: 314, an HC CDR2 comprising the amino acid sequence of SEQ ID NO: 341, and an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410, and a VL comprising an LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1154, an LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; and (i) the VH comprises an amino acid sequence that is at least 86% (e.g., at least 90, 92, 95, 96, 97, 98, or 99%) identical to the amino acid sequence of any one of SEQ ID NOs: 67 to 71; and / or (ii) the VL comprises an amino acid sequence at least 91% (e.g., at least 92, 95, 96, 97, 98, or 99%) identical to the amino acid sequence of any one of SEQ ID NOs: 72 to 76; and / or The antibody.

[0031] 5. The antibody of any one of embodiments 1 to 4, wherein the HC CDR1 comprises the amino acid sequence of SEQ ID NO: 64, the HC CDR2 comprises the amino acid sequence of SEQ ID NO: 1145, the HC CDR3 comprises the amino acid sequence of SEQ ID NO: 1167, the LC CDR1 comprises the amino acid sequence of SEQ ID NO: 1146, the LC CDR2 comprises the amino acid sequence of SEQ ID NO: 529, and the LC CDR3 comprises the amino acid sequence of SEQ ID NO: 571.

[0032] 6. The antibody of any one of embodiments 1 to 5, wherein the HC CDR1 comprises the amino acid sequence of SEQ ID NO: 1144, the HC CDR2 comprises the amino acid sequence of SEQ ID NO: 1145, the HC CDR3 comprises the amino acid sequence of SEQ ID NO: 410, the LC CDR1 comprises the amino acid sequence of SEQ ID NO: 1146, the LC CDR2 comprises the amino acid sequence of SEQ ID NO: 529, and the LC CDR3 comprises the amino acid sequence of SEQ ID NO: 571.

[0033] 7. The antibody of any one of embodiments 1 to 6, wherein the HC CDR1 comprises the amino acid sequence of SEQ ID NO: 1165, the HC CDR2 comprises the amino acid sequence of SEQ ID NO: 1166, the HC CDR3 comprises the amino acid sequence of SEQ ID NO: 1167, the LC CDR1 comprises the amino acid sequence of SEQ ID NO: 473, the LC CDR2 comprises the amino acid sequence of RVS, and the LC CDR3 comprises the amino acid sequence of SEQ ID NO: 571.

[0034] 8. The antibody of any one of embodiments 1 to 7, wherein the HC CDR1 comprises the amino acid sequence of SEQ ID NO: 314, the HC CDR2 comprises the amino acid sequence of SEQ ID NO: 341, the HC CDR3 comprises the amino acid sequence of SEQ ID NO: 410, the LC CDR1 comprises the amino acid sequence of SEQ ID NO: 1154, the LC CDR2 comprises the amino acid sequence of SEQ ID NO: 529, and the LC CDR3 comprises the amino acid sequence of SEQ ID NO: 571.

[0035] 9. The antibody of any one of embodiments 1 to 8, wherein the VH comprises an amino acid sequence including 1, 2, 3, 4, 5, 6, 7, 8, 9, or all of the following amino acids other than Q at position 5, P at position 7, T at position 9, L at position 11, V at position 12, N at position 19, L at position 20, K at position 67, A at position 68, and / or S at position 76, numbered according to SEQ ID NO: 21.

[0036] 10. 10. The antibody of any one of embodiments 1 to 9, wherein the VH is: (a) one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, or all of the following amino acids, numbered according to SEQ ID NO: 21: an amino acid other than Q at position 5, an amino acid other than Q at position 6, an amino acid other than P at position 7, an amino acid other than T at position 9, an amino acid other than L at position 11, an amino acid other than V at position 12, an amino acid other than S at position 16, an amino acid other than N at position 19, an amino acid other than L at position 20, an amino acid other than I at position 48, an amino acid other than K at position 67, an amino acid other than A at position 68, an amino acid other than L at position 70, an amino acid other than S at position 76, an amino acid other than T at position 77, an amino acid other than V at position 79, an amino acid other than F at position 80, an amino acid other than I at position 81, an amino acid other than Q at position 82, an amino acid other than T at position 87, an amino acid other than S at position 91, and / or an amino acid other than S at position 113; (b) one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, or all of the following, numbered according to SEQ ID NO: 21: an amino acid other than Q at position 5, an amino acid other than P at position 7, an amino acid other than T at position 9, an amino acid other than L at position 11, an amino acid other than V at position 12, an amino acid other than S at position 16, an amino acid other than N at position 19, an amino acid other than L at position 20, an amino acid other than K at position 38, an amino acid other than K at position 67, an amino acid other than A at position 68, an amino acid other than L at position 70, an amino acid other than S at position 76, an amino acid other than T at position 77, an amino acid other than V at position 79, an amino acid other than F at position 80, an amino acid other than I at position 81, an amino acid other than Q at position 82, an amino acid other than T at position 87, an amino acid other than E at position 89, and / or an amino acid other than S at position 113; (c) one, two, three, four, five, six, seven, eight, nine, ten, one eleven, one twenty, one eleven, one twelve, one thirteen ... (d) one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, or all of the following, numbered according to SEQ ID NO: 21: an amino acid other than Q at position 1, an amino acid other than Q at position 5, an amino acid other than P at position 7, an amino acid other than T at position 9, an amino acid other than L at position 11, an amino acid other than V at position 12, an amino acid other than N at position 19, an amino acid other than L at position 20, an amino acid other than K at position 67, an amino acid other than A at position 68, an amino acid other than L at position 70, an amino acid other than S at position 76, an amino acid other than V at position 79, an amino acid other than F at position 80, an amino acid other than I at position 81, an amino acid other than Q at position 82, an amino acid other than S at position 85, an amino acid other than E at position 89, an amino acid other than S at position 113, and / or an amino acid other than T at position 115; or (e) 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or all of the following amino acids, numbered according to SEQ ID NO: 21: an amino acid other than Q at position 5, an amino acid other than P at position 7, an amino acid other than T at position 9, an amino acid other than L at position 11, an amino acid other than V at position 12, an amino acid other than S at position 16, an amino acid other than N at position 19, an amino acid other than L at position 20, an amino acid other than H at position 43, an amino acid other than I at position 48, an amino acid other than K at position 67, an amino acid other than A at position 68, an amino acid other than L at position 70, an amino acid other than S at position 76, an amino acid other than T at position 77, an amino acid other than T at position 87, and / or an amino acid other than S at position 91 The antibody comprising:

[0037] 11. the VH contains, in the numbering according to SEQ ID NO: 21, an amino acid other than Q at position 5, an amino acid other than P at position 7, an amino acid other than T at position 9, an amino acid other than L at position 11, an amino acid other than V at position 12, an amino acid other than P at position 14, an amino acid other than S at position 16, an amino acid other than N at position 19, an amino acid other than L at position 20, an amino acid other than K at position 38, an amino acid other than E at position 39, an amino acid other than R at position 40, an amino acid other than H at position 43, and an amino acid other than K at position 67; 11. The antibody of any one of embodiments 1 to 10, comprising one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, or all of an amino acid other than A at position 68, an amino acid other than T at position 71, an amino acid other than V at position 72, an amino acid other than H at position 73, an amino acid other than K at position 74, an amino acid other than S at position 76, an amino acid other than S at position 84, and / or an amino acid other than S at position 113.

[0038] 12. the VH contains, in numbering according to SEQ ID NO: 21, an amino acid other than Q at position 5, an amino acid other than Q at position 6, an amino acid other than P at position 7, an amino acid other than T at position 9, an amino acid other than L at position 11, an amino acid other than V at position 12, an amino acid other than S at position 16, an amino acid other than N at position 19, an amino acid other than L at position 20, an amino acid other than I at position 48, an amino acid other than K at position 67, an amino acid other than A at position 68, an amino acid other than L at position 70, and an amino acid other than S at position 76; 11. The antibody of any one of embodiments 1 to 10, comprising one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, or all of an amino acid other than T at position 77, an amino acid other than V at position 79, an amino acid other than F at position 80, an amino acid other than I at position 81, an amino acid other than Q at position 82, an amino acid other than T at position 87, an amino acid other than S at position 91, and / or an amino acid other than S at position 113.

[0039] 13. 11. The antibody of any one of embodiments 1 to 10, wherein the VH comprises one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, or all of the following amino acids, numbered according to SEQ ID NO: 21: an amino acid other than Q at position 1, an amino acid other than Q at position 5, an amino acid other than P at position 7, an amino acid other than T at position 9, an amino acid other than L at position 11, an amino acid other than V at position 12, an amino acid other than N at position 19, an amino acid other than L at position 20, an amino acid other than K at position 67, an amino acid other than A at position 68, an amino acid other than L at position 70, an amino acid other than S at position 76, an amino acid other than V at position 79, an amino acid other than F at position 80, an amino acid other than I at position 81, an amino acid other than Q at position 82, an amino acid other than S at position 85, an amino acid other than E at position 89, an amino acid other than S at position 113, and / or an amino acid other than T at position 115.

[0040] 14. 11. The antibody of any one of embodiments 1 to 10, wherein the VH comprises one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, or all of the following amino acids, numbered according to SEQ ID NO: 21: an amino acid other than Q at position 5, an amino acid other than P at position 7, an amino acid other than T at position 9, an amino acid other than L at position 11, an amino acid other than V at position 12, an amino acid other than S at position 16, an amino acid other than N at position 19, an amino acid other than L at position 20, an amino acid other than H at position 43, an amino acid other than I at position 48, an amino acid other than K at position 67, an amino acid other than A at position 68, an amino acid other than L at position 70, an amino acid other than S at position 76, an amino acid other than T at position 77, an amino acid other than T at position 87, and / or an amino acid other than S at position 91.

[0041] 15. 15. The antibody of any one of embodiments 1 to 14, wherein the VH comprises an amino acid sequence including one, two, three, four, five, six, seven, eight, or all of the following: V at position 5, S at position 7, A at position 9, V at position 11, K at position 12, K at position 19, V at position 20, R at position 67, and / or V at position 68, numbered according to SEQ ID NO: 21.

[0042] 16. 16. The antibody of any one of embodiments 1 to 15, wherein the VH is: (a) one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, or all of: V at position 5, E at position 6, S at position 7, A at position 9, V at position 11, K at position 12, A at position 16, K at position 19, V at position 20, M at position 48, R at position 67, V at position 68, I at position 70, A at position 76, S at position 77, A at position 79, Y at position 80, M at position 81, E at position 82, R at position 87, T at position 91, and / or T at position 113, numbered according to SEQ ID NO: 21; (b) one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, or all of the following, numbered according to SEQ ID NO: 21: V at position 5, S at position 7, A at position 9, V at position 11, K at position 12, A at position 16, K at position 19, V at position 20, R at position 38, R at position 67, V at position 68, M at position 70, I at position 76, S at position 77, A at position 79, Y at position 80, M at position 81, E at position 82, R at position 87, D at position 89, and / or L at position 113; (c) one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, or all of the following, numbered according to SEQ ID NO: 21: V at position 5, S at position 7, A at position 9, V at position 11, K at position 12, S at position 14, A at position 16, K at position 19, V at position 20, R at position 38, Q at position 39, A at position 40, Q at position 43, R at position 67, V at position 68, I at position 71, R at position 72, D at position 73, T at position 74, T at position 76, T at position 84, and / or L at position 113; (d) one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, or all of E at position 1, V at position 5, S at position 7, A at position 9, V at position 11, K at position 12, K at position 19, V at position 20, R at position 67, V at position 68, M at position 70, I at position 76, A at position 79, Y at position 80, M at position 81, E at position 82, R at position 85, D at position 89, L at position 113, and / or S at position 115, numbered according to SEQ ID NO: 21; or (e) one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, or all of the following, numbered according to SEQ ID NO: 21: V at position 5, S at position 7, A at position 9, V at position 11, K at position 12, A at position 16, K at position 19, V at position 20, Q at position 43, M at position 48, R at position 67, V at position 68, M at position 70, T at position 76, S at position 77, R at position 87, and / or T at position 91 The antibody comprising:

[0043] 17. 17. The antibody of any one of embodiments 1 to 11, 15, or 16, wherein the VH comprises one, two, three, four, five, six, seven, eight, nine, ten, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or all of: V at position 5, S at position 7, A at position 9, V at position 11, K at position 12, S at position 14, A at position 16, K at position 19, V at position 20, R at position 38, Q at position 39, A at position 40, Q at position 43, R at position 67, V at position 68, I at position 71, R at position 72, D at position 73, T at position 74, T at position 76, T at position 84, and / or L at position 113, numbered according to SEQ ID NO: 21.

[0044] 18. 17. The antibody of any one of embodiments 1 to 10, 12, 15, or 16, wherein the VH comprises one, two, three, four, five, six, seven, eight, nine, ten, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or all of the following: V at position 5, E at position 6, S at position 7, A at position 9, V at position 11, K at position 12, A at position 16, K at position 19, V at position 20, M at position 48, R at position 67, V at position 68, I at position 70, A at position 76, S at position 77, A at position 79, Y at position 80, M at position 81, E at position 82, R at position 87, T at position 91, and / or T at position 113, numbered according to SEQ ID NO: 21.

[0045] 19. 17. The antibody of any one of embodiments 1 to 10, 13, 15, or 16, wherein the VH comprises one, two, three, four, five, six, seven, eight, nine, ten, 11, 12, 13, 14, 15, 16, 17, 18, 19, or all of the following: E ​​at position 1, V at position 5, S at position 7, A at position 9, V at position 11, K at position 12, K at position 19, V at position 20, R at position 67, V at position 68, M at position 70, I at position 76, A at position 79, Y at position 80, M at position 81, E at position 82, R at position 85, D at position 89, L at position 113, and / or S at position 115, numbered according to SEQ ID NO: 21.

[0046] 20. 17. The antibody of any one of embodiments 1 to 10 or 14 to 16, wherein the VH comprises one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, or all of the following: V at position 5, S at position 7, A at position 9, V at position 11, K at position 12, A at position 16, K at position 19, V at position 20, Q at position 43, M at position 48, R at position 67, V at position 68, M at position 70, T at position 76, S at position 77, R at position 87, and / or T at position 91, numbered according to SEQ ID NO: 21.

[0047] twenty one. An antibody described in any one of embodiments 1 to 20, wherein the VL comprises an amino acid sequence numbered according to SEQ ID NO: 93, including one, two, or all of the amino acids other than D at position 17, Q at position 18, and / or G at position 68.

[0048] twenty two. 22. The antibody of any one of embodiments 1 to 21, wherein the VL is: (a) one, two, three, four, five, six, seven, eight, nine, ten, or all of an amino acid other than T at position 7, an amino acid other than S at position 14, an amino acid other than D at position 17, an amino acid other than Q at position 18, an amino acid other than L at position 42, an amino acid other than K at position 44, an amino acid other than K at position 50, an amino acid other than G at position 68, an amino acid other than L at position 88, an amino acid other than F at position 92, and / or an amino acid other than G at position 105, numbered according to SEQ ID NO: 93; (b) one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, or all of an amino acid other than V at position 2, an amino acid other than T at position 7, an amino acid other than P at position 12, an amino acid other than S at position 14, an amino acid other than L at position 15, an amino acid other than D at position 17, an amino acid other than Q at position 18, an amino acid other than K at position 50, an amino acid other than G at position 68, an amino acid other than L at position 88, an amino acid other than F at position 92, an amino acid other than G at position 105, and / or an amino acid other than L at position 109, numbered according to SEQ ID NO: 93; (c) one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, or all of an amino acid other than V at position 2, an amino acid other than L at position 11, an amino acid other than T at position 14, an amino acid other than D at position 17, an amino acid other than Q at position 18, an amino acid other than L at position 42, an amino acid other than K at position 44, an amino acid other than S at position 48, an amino acid other than K at position 50, an amino acid other than G at position 68, an amino acid other than S at position 72, an amino acid other than S at position 81, an amino acid other than L at position 88, and / or an amino acid other than G at position 105, numbered according to SEQ ID NO: 93; (d) one, two, three, four, five, six, seven, eight, nine, ten, eleven, or all of an amino acid other than V at position 2, an amino acid other than V at position 3, an amino acid other than T at position 7, an amino acid other than S at position 14, an amino acid other than D at position 17, an amino acid other than Q at position 18, an amino acid other than L at position 42, an amino acid other than K at position 44, an amino acid other than K at position 50, an amino acid other than L at position 51, an amino acid other than G at position 68, and / or an amino acid other than L at position 88, numbered according to SEQ ID NO: 93; or (e) In the numbering according to SEQ ID NO: 93, one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, or all of an amino acid other than D at position 1, an amino acid other than V at position 2, an amino acid other than M at position 4, an amino acid other than T at position 7, an amino acid other than L at position 9, an amino acid other than S at position 10, an amino acid other than P at position 12, an amino acid other than V at position 13, an amino acid other than L at position 15, an amino acid other than D at position 17, an amino acid other than Q at position 18, an amino acid other than S at position 20, an amino acid other than I at position 21, an amino acid other than S at position 48, an amino acid other than V at position 63, an amino acid other than G at position 68, an amino acid other than S at position 72, an amino acid other than K at position 79, an amino acid other than R at position 82, an amino acid other than V at position 83, an amino acid other than A at position 85, and / or an amino acid other than G at position 89. The antibody comprising:

[0049] twenty three. 23. The antibody of any one of embodiments 1 to 22, wherein the VL comprises one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, or all of the following amino acids, numbered according to SEQ ID NO: 93: an amino acid other than V at position 2, an amino acid other than T at position 7, an amino acid other than P at position 12, an amino acid other than S at position 14, an amino acid other than L at position 15, an amino acid other than D at position 17, an amino acid other than Q at position 18, an amino acid other than K at position 50, an amino acid other than G at position 68, an amino acid other than L at position 88, an amino acid other than F at position 92, an amino acid other than G at position 105, and / or an amino acid other than L at position 109.

[0050] twenty four. 23. The antibody of any one of embodiments 1 to 22, wherein the VL comprises one, two, three, four, five, six, seven, eight, nine, ten, or all of the following amino acids: an amino acid other than T at position 7, an amino acid other than S at position 14, an amino acid other than D at position 17, an amino acid other than Q at position 18, an amino acid other than L at position 42, an amino acid other than K at position 44, an amino acid other than K at position 50, an amino acid other than G at position 68, an amino acid other than L at position 88, an amino acid other than F at position 92, and / or an amino acid other than G at position 105, numbered according to SEQ ID NO: 93.

[0051] twenty five. 23. The antibody of any one of embodiments 1 to 22, wherein the VL comprises one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, or all of the following amino acids: an amino acid other than V at position 2, an amino acid other than L at position 11, an amino acid other than T at position 14, an amino acid other than D at position 17, an amino acid other than Q at position 18, an amino acid other than L at position 42, an amino acid other than K at position 44, an amino acid other than S at position 48, an amino acid other than K at position 50, an amino acid other than G at position 68, an amino acid other than S at position 72, an amino acid other than S at position 81, an amino acid other than L at position 88, and / or an amino acid other than G at position 105, numbered according to SEQ ID NO: 93.

[0052] 26. An antibody described in any one of embodiments 1 to 25, wherein the VL comprises an amino acid sequence numbered according to SEQ ID NO: 93, including one, two, or all of Q or E at position 17, P or R at position 18, and / or S at position 68.

[0053] 27. 27. The antibody of any one of embodiments 1 to 26, wherein the VL is: (a) one, two, three, four, five, six, seven, eight, nine, ten, or all of S at position 7, T at position 14, Q at position 17, P at position 18, Q at position 42, R at position 44, R at position 50, S at position 68, V at position 88, Y at position 92, and / or Q at position 105, numbered according to SEQ ID NO: 93; (b) one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, or all of: I at position 2, S at position 7, S at position 12, T at position 14, P at position 15, Q at position 17, P at position 18, Q at position 50, S at position 68, V at position 88, Y at position 92, Q at position 105, and / or V at position 109, numbered according to SEQ ID NO: 93; (c) one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, or all of the following, numbered according to SEQ ID NO: 93: I at position 2, S at position 11, T at position 14, Q at position 17, P at position 18, Q at position 42, R at position 44, P at position 48, R at position 50, S at position 68, A at position 72, N at position 81, V at position 88, and / or Q at position 105; (d) one, two, three, four, five, six, seven, eight, nine, ten, eleven, or all of: I at position 2, E at position 3, S at position 7, T at position 14, Q at position 17, P at position 18, Q at position 42, R at position 44, R at position 50, R at position 51, S at position 68, and / or V at position 88, numbered according to SEQ ID NO: 93; or (e) 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or all of the following, numbered according to SEQ ID NO: 93: E at position 1, I at position 2, L at position 4, S at position 7, A at position 9, T at position 10, S at position 12, L at position 13, P at position 15, E at position 17, R at position 18, T at position 20, L at position 21, A at position 48, I at position 63, S at position 68, P at position 72, T at position 79, S at position 82, L at position 83, P at position 85, and / or A at position 89. The antibody comprising:

[0054] 28. 28. The antibody of any one of embodiments 1 to 23, 26, or 27, wherein the VL comprises one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, or all of the following: I at position 2, S at position 7, S at position 12, T at position 14, P at position 15, Q at position 17, P at position 18, Q at position 50, S at position 68, V at position 88, Y at position 92, Q at position 105, and / or V at position 109, numbered according to SEQ ID NO: 93.

[0055] 29. 28. The antibody of any one of embodiments 1 to 22, 24, 26, or 27, wherein the VL comprises one, two, three, four, five, six, seven, eight, nine, ten, or all of S at position 7, T at position 14, Q at position 17, P at position 18, Q at position 42, R at position 44, R at position 50, S at position 68, V at position 88, Y at position 92, and / or Q at position 105, numbered according to SEQ ID NO: 93.

[0056] 30. 28. The antibody of any one of embodiments 1 to 22 or 24 to 27, wherein the VL comprises one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, or all of the following: I at position 2, S at position 11, T at position 14, Q at position 17, P at position 18, Q at position 42, R at position 44, P at position 48, R at position 50, S at position 68, A at position 72, N at position 81, V at position 88, and / or Q at position 105, numbered according to SEQ ID NO: 93.

[0057] 31. The antibody according to any one of embodiments 1 to 30, (i) the VH comprises one, two, three, or four framework regions, e.g., one, two, three, or all of FRH1, FRH2, FRH3, and / or FRH4, and optionally the VH comprises, from N-terminus to C-terminus, FRH1-CDRH1-FRH2-CDRH2-FRH3-CDRH3-FRH4; and / or (ii) the VL comprises one, two, three, or four framework regions, e.g., one, two, three, or all of FRL1, FRL2, FRL3, and / or FRL4, and optionally the VL comprises, from N-terminus to C-terminus, FRL1-CDRL1-FRL2-CDRL2-FRL3-CDRL3-FRL4; The antibody.

[0058] 32. 32. The antibody of embodiment 31, (a)(i) the FRH1 corresponds to positions 1 to 25 of the heavy chain variable region in the numbering scheme according to SEQ ID NO: 21 or any one of 67 to 71; the FRH2 corresponds to positions 36 to 49 of the numbering scheme according to SEQ ID NO: 21 or any one of 67 to 71; the FRH3 corresponds to positions 67 to 96 of the numbering scheme according to SEQ ID NO: 21 or any one of 67 to 71; and / or the FRH4 corresponds to positions 108 to 118 of the numbering scheme according to SEQ ID NO: 21 or any one of 67 to 71; or (ii) the FRH1 corresponds to positions 1 to 30 of the heavy chain variable region in the numbering scheme according to SEQ ID NO: 21 or any one of SEQ ID NO: 67 to 71; the FRH2 corresponds to positions 36 to 49 of the numbering scheme according to SEQ ID NO: 21 or any one of SEQ ID NO: 67 to 71; the FRH3 corresponds to positions 67 to 98 of the numbering scheme according to SEQ ID NO: 21 or any one of SEQ ID NO: 67 to 71; and / or the FRH4 corresponds to positions 108 to 118 of the numbering scheme according to SEQ ID NO: 21 or any one of SEQ ID NO: 67 to 71; and / or (b) the FRL1 corresponds to positions 1 to 23 of the light chain variable region in the numbering scheme according to any one of SEQ ID NOs: 72 to 76 or 93; the FRL2 corresponds to positions 40 to 54 of the light chain variable region in the numbering scheme according to any one of SEQ ID NOs: 72 to 76 or 93; the FRL3 corresponds to positions 62 to 93 of the light chain variable region in the numbering scheme according to any one of SEQ ID NOs: 72 to 76 or 93; and / or the FRL4 corresponds to positions 103 to 112 of the numbering scheme according to any one of SEQ ID NOs: 72 to 76 or 93. The antibody.

[0059] 33. 1. The antibody of any one of the preceding embodiments, (a) the VH is (i) FRH1 comprising amino acids 1 to 25 or 1 to 30 of any one of SEQ ID NOs: 67 to 71 (optionally, any one of SEQ ID NOs: 67 or 69 to 72); an amino acid sequence that includes one, two, three, but not more than four modifications (e.g., substitutions, e.g., conservative substitutions) to amino acids 1 to 25 or 1 to 30 of any one of SEQ ID NOs: 67 to 71 (optionally, any one of SEQ ID NOs: 67 or 69 to 72); or an amino acid sequence that includes one, two, three, but not more than four different amino acids to amino acids 1 to 25 or 1 to 30 of any one of SEQ ID NOs: 67 to 71 (optionally, any one of SEQ ID NOs: 67 or 69 to 72), (ii) FRH2 comprising amino acids 36 to 49 of any one of SEQ ID NOs: 67 to 71 (optionally, any one of SEQ ID NOs: 67 or 69 to 72); an amino acid sequence comprising one, two, three, but not more than four modifications (e.g., substitutions, e.g., conservative substitutions) relative to amino acids 36 to 49 of any one of SEQ ID NOs: 67 to 71 (optionally, any one of SEQ ID NOs: 67 or 69 to 72); or an amino acid sequence comprising one, two, three, but not more than four different amino acids relative to amino acids 36 to 49 of any one of SEQ ID NOs: 67 to 71 (optionally, any one of SEQ ID NOs: 67 or 69 to 72), (iii) FRH3 comprising amino acids 67 to 96 or 67 to 98 of any one of SEQ ID NOs: 67 to 71 (optionally, any one of SEQ ID NOs: 67 or 69 to 72); an amino acid sequence that includes one, two, three, but not more than four modifications (e.g., substitutions, e.g., conservative substitutions) relative to amino acids 67 to 96 or 67 to 98 of any one of SEQ ID NOs: 67 to 71 (optionally, any one of SEQ ID NOs: 67 or 69 to 72); or an amino acid sequence that includes one, two, three, but not more than four different amino acids relative to amino acids 67 to 96 or 67 to 98 of any one of SEQ ID NOs: 67 to 71 (optionally, any one of SEQ ID NOs: 67 or 69 to 72), and / or (iv) FRH4 comprising amino acids 108 to 118 of any one of SEQ ID NOs: 67 to 71 (optionally, any one of SEQ ID NOs: 67 or 69 to 72); an amino acid sequence that includes one, two, three, but not more than four modifications (e.g., substitutions, e.g., conservative substitutions) relative to amino acids 108 to 118 of any one of SEQ ID NOs: 67 to 71 (optionally, any one of SEQ ID NOs: 67 or 69 to 72); or an amino acid sequence that includes one, two, three, but not more than four different amino acids relative to amino acids 108 to 118 of any one of SEQ ID NOs: 67 to 71 (optionally, any one of SEQ ID NOs: 67 or 69 to 72). and / or (b) the VL is (i) FRL1 comprising amino acids 1 to 23 of any one of SEQ ID NOs: 72 to 76 (optionally, any one of SEQ ID NOs: 72 to 74); an amino acid sequence comprising one, two, three, but not more than four modifications (e.g., substitutions, e.g., conservative substitutions) relative to amino acids 1 to 23 of any one of SEQ ID NOs: 72 to 76 (optionally, any one of SEQ ID NOs: 72 to 74); or an amino acid sequence comprising one, two, three, but not more than four different amino acids relative to amino acids 1 to 23 of any one of SEQ ID NOs: 72 to 76 (optionally, any one of SEQ ID NOs: 72 to 74), (ii) FRL2 comprising amino acids 40 to 54 of any one of SEQ ID NOs: 72 to 76 (optionally, any one of SEQ ID NOs: 72 to 74); an amino acid sequence comprising one, two, three, but not more than four modifications (e.g., substitutions, e.g., conservative substitutions) relative to amino acids 40 to 54 of any one of SEQ ID NOs: 72 to 76 (optionally, any one of SEQ ID NOs: 72 to 74); or an amino acid sequence comprising one, two, three, but not more than four different amino acids relative to amino acids 40 to 54 of any one of SEQ ID NOs: 72 to 76 (optionally, any one of SEQ ID NOs: 72 to 74), (iii) FRL3, comprising amino acids 62 to 93 of any one of SEQ ID NOs: 72 to 76 (optionally, any one of SEQ ID NOs: 72 to 74); an amino acid sequence that includes one, two, three, but not more than four modifications (e.g., substitutions, e.g., conservative substitutions) relative to amino acids 62 to 93 of any one of SEQ ID NOs: 72 to 76 (optionally, any one of SEQ ID NOs: 72 to 74); or an amino acid sequence that includes one, two, three, but not more than four different amino acids relative to amino acids 62 to 93 of any one of SEQ ID NOs: 72 to 76 (optionally, any one of SEQ ID NOs: 72 to 74), and / or (iv) FRL4 comprising amino acids 103 to 112 of any one of SEQ ID NOs: 72 to 76 (optionally, any one of SEQ ID NOs: 72 to 74); an amino acid sequence comprising one, two, three, but not more than four modifications (e.g., substitutions, e.g., conservative substitutions) relative to amino acids 103 to 112 of any one of SEQ ID NOs: 72 to 76 (optionally, any one of SEQ ID NOs: 72 to 74); or an amino acid sequence comprising one, two, three, but not more than four different amino acids relative to amino acids 103 to 112 of any one of SEQ ID NOs: 72 to 76 (optionally, any one of SEQ ID NOs: 72 to 74). The antibody comprises one, two, three, or all of the following:

[0060] 34. The antibody of any one of embodiments 1 to 33, (i) the VH does not contain one, two, three, or all of FRH1 comprising amino acids 1 to 25 or 1 to 30 of SEQ ID NO: 21; FRH2 comprising amino acids 36 to 49 of SEQ ID NO: 21; FRH3 comprising amino acids 67 to 96 or 67 to 98 of SEQ ID NO: 21; and / or FRH4 comprising amino acids 108 to 118 of SEQ ID NO: 21; and / or (ii) the VL does not contain one, two, three, or all of FRL1, which contains amino acids 1 to 23 of SEQ ID NO: 93; FRL2, which contains amino acids 40 to 54 of SEQ ID NO: 93; FRL3, which contains amino acids 62 to 93 of SEQ ID NO: 93; and / or FRL4, which contains amino acids 103 to 112 of SEQ ID NO: 93; The antibody.

[0061] 35. An antibody described in any one of embodiments 1 to 34, wherein the VH comprises an amino acid sequence of any one of SEQ ID NOs: 67 to 71, or an amino acid sequence that is at least 86% (e.g., at least 90, 92, 95, 96, 97, 98, or 99%) identical to the amino acid sequence of any one of SEQ ID NOs: 67 to 71.

[0062] 36. An antibody described in any one of embodiments 1 to 35, wherein the VH comprises an amino acid sequence containing at least 1, 2, 3, 4, or 5, but not more than 16, modifications, e.g., substitutions (e.g., conservative substitutions), relative to the amino acid sequence of any one of SEQ ID NOs: 67 to 71.

[0063] 37. An antibody described in any one of embodiments 1 to 36, wherein the VH comprises an amino acid sequence containing at least 1, 2, 3, 4, or 5, but not more than 16, different amino acids from the amino acid sequence of any one of SEQ ID NOs: 67 to 71.

[0064] 38. The antibody of any one of embodiments 1 to 11, 15 to 17, or 21 to 37, wherein the VH comprises an amino acid sequence of SEQ ID NO: 69 or an amino acid sequence at least 86% (e.g., at least 90, 92, 95, 96, 97, 98, or 99%) identical to the amino acid sequence of SEQ ID NO: 69.

[0065] 39. The antibody of any one of embodiments 1 to 11, 15 to 17, or 21 to 38, wherein the VH comprises an amino acid sequence containing at least 1, 2, 3, 4, or 5, but not more than 16, modifications, e.g., substitutions (e.g., conservative substitutions), relative to the amino acid sequence of SEQ ID NO: 69.

[0066] 40. The antibody of any one of embodiments 1 to 11, 15 to 17, or 21 to 39, wherein the VH comprises an amino acid sequence that contains at least 1, 2, 3, 4, or 5, but not more than 16, different amino acids from the amino acid sequence of SEQ ID NO: 69.

[0067] 41. 38. The antibody of any one of embodiments 1 to 10, 12, 15, 16, 18, or 21 to 37, wherein VH is: (i) the amino acid sequence of SEQ ID NO: 67, or an amino acid sequence at least 86% (e.g., at least 90, 92, 95, 96, 97, 98, or 99%) identical to the amino acid sequence of SEQ ID NO: 67; (ii) an amino acid sequence that contains at least one, two, three, four, or five, but not more than 16, modifications, e.g., substitutions (e.g., conservative substitutions), relative to the amino acid sequence of SEQ ID NO: 67; or (iii) an amino acid sequence containing at least 1, 2, 3, 4, or 5, but not more than 16, amino acids that differ from the amino acid sequence of SEQ ID NO: 67; The antibody comprising:

[0068] 42. 38. The antibody of any one of embodiments 1 to 10, 13, 15, 16, 19, or 21 to 37, wherein VH is: (i) the amino acid sequence of SEQ ID NO: 70, or an amino acid sequence at least 86% (e.g., at least 90, 92, 95, 96, 97, 98, or 99%) identical to the amino acid sequence of SEQ ID NO: 70; (ii) an amino acid sequence that contains at least one, two, three, four, or five, but not more than 16, modifications, e.g., substitutions (e.g., conservative substitutions), relative to the amino acid sequence of SEQ ID NO: 70; or (iii) an amino acid sequence containing at least 1, 2, 3, 4, or 5, but not more than 16, amino acids that differ from the amino acid sequence of SEQ ID NO: 70; The antibody comprising:

[0069] 43. 38. The antibody of any one of embodiments 1 to 10, 15, 16, or 20 to 37, wherein VH is: (i) the amino acid sequence of SEQ ID NO: 71, or an amino acid sequence at least 86% (e.g., at least 90, 92, 95, 96, 97, 98, or 99%) identical to the amino acid sequence of SEQ ID NO: 71; (ii) an amino acid sequence that contains at least one, two, three, four, or five, but not more than 16, modifications, e.g., substitutions (e.g., conservative substitutions), relative to the amino acid sequence of SEQ ID NO: 71; or (iii) an amino acid sequence containing at least 1, 2, 3, 4, or 5, but not more than 16, amino acids that differ from the amino acid sequence of SEQ ID NO: 71; The antibody comprising:

[0070] 44. An antibody described in any one of embodiments 1 to 43, wherein the VL comprises an amino acid sequence of any one of SEQ ID NOs: 72 to 76, or an amino acid sequence that is at least 91% (e.g., at least 92, 95, 96, 97, 98, or 99%) identical to the amino acid sequence of any one of SEQ ID NOs: 72 to 76.

[0071] 45. An antibody described in any one of embodiments 1 to 44, wherein the VL comprises an amino acid sequence containing at least 1, 2, 3, 4, or 5, but not more than 10, modifications, e.g., substitutions (e.g., conservative substitutions), relative to the amino acid sequence of any one of SEQ ID NOs: 72 to 76.

[0072] 46. An antibody described in any one of embodiments 1 to 45, wherein the VL comprises an amino acid sequence containing at least 1, 2, 3, 4, or 5, but not more than 10, different amino acids from the amino acid sequence of any one of SEQ ID NOs: 72 to 76.

[0073] 47. The antibody of any one of embodiments 1 to 23, 26 to 28, or 31 to 46, wherein the VL comprises an amino acid sequence of SEQ ID NO: 73 or an amino acid sequence at least 91% (e.g., at least 92, 95, 96, 97, 98, or 99%) identical to the amino acid sequence of SEQ ID NO: 73.

[0074] 48. The antibody of any one of embodiments 1 to 23, 26 to 28, or 31 to 47, wherein the VL comprises an amino acid sequence that contains at least 1, 2, 3, 4, or 5, but not more than 10, modifications, e.g., substitutions (e.g., conservative substitutions), relative to the amino acid sequence of SEQ ID NO: 73.

[0075] 49. The antibody of any one of embodiments 1 to 23, 26 to 28, or 31 to 48, wherein the VL comprises an amino acid sequence that contains at least 1, 2, 3, 4, or 5, but not more than 10, different amino acids from the amino acid sequence of SEQ ID NO: 73.

[0076] 50. The antibody of any one of embodiments 1 to 22, 24, 26, 27, 29, or 31 to 46, wherein the VL is: (i) the amino acid sequence of SEQ ID NO: 72, or an amino acid sequence at least 91% (e.g., at least 92, 95, 96, 97, 98, or 99%) identical to the amino acid sequence of SEQ ID NO: 72; (ii) an amino acid sequence containing at least one, two, three, four, or five, but not more than ten, modifications, e.g., substitutions (e.g., conservative substitutions), relative to the amino acid sequence of SEQ ID NO: 72; (iii) an amino acid sequence containing at least 1, 2, 3, 4, or 5, but not more than 10, amino acids that differ from the amino acid sequence of SEQ ID NO: 72; The antibody comprising:

[0077] 51. The antibody of any one of embodiments 1 to 22, 24 to 27, or 30 to 46, wherein the VL is: (i) the amino acid sequence of SEQ ID NO: 74, or an amino acid sequence at least 91% (e.g., at least 92, 95, 96, 97, 98, or 99%) identical to the amino acid sequence of SEQ ID NO: 74; (ii) an amino acid sequence containing at least one, two, three, four, or five, but not more than ten, modifications, e.g., substitutions (e.g., conservative substitutions), relative to the amino acid sequence of SEQ ID NO: 74; (iii) an amino acid sequence containing at least 1, 2, 3, 4, or 5, but not more than 10, amino acids that differ from the amino acid sequence of SEQ ID NO: 74; The antibody comprising:

[0078] 52. The antibody of any one of embodiments 1 to 51, (a) the VH comprises the amino acid sequence of any one of SEQ ID NOs: 67 to 71; or an amino acid sequence that is at least 86% (e.g., at least 90, 92, 95, 96, 97, 98, or 99%) identical to the amino acid sequence of any one of SEQ ID NOs: 67 to 71; an amino acid sequence that contains at least 1, 2, 3, 4, or 5, but not more than 10, modifications, e.g., substitutions (e.g., conservative substitutions), relative to the amino acid sequence of any one of SEQ ID NOs: 67 to 71; or an amino acid sequence that contains at least 1, 2, 3, 4, or 5, but not more than 16, different amino acids relative to the amino acid sequence of any one of SEQ ID NOs: 67 to 71, (b) the VL comprises an amino acid sequence of any one of SEQ ID NOs: 72 to 76; or an amino acid sequence that is at least 91% (e.g., at least 92, 95, 96, 97, 98, or 99%) identical to the amino acid sequence of any one of SEQ ID NOs: 72 to 76; an amino acid sequence that contains at least 1, 2, 3, 4, or 5, but not more than 10, modifications, e.g., substitutions (e.g., conservative substitutions), relative to the amino acid sequence of any one of SEQ ID NOs: 72 to 76; or an amino acid sequence that contains at least 1, 2, 3, 4, or 5, but not more than 10, different amino acids from the amino acid sequence of any one of SEQ ID NOs: 72 to 76, The antibody.

[0079] 53. The antibody of any one of embodiments 1 to 52, (a) the VH comprises the amino acid sequence of any one of SEQ ID NOs: 67 or 69 to 71; or an amino acid sequence that is at least 86% (e.g., at least 90, 92, 95, 96, 97, 98, or 99%) identical to the amino acid sequence of any one of SEQ ID NOs: 67 or 69 to 71; an amino acid sequence that contains at least 1, 2, 3, 4, or 5, but not more than 10, modifications, e.g., substitutions (e.g., conservative substitutions), relative to the amino acid sequence of any one of SEQ ID NOs: 67 or 69 to 71; or an amino acid sequence that contains at least 1, 2, 3, 4, or 5, but not more than 16, different amino acids relative to the amino acid sequence of any one of SEQ ID NOs: 67 or 69 to 71; (b) the VL comprises an amino acid sequence of any one of SEQ ID NOs: 72 to 74; or an amino acid sequence that is at least 91% (e.g., at least 92, 95, 96, 97, 98, or 99%) identical to the amino acid sequence of any one of SEQ ID NOs: 72 to 74; an amino acid sequence that contains at least 1, 2, 3, 4, or 5, but not more than 10, modifications, e.g., substitutions (e.g., conservative substitutions), relative to the amino acid sequence of any one of SEQ ID NOs: 72 to 74; or an amino acid sequence that contains at least 1, 2, 3, 4, or 5, but not more than 10, different amino acids relative to the amino acid sequence of any one of SEQ ID NOs: 72 to 74, The antibody.

[0080] 54. The antibody of any one of embodiments 1 to 53, (a) the VH comprises the amino acid sequence of any one of SEQ ID NOs: 67 to 71, or an amino acid sequence at least 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NOs: 67 to 71; (b) the VL comprises an amino acid sequence of any one of SEQ ID NOs: 72 to 76, or an amino acid sequence that is at least 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NOs: 72 to 76; The antibody.

[0081] 55. The antibody of any one of embodiments 1 to 54, (a) the VH comprises the amino acid sequence of any one of SEQ ID NOs: 67 or 69 to 71, or an amino acid sequence at least 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NOs: 67 or 69 to 71; (b) the VL comprises an amino acid sequence of any one of SEQ ID NOs: 72 to 74, or an amino acid sequence that is at least 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NOs: 72 to 74; The antibody.

[0082] 56. The antibody of any one of embodiments 1 to 58, (i) the VH comprises the amino acid sequence of SEQ ID NO: 67 or an amino acid sequence at least 86%, 87%, 88%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 67, and the VL comprises the amino acid sequence of SEQ ID NO: 72 or an amino acid sequence at least 91%, 93%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 72; or (ii) the VH comprises the amino acid sequence of SEQ ID NO: 67 or an amino acid sequence at least 86%, 87%, 88%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 67, and the VL comprises the amino acid sequence of SEQ ID NO: 73 or an amino acid sequence at least 91%, 93%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 73; or (iii) the VH comprises the amino acid sequence of SEQ ID NO: 67 or an amino acid sequence at least 86%, 87%, 88%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 67, and the VL comprises the amino acid sequence of SEQ ID NO: 74 or an amino acid sequence at least 91%, 93%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 74; or (iv) the VH comprises the amino acid sequence of SEQ ID NO: 67 or an amino acid sequence at least 86%, 87%, 88%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 67, and the VL comprises the amino acid sequence of SEQ ID NO: 75 or an amino acid sequence at least 91%, 93%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 75; or (v) the VH comprises the amino acid sequence of SEQ ID NO: 67 or an amino acid sequence at least 86%, 87%, 88%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 67, and the VL comprises the amino acid sequence of SEQ ID NO: 76 or an amino acid sequence at least 91%, 93%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 76; or (vi) the VH comprises the amino acid sequence of SEQ ID NO: 68 or an amino acid sequence at least 86%, 87%, 88%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 68, and the VL comprises the amino acid sequence of SEQ ID NO: 72 or an amino acid sequence at least 91%, 93%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 72; or (vii) the VH comprises the amino acid sequence of SEQ ID NO: 68 or an amino acid sequence at least 86%, 87%, 88%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 68, and the VL comprises the amino acid sequence of SEQ ID NO: 73 or an amino acid sequence at least 91%, 93%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 73; or (viii) the VH comprises the amino acid sequence of SEQ ID NO: 68 or an amino acid sequence at least 86%, 87%, 88%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 68, and the VL comprises the amino acid sequence of SEQ ID NO: 74 or an amino acid sequence at least 91%, 93%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 74; or (ix) the VH comprises the amino acid sequence of SEQ ID NO: 68 or an amino acid sequence at least 86%, 87%, 88%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 68, and the VL comprises the amino acid sequence of SEQ ID NO: 75 or an amino acid sequence at least 91%, 93%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 75; or (x) the VH comprises the amino acid sequence of SEQ ID NO: 68 or an amino acid sequence at least 86%, 87%, 88%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 68, and the VL comprises the amino acid sequence of SEQ ID NO: 76 or an amino acid sequence at least 91%, 93%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 76; or (xi) the VH comprises the amino acid sequence of SEQ ID NO: 69 or an amino acid sequence at least 86%, 87%, 88%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 69, and the VL comprises the amino acid sequence of SEQ ID NO: 72 or an amino acid sequence at least 91%, 93%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 72; or (xii) the VH comprises the amino acid sequence of SEQ ID NO: 69 or an amino acid sequence at least 86%, 87%, 88%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 69, and the VL comprises the amino acid sequence of SEQ ID NO: 73 or an amino acid sequence at least 91%, 93%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 73; or (xiii) the VH comprises the amino acid sequence of SEQ ID NO: 69 or an amino acid sequence at least 86%, 87%, 88%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 69, and the VL comprises the amino acid sequence of SEQ ID NO: 74 or an amino acid sequence at least 91%, 93%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 74; or (xiv) the VH comprises the amino acid sequence of SEQ ID NO: 69 or an amino acid sequence at least 86%, 87%, 88%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 69, and the VL comprises the amino acid sequence of SEQ ID NO: 75 or an amino acid sequence at least 91%, 93%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 75; or (xv) the VH comprises the amino acid sequence of SEQ ID NO: 69 or an amino acid sequence at least 86%, 87%, 88%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 69, and the VL comprises the amino acid sequence of SEQ ID NO: 76 or an amino acid sequence at least 91%, 93%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 76; or (xvi) the VH comprises the amino acid sequence of SEQ ID NO: 70 or an amino acid sequence at least 86%, 87%, 88%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 70, and the VL comprises the amino acid sequence of SEQ ID NO: 72 or an amino acid sequence at least 91%, 93%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 72; or (xvii) the VH comprises the amino acid sequence of SEQ ID NO: 70 or an amino acid sequence at least 86%, 87%, 88%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 70, and the VL comprises the amino acid sequence of SEQ ID NO: 73 or an amino acid sequence at least 91%, 93%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 73; or (xviii) the VH comprises the amino acid sequence of SEQ ID NO: 70 or an amino acid sequence at least 86%, 87%, 88%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 70, and the VL comprises the amino acid sequence of SEQ ID NO: 74 or an amino acid sequence at least 91%, 93%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 74; or (xix) the VH comprises the amino acid sequence of SEQ ID NO: 70 or an amino acid sequence at least 86%, 87%, 88%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 70, and the VL comprises the amino acid sequence of SEQ ID NO: 75 or an amino acid sequence at least 91%, 93%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 75; or (xx) the VH comprises the amino acid sequence of SEQ ID NO: 70 or an amino acid sequence at least 86%, 87%, 88%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 70, and the VL comprises the amino acid sequence of SEQ ID NO: 76 or an amino acid sequence at least 91%, 93%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 76; or (xxi) the VH comprises the amino acid sequence of SEQ ID NO: 71 or an amino acid sequence at least 86%, 87%, 88%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 71, and the VL comprises the amino acid sequence of SEQ ID NO: 72 or an amino acid sequence at least 91%, 93%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 72; or (xxii) the VH comprises the amino acid sequence of SEQ ID NO: 71 or an amino acid sequence at least 86%, 87%, 88%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 71, and the VL comprises the amino acid sequence of SEQ ID NO: 73 or an amino acid sequence at least 91%, 93%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 73; or (xxiii) the VH comprises the amino acid sequence of SEQ ID NO: 71 or an amino acid sequence at least 86%, 87%, 88%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 71, and the VL comprises the amino acid sequence of SEQ ID NO: 74 or an amino acid sequence at least 91%, 93%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 74; or (xxiv) the VH comprises the amino acid sequence of SEQ ID NO: 71 or an amino acid sequence at least 86%, 87%, 88%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 71, and the VL comprises the amino acid sequence of SEQ ID NO: 75 or an amino acid sequence at least 91%, 93%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 75; or (xv) the VH comprises the amino acid sequence of SEQ ID NO: 71 or an amino acid sequence at least 86%, 87%, 88%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 71, and the VL comprises the amino acid sequence of SEQ ID NO: 76 or an amino acid sequence at least 91%, 93%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 76; The antibody.

[0083] 57. The antibody of any one of embodiments 1 to 11, 15 to 17, 21 to 23, 26 to 28, 31 to 38, 44 to 49, or 52 to 56, (i) the VH comprises an amino acid sequence of SEQ ID NO: 69, or an amino acid sequence at least 86%, 87%, 88%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 69; an amino acid sequence that contains at least one, two, three, four, or five, but not more than ten, modifications, e.g., substitutions (e.g., conservative substitutions), relative to the amino acid sequence of SEQ ID NO: 69; or an amino acid sequence that contains at least one, two, three, four, or five, but not more than 16, different amino acids relative to any one of the amino acid sequences of SEQ ID NO: 69; (ii) the VL comprises an amino acid sequence of SEQ ID NO: 73, or an amino acid sequence at least 91%, 93%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 73; an amino acid sequence that contains at least one, two, three, four, or five, but not more than 10, modifications, e.g., substitutions (e.g., conservative substitutions), relative to the amino acid sequence of SEQ ID NO: 73; or an amino acid sequence that contains at least one, two, three, four, or five, but not more than 16, different amino acids relative to any one of the amino acid sequences of SEQ ID NO: 73. The antibody.

[0084] 58. The antibody of any one of embodiments 1 to 11, 15 to 17, 21 to 23, 26 to 28, 31 to 38, 44 to 49, or 52 to 57, wherein the VH comprises the amino acid sequence of SEQ ID NO: 69 and the VL comprises the amino acid sequence of SEQ ID NO: 73.

[0085] 59. The antibody of any one of embodiments 1 to 10, 12, 15, 16, 18, 21, 22, 24, 26, 27, 29, 31 to 37, 41, 44 to 46, 50, or 52 to 56, (i) the VH comprises an amino acid sequence of SEQ ID NO: 67, or an amino acid sequence at least 86%, 87%, 88%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 67; an amino acid sequence that contains at least one, two, three, four, or five, but not more than ten, modifications, e.g., substitutions (e.g., conservative substitutions), relative to the amino acid sequence of SEQ ID NO: 67; or an amino acid sequence that contains at least one, two, three, four, or five, but not more than 16, different amino acids relative to any one of the amino acid sequences of SEQ ID NO: 67; (ii) the VL comprises an amino acid sequence of SEQ ID NO: 72, or an amino acid sequence at least 91%, 93%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 72; an amino acid sequence that contains at least one, two, three, four, or five, but not more than 10, modifications, e.g., substitutions (e.g., conservative substitutions), relative to the amino acid sequence of SEQ ID NO: 72; or an amino acid sequence that contains at least one, two, three, four, or five, but not more than 16, different amino acids relative to any one of the amino acid sequences of SEQ ID NO: 72. The antibody.

[0086] 60. The antibody of any one of embodiments 1 to 10, 13, 15, 16, 19, 21, 22, 24, 26, 27, 29, 31 to 37, 42, 44 to 46, 50, or 52 to 56, (i) the VH comprises an amino acid sequence of SEQ ID NO: 70, or an amino acid sequence at least 86%, 87%, 88%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 70; an amino acid sequence that contains at least one, two, three, four, or five, but not more than ten, modifications, e.g., substitutions (e.g., conservative substitutions), relative to the amino acid sequence of SEQ ID NO: 70; or an amino acid sequence that contains at least one, two, three, four, or five, but not more than 16, different amino acids relative to any one of the amino acid sequences of SEQ ID NO: 70; (ii) the VL comprises an amino acid sequence of SEQ ID NO: 72, or an amino acid sequence at least 91%, 93%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 72; an amino acid sequence that contains at least one, two, three, four, or five, but not more than 10, modifications, e.g., substitutions (e.g., conservative substitutions), relative to the amino acid sequence of SEQ ID NO: 72; or an amino acid sequence that contains at least one, two, three, four, or five, but not more than 16, different amino acids relative to any one of the amino acid sequences of SEQ ID NO: 72. The antibody.

[0087] 61. The antibody of any one of embodiments 1 to 10, 14 to 16, 20 to 23, 31 to 37, 43 to 49, or 52 to 56, (i) the VH comprises an amino acid sequence of SEQ ID NO: 71, or an amino acid sequence at least 86%, 87%, 88%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 71; an amino acid sequence that contains at least one, two, three, four, or five, but not more than ten, modifications, e.g., substitutions (e.g., conservative substitutions), relative to the amino acid sequence of SEQ ID NO: 71; or an amino acid sequence that contains at least one, two, three, four, or five, but not more than 16, different amino acids relative to any one of the amino acid sequences of SEQ ID NO: 71; (ii) the VL comprises an amino acid sequence of SEQ ID NO: 73, or an amino acid sequence at least 91%, 93%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 73; an amino acid sequence that contains at least one, two, three, four, or five, but not more than 10, modifications, e.g., substitutions (e.g., conservative substitutions), relative to the amino acid sequence of SEQ ID NO: 73; or an amino acid sequence that contains at least one, two, three, four, or five, but not more than 16, different amino acids relative to any one of the amino acid sequences of SEQ ID NO: 73. The antibody.

[0088] 62. The antibody according to any one of embodiments 1 to 10, 14 to 16, 20 to 22, 25 to 27, 30 to 37, 43 to 46, or 51 to 56, (i) the VH comprises an amino acid sequence of SEQ ID NO: 71, or an amino acid sequence at least 86%, 87%, 88%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 71; an amino acid sequence that contains at least one, two, three, four, or five, but not more than ten, modifications, e.g., substitutions (e.g., conservative substitutions), relative to the amino acid sequence of SEQ ID NO: 71; or an amino acid sequence that contains at least one, two, three, four, or five, but not more than 16, different amino acids relative to any one of the amino acid sequences of SEQ ID NO: 71; (ii) the VL comprises an amino acid sequence of SEQ ID NO: 74, or an amino acid sequence at least 91%, 93%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 74; an amino acid sequence that contains at least one, two, three, four, or five, but not more than 10, modifications, e.g., substitutions (e.g., conservative substitutions), relative to the amino acid sequence of SEQ ID NO: 74; or an amino acid sequence that contains at least one, two, three, four, or five, but not more than 16, different amino acids relative to any one of the amino acid sequences of SEQ ID NO: 74. The antibody.

[0089] 63. The antibody of any one of embodiments 1 to 62, (i) the nucleotide sequence encoding the VH comprises the nucleotide sequence of any one of SEQ ID NOs: 156-160, or a nucleotide sequence at least 80% (e.g., at least 85%, 87%, 90%, 91%, 95%, 96%, 97%, 98%, or 99%) identical thereto; and / or (ii) the nucleotide sequence encoding the VL comprises the nucleotide sequence of any one of SEQ ID NOs: 161 to 165, or a nucleotide sequence at least 80% (e.g., at least 85%, 87%, 90%, 91%, 95%, 96%, 97%, 98%, or 99%) identical thereto; The antibody.

[0090] 64. 64. The antibody of any one of embodiments 1 to 63, (i) the nucleotide sequence encoding the VH comprises the nucleotide sequence of any one of SEQ ID NOs: 156 or 158-160, or a nucleotide sequence at least 80% (e.g., at least 85%, 87%, 90%, 91%, 95%, 96%, 97%, 98%, or 99%) identical thereto; and / or (ii) the nucleotide sequence encoding the VL comprises the nucleotide sequence of any one of SEQ ID NOs: 161 to 163, or a nucleotide sequence at least 80% (e.g., at least 85%, 87%, 90%, 91%, 95%, 96%, 97%, 98%, or 99%) identical thereto; The antibody.

[0091] 65. 65. The antibody of any one of embodiments 1 to 11, 15 to 17, 21 to 23, 26 to 28, 31 to 38, 44 to 49, 52 to 58, 63, or 64, (i) the nucleotide sequence encoding the VH comprises the nucleotide sequence of SEQ ID NO: 158, or a nucleotide sequence at least 80% (e.g., at least 85%, 87%, 90%, 91%, 95%, 96%, 97%, 98%, or 99%) identical thereto; and / or (ii) the nucleotide sequence encoding the VL comprises the nucleotide sequence of any one of SEQ ID NO: 162, or a nucleotide sequence at least 80% (e.g., at least 85%, 87%, 90%, 91%, 95%, 96%, 97%, 98%, or 99%) identical thereto; The antibody.

[0092] 66. 64. The antibody of any one of embodiments 1 to 10, 12, 15, 16, 18, 21, 22, 24, 26, 27, 29, 31 to 37, 41, 44 to 46, 50, 52 to 56, 59, 63, or 64, (i) the nucleotide sequence encoding the VH comprises the nucleotide sequence of SEQ ID NO: 156, or a nucleotide sequence at least 80% (e.g., at least 85%, 87%, 90%, 91%, 95%, 96%, 97%, 98%, or 99%) identical thereto; and / or (ii) the nucleotide sequence encoding the VL comprises the nucleotide sequence of any one of SEQ ID NO: 161, or a nucleotide sequence at least 80% (e.g., at least 85%, 87%, 90%, 91%, 95%, 96%, 97%, 98%, or 99%) identical thereto; The antibody.

[0093] 67. 64. The antibody of any one of embodiments 1 to 10, 13, 15, 16, 19, 21, 22, 24, 26, 27, 29, 31 to 37, 42, 44 to 46, 50, 52 to 56, 60, 63, or 64, (i) the nucleotide sequence encoding the VH comprises the nucleotide sequence of SEQ ID NO: 159, or a nucleotide sequence at least 80% (e.g., at least 85%, 87%, 90%, 91%, 95%, 96%, 97%, 98%, or 99%) identical thereto; and / or (ii) the nucleotide sequence encoding the VL comprises the nucleotide sequence of any one of SEQ ID NO: 161, or a nucleotide sequence at least 80% (e.g., at least 85%, 87%, 90%, 91%, 95%, 96%, 97%, 98%, or 99%) identical thereto; The antibody.

[0094] 68. The antibody according to any one of embodiments 1 to 10, 14 to 16, 20 to 23, 25 to 27, 30 to 37, 43 to 49, 51 to 56, and 61 to 64, (i) the nucleotide sequence encoding the VH comprises the nucleotide sequence of SEQ ID NO: 160, or a nucleotide sequence at least 80% (e.g., at least 85%, 87%, 90%, 91%, 95%, 96%, 97%, 98%, or 99%) identical thereto; and / or (ii) the nucleotide sequence encoding the VL comprises the nucleotide sequence of any one of SEQ ID NOs: 162 or 163, or a nucleotide sequence at least 80% (e.g., at least 85%, 87%, 90%, 91%, 95%, 96%, 97%, 98%, or 99%) identical thereto; The antibody.

[0095] 69. 2. The antibody of any one of the preceding embodiments, which does not comprise the amino acid sequence of SEQ ID NO: 21 and / or the amino acid sequence of SEQ ID NO: 93.

[0096] 70. An antibody that binds to human tau, (a) a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (HC CDR1) comprising the amino acid sequence of SEQ ID NO: 64, a heavy chain complementarity determining region 2 (HC CDR2) comprising the amino acid sequence of SEQ ID NO: 1145, and a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of SEQ ID NO: 1167; and a light chain variable region (VL) comprising a light chain complementarity determining region 1 (LC CDR1) comprising the amino acid sequence of SEQ ID NO: 1146, a light chain complementarity determining region 2 (LC CDR2) comprising the amino acid sequence of SEQ ID NO: 529, and a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of SEQ ID NO: 571; (b) a VH comprising an HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1144, an HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1145, and an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410; and a VL comprising an LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1146, an LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; (c) a VH comprising an HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1165, an HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1166, and an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 1167, and a VL comprising an LC CDR1 comprising the amino acid sequence of SEQ ID NO: 473, an LC CDR2 comprising the amino acid sequence of RVS, and an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; or (d) a VH comprising an HC CDR1 comprising the amino acid sequence of SEQ ID NO: 314, an HC CDR2 comprising the amino acid sequence of SEQ ID NO: 341, and an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410, and a VL comprising an LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1154, an LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; and (i) the VH comprises one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, or all of: V at position 5, S at position 7, A at position 9, V at position 11, K at position 12, S at position 14, A at position 16, K at position 19, V at position 20, R at position 38, Q at position 39, A at position 40, Q at position 43, R at position 67, V at position 68, I at position 71, R at position 72, D at position 73, T at position 74, T at position 76, T at position 84, and / or L at position 113, numbered according to SEQ ID NO: 21; (ii) the VL contains one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, or all of: I at position 2, S at position 7, S at position 12, T at position 14, P at position 15, Q at position 17, P at position 18, Q at position 50, S at position 68, V at position 88, Y at position 92, Q at position 105, and / or V at position 109, numbered according to SEQ ID NO: 93; The antibody.

[0097] 71. An antibody that binds to human tau, (a) a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (HC CDR1) comprising the amino acid sequence of SEQ ID NO: 64, a heavy chain complementarity determining region 2 (HC CDR2) comprising the amino acid sequence of SEQ ID NO: 1145, and a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of SEQ ID NO: 1167; and a light chain variable region (VL) comprising a light chain complementarity determining region 1 (LC CDR1) comprising the amino acid sequence of SEQ ID NO: 1146, a light chain complementarity determining region 2 (LC CDR2) comprising the amino acid sequence of SEQ ID NO: 529, and a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of SEQ ID NO: 571; (b) a VH comprising an HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1144, an HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1145, and an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410; and a VL comprising an LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1146, an LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; (c) a VH comprising an HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1165, an HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1166, and an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 1167, and a VL comprising an LC CDR1 comprising the amino acid sequence of SEQ ID NO: 473, an LC CDR2 comprising the amino acid sequence of RVS, and an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; or (d) a VH comprising an HC CDR1 comprising the amino acid sequence of SEQ ID NO: 314, an HC CDR2 comprising the amino acid sequence of SEQ ID NO: 341, and an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410, and a VL comprising an LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1154, an LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; and (i) the VH comprises the amino acid sequence of SEQ ID NO: 69, or an amino acid sequence at least 86% (e.g., at least 90, 92, 95, 96, 97, 98, or 99%) identical to the amino acid sequence of SEQ ID NO: 69; and / or (ii) the VL comprises the amino acid sequence of SEQ ID NO: 73, or an amino acid sequence at least 91% (e.g., at least 92, 95, 96, 97, 98, or 99%) identical to the amino acid sequence of SEQ ID NO: 73; The antibody.

[0098] 72. An antibody that binds to human tau, comprising a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 69 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 73.

[0099] 73. An antibody that binds to human tau, (a) a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (HC CDR1) comprising the amino acid sequence of SEQ ID NO: 64, a heavy chain complementarity determining region 2 (HC CDR2) comprising the amino acid sequence of SEQ ID NO: 1145, and a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of SEQ ID NO: 1167; and a light chain variable region (VL) comprising a light chain complementarity determining region 1 (LC CDR1) comprising the amino acid sequence of SEQ ID NO: 1146, a light chain complementarity determining region 2 (LC CDR2) comprising the amino acid sequence of SEQ ID NO: 529, and a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of SEQ ID NO: 571; (b) a VH comprising an HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1144, an HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1145, and an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410; and a VL comprising an LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1146, an LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; (c) a VH comprising an HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1165, an HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1166, and an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 1167, and a VL comprising an LC CDR1 comprising the amino acid sequence of SEQ ID NO: 473, an LC CDR2 comprising the amino acid sequence of RVS, and an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; or (d) a VH comprising an HC CDR1 comprising the amino acid sequence of SEQ ID NO: 314, an HC CDR2 comprising the amino acid sequence of SEQ ID NO: 341, and an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410, and a VL comprising an LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1154, an LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; and (i) the VH comprises one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, or all of: V at position 5, E at position 6, S at position 7, A at position 9, V at position 11, K at position 12, A at position 16, K at position 19, V at position 20, M at position 48, R at position 67, V at position 68, I at position 70, A at position 76, S at position 77, A at position 79, Y at position 80, M at position 81, E at position 82, R at position 87, T at position 91, and / or T at position 113, numbered according to SEQ ID NO: 21; (ii) the VL contains one, two, three, four, five, six, seven, eight, nine, ten, or all of S at position 7, T at position 14, Q at position 17, P at position 18, Q at position 42, R at position 44, R at position 50, S at position 68, V at position 88, Y at position 92, and / or Q at position 105, numbered according to SEQ ID NO: 93; The antibody.

[0100] 74. An antibody that binds to human tau, (a) a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (HC CDR1) comprising the amino acid sequence of SEQ ID NO: 64, a heavy chain complementarity determining region 2 (HC CDR2) comprising the amino acid sequence of SEQ ID NO: 1145, and a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of SEQ ID NO: 1167; and a light chain variable region (VL) comprising a light chain complementarity determining region 1 (LC CDR1) comprising the amino acid sequence of SEQ ID NO: 1146, a light chain complementarity determining region 2 (LC CDR2) comprising the amino acid sequence of SEQ ID NO: 529, and a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of SEQ ID NO: 571; (b) a VH comprising an HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1144, an HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1145, and an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410; and a VL comprising an LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1146, an LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; (c) a VH comprising an HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1165, an HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1166, and an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 1167, and a VL comprising an LC CDR1 comprising the amino acid sequence of SEQ ID NO: 473, an LC CDR2 comprising the amino acid sequence of RVS, and an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; or (d) a VH comprising an HC CDR1 comprising the amino acid sequence of SEQ ID NO: 314, an HC CDR2 comprising the amino acid sequence of SEQ ID NO: 341, and an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410, and a VL comprising an LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1154, an LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; and (i) the VH comprises the amino acid sequence of SEQ ID NO: 67, or an amino acid sequence at least 86% (e.g., at least 90, 92, 95, 96, 97, 98, or 99%) identical to the amino acid sequence of SEQ ID NO: 67; and / or (ii) the VL comprises the amino acid sequence of SEQ ID NO: 72, or an amino acid sequence at least 91% (e.g., at least 92, 95, 96, 97, 98, or 99%) identical to the amino acid sequence of SEQ ID NO: 72; The antibody.

[0101] 75. An antibody that binds to human tau, comprising a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 67 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 72.

[0102] 76. An antibody that binds to human tau, (a) a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (HC CDR1) comprising the amino acid sequence of SEQ ID NO: 64, a heavy chain complementarity determining region 2 (HC CDR2) comprising the amino acid sequence of SEQ ID NO: 1145, and a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of SEQ ID NO: 1167; and a light chain variable region (VL) comprising a light chain complementarity determining region 1 (LC CDR1) comprising the amino acid sequence of SEQ ID NO: 1146, a light chain complementarity determining region 2 (LC CDR2) comprising the amino acid sequence of SEQ ID NO: 529, and a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of SEQ ID NO: 571; (b) a VH comprising an HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1144, an HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1145, and an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410; and a VL comprising an LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1146, an LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; (c) a VH comprising an HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1165, an HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1166, and an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 1167, and a VL comprising an LC CDR1 comprising the amino acid sequence of SEQ ID NO: 473, an LC CDR2 comprising the amino acid sequence of RVS, and an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; or (d) a VH comprising an HC CDR1 having the amino acid sequence of SEQ ID NO: 314, an HC CDR2 comprising the amino acid sequence of SEQ ID NO: 341, and an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410, and a VL comprising an LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1154, an LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; and (i) the VH comprises one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, or all of E at position 1, V at position 5, S at position 7, A at position 9, V at position 11, K at position 12, K at position 19, V at position 20, R at position 67, V at position 68, M at position 70, I at position 76, A at position 79, Y at position 80, M at position 81, E at position 82, R at position 85, D at position 89, L at position 113, and / or S at position 115, numbered according to SEQ ID NO: 21; (ii) the VL contains one, two, three, four, five, six, seven, eight, nine, ten, or all of S at position 7, T at position 14, Q at position 17, P at position 18, Q at position 42, R at position 44, R at position 50, S at position 68, V at position 88, Y at position 92, and / or Q at position 105, numbered according to SEQ ID NO: 93; The antibody.

[0103] 77. An antibody that binds to human tau, (a) a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (HC CDR1) comprising the amino acid sequence of SEQ ID NO: 64, a heavy chain complementarity determining region 2 (HC CDR2) comprising the amino acid sequence of SEQ ID NO: 1145, and a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of SEQ ID NO: 1167; and a light chain variable region (VL) comprising a light chain complementarity determining region 1 (LC CDR1) comprising the amino acid sequence of SEQ ID NO: 1146, a light chain complementarity determining region 2 (LC CDR2) comprising the amino acid sequence of SEQ ID NO: 529, and a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of SEQ ID NO: 571; (b) a VH comprising an HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1144, an HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1145, and an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410; and a VL comprising an LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1146, an LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; (c) a VH comprising an HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1165, an HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1166, and an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 1167, and a VL comprising an LC CDR1 comprising the amino acid sequence of SEQ ID NO: 473, an LC CDR2 comprising the amino acid sequence of RVS, and an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; or (d) a VH comprising an HC CDR1 comprising the amino acid sequence of SEQ ID NO: 314, an HC CDR2 comprising the amino acid sequence of SEQ ID NO: 341, and an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410, and a VL comprising an LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1154, an LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; and (i) the VH comprises the amino acid sequence of SEQ ID NO: 70, or an amino acid sequence at least 86% (e.g., at least 90, 92, 95, 96, 97, 98, or 99%) identical to the amino acid sequence of SEQ ID NO: 70; and / or (ii) the VL comprises the amino acid sequence of SEQ ID NO: 72, or an amino acid sequence at least 91% (e.g., at least 92, 95, 96, 97, 98, or 99%) identical to the amino acid sequence of SEQ ID NO: 72; The antibody.

[0104] 78. An antibody that binds to human tau, comprising a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 70 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 72.

[0105] 79. An antibody that binds to human tau, (a) a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (HC CDR1) comprising the amino acid sequence of SEQ ID NO: 64, a heavy chain complementarity determining region 2 (HC CDR2) comprising the amino acid sequence of SEQ ID NO: 1145, and a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of SEQ ID NO: 1167; and a light chain variable region (VL) comprising a light chain complementarity determining region 1 (LC CDR1) comprising the amino acid sequence of SEQ ID NO: 1146, a light chain complementarity determining region 2 (LC CDR2) comprising the amino acid sequence of SEQ ID NO: 529, and a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of SEQ ID NO: 571; (b) a VH comprising an HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1144, an HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1145, and an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410; and a VL comprising an LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1146, an LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; (c) a VH comprising an HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1165, an HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1166, and an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 1167, and a VL comprising an LC CDR1 comprising the amino acid sequence of SEQ ID NO: 473, an LC CDR2 comprising the amino acid sequence of RVS, and an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; or (d) a VH comprising an HC CDR1 comprising the amino acid sequence of SEQ ID NO: 314, an HC CDR2 comprising the amino acid sequence of SEQ ID NO: 341, and an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410, and a VL comprising an LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1154, an LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; and (i) the VH comprises one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, or all of: V at position 5, S at position 7, A at position 9, V at position 11, K at position 12, A at position 16, K at position 19, V at position 20, Q at position 43, M at position 48, R at position 67, V at position 68, M at position 70, T at position 76, S at position 77, R at position 87, and / or T at position 91, numbered according to SEQ ID NO: 21; (ii) the VL contains one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, or all of: I at position 2, S at position 7, S at position 12, T at position 14, P at position 15, Q at position 17, P at position 18, Q at position 50, S at position 68, V at position 88, Y at position 92, Q at position 105, and / or V at position 109, numbered according to SEQ ID NO: 93; The antibody.

[0106] 80. An antibody that binds to human tau, (a) a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (HC CDR1) comprising the amino acid sequence of SEQ ID NO: 64, a heavy chain complementarity determining region 2 (HC CDR2) comprising the amino acid sequence of SEQ ID NO: 1145, and a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of SEQ ID NO: 1167; and a light chain variable region (VL) comprising a light chain complementarity determining region 1 (LC CDR1) comprising the amino acid sequence of SEQ ID NO: 1146, a light chain complementarity determining region 2 (LC CDR2) comprising the amino acid sequence of SEQ ID NO: 529, and a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of SEQ ID NO: 571; (b) a VH comprising an HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1144, an HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1145, and an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410; and a VL comprising an LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1146, an LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; (c) a VH comprising an HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1165, an HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1166, and an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 1167, and a VL comprising an LC CDR1 comprising the amino acid sequence of SEQ ID NO: 473, an LC CDR2 comprising the amino acid sequence of RVS, and an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; or (d) a VH comprising an HC CDR1 comprising the amino acid sequence of SEQ ID NO: 314, an HC CDR2 comprising the amino acid sequence of SEQ ID NO: 341, and an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410, and a VL comprising an LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1154, an LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; and (i) the VH comprises the amino acid sequence of SEQ ID NO: 71, or an amino acid sequence at least 86% (e.g., at least 90, 92, 95, 96, 97, 98, or 99%) identical to the amino acid sequence of SEQ ID NO: 71; and / or (ii) the VL comprises the amino acid sequence of SEQ ID NO: 73, or an amino acid sequence at least 91% (e.g., at least 92, 95, 96, 97, 98, or 99%) identical to the amino acid sequence of SEQ ID NO: 73; The antibody.

[0107] 81. An antibody that binds to human tau, comprising a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 71 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 73.

[0108] 82. An antibody that binds to human tau, (a) a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (HC CDR1) comprising the amino acid sequence of SEQ ID NO: 64, a heavy chain complementarity determining region 2 (HC CDR2) comprising the amino acid sequence of SEQ ID NO: 1145, and a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of SEQ ID NO: 1167; and a light chain variable region (VL) comprising a light chain complementarity determining region 1 (LC CDR1) comprising the amino acid sequence of SEQ ID NO: 1146, a light chain complementarity determining region 2 (LC CDR2) comprising the amino acid sequence of SEQ ID NO: 529, and a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of SEQ ID NO: 571; (b) a VH comprising an HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1144, an HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1145, and an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410; and a VL comprising an LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1146, an LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; (c) a VH comprising an HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1165, an HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1166, and an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 1167, and a VL comprising an LC CDR1 comprising the amino acid sequence of SEQ ID NO: 473, an LC CDR2 comprising the amino acid sequence of RVS, and an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; or (d) a VH comprising an HC CDR1 comprising the amino acid sequence of SEQ ID NO: 314, an HC CDR2 comprising the amino acid sequence of SEQ ID NO: 341, and an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410, and a VL comprising an LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1154, an LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; and (i) the VH comprises one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, or all of: V at position 5, S at position 7, A at position 9, V at position 11, K at position 12, A at position 16, K at position 19, V at position 20, Q at position 43, M at position 48, R at position 67, V at position 68, M at position 70, T at position 76, S at position 77, R at position 87, and / or T at position 91, numbered according to SEQ ID NO: 21; (ii) the VL contains one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, or all of: I at position 2, S at position 11, T at position 14, Q at position 17, P at position 18, Q at position 42, R at position 44, P at position 48, R at position 50, S at position 68, A at position 72, N at position 81, V at position 88, and / or Q at position 105, numbered according to SEQ ID NO: 93; The antibody.

[0109] 83. An antibody that binds to human tau, (a) a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (HC CDR1) comprising the amino acid sequence of SEQ ID NO: 64, a heavy chain complementarity determining region 2 (HC CDR2) comprising the amino acid sequence of SEQ ID NO: 1145, and a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of SEQ ID NO: 1167; and a light chain variable region (VL) comprising a light chain complementarity determining region 1 (LC CDR1) comprising the amino acid sequence of SEQ ID NO: 1146, a light chain complementarity determining region 2 (LC CDR2) comprising the amino acid sequence of SEQ ID NO: 529, and a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of SEQ ID NO: 571; (b) a VH comprising an HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1144, an HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1145, and an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410; and a VL comprising an LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1146, an LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; (c) a VH comprising an HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1165, an HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1166, and an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 1167, and a VL comprising an LC CDR1 comprising the amino acid sequence of SEQ ID NO: 473, an LC CDR2 comprising the amino acid sequence of RVS, and an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; or (d) a VH comprising an HC CDR1 comprising the amino acid sequence of SEQ ID NO: 314, an HC CDR2 comprising the amino acid sequence of SEQ ID NO: 341, and an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410, and a VL comprising an LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1154, an LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; and (i) the VH comprises the amino acid sequence of SEQ ID NO: 71, or an amino acid sequence at least 86% (e.g., at least 90, 92, 95, 96, 97, 98, or 99%) identical to the amino acid sequence of SEQ ID NO: 71; and / or (ii) the VL comprises the amino acid sequence of SEQ ID NO: 74, or an amino acid sequence at least 91% (e.g., at least 92, 95, 96, 97, 98, or 99%) identical to the amino acid sequence of SEQ ID NO: 74; The antibody.

[0110] 84. An antibody that binds to human tau, comprising a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 71 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 74.

[0111] 85. 10. The antibody of any one of the preceding embodiments, wherein the antibody is a humanized antibody. 86. The antibody of any one of the preceding embodiments, which is a full-length antibody, a bispecific antibody, a Fab, a F(ab')2, an Fv, or a single-chain Fv fragment (scFv).

[0112] 87. 10. The antibody of any one of the preceding embodiments, comprising a heavy chain constant region selected from IgG1, IgG2, IgG3, IgG4, and / or a light chain constant region of kappa or lambda.

[0113] 88. 10. The antibody of any one of the preceding embodiments, comprising an IgG4 heavy chain constant region and a kappa light chain constant region.

[0114] 89. 1. The antibody of any one of the preceding embodiments, (i) the antibody comprises a human IgG4 constant region comprising an amino acid other than serine at position 228 according to EU numbering; (ii) the antibody comprises a human IgG4 constant region comprising a serine to proline substitution (e.g., mutation) at position 228 according to EU numbering; (iii) the antibody comprises a heavy chain constant region (e.g., a human IgG4 constant region) comprising the amino acid sequence of SEQ ID NO: 194, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 194; and / or (iv) the antibody comprises a heavy chain constant region (e.g., a human IgG4 constant region), and the nucleotide sequence encoding the heavy chain constant region comprises the nucleotide sequence of any one of SEQ ID NOs: 195, 196, 198, or 199, or a nucleotide sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 195, 196, 198, or 199; The antibody.

[0115] 90. 36. The antibody of any one of embodiments 1 to 35, wherein the antibody comprises a light chain constant region (e.g., a kappa light chain constant region); (i) the light chain constant region comprises the amino acid sequence of SEQ ID NO: 200, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 200; and / or (ii) the nucleotide sequence encoding the light chain constant region comprises SEQ ID NO: 201 or 202, or a nucleotide sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 201 or 202; The antibody.

[0116] 91. 91. The antibody of any one of embodiments 1 to 90, wherein the antibody comprises a heavy chain comprising the amino acid sequence of any one of SEQ ID NOs: 170 to 174, or an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NOs: 170 to 174.

[0117] 92. 92. The antibody of any one of embodiments 1 to 91, wherein the antibody comprises a light chain comprising the amino acid sequence of any one of SEQ ID NOs: 175 to 179, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NOs: 175 to 179.

[0118] 93. The antibody of any one of embodiments 1 to 92, wherein the antibody is (i) a heavy chain comprising an amino acid sequence of any one of SEQ ID NOs: 170 to 174, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 170 to 174; (ii) a light chain comprising the amino acid sequence of any one of SEQ ID NOs: 175 to 179, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 175 to 179; The antibody comprising:

[0119] 94. 94. The antibody of any one of embodiments 1 to 93, wherein the antibody is (i) a heavy chain comprising the amino acid sequence of any one of SEQ ID NOs: 170 or 172 to 174, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 170 or 172 to 174; (ii) a light chain comprising the amino acid sequence of any one of SEQ ID NOs: 175 to 177, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 175 to 177; The antibody comprising:

[0120] 95. 1. The antibody of any one of the preceding embodiments, (i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 170, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 170, and a light chain comprising the amino acid sequence of SEQ ID NO: 175, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 175; (ii) a heavy chain comprising the amino acid sequence of SEQ ID NO: 170, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 170, and a light chain comprising the amino acid sequence of SEQ ID NO: 176, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 176; (iii) a heavy chain comprising the amino acid sequence of SEQ ID NO: 170, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 170, and a light chain comprising the amino acid sequence of SEQ ID NO: 177, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 177; (iv) a heavy chain comprising the amino acid sequence of SEQ ID NO: 170, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 170, and a light chain comprising the amino acid sequence of SEQ ID NO: 178, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 178; (v) a heavy chain comprising the amino acid sequence of SEQ ID NO: 170, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 170, and a light chain comprising the amino acid sequence of SEQ ID NO: 179, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 179; (vi) a heavy chain comprising the amino acid sequence of SEQ ID NO: 171, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 171, and a light chain comprising the amino acid sequence of SEQ ID NO: 175, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 175; (vii) a heavy chain comprising the amino acid sequence of SEQ ID NO: 171, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 171, and a light chain comprising the amino acid sequence of SEQ ID NO: 176, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 176; (viii) a heavy chain comprising the amino acid sequence of SEQ ID NO: 171, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 171, and a light chain comprising the amino acid sequence of SEQ ID NO: 177, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 177; (ix) a heavy chain comprising the amino acid sequence of SEQ ID NO: 171, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 171, and a light chain comprising the amino acid sequence of SEQ ID NO: 178, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 178; (x) a heavy chain comprising the amino acid sequence of SEQ ID NO: 171, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 171, and a light chain comprising the amino acid sequence of SEQ ID NO: 179, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 179; (xi) a heavy chain comprising the amino acid sequence of SEQ ID NO: 172, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 172, and a light chain comprising the amino acid sequence of SEQ ID NO: 175, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 175; (xii) a heavy chain comprising the amino acid sequence of SEQ ID NO: 172, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 172, and a light chain comprising the amino acid sequence of SEQ ID NO: 176, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 176; (xiii) a heavy chain comprising the amino acid sequence of SEQ ID NO: 172, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 172, and a light chain comprising the amino acid sequence of SEQ ID NO: 177, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 177; (xiv) a heavy chain comprising the amino acid sequence of SEQ ID NO: 172, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 172, and a light chain comprising the amino acid sequence of SEQ ID NO: 178, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 178; (xv) a heavy chain comprising the amino acid sequence of SEQ ID NO: 172, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 172, and a light chain comprising the amino acid sequence of SEQ ID NO: 179, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 179; (xvi) a heavy chain comprising the amino acid sequence of SEQ ID NO: 173, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 173, and a light chain comprising the amino acid sequence of SEQ ID NO: 175, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 175; (xvii) a heavy chain comprising the amino acid sequence of SEQ ID NO: 173, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 173, and a light chain comprising the amino acid sequence of SEQ ID NO: 176, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 176; (xviii) a heavy chain comprising the amino acid sequence of SEQ ID NO: 173, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 173, and a light chain comprising the amino acid sequence of SEQ ID NO: 177, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 177; (xix) a heavy chain comprising the amino acid sequence of SEQ ID NO: 173, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 173, and a light chain comprising the amino acid sequence of SEQ ID NO: 178, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 178; (xx) a heavy chain comprising the amino acid sequence of SEQ ID NO: 173, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 173, and a light chain comprising the amino acid sequence of SEQ ID NO: 179, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 179; (xxi) a heavy chain comprising the amino acid sequence of SEQ ID NO: 174, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 174, and a light chain comprising the amino acid sequence of SEQ ID NO: 175, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 175; (xxii) a heavy chain comprising the amino acid sequence of SEQ ID NO: 174, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 174, and a light chain comprising the amino acid sequence of SEQ ID NO: 176, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 176; (xxiii) a heavy chain comprising the amino acid sequence of SEQ ID NO: 174, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 174, and a light chain comprising the amino acid sequence of SEQ ID NO: 177, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 177; (xxiv) a heavy chain comprising the amino acid sequence of SEQ ID NO: 174, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 174, and a light chain comprising the amino acid sequence of SEQ ID NO: 178, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 178; or (xxv) a heavy chain comprising the amino acid sequence of SEQ ID NO: 174, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 174, and a light chain comprising the amino acid sequence of SEQ ID NO: 179, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 179. The antibody comprising:

[0121] 96. 17. The antibody of any one of embodiments 1-11, 15-17, 21-23, 26-28, 31-38, 44-49, 52-58, 63-65, 70-72, or 85-95, comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 172, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 172, and a light chain comprising the amino acid sequence of SEQ ID NO: 176, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 176.

[0122] 97. The antibody of any one of embodiments 1 to 11, 15 to 17, 21 to 23, 26 to 28, 31 to 38, 44 to 49, 52 to 58, 63 to 65, 69 to 72, or 85 to 96, comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 172 and a light chain comprising the amino acid sequence of SEQ ID NO: 176.

[0123] 98. 17. The antibody of any one of embodiments 1-10, 12, 15, 16, 18, 21, 22, 24, 26, 27, 29, 31-37, 41, 44-46, 50, 52-56, 59, 63, 64, 69, 73-75, or 85-95, comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 170, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 170, and a light chain comprising the amino acid sequence of SEQ ID NO: 175, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 175.

[0124] 99. 17. The antibody of any one of embodiments 1-10, 13, 15, 16, 19, 21, 22, 24, 26, 27, 29, 31-37, 42, 44-46, 50, 52-56, 60, 63, 64, 67, 69, 76-78, or 85-95, comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 173, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 173, and a light chain comprising the amino acid sequence of SEQ ID NO: 175, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 175.

[0125] 100. 17. The antibody of any one of embodiments 1 to 10, 14 to 16, 20 to 23, 31 to 37, 43 to 49, 52 to 56, 51, 63, 64, 68, 69, 79 to 81, 85 to 95, comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 174, or an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 174, and a light chain comprising the amino acid sequence of SEQ ID NO: 176, or an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 176.

[0126] 101. 17. The antibody of any one of embodiments 1 to 10, 14 to 16, 20 to 22, 25 to 27, 30 to 37, 43 to 46, 51 to 56, 62 to 64, 68, 69, 82 to 95, comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 174, or an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 174, and a light chain comprising the amino acid sequence of SEQ ID NO: 177, or an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 177.

[0127] 102. 1. The antibody of any one of the preceding embodiments, (i) a heavy chain, wherein the nucleotide sequence encoding said heavy chain comprises the nucleotide sequence of any one of SEQ ID NOs: 180 to 184, or a nucleotide sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 180 to 184; and / or (ii) a light chain, wherein the nucleotide sequence encoding the light chain comprises the nucleotide sequence of any one of SEQ ID NOs: 185 to 189, or a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 185 to 189. The antibody comprising:

[0128] 103. 1. The antibody of any one of the preceding embodiments, (i) a heavy chain, wherein the nucleotide sequence encoding the heavy chain comprises the nucleotide sequence of any one of SEQ ID NOs: 180 or 182 to 184, or a nucleotide sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 180 or 182 to 184; and / or (ii) a light chain, wherein the nucleotide sequence encoding the light chain comprises the nucleotide sequence of any one of SEQ ID NOs: 185 to 187, or a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 185 to 187. The antibody comprising:

[0129] 104. The antibody of any one of embodiments 1 to 11, 15 to 17, 21 to 23, 26 to 28, 31 to 38, 44 to 49, 52 to 58, 63 to 65, 70 to 72, 85 to 98, 102, or 103, (i) a heavy chain, wherein the nucleotide sequence encoding said heavy chain comprises the nucleotide sequence of SEQ ID NO: 182, or a nucleotide sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 182; and / or (ii) a light chain, wherein the nucleotide sequence encoding said light chain comprises the nucleotide sequence of SEQ ID NO: 186, or a nucleotide sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 186. The antibody comprising:

[0130] 105. 104. The antibody of any one of embodiments 1 to 10, 12, 15, 16, 18, 21, 22, 24, 26, 27, 29, 31 to 37, 41, 44 to 46, 50, 52 to 56, 59, 63, 64, 69, 73 to 75, 85 to 95, 98, 102, or 103, (i) a heavy chain, wherein the nucleotide sequence encoding said heavy chain comprises the nucleotide sequence of SEQ ID NO: 180, or a nucleotide sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 180; and / or (ii) a light chain, wherein the nucleotide sequence encoding said light chain comprises the nucleotide sequence of SEQ ID NO: 185, or a nucleotide sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 185. The antibody comprising:

[0131] 106. 104. The antibody of any one of embodiments 1 to 10, 13, 15, 16, 19, 21, 22, 24, 26, 27, 29, 31 to 37, 42, 44 to 46, 50, 52 to 56, 60, 63, 64, 67, 69, 76 to 78, 85 to 95, 99, 102, or 103, (i) a heavy chain, wherein the nucleotide sequence encoding said heavy chain comprises the nucleotide sequence of SEQ ID NO: 183, or a nucleotide sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 183; and / or (ii) a light chain, wherein the nucleotide sequence encoding said light chain comprises the nucleotide sequence of SEQ ID NO: 185, or a nucleotide sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 185. The antibody comprising:

[0132] 107. The antibody according to any one of embodiments 1 to 10, 14 to 16, 20 to 23, 25 to 27, 30 to 37, 43 to 49, 51 to 56, 51, 62 to 65, 68, 69, 79 to 95, or 100 to 103, (i) a heavy chain, wherein the nucleotide sequence encoding said heavy chain comprises the nucleotide sequence of SEQ ID NO: 184, or a nucleotide sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 184; and / or (ii) a light chain, wherein the nucleotide sequence encoding said light chain comprises the nucleotide sequence of SEQ ID NO: 186 or 187, or a nucleotide sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 186 or 187. The antibody comprising:

[0133] 108. 10. The antibody of any one of the preceding embodiments, wherein the antibody binds to the C-terminus of tau protein, e.g., residues 409-436 numbered according to SEQ ID NO: 920.

[0134] 109. 10. The antibody of any one of the preceding embodiments, wherein the antibody binds to a phosphorylated residue of tau protein.

[0135] 110. The antibody of any one of the preceding embodiments, wherein the antibody binds to a phosphorylated serine at position 422, numbered according to SEQ ID NO: 920 (e.g., pS422).

[0136] 111. The antibody of any one of the preceding embodiments, wherein the antibody preferentially binds to pathological tau (e.g., PHF tau or ePHF) compared to wild-type tau, e.g., as measured by an assay, e.g., an ELISA assay, an SPR assay, or a Biacore assay, e.g., an assay described in Example 1 or Example 8.

[0137] 112. 10. The antibody of any one of the preceding embodiments, which reduces, e.g., inhibits, the aggregation of tau. 113. 10. The antibody of any one of the preceding embodiments, which binds to an epitope comprising a region formed by a complex of at least two tau proteins, e.g., a tau dimer.

[0138] 114. 1. The antibody of any one of the preceding embodiments, (i) being capable of binding to iPHF with an affinity of at least about 24-50 pM (e.g., an affinity of at least about 24, 29, 30, 32, 33, 35, 37, 39, 41, 43, 45, 47, or 48 pM), e.g., as measured by an assay (e.g., an SPR or Biacore assay), e.g., the assay described in Example 8; (ii) being able to bind to a phosphorylated serine at position 422 (e.g., pS422) of human tau numbered according to SEQ ID NO:920 (e.g., a peptide comprising the amino acid sequence of SEQ ID NO:33) with an affinity of at least about 29-77 pM (e.g., an affinity of at least about 29, 33, 35, 38, 39, 40, 41, 43, 44, 45, 47, 50, 53, 54, 55, 60, 65, 70, 75, 76, or 77 pM), e.g., as measured by an assay (e.g., an SPR or Biacore assay), e.g., the assay described in Example 8; (iii) being able to bind to ePHF with an affinity of at least about 0.08 to 0.2 nM (e.g., at least about 0.08, 0.085, 0.09, 0.095, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, or 0.2 nM), e.g., as measured by an assay (e.g., an ELISA assay), e.g., the assay described in Example 8; (iv) the property of exhibiting low polyspecificity, e.g., a BVP score of at least about 1.6 to 6 (e.g., a BVP of at least about 1.6, 1.7, 1.8, 2, 2.2, 2.5, 2.7, 3, 3.2, 3.5, 3.7, 3.9, 4, 4.5, 5, 5.5, or 6), e.g., as measured by an assay (e.g., a BVP ELISA assay), e.g., the assay described in Example 8; (v) the property of being able to bind to pathological tau, e.g., as measured by an assay, e.g., an IHC assay, e.g., the assay described in Example 8; and / or (vi) the property of preferentially binding to pathological tau (e.g., PHF tau or ePHF) relative to wild-type tau, e.g., as measured by an assay, e.g., an ELISA assay, an SPR assay, or a Biacore assay, e.g., the assay described in Example 8. The antibody having one, two, three, four, five, or all of the following:

[0139] 115. The antibody of any one of the preceding embodiments, wherein the antibody exhibits a low immunogenicity risk (e.g., has a donor response rate (e.g., in PBMC cells isolated from the donor) of about 55% or less (e.g., about 50, 46, 48, 30, 24, or 20% or less), e.g., as measured by an assay such as a T cell proliferation assay, e.g., an assay described in Example 8).

[0140] 116. An antibody that competes for binding to tau with the antibody of any one of the preceding embodiments. 117. An antibody that binds to the same epitope as, substantially the same epitope as, or an overlapping epitope with, the epitope of the antibody of any one of the preceding embodiments.

[0141] 118. A nucleic acid encoding an antibody according to any one of the preceding claims. 119. 119. The nucleic acid of embodiment 118, (i) a VH, wherein the nucleotide sequence encoding the VH comprises the nucleotide sequence of any one of SEQ ID NOs: 156 to 160, or a nucleotide sequence at least 86% (e.g., at least 87%, 90%, 95%, 96%, 97%, 98%, or 99%) identical thereto; and / or (ii) A VL, wherein the nucleotide sequence encoding the VL comprises the nucleotide sequence of any one of SEQ ID NOs: 161 to 165, or a nucleotide sequence at least 86% (e.g., at least 91%, 95%, 96%, 97%, 98%, or 99%) identical thereto. The nucleic acid encoding the

[0142] 120. 120. The nucleic acid of embodiment 118 or 119, (i) a VH, wherein the nucleotide sequence encoding the VH comprises the nucleotide sequence of any one of SEQ ID NOs: 156 or 158 to 160, or a nucleotide sequence at least 86% (e.g., at least 87%, 90%, 95%, 96%, 97%, 98%, or 99%) identical thereto; and / or (ii) A VL, wherein the nucleotide sequence encoding the VL comprises the nucleotide sequence of any one of SEQ ID NOs: 161 to 163, or a nucleotide sequence at least 86% (e.g., at least 91%, 95%, 96%, 97%, 98%, or 99%) identical thereto. The nucleic acid encoding the

[0143] 121. 121. The nucleic acid according to any one of embodiments 118 to 120, (i) a heavy chain, wherein the nucleotide sequence encoding the heavy chain comprises the nucleotide sequence of any one of SEQ ID NOs: 180 to 184, or a nucleotide sequence at least 86% (e.g., at least 87%, 90%, 95%, 96%, 97%, 98%, or 99%) identical thereto; and / or (ii) a light chain, wherein the nucleotide sequence encoding the light chain comprises the nucleotide sequence of any one of SEQ ID NOs: 185 to 189, or a nucleotide sequence at least 86% (e.g., at least 91%, 95%, 96%, 97%, 98%, or 99%) identical thereto; The nucleic acid encoding the

[0144] 122. 122. The nucleic acid according to any one of embodiments 118 to 121, (i) a heavy chain, wherein the nucleotide sequence encoding the heavy chain comprises the nucleotide sequence of any one of SEQ ID NOs: 180 or 182-184, or a nucleotide sequence at least 86% (e.g., at least 87%, 90%, 95%, 96%, 97%, 98%, or 99%) identical thereto; and / or (ii) a light chain, wherein the nucleotide sequence encoding the light chain comprises the nucleotide sequence of any one of SEQ ID NOs: 185 to 187, or a nucleotide sequence at least 86% (e.g., at least 91%, 95%, 96%, 97%, 98%, or 99%) identical thereto; The nucleic acid encoding the

[0145] one two three. 123. The nucleic acid according to any one of embodiments 118 to 122, (i) a VH, wherein the nucleotide sequence encoding the VH comprises the nucleotide sequence of SEQ ID NO: 158, or a nucleotide sequence at least 86% (e.g., at least 87%, 90%, 95%, 96%, 97%, 98%, or 99%) identical thereto, and a VL, wherein the nucleotide sequence encoding the VL comprises the nucleotide sequence of SEQ ID NO: 162, or a nucleotide sequence at least 86% (e.g., at least 91%, 95%, 96%, 97%, 98%, or 99%) identical thereto; and / or (ii) a heavy chain, wherein the nucleotide sequence encoding the heavy chain comprises the nucleotide sequence of SEQ ID NO: 182, or a nucleotide sequence at least 86% (e.g., at least 87%, 90%, 95%, 96%, 97%, 98%, or 99%) identical thereto, and a light chain, wherein the nucleotide sequence encoding the light chain comprises the nucleotide sequence of SEQ ID NO: 186, or a nucleotide sequence at least 86% (e.g., at least 91%, 95%, 96%, 97%, 98%, or 99%) identical thereto. The nucleic acid encoding the

[0146] 124. 124. The nucleic acid of any one of embodiments 118 to 123, which is codon-optimized. 125. An antibody encoded by a nucleic acid described in any one of embodiments 118 to 124.

[0147] 126. The antibody of any one of embodiments 1 to 117 or 125 or the nucleic acid of any one of embodiments 118 to 124, which is isolated, eg, recombinant.

[0148] 127. A vector comprising a nucleic acid according to any one of embodiments 118 to 124 or 126, or a nucleic acid encoding an antibody according to any one of embodiments 1 to 117, 125 or 126.

[0149] 128. A host cell comprising a nucleic acid according to any one of embodiments 118 to 124 or 126, a nucleic acid encoding an antibody according to any one of embodiments 1 to 117, 125 or 126, an antibody according to any one of embodiments 1 to 117, 125 or 126, or a vector according to embodiment 127.

[0150] 129. 129. The host cell of embodiment 128, wherein the host cell is an insect cell, a bacterial cell, or a mammalian cell.

[0151] 130. 130. A method for producing an antibody, comprising culturing a host cell of embodiment 128 or 129 under conditions suitable for gene expression.

[0152] 131. 127. An isolated nucleic acid encoding a payload, wherein the encoded payload comprises an antibody of any one of embodiments 1-117, 125, or 126.

[0153] 132. 132. The nucleic acid of embodiment 131, further encoding a signal sequence, optionally wherein the nucleotide sequence encoding said signal sequence comprises the nucleotide sequence of any of the signal sequences listed in Table 14, or a nucleotide sequence with at least 95% sequence identity thereto.

[0154] 133. 133. The nucleic acid of embodiment 131 or 132, further encoding a second signal sequence, optionally wherein the nucleotide sequence encoding said signal sequence comprises the nucleotide sequence of any of the signal sequences listed in Table 14, or a nucleotide sequence with at least 95% sequence identity thereto.

[0155] 134. 134. The nucleic acid according to any one of embodiments 131 to 133, (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.

[0156] 135. 135. The nucleic acid of any one of embodiments 131 to 134, wherein the encoded VH and VL sequences are directly connected, for example, without a linker.

[0157] 136. 136. The nucleic acid of any one of embodiments 131 to 135, wherein the encoded VH and VL sequences are connected via a linker.

[0158] 137. 137. The nucleic acid of embodiment 136, wherein said linker comprises the nucleotide sequence of any of the linker sequences presented in Table 15, or a nucleotide sequence having at least 95% sequence identity thereto.

[0159] 138. 138. The nucleic acid of any one of embodiments 131 to 137, wherein the encoded payload is a full-length antibody, a bispecific antibody, a Fab, a F(ab')2, an Fv, or a single-chain Fv fragment (scFv).

[0160] 139. A viral genome comprising a promoter operably linked to the nucleic acid encoding a payload comprising the antibody of any one of embodiments 1-117, 125, or 126, or the nucleic acid of any one of embodiments 131-138.

[0161] 140. 140. The viral genome of embodiment 139, wherein the promoter: (i) human elongation factor 1 α-subunit (EF1α), cytomegalovirus (CMV) immediate early enhancer and / or promoter, chicken β-actin (CBA) and its derivatives CAG, β-glucuronidase (GUSB), or ubiquitin C (UBC), neuron-specific enolase (NSE), platelet-derived growth factor (PDGF), platelet-derived growth factor B chain (PDGF-β), intercellular adhesion molecule 2 (ICAM-2), synapsin (Syn), methyl-CpG-binding protein 2 (MeCP2), Ca2+ / calmodulin and / or are selected from: dependent protein kinase II (CaMKII), metabotropic glutamate receptor 2 (mGluR2), neurofilament light chain (NFL) or neurofilament heavy chain (NFH), beta-globin minigene nβ2, preproenkephalin (PPE), enkephalin (Enk) and excitatory amino acid transporter 2 (EAAT2), glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), or fragments, e.g. truncations, or functional variants thereof; and / or (ii) comprises the nucleotide sequence of any of the promoter sequences listed in Table 11, or a nucleotide sequence that is at least 95% identical thereto; The viral genome.

[0162] 141. 141. The viral genome of embodiment 139 or 140, further comprising an enhancer, optionally wherein the enhancer is a CMV immediate-early (CMVie) enhancer.

[0163] 142. 142. The viral genome of any one of embodiments 139 to 141, further comprising a polyadenylation (polyA) signal region.

[0164] 143. 143. The viral genome of embodiment 142, wherein the polyA signal region comprises a nucleotide sequence of any of SEQ ID NOs: 1134 to 1136, or a nucleotide sequence having at least 95% identity thereto.

[0165] 144. 144. The viral genome of any one of embodiments 139 to 143, further comprising an inverted terminal repeat (ITR) sequence.

[0166] 145. 145. The viral genome of embodiment 144, (i) the ITR sequences are positioned 5' to the encoded payload, and / or (ii) the ITR sequence is positioned 3' to the encoded payload; The viral genome.

[0167] 146. 146. A viral genome according to any one of embodiments 139 to 145, comprising an ITR sequence positioned 5' to the encoded payload and an ITR sequence positioned 3' to the encoded payload.

[0168] 147. 147. The viral genome of any one of embodiments 139 to 146, wherein the ITR sequence comprises the nucleotide sequence of any one of SEQ ID NOs: 1035 to 1038, or a nucleotide sequence having at least 80%, 85%, 90%, or 95% sequence identity thereto.

[0169] 148. 148. The viral genome of any one of embodiments 139 to 147, further comprising an intron region.

[0170] 149. 149. The viral genome of embodiment 148, wherein the intron region comprises the nucleotide sequence of any of the intron regions listed in Table 13, or a nucleotide sequence with at least 95% identity thereto.

[0171] 150. 150. The viral genome of any one of embodiments 139 to 149, comprising at least one, two, or three intron regions.

[0172] 151. 151. A viral genome according to any one of embodiments 139 to 150, further comprising an exon region.

[0173] 152. 152. The viral genome of embodiment 151, wherein the exon region comprises a nucleotide sequence of any of the exon sequences in Table 12, or a nucleotide sequence with at least 95% identity thereto.

[0174] 153. 153. A viral genome according to any one of embodiments 139 to 152, comprising at least one, two, or three exon regions.

[0175] 154. 154. The viral genome of any one of embodiments 139 to 153, further comprising a Kozak sequence, optionally wherein the Kozak sequence comprises the nucleotide sequence GCCGCCACCATG (SEQ ID NO: 1079) or GAGGAGCCACC (SEQ ID NO: 1089).

[0176] 155. The viral genome of any one of embodiments 139 to 154, further comprising a nucleotide sequence encoding an miR binding site, such as an miR binding site that regulates, e.g., reduces, expression of the payload encoded by the viral genome in cells or tissues in which the corresponding miRNA is expressed.

[0177] 156. The viral genome of embodiment 155, comprising at least 1 to 5 copies, for example at least 1, 2, 3, 4, or 5 copies, of the encoded miR binding site.

[0178] 157. 157. The viral genome of any one of embodiments 139 to 156, comprising at least three copies of the encoded miR binding site, optionally wherein all three copies comprise the same miR binding site, or wherein at least one, two, or all copies comprise different miR binding sites.

[0179] 158. 158. The viral genome of any one of embodiments 139 to 157, comprising at least four copies of the encoded miR binding site, optionally wherein all four copies comprise the same miR binding site, or wherein at least one, two, three, or all copies comprise different miR binding sites.

[0180] 159. 159. The viral genome of any one of embodiments 155-158, wherein the encoded miR binding site comprises a miR122 binding site, a miR183 binding site, a miR-142-3p, or a combination thereof, and optionally: (i) the encoded miR122 binding site comprises the nucleotide sequence of SEQ ID NO: 1029, or a nucleotide sequence substantially identical thereto (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity), or a nucleotide sequence having at least 1, 2, 3, 4, 5, 6, or 7 modifications, but not more than 10 modifications, of SEQ ID NO: 1029; (ii) the encoded miR183-binding site comprises the nucleotide sequence of SEQ ID NO: 1032, or a nucleotide sequence substantially identical thereto (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity), or a nucleotide sequence having at least 1, 2, 3, 4, 5, 6, or 7 modifications, but not more than 10 modifications, of SEQ ID NO: 1032; and / or (iii) the encoded miR-142-3p binding site comprises the nucleotide sequence of SEQ ID NO: 1031, or a nucleotide sequence substantially identical thereto (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity), or a nucleotide sequence having at least 1, 2, 3, 4, 5, 6, or 7 modifications, but not more than 10 modifications, of SEQ ID NO: 1031; The viral genome.

[0181] 160. 160. The viral genome of any one of embodiments 139 to 159, which is single-stranded or self-complementary.

[0182] 161. 161. The viral genome of any one of embodiments 139 to 160, (i) a nucleotide sequence encoding a Rep protein, such as a nonstructural protein, wherein the Rep protein comprises a Rep78 protein, a Rep68 protein, a Rep52 protein, and / or a Rep40 protein; or (ii) a second nucleic acid comprising a nucleotide sequence encoding a Rep protein, such as a nonstructural protein, wherein the Rep protein comprises a Rep78 protein, a Rep68 protein, a Rep52 protein, and / or a Rep40 protein; The viral genome further comprises:

[0183] 162. The viral genome of embodiment 161, wherein the Rep78 protein, the Rep68 protein, the Rep52 protein, and / or the Rep40 protein are encoded by at least one Rep gene.

[0184] 163. A viral genome according to any one of embodiments 139 to 162, (i) a nucleotide sequence encoding a capsid protein, such as a structural protein, wherein the capsid protein comprises a VP1 polypeptide, a VP2 polypeptide, and / or a VP3 polypeptide; or (ii) a second nucleic acid comprising a nucleotide sequence encoding a capsid protein, such as a structural protein, wherein the capsid protein comprises a VP1 polypeptide, a VP2 polypeptide, and / or a VP3 polypeptide; The viral genome further comprises:

[0185] 164. 164. The viral genome of embodiment 163, wherein the VP1 polypeptide, the VP2 polypeptide, and / or the VP3 polypeptide are encoded by at least one Cap gene.

[0186] 165. A vector comprising a viral genome according to any one of embodiments 139 to 164. 166. (i) a capsid protein, and (ii) a nucleic acid according to any one of embodiments 131 to 138 or a viral genome according to any one of embodiments 139 to 164 An isolated, e.g., recombinant, AAV particle comprising:

[0187] 167. 167. The isolated AAV particle of embodiment 166, (i) the capsid protein comprises the amino acid sequence of SEQ ID NO: 1003, or an amino acid sequence having at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto; (ii) the capsid protein comprises an amino acid sequence having at least one, two, or three modifications, but no more than 30, no more than 20, or no more than 10 modifications, of the amino acid sequence of SEQ ID NO: 1003; (iii) the capsid protein comprises the amino acid sequence of SEQ ID NO: 1011, or an amino acid sequence having at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto; (iv) the capsid protein comprises an amino acid sequence having at least one, two, or three modifications, but no more than 30, no more than 20, or no more than 10 modifications, of the amino acid sequence of SEQ ID NO: 1011; (v) the capsid protein comprises an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 1002, or a sequence having at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto; and / or (vi) the nucleotide sequence encoding the capsid protein comprises the nucleotide sequence of SEQ ID NO: 1002, or a sequence having at least 80% (e.g., at least about 85, 90, 95, 96, 97, 98, or 99%) sequence identity thereto; The isolated AAV particles.

[0188] 168. 168. The isolated AAV particle of embodiment 166 or 167, wherein the capsid protein comprises: (i) an amino acid substitution at position K449 numbered according to SEQ ID NO: 1003, e.g., a K449R substitution; (ii) an insert comprising the amino acid sequence of TLAVPFK (SEQ ID NO: 1151), optionally located immediately after position 588 relative to the reference sequence numbered according to SEQ ID NO: 1003; (iii) an amino acid other than "A" at position 587 and / or an amino acid other than "Q" at position 588, numbered according to SEQ ID NO: 1003; and / or (iv) an amino acid substitution of A587D and / or Q588G numbered according to SEQ ID NO: 1003 The isolated AAV particle comprising:

[0189] 169. An AAV particle described in any one of embodiments 166 to 168, wherein the capsid protein comprises (i) an amino acid substitution of K449R numbered according to SEQ ID NO: 1003, and (ii) an insert comprising the amino acid sequence of TLAVPFK (SEQ ID NO: 1151), optionally located immediately after position 588 of SEQ ID NO: 1003.

[0190] 170. An AAV particle described in any one of embodiments 166 to 169, wherein the capsid protein comprises (i) an amino acid substitution of K449R numbered according to SEQ ID NO: 1003, (ii) an insert comprising the amino acid sequence of TLAVPFK (SEQ ID NO: 1151), optionally located immediately after position 588 relative to the reference sequence numbered according to SEQ ID NO: 1003, and (iii) amino acid substitutions of A587D and Q588G numbered according to SEQ ID NO: 1003.

[0191] 171. An AAV particle described in any one of embodiments 166 to 169, wherein the capsid protein comprises (i) an insert comprising the amino acid sequence of TLAVPFK (sequence number 1151), optionally located immediately after position 588 relative to the reference sequence numbered according to SEQ ID NO: 1003, and (ii) amino acid substitutions A587D and Q588G numbered according to SEQ ID NO: 1003.

[0192] 172. The capsid protein is VOY101, VOY201, AAVPHP.B (PHP.B), AAVPHP.A (PHP.A), AAVG2B-26, AAVG2B-13, AA VTH1.1-32, AAVTH1.1-35, AAVPHP.B2(PHP.B2), AAVPHP.B3(PHP.B3), AAVPHP.N / PHP.B-DGT, AAVP HP.B-EST, AAVPHP.B-GGT, AAVPHP.B-ATP, AAVPHP.B-ATT-T, AAVPHP.B-DGT-T, AAVPHP.B-GGT-T, AAVPHP.B-SGS, AAVPHP.B-AQP, AAVPHP.B-QQP, AAVPHP.B-SNP(3), AAVPHP.B-SNP, AAVPHP.B-QGT, A AVPHP.B-NQT, AAVPHP.B-EGS, AAVPHP.B-SGN, AAVPHP.B-EGT, AAVPHP.B-DST, AAVPHP.B-DST, AAVPHP.B-STP, AAVPHP.B-PQP, AAVPHP.B-SQP, AAVPHP.B-QLP, AAVPHP.B-TMP, AAVPHP.B-TTP, AAVPHP. S / G2A12, AAVG2A15 / G2A3(G2A3), AAVG2B4(G2B4), AAVG2B5(G2B5), AAVPHP.N(PHP.N), PHP.S, AAV 1, AAV2, AAV2 variant, AAV2 / 3 variant, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9.47, AAV9(hu14), AAV9, AAV9 An AAV particle described in any one of embodiments 166 to 171, comprising a K449R, AAV10, AAV11, AAV12, AAVrh8, AAVrh10, AAVDJ, AAVDJ8, or AAV2G9 capsid protein, or a functional variant thereof.

[0193] 173. An AAV particle described in any one of embodiments 166 to 172, wherein the capsid protein comprises an AAV5 capsid protein or a variant thereof, or an AAV9 capsid protein or a variant thereof.

[0194] 174. 174. The AAV particle of any one of embodiments 166-173, wherein the capsid protein comprises: (i) the amino acid sequence of SEQ ID NO: 1023, or an amino acid sequence substantially identical thereto (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity); (ii) an amino acid sequence that contains at least one, two, or three modifications, but no more than 30, no more than 20, or no more than 10 modifications, e.g., substitutions, relative to the amino acid sequence of SEQ ID NO: 1023; or (iii) an amino acid sequence encoded by the nucleotide sequence of SEQ ID NO: 1022, or a nucleotide sequence substantially identical thereto (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity). The AAV particle comprising:

[0195] 175. The AAV particle of embodiment 174, wherein the nucleotide sequence encoding the capsid protein comprises the nucleotide sequence of SEQ ID NO: 1022, or a nucleotide sequence substantially identical thereto (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity).

[0196] 176. A host cell comprising a nucleic acid described in any one of embodiments 131 to 138, a viral genome described in any one of embodiments 139 to 164, or an AAV particle described in any one of embodiments 166 to 175, wherein the host cell is optionally an insect cell, a bacterial cell, or a mammalian cell.

[0197] 177. A nucleic acid encoding a viral genome according to any one of embodiments 139 to 164 and a scaffold region suitable for replication of said viral genome in a cell, such as a bacterial cell (e.g., said scaffold region comprises one or both of a bacterial origin of replication and a selectable marker).

[0198] 178. 1. A method for producing a viral genome, comprising: (i) providing a nucleic acid molecule comprising a viral genome according to any one of embodiments 139 to 164; (ii) excising the viral genome from the backbone region, for example, by cleaving the nucleic acid molecule upstream and downstream of the viral genome; The method comprising:

[0199] 179. A method for producing isolated, e.g., recombinant, AAV particles, comprising: (i) providing a host cell containing the viral genome of embodiment 176; (ii) incubating the host cells under conditions suitable for encapsulating the viral genome in capsid proteins; This results in the production of isolated AAV particles.

[0200] 180. 180. The method of embodiment 179, further comprising, prior to step (i), introducing into said host cell a first nucleic acid molecule comprising said viral genome.

[0201] 181. 181. The method of any one of embodiments 178-180, wherein the host cell comprises a second nucleic acid encoding a capsid protein.

[0202] 182. 182. The method of embodiment 181, wherein said second nucleic acid molecule is introduced into said host cell before, simultaneously with, or after said first nucleic acid molecule.

[0203] 183. A pharmaceutical composition comprising an antibody described in any one of embodiments 1 to 117, 125, or 126, an AAV particle described in any one of embodiments 166 to 175, or an AAV particle comprising a viral genome described in any one of embodiments 139 to 164, or an isolated nucleic acid described in any one of embodiments 131 to 138, and a pharmaceutically acceptable excipient.

[0204] 184. A method for delivering an exogenous antibody that binds to tau to a subject, the method comprising administering an effective amount of the pharmaceutical composition of embodiment 183, the antibody of any one of embodiments 1 to 117, 125, or 126, the AAV particle of any one of embodiments 166 to 175, or the AAV particle comprising the viral genome of any one of embodiments 139 to 164, or the isolated nucleic acid of any one of embodiments 131 to 138.

[0205] 185. The method of embodiment 184, wherein the subject has, has been diagnosed with, or is at risk of having a disease associated with tau expression, such as abnormal tau expression.

[0206] 186. The method of embodiment 184 or 185, wherein the subject has, has been diagnosed with, or is at risk of having a neurological disorder, such as a neurodegenerative disorder, mild cognitive impairment, or traumatic brain injury (TBI).

[0207] 187. The method of any one of embodiments 184-186, wherein the subject has, has been diagnosed with, or is at risk of having a tauopathy.

[0208] 188. A method for treating a subject having or diagnosed as having a disease associated with tau expression, comprising administering to the subject an effective amount of the pharmaceutical composition of embodiment 183, the antibody of any one of embodiments 1 to 117, 125, or 126, the AAV particle of any one of embodiments 166 to 175, or the AAV particle comprising the viral genome of any one of embodiments 139 to 164, or the isolated nucleic acid of any one of embodiments 131 to 138.

[0209] 189. A method for treating a subject having or diagnosed as having a neurological disorder, such as a neurodegenerative disorder, or traumatic brain injury (TBI), comprising administering to the subject an effective amount of the pharmaceutical composition of embodiment 183, the antibody of any one of embodiments 1 to 117, 125, or 126, the AAV particle of any one of embodiments 166 to 175, or the AAV particle comprising the viral genome of any one of embodiments 139 to 164, or the isolated nucleic acid of any one of embodiments 131 to 138.

[0210] 190. A method for treating a subject having or diagnosed as having a tauopathy, comprising administering to the subject an effective amount of the pharmaceutical composition of embodiment 183, the antibody of any one of embodiments 1 to 117, 125, or 126, the AAV particle of any one of embodiments 166 to 175, or the AAV particle comprising the viral genome of any one of embodiments 139 to 164, or the isolated nucleic acid of any one of embodiments 131 to 138.

[0211] 191. The method of any one of embodiments 185-190, wherein the disease, neurological disorder, or tauopathy associated with tau expression comprises AD, FTDP-17, FTLD, FTD, CTE, PSP, Down syndrome, Pick's disease, CBD, corticobasal syndrome, ALS, prion disease, CJD, multiple system atrophy, mild cognitive impairment, neurofibrillary senile dementia, or progressive subcortical gliosis.

[0212] 192. The method of any one of embodiments 188-191, wherein treatment comprises preventing progression of said disease in said subject.

[0213] 193. The method of any one of embodiments 184 to 192, wherein the subject is a human. 194. The method of any one of embodiments 184 to 193, wherein the antibody or AAV particle is administered to the subject intravenously, intramuscularly, via intraparenchymal administration, intracerebroventricularly, via intracisternal (ICM) injection, intrathecally, via focused ultrasound (FUS), for example, in combination with intravenous administration of microbubbles (FUS-MB), or via MRI-guided FUS in combination with intravenous administration.

[0214] 195. The method of any one of embodiments 184 to 194, wherein the antibody or the AAV particles are administered intravenously to the subject.

[0215] 196. The method of any one of embodiments 184 to 194, wherein the antibody or the AAV particles are administered to the subject via intracisternal injection (ICM).

[0216] 197. The method of any one of embodiments 184 to 196, further comprising assessing, e.g., measuring, the level of antibodies produced in the subject, e.g., in cells or tissues of said subject.

[0217] 198. The method of any one of embodiments 184 to 197, wherein the administration results in the production of antibodies in the subject, e.g., in cells or tissues of the subject, e.g., 0.001 μg / mL to 100 mg / mL of antibodies.

[0218] 199. 200. The method of embodiment 198, wherein the cell is a neuronal cell. 200. 199. The method of embodiment 198, wherein the tissue is central nervous system tissue, e.g., brain tissue.

[0219] 201. The method of any one of embodiments 184 to 200, further comprising performing a blood test, an imaging test (e.g., a PET scan, or a PET scan combined with a biomarker, such as a serum biomarker stain), a CNS biopsy sample, or an aqueous cerebrospinal fluid biopsy.

[0220] 202. The method of any one of embodiments 197 to 201, wherein the measurement of the level of the antibody is performed before, during, or after treatment with the antibody or AAV particles.

[0221] 203. The method of any one of embodiments 184 to 202, wherein the subject has a level of the antibody that is higher than a reference level, e.g., a subject that has not been treated with the antibody or the AAV particles, e.g., a subject that has not been administered the antibody or the AAV particles.

[0222] 204. The method of any one of embodiments 184 to 203, further comprising the administration of an additional therapeutic agent and / or therapy suitable for the treatment or prevention of a disorder associated with tau expression, a neurological disorder, for example a neurodegenerative disorder.

[0223] 205. The method of embodiment 204, wherein the additional therapeutic agents and / or therapies comprise a cholinesterase inhibitor (e.g., donepezil, rivastigmine, and / or galantamine), an N-methyl D-aspartate (NMDA) antagonist (e.g., memantine), an antipsychotic, an anxiolytic, an anticonvulsant, a dopamine agonist (e.g., pramipexole, ropinirole, rotigotine, and / or apomorphine), an MAO B inhibitor (e.g., selegiline, rasagiline, and / or safinamide), a catechol O-methyltransferase (COMT) inhibitor (entacapone, opicapone, and / or tolcapone), an anticholinergic (e.g., benztropine and / or trihexyphenidyl), amantadine, carbidopa-levodopa, deep brain stimulation (DBS), or a combination thereof.

[0224] 206. An antibody described in any one of embodiments 1 to 117, 125, or 126, a pharmaceutical composition described in embodiment 183, or an AAV particle described in any one of embodiments 166 to 175, for use in the manufacture of a medicament.

[0225] 207. An antibody described in any one of embodiments 1 to 117, 125, or 126, a pharmaceutical composition described in embodiment 183, or an AAV particle described in any one of embodiments 166 to 175, for use in treating a disease associated with tau expression.

[0226] 208. An antibody described in any one of embodiments 1 to 117, 125, or 126, a pharmaceutical composition described in embodiment 183, or an AAV particle described in any one of embodiments 166 to 175, for use in treating a neurological disorder, such as a neurodegenerative disorder, or traumatic brain injury (TBI).

[0227] 209. An antibody described in any one of embodiments 1 to 117, 125, or 126, a pharmaceutical composition described in embodiment 183, or an AAV particle described in any one of embodiments 166 to 175, for use in the treatment of a tauopathy.

[0228] 210. Use of an effective amount of an antibody described in any one of embodiments 1 to 117, 125, or 126, a pharmaceutical composition described in embodiment 183, or an AAV particle described in any one of embodiments 166 to 175 in the manufacture of a medicament.

[0229] 211. Use of an antibody described in any one of embodiments 1 to 117, 125, or 126, a pharmaceutical composition described in embodiment 183, or an AAV particle described in any one of embodiments 166 to 175 in the manufacture of a medicament for treating a disease associated with tau expression, a neurological disorder, such as a neurodegenerative disorder, a tauopathy, mild cognitive impairment, or traumatic brain injury (TBI).

[0230] 212. An AAV viral genome comprising a nucleotide sequence encoding an antibody, fragment or variant thereof that binds to tau, the nucleotide sequence being, in 5' to 3' order: (i) a 5' adeno-associated (AAV) ITR, optionally comprising the nucleotide sequence of SEQ ID NO: 1035, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical thereto; (ii) an enhancer, optionally comprising a nucleotide sequence of 1050, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical thereto; (iii) a promoter (e.g., a CBA promoter or a variant thereof), optionally comprising the nucleotide sequence of SEQ ID NO: 1042, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical thereto; (iv) an intron, optionally comprising the nucleotide sequence of SEQ ID NO: 1067, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical thereto; (v) a nucleotide sequence encoding a first signal sequence, optionally (a) the first encoded signal sequence comprises the amino acid sequence of SEQ ID NO: 1, an amino acid sequence that contains one, two, three, but not more than four different amino acids relative to SEQ ID NO: 1, or an amino acid sequence that contains one, two, three, but not more than four modifications, e.g., substitutions, e.g., conservative substitutions, relative to SEQ ID NO: 1; and / or (b) the nucleotide sequence encoding the first signal sequence comprises the sequence of SEQ ID NO: 1083, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical thereto; the nucleotide sequence; (vi) a nucleotide sequence encoding a heavy chain variable region, (a) the encoded heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 21, or an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical thereto; and / or (b) the nucleotide sequence encoding the heavy chain variable region comprises the nucleotide sequence of SEQ ID NO: 7, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical thereto; the nucleotide sequence; (v) a nucleotide sequence encoding a heavy chain constant region, optionally (a) the encoded heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 16, or an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical thereto; and / or (b) the nucleotide sequence encoding the heavy chain constant region comprises the nucleotide sequence of SEQ ID NO: 805, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical thereto; the nucleotide sequence; (vi) a first linker, optionally comprising the nucleotide sequence of SEQ ID NO: 1724; a nucleotide sequence that comprises one, two, three, but not more than four different nucleotides relative to the nucleotide sequence of SEQ ID NO: 1724; or a nucleotide sequence that comprises one, two, three, but not more than four modifications, e.g., substitutions, relative to SEQ ID NO: 1724; (vii) a second linker, optionally comprising the nucleotide sequence of SEQ ID NO: 1726; a nucleotide sequence that comprises one, two, three, but not more than four different nucleotides relative to the nucleotide sequence of SEQ ID NO: 1726; or a nucleotide sequence that comprises one, two, three, but not more than four modifications, e.g., substitutions, relative to SEQ ID NO: 1726; (viii) a nucleotide sequence encoding a second signal sequence, optionally (a) the first encoded signal sequence comprises the amino acid sequence of SEQ ID NO:2, an amino acid sequence that contains one, two, three, but not more than four amino acids that differ from SEQ ID NO:2, or an amino acid sequence that contains one, two, three, but not more than four modifications, e.g., substitutions, e.g., conservative substitutions, relative to SEQ ID NO:2; and / or (b) the nucleotide sequence encoding the second signal sequence comprises the sequence of SEQ ID NO: 1085, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical thereto; the nucleotide sequence; (ix) a nucleotide sequence encoding a light chain variable region, (a) the encoded light chain variable region comprises the amino acid sequence of SEQ ID NO: 93, or an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical thereto; and / or (b) the nucleotide sequence encoding the light chain variable region comprises the nucleotide sequence of SEQ ID NO: 11, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical thereto; the nucleotide sequence; (x) a nucleotide sequence encoding a light chain constant region, optionally (a) the encoded light chain constant region comprises the amino acid sequence of SEQ ID NO: 18, or an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical thereto; and / or (b) the nucleotide sequence encoding the light chain constant region comprises the nucleotide sequence of SEQ ID NO: 17, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical thereto; the nucleotide sequence; (xi) a polyA signal sequence, optionally comprising the nucleotide sequence of SEQ ID NO: 1134, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical thereto; (xii) a 3' AAV ITR, optionally comprising the nucleotide sequence of SEQ ID NO: 1037, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical thereto; and The AAV viral genome comprising:

[0231] 213. An AAV viral genome comprising the nucleotide sequence of SEQ ID NO: 15, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical thereto.

[0232] 214. 213. The viral genome of any one of embodiments 139 to 164 or 212, comprising the nucleotide sequence of SEQ ID NO: 15, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical thereto. [Brief explanation of the drawings]

[0233] [Figure 1] 1 is a graph showing the stimulation index (ratio of proliferating T cell counts in sample to blank) for each antibody after incubation with PBMC cells from 50 healthy donors representative of the world population based on HLA-DRB1 expression as a measure of relative immunogenicity risk. Antibodies tested include, from left to right on the X-axis, Herceptin control, Ab2, Ab1, Ab3, Ab4, and Ab5. A stimulation index of 2.0 or greater is considered a positive response. DETAILED DESCRIPTION OF THE INVENTION

[0234] I. Composition In some embodiments, the present disclosure provides compositions that interact with the human microtubule-associated protein tau. Such compositions can be antibodies that bind to tau protein epitopes, referred to herein as anti-tau antibodies. Tau dysfunction and / or aggregation are found in a class of neurodegenerative diseases called tauopathies. Hyperphosphorylation of tau leads to aggregation and inhibition of tau-dependent microtubule assembly. In tauopathies, tau aggregates form paired helical filaments (PHFs) found in neurofibrillary tangles (NFTs). These aggregates lead to neuronal loss and cognitive decline. The anti-tau antibodies of the present disclosure can be useful for the treatment and / or diagnosis of tauopathies, as well as other uses described herein.

[0235] antibody In some embodiments, the compounds (e.g., anti-tau antibodies) and compositions of the present disclosure comprise an antibody or fragment thereof. In some embodiments, the antibodies described herein bind to tau. For example, the antibody binds to an epitope on tau, e.g., a conformational epitope, a phosphorylated epitope, or a linear epitope, e.g., as described herein.

[0236] As used herein, the term "antibody" is used in the broadest sense and specifically encompasses a variety of embodiments, including, but not limited to, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies formed from at least two intact antibodies), single-chain Fv (scFv) formats, and antibody fragments (e.g., Fab, F(ab'), F(ab'), Fv, etc.), so long as they exhibit the desired functional or biological activity. Antibodies are primarily amino acid-based molecules, but may contain one or more modifications (including, but not limited to, the addition of a sugar moiety, a fluorescent moiety, a chemical tag, etc.).

[0237] Antibodies (including antigen-binding fragments thereof) of the present disclosure may include, but are not limited to, polyclonal, monoclonal, multispecific, bispecific, trispecific, human, humanized, chimeric, single-chain, diabodies, linear antibodies, Fab fragments, F(ab') fragments, F(ab')2 fragments, Fv fragments, fragments produced by an Fab expression library, variable domains, anti-idiotypic (anti-Id) antibodies (including, for example, anti-Id antibodies to antibodies of the invention), intracellularly produced antibodies (i.e., intrabodies), codon-optimized antibodies, scFv fragments, tandem scFv antibodies, bispecific T cell engagers, mAb2 antibodies, chimeric antigen receptors (CARs), tetravalent bispecific antibodies, biosynthetic antibodies, natural antibodies, miniaturized antibodies, unibodies, maxibodies, and epitope-binding fragments of any of the above.

[0238] In some embodiments, an antibody comprises at least one immunoglobulin variable domain sequence. Antibodies can include, for example, full-length mature antibodies and antigen-binding fragments of antibodies. For example, an antibody can comprise a heavy (H) chain variable domain sequence (abbreviated herein as VH) and a light (L) chain variable domain sequence (abbreviated herein as VL). In another example, an antibody comprises two heavy (H) chain variable domain sequences and two light (L) chain variable domain sequences, thereby forming two antigen-binding sites, such as Fab, Fab', F(ab')2, Fc, Fd, Fd', Fv, single-chain antibodies (e.g., scFv), single variable domain antibodies, diabodies (Dab) (bivalent and bispecific), and chimeric (e.g., humanized) antibodies, which can be produced by modification of whole antibodies or those synthesized de novo using recombinant DNA technology. These functional antibody fragments retain the ability to selectively bind to their respective antigens or receptors. The antibodies and antibody fragments may be from any class of antibody, including, but not limited to, IgG, IgA, IgM, IgD, and IgE, and any subclass of antibody (e.g., human IgG1, IgG2, IgG3, and IgG4, and mouse IgG1, IgG2a, IgG2b, IgG2c, and IgG3). The antibodies of the present disclosure may be monoclonal or polyclonal. The antibodies may also be human, humanized, CDR-grafted, or in vitro-generated. The antibodies may have a heavy chain constant region selected from, for example, IgG1, IgG2, IgG3, or IgG4. The antibodies may have a light chain selected from, for example, kappa or lambda.

[0239] In some embodiments, the antibodies of the present disclosure include functional fragments or variants thereof. The constant region of the antibody can be altered, e.g., mutated, to modify the properties of the antibody (e.g., to increase or decrease one or more of Fc receptor binding, antibody glycosylation, the number of cysteine ​​residues, effector cell function, or complement function).

[0240] As used herein, the term "antibody fragment" refers to a portion of an intact antibody or a fusion protein thereof, optionally comprising at least one antigen-binding region. Examples of antigen-binding fragments include: (i) a Fab fragment, i.e., a monovalent fragment consisting of the VL, VH, CL, and CH1 domains; (ii) a F(ab')2 fragment, i.e., a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CH1 domains; (iv) a Fv fragment consisting of the VL and VH domains of one arm of an antibody; (v) a diabody (dAb) fragment consisting of a VH domain; (vi) a camelid or camelized variable domain; (vii) a single-chain Fv (scFv) (see, e.g., Bird et al. (1988) Science 242:423-426, and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883); and (viii) a single-domain antibody. These antibody fragments are obtained using conventional techniques known to those of skill in the art, and the fragments are screened for utility in the same manner as intact antibodies. Antibody fragments can also be assembled into single-domain antibodies, maxibodies, minibodies, nanobodies, intrabodies, diabodies, triabodies, tetrabodies, v-NARs, and bis-scFvs (see, e.g., Hollinger and Hudson, Nature Biotechnology 23:1126-1136, 2005). In some embodiments, papain digestion of antibodies produces two identical antigen-binding fragments, called "Fab" fragments, each with a single antigen-binding site. A residual "Fc" fragment is also produced, the name reflecting its ability to readily crystallize. Pepsin treatment yields an F(ab')2 fragment, which has two antigen-binding sites and is still capable of cross-linking antigen. Antibodies of the present disclosure may comprise one or more of these fragments and can be produced, for example, by enzymatic digestion of whole antibodies or by recombinant expression.

[0241] In some embodiments, the antibody may be a single-domain antibody. Single-domain antibodies may include antibodies whose complementarity-determining regions are part of a single-domain polypeptide. Examples include, but are not limited to, heavy-chain antibodies, antibodies naturally devoid of light chains, single-domain antibodies derived from conventional four-chain antibodies, engineered antibodies, and single-domain scaffolds other than those derived from antibodies. The single-domain antibody may be any known or future single-domain antibody in the art. The single-domain antibody may be derived from any species, including, but not limited to, mouse, human, camel, llama, fish, shark, goat, rabbit, and cow. According to another aspect of the present invention, the single-domain antibody is a naturally occurring single-domain antibody known as a heavy-chain antibody devoid of light chains. Such single-domain antibodies are disclosed, for example, in WO9404678. For clarity, this variable domain derived from a heavy-chain antibody naturally devoid of light chains is referred to herein as a VHH or nanobody to distinguish it from the conventional VH of four-chain immunoglobulins. Such VHH molecules may be derived from antibodies produced in Camelidae species, such as camel, llama, dromedary, alpaca, and guanaco. Non-Camelidae species may also produce heavy chain antibodies that are naturally devoid of light chains, and such VHHs are within the scope of the present invention.

[0242] "Native antibodies" are typically heterotetrameric glycoproteins of about 150,000 daltons composed of two identical light (L) chains and two identical heavy (H) chains. The genes encoding antibody heavy and light chains are known, and the constituent segments of each have been well characterized and described (Matsuda, F. et al., 1998. The Journal of Experimental Medicine. 188(11); 2151-62 and Li, A. et al., 2004. Blood. 103(12:4602-9, the contents of each of which are incorporated herein by reference in their entirety). Each light chain is linked to a heavy chain by one covalent disulfide bond, while the number of disulfide linkages varies among the heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide bridges. Each heavy chain contains a variable domain (V) at one end and a variable domain (V) at the other end. H ) followed by several constant domains. Each light chain has a variable domain (V L ) at its other end and a constant domain. The constant domain of the light chain is aligned with the first constant domain of the heavy chain, and the light chain variable domain is aligned with the variable domain of the heavy chain.

[0243] As used herein, the term "variable domain" refers to specific antibody domains found in both the heavy and light chains of antibodies, which vary significantly in sequence among antibodies, and which are used in the binding and specificity of each particular antibody for its particular antigen. In some embodiments, the VH and VL regions of antibodies described herein can be subdivided into regions of hypervariability, called complementarity-determining regions (CDRs), interspersed with highly conserved regions called framework regions (FRs).

[0244] As used herein, the term "hypervariable region" refers to a region within a variable domain that contains amino acid residues involved in antigen binding. The amino acids present in the hypervariable region determine the structure of the complementarity-determining region (CDR), which becomes part of the antigen-binding site of an antibody.

[0245] As used herein, the term "CDR" refers to the region of an antibody that contains the structure complementary to its target antigen or epitope. The CDR region generally confers antigen specificity and binding affinity. The other parts of the variable domain that do not interact with the antigen are each called the "framework region" (FR). The antigen-binding site (also known as the antigen combining site or paratope) contains the amino acid residues necessary for interacting with a specific antigen. The exact residues that make up the antigen-binding site can be determined by CDR analysis.

[0246] As used herein, the term "CDR analysis" refers to any process used to determine which antibody variable domain residues constitute CDRs. The extent of framework regions and CDRs has been precisely defined by several methods (see Kabat, E.A., et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, USDapartment of Health and Human Services, NIH Publication No. 91-3242; Chothia, C. et al. (1987) J. Mol. Biol. 196:901-917; and the AbM definitions used by Oxford Molecular's AbM antibody modeling software). In general, see, for example, Protein Sequence and Structure Analysis of Antibody Variable Domains. In: Antibody Engineering Lab Manual (Ed.: Duebel, S. and Kontermann, R., Springer-Verlag, Heidelberg). CDR analysis can be performed by co-crystallography with bound antigen. In some embodiments, CDR analysis may include computational evaluation based on comparison with other antibodies (Strohl, WR Therapeutic Antibody Engineering. Woodhead Publishing, Philadelphia PA. 2012. Ch. 3, p47-54, the contents of which are incorporated herein by reference in their entirety).CDR analysis and / or precise amino acid sequence boundaries may be performed using methods such as those described by Kabat [Wu, TT et al., 1970, JEM, 132(2):211-50 and Johnson, G. et al., 2000, Nucleic Acids Res. 28(1):214-8, the contents of each of which are incorporated herein by reference in their entirety], Chothia [Chothia and Lesk, J. Mol. Biol. 196, 901(1987); Chothia et al., Nature 342, 877(1989); and Al-Lazikani, B. et al., 1997, J. Mol. Biol. 273(4):927-48, the contents of each of which are incorporated herein by reference in their entirety], Lefranc [Lefranc, MP et al., 2005, Immunome Res. 1:3), and Honegger (Honegger, A. and Pluckthun, A. 2001. J. Mol. Biol. 309(3):657-70, the contents of which are incorporated herein by reference in their entirety). In some embodiments, CDRs defined according to the Chothia numbering scheme may also be referred to as hypervariable loops.

[0247] For example, in Kabat, the CDR amino acid residues of the heavy chain variable domain (VH) are numbered 31 to 35 (HCDR1), 50 to 65 (HCDR2), and 95 to 102 (HCDR3), and the CDR amino acid residues of the light chain variable domain (VL) are numbered 24 to 34 (LCDR1), 50 to 56 (LCDR2), and 89 to 97 (LCDR3).

[0248] For example, in Chothia, the CDR amino acids of the VH are numbered 26-32 (HCDR1), 52-56 (HCDR2), and 95-102 (HCDR3), and the amino acid residues of the VL are numbered 26-32 (LCDR1), 50-52 (LCDR2), and 91-96 (LCDR3).

[0249] For example, combining the CDR definitions of both Kabat and Chothia, the CDRs consist of amino acid residues 26-35 (HCDR1), 50-65 (HCDR2), and 95-102 (HCDR3) in human VH, and amino acid residues 24-34 (LCDR1), 50-56 (LCDR2), and 89-97 (LCDR3) in human VL.

[0250] Generally, the VH and VL domains each have three CDRs. The VL CDRs are referred to herein as LC CDR1, LC CDR2, and LC CDR3, in 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 HC CDR1, HC CDR2, and HC CDR3, in order of appearance when moving from the N-terminus to the C-terminus along the variable domain polypeptide. Each CDR has a preferred canonical structure, with the exception of HC CDR3, which contains an amino acid sequence that is highly variable in sequence and length between antibodies and can result in various three-dimensional structures of the antigen-binding domain (Nikoloudis, D. et al., 2014. Peer J. 2:e456). In some cases, CDRH3s may be analyzed in a group of related antibodies to assess antibody diversity. Various methods of determining CDR sequences are known in the art and can be applied to known antibody sequences (Strohl, WR Therapeutic Antibody Engineering. Woodhead Publishing, Philadelphia PA. 2012. Ch. 3, p47-54, the contents of which are incorporated herein by reference in their entirety).

[0251] In some embodiments, the antigen-binding domain of an antibody of the present disclosure is the portion of the antibody that contains determinants that form an interface that binds to a tau polypeptide or its epitope. For proteins (or protein mimetics), the antigen-binding site typically includes one or more loops (consisting of at least four amino acids or amino acid mimetics) that form an interface that binds to the tau polypeptide. Typically, the antigen-binding site of an antibody includes at least one or two CDRs and / or hypervariable loops, and more typically includes at least three, four, five, or six CDRs and / or hypervariable loops.

[0252] In yet other embodiments, the antibody has a heavy chain constant region chosen from, e.g., the heavy chain constant regions of IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE, particularly, the human heavy chain constant regions of, e.g., IgG1, IgG2, IgG3, and IgG4, or the murine heavy chain constant regions of IgG1, IgG2a, IgG2b, IgG2c, and IgG3. In another embodiment, the antibody has a light chain constant region chosen from, e.g., the kappa or lambda (e.g., murine or human) light chain constant regions.

[0253] The constant region can be altered, e.g., mutated, to modify the properties of the antibody (e.g., to increase or decrease one or more of Fc receptor binding, antibody glycosylation, the number of cysteine ​​residues, effector cell function, and / or complement function). In some embodiments, the antibody has effector function and is capable of fixing complement. In other embodiments, the antibody neither recruits effector cells nor fixes complement. In other embodiments, the ability of the antibody to bind to Fc receptors is reduced or absent. For example, the antibody is an isotype or subtype, fragment, or other variant that does not support binding to Fc receptors, e.g., the Fc receptor binding region thereof is mutated or deleted.

[0254] Methods for altering antibody constant regions are known in the art. Antibodies with altered function, e.g., altered affinity for effector ligands such as FcR on cells or the C1 component of complement, can be produced by substituting at least one amino acid residue in the constant portion of the antibody with a different residue (see, e.g., EP 388,151 A1, U.S. Pat. No. 5,624,821, and U.S. Pat. No. 5,648,260, the contents of all of which are incorporated herein by reference). Similar types of alterations may be described that, when applied to immunoglobulins of mice or other species, reduce or eliminate these functions.

[0255] As used herein, the term "Fv" refers to an antibody fragment that contains the minimum fragment of an antibody necessary to form a complete antigen-binding site. This region consists of a dimer of one heavy-chain variable domain and one light-chain variable domain in tight, non-covalent association. Fv fragments can be generated by proteolytic cleavage, but most are unstable. Recombinant methods for generating stable Fv fragments are known in the art, typically by inserting a flexible linker between the light-chain variable domain and the heavy-chain variable domain (thereby forming a single-chain Fv (scFv)) or by introducing a disulfide bridge between the heavy-chain variable domain and the light-chain variable domain (Strohl, WR Therapeutic Antibody Engineering. Woodhead Publishing, Philadelphia PA. 2012. Ch. 3, p. 46-47, the contents of which are incorporated herein by reference in their entirety).

[0256] Antibody "light chains" from any vertebrate species can be assigned to one of two clearly distinct types, called kappa and lambda, based on the amino acid sequence of their constant domain. Antibodies can be assigned to different classes depending on the amino acid sequence of the constant domain of their heavy chain.

[0257] As used herein, the term "single-chain Fv" or "scFv" refers to a fusion protein of a VH antibody domain and a VL antibody domain, linked together by a flexible peptide linker into a single polypeptide chain. In some embodiments, the Fv polypeptide linker allows the scFv to form the desired structure for antigen binding. In some embodiments, scFvs are utilized in conjunction with phage display, yeast display, or other display methods, where the scFvs are expressed in association with a surface member (e.g., a phage coat protein) and can be used to identify high-affinity peptides against a given antigen. In some embodiments, antibodies of the present disclosure are prepared as scFvFc antibodies. The term "scFvFc" refers to an antibody format comprising a fusion of one or more scFvs with an antibody Fc domain.

[0258] The term "chimeric antibody" refers to an antibody having portions derived from more than one source. A chimeric antibody may contain portions derived from different species. For example, a chimeric antibody may contain an antibody having a murine variable domain and a human constant domain. Further examples of chimeric antibodies and methods for producing them include those described in Morrison, SL, Transfectomas provide novel chimeric antibodies. Science. 1985 Sep 20;229(4719):1202-7; Gillies, SD et al., High-level expression of chimeric antibodies using adapted cDNA variable region cassettes. J Immunol Methods. 1989 Dec 20;125(1-2):191-202; and U.S. Patent Nos. 5,807,715, 4,816,567, and 4,816,397, all of which are incorporated herein by reference in their entirety.

[0259] The term "diabody" refers to a small antibody fragment that has two antigen-binding sites, one light-chain variable domain V, in the same polypeptide chain. L heavy chain variable domain V connected to H Diabodies refer to fragments comprising the following: (a) a diabody fragment (or fragments) comprising: (a) a diabody fragment (or fragments) comprising: (a) a diabody fragment (or fragments) comprising: (b ...b) a diabody fragment (or fragments) comprising: (a) a diabody fragment (or fragments) comprising: (b) a diabody fragment (or fragments) comprising: (a) a diabody fragment (or fragments) comprising: (b) a diabody fragment (or fragments) comprising: (b) a diabody fragment (or fragments) comprising: (a) a diabody fragment (or fragments) comprising: (b) a diabody fragment (or fragments) comprising: (b) a diabody fragment (or fragments) comprising: (a) a diabody fragment (or fragments) comprising: (b) a diabody fragment (or fragments) comprising: (b) a diabody fragment (or fragments) comprising: (c) a diabody fragment (or fragments) comprising: (c) a diabody fragment (or fragments) comprising: (a) a diabody fragment (or fragments) comprising: (a) a diabody fragment (or fragments) comprising: (b) a diabody fragment (or fragments) comprising: (c) a

[0260] The term "intrabody" refers to a form of antibody that is not secreted from the cell in which it is produced, but instead targets one or more intracellular protein(s). Intrabodies can be used to affect numerous cellular processes, including, but not limited to, intracellular trafficking, transcription, translation, metabolic processes, proliferative signaling, and cell division. In some embodiments, methods of the invention can involve intrabody-based therapy. In some such embodiments, the variable domain sequences and / or CDR sequences disclosed herein can be incorporated into one or more constructs for intrabody-based therapy. In some cases, intrabodies of the invention can target one or more glycosylated intracellular proteins or modulate the interaction of one or more glycosylated intracellular proteins with alternative proteins.

[0261] As used herein, the term "chimeric antigen receptor" or "CAR" refers to an artificial receptor that is engineered to be expressed on the surface of immune effector cells and to specifically target cells that express an entity that binds to the artificial receptor with high affinity. CARs can be designed to contain one or more segments of an antibody, antibody variable domain, and / or antibody CDR, such that when such a CAR is expressed on an immune effector cell, the immune effector cell binds to and eliminates cells recognized by the antibody portion of the CAR. In some cases, CARs are designed to specifically bind to cancer cells, resulting in their immune-modulatory clearance.

[0262] The antibodies of the present invention may be monoclonal or polyclonal. As used herein, the term "monoclonal antibody" refers to an antibody obtained from a population of substantially homogeneous cells (or clones), e.g., the individual antibodies comprising the population are identical and / or bind to the same epitope, excluding possible variants that may arise during monoclonal antibody production, which are generally present in minor amounts. Unlike polyclonal antibody preparations, which typically contain different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen.

[0263] The modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method.

[0264] In some embodiments, the antibody comprises a variable region or portion thereof, e.g., a CDR, comprising the amino acid sequence of an antibody generated in a non-human organism, e.g., a rat or a mouse. Antibodies, including chimeric antibodies, CDR-grafted antibodies, and humanized antibodies, are within the scope of the present invention. Antibodies comprising the sequence of an antibody generated in a non-human organism, e.g., a rat or a mouse, and then modified, e.g., in the variable framework or constant region, to reduce antigenicity in humans are within the scope of the present invention.

[0265] As used herein, monoclonal antibodies include "chimeric" antibodies (immunoglobulins) in which a portion of the heavy and / or light chain is identical or homologous to corresponding sequences in antibodies from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical or homologous to corresponding sequences in antibodies from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies.

[0266] Antibodies of the present disclosure may be from any animal origin, including mammals, birds, reptiles, and insects. Mammalian antibodies may be, for example, of human, murine (e.g., mouse or rat), donkey, sheep, rabbit, goat, guinea pig, camel, bovine, or equine origin.

[0267] In some embodiments, the antibody of the present disclosure may be an antibody mimetic. The term "antibody mimetic" refers to any molecule that mimics the function or effect of an antibody and binds specifically and with high affinity to its molecular target. In some embodiments, the antibody mimetic may be a monobody designed to incorporate a fibronectin type III domain (Fn3) as a protein scaffold (US Pat. No. 6,673,901, US Pat. No. 6,348,584). In some embodiments, the antibody mimetic may be any known in the art, including, but not limited to, affibody molecules, affilins, affitins, anticalins, avimers, DARPins, Fynomers, and Kunitz, as well as domain peptides. In other embodiments, the antibody mimetic may include one or more non-peptide regions.

[0268] As used herein, the term "antibody variant" refers to a biomolecule that is similar in structure, sequence and / or function to an antibody, but contains some differences in its amino acid sequence, composition or structure compared to another antibody or a naturally occurring antibody.

[0269] multispecific antibody In some embodiments, the antibody is a multispecific antibody, e.g., comprises a plurality of immunoglobulin variable domain sequences, wherein a first immunoglobulin variable domain sequence of the plurality has binding specificity for a first epitope and a second immunoglobulin variable domain sequence of the plurality has binding specificity for a second epitope. In some embodiments, the first and second epitopes are on the same antigen, e.g., the same protein (or subunit of a multimeric protein). In some embodiments, the first and second epitopes overlap. In some embodiments, the first and second epitopes do not overlap. In some embodiments, the first and second epitopes are on different antigens, e.g., different proteins (or different subunits of a multimeric protein). In some embodiments, the multispecific antibody comprises a third, fourth, or fifth immunoglobulin variable domain. In some embodiments, the multispecific antibody is a bispecific antibody, a trispecific antibody, or a tetraspecific antibody. In some embodiments, the anti-tau antibody is a multispecific antibody.

[0270] In some embodiments, a multispecific antibody is a bispecific antibody. A bispecific antibody does not have specificity for more than two antigens. A bispecific antibody is characterized by a first immunoglobulin variable domain sequence that has binding specificity for a first epitope and a second immunoglobulin variable domain sequence that has binding specificity for a second epitope. In some embodiments, the first and second epitopes are on the same antigen, e.g., the same protein (or subunit of a multimeric protein). In some embodiments, the first and second epitopes overlap. In some embodiments, the first and second epitopes do not overlap. In some embodiments, the first and second epitopes are on different antigens, e.g., different proteins (or different subunits of a multimeric protein). In some embodiments, a bispecific antibody comprises heavy and light chain variable domain sequences that have binding specificity for a first epitope and heavy and light chain variable domain sequences that have binding specificity for a second epitope. In some embodiments, the bispecific antibody comprises a half antibody having binding specificity for a first epitope and a half antibody having binding specificity for a second epitope. In some embodiments, the bispecific antibody comprises a half antibody, or fragment thereof, having binding specificity for a first epitope and a half antibody, or fragment thereof, having binding specificity for a second epitope. In some embodiments, the bispecific antibody comprises an scFv, or fragment thereof, having binding specificity for a first epitope and an scFv, or fragment thereof, having binding specificity for a second epitope. In certain embodiments, the anti-tau antibody is a bispecific antibody.

[0271] In some embodiments, antibody sequences of the present disclosure can be generated from bispecific or heterodimeric antibodies produced using protocols known in the art, such as the "knobs-in-holes" approach described, for example, in U.S. Pat. No. 5,731,168; electrostatic steering Fc pairing described, for example, in WO 09 / 089004, WO 06 / 106905, and WO 2010 / 129304; or Strand Exchange Engineered (SEED) technology described, for example, in WO 07 / 110205. Fab arm exchange, as described, for example, in WO 08 / 119353, WO 2011 / 131746, and WO 2013 / 060867; biantibody conjugates, for example, by crosslinking antibodies using heterobifunctional reagents with amine-reactive groups and sulfhydryl-reactive groups to generate bispecific structures, as described, for example, in US 4,433,059; bispecific antibody determinants generated by recombining half antibodies (heavy chain-light chain pairs or Fab) from different antibodies through cycles of reduction and oxidation of the disulfide bond between the two heavy chains, as described, for example, in US 4,444,878; trifunctional antibodies, for example, three Fab' fragments crosslinked via sulfhydryl-reactive groups, as described, for example, in US 5,273,743; biosynthetic binding proteins, for example, as described, for example, in US 5,534,254 for example, pairs of scFvs cross-linked through their C-terminal tails, preferably via disulfide or amine-reactive chemical cross-linking; bifunctional antibodies, e.g., Fab fragments with different binding specificities dimerized via leucine zippers (e.g., c-fos and c-jun) replacing the constant domains, as described, for example, in US Pat. No. 5,582,996; bispecific and oligospecific monovalent and oligovalent receptors, e.g., the VH-CH1 regions of two antibodies (two Fab fragments) linked via a polypeptide spacer between the CH1 region of one antibody and the VH region of the other antibody, typically with an associated light chain, as described, for example, in US Pat. No. 5,591,828; bispecific DNA-antibody conjugates, e.g., cross-linking of antibodies or Fab fragments via a double-stranded portion of DNA, as described, for example, in US Pat. No. 5,635,602;Bispecific fusion proteins, such as those described in US Pat. No. 5,637,481, include expression constructs comprising two scFvs and a complete constant region with a hydrophilic helical peptide linker between them; multivalent and multispecific binding proteins, such as those described in US Pat. No. 5,837,242, include polypeptide dimers, commonly referred to as diabodies, having a first domain with an Ig heavy chain variable region binding region and a second domain with an Ig light chain variable region binding region (higher order structures creating bispecific, trispecific, or tetraspecific molecules are also disclosed); minibody constructs, such as those described in US Pat. No. 5,837,821, including those having linked VL and VH chains further connected by a peptide spacer to antibody hinge and CH3 regions, which can be dimerized to form bispecific / multivalent molecules; and short peptide linkers (e.g., 5 or 10 amino acids). These include, but are not limited to, VH and VL domains linked via a peptide bond, or with no linker at all in either orientation, which can dimerize to form bispecific diabodies; trimers and tetramers, as described, for example, in US 5,844,094; consecutive VH domains (or VL domains of family members) connected at their C-termini by a peptide bond to a crosslinking group and further associated with a VL domain to form a series of FVs (or scFvs), as described, for example, in US 5,864,019; and single-chain binding polypeptides, as described, for example, in US 5,869,620, in which both VH and VL domains linked via peptide linkers are joined into multivalent structures via non-covalent or chemical crosslinking to form, for example, homobivalent, heterobivalent, trivalent, and tetravalent structures using both scFV or diabody-type formats.

[0272] Intrabody In some embodiments, the payload may encode an intrabody. Intrabodies are a form of antibody that is not secreted from the cell in which the antibody is produced but instead targets one or more intracellular proteins. Intrabodies are expressed and function intracellularly and can be used to affect numerous cellular processes, including, but not limited to, intracellular trafficking, transcription, translation, metabolic processes, proliferative signaling, and cell division. In some embodiments, the methods described herein involve intrabody-based therapy. In some such embodiments, the variable domain sequences and / or CDR sequences disclosed herein are incorporated into one or more constructs for intrabody-based therapy. For example, an intrabody may target one or more glycosylated intracellular proteins or modulate the interaction of one or more glycosylated intracellular proteins with alternative proteins.

[0273] Intrabodies against intracellular targets were first reported over 20 years ago (Biocca, Neuberger, and Cattaneo, EMBO J. 9:101-108, 1990). Intracellular expression of intrabodies in various compartments of mammalian cells allows them to block or modulate the function of endogenous molecules (Biocca, et al., EMBO J. 9:101-108, 1990; Colby et al., Proc. Natl. Acad. Sci. USA 101: 17616-21, 2004). Intrabodies can alter protein folding, protein-protein, protein-DNA, and protein-RNA interactions, and protein modifications. They can induce phenotypic knockouts and function as neutralizing agents by directly binding to target antigens, altering their intracellular trafficking, or inhibiting their association with binding partners. They have primarily been used as research tools and are emerging as therapeutic molecules for treating human diseases such as viral pathologies, cancer, and misfolded diseases. The rapidly growing recombinant antibody biotechnology market offers intrabodies with enhanced binding specificity, stability, and solubility, as well as reduced immunogenicity, for use in therapy (Biocca, Abstract in Antibody Expression and Production Cell Engineering Volume 7, 2011, pp. 179-195).

[0274] In some embodiments, intrabodies have advantages over interfering RNA (iRNA). For example, iRNA has been shown to exert multiple non-specific effects, whereas intrabodies have been shown to have high specificity and affinity for target antigens. Furthermore, as proteins, intrabodies have a much longer half-life of activity than iRNA. Thus, if the intracellular target molecule has a long half-life of activity, iRNA-mediated gene silencing may be slow to take effect, whereas the effect of intrabody expression can be almost immediate. Finally, it is possible to design intrabodies that block specific binding interactions of specific target molecules while sparing others.

[0275] Intrabodies are often single-chain variable fragments (scFv) that are expressed from recombinant nucleic acid molecules and engineered to be retained intracellularly (e.g., in the cytoplasm, endoplasmic reticulum, or periplasm). Intrabodies can be used, for example, to eliminate the function of the protein to which they bind. Intrabody expression can also be regulated through the use of an inducible promoter in the nucleic acid expression vector containing the intrabody. Intrabodies are, for example, (Marasco et al., 1993 Proc. Natl. Acad. Sci. USA, 90:7889-7893, Chen et al., 1994, Hum. al.,1994,Proc.Natl.Acad.Sci.USA,91:5932-5936, Maciejewski et al.,1995,Nature Med.,1:667-673,Marasco,1995,Immunotech,1:1-19,Mhashilkar,et al.,1995,EMBO J.14:1542-51,Chen et al.,1996,Hum.Gene Therap.,7:1515-1525,Marasco,Gene Ther.4:11-15,1997, London and Marasco,1997, Annu.Rev.Microbiol.51:257-283, Cohen, et al.,1998, Oncogene 17:2445-56, Proba et al.,1998, J.Mol.Biol.275:245-253, Cohen et al. al.,1998,Oncogene 17:2445-2456, Hassanzadeh,et al.,1998,FEBS Lett.437:81-6,Richardson et al.,1998,Gene Ther.5:635-44,Ohage and Steipe,1999,J.Mol.Biol.291:1119-1128,Ohage et al. al., 1999, J. Mol. Biol. 291:1129-1134, Wirtz and Steipe, 1999, Protein Sci. 8: 2245-2250, Zhu et al., 1999, J. Immunol.Methods 231:207-222; Arafat et al., 2000, Cancer Gene Ther. 7:1250-6; der Maur et al., 2002, J. Biol. Chem. 277:45075-85; Mhashilkar et al., 2002, Gene Ther. 9:307-19; and Wheeler et al., 2003, FASEB J. 17:1733-5, and references cited therein. In particular, CCR5 intrabodies have been produced by Steinberger et al., 2000, Proc. Natl. Acad. Sci. USA 97:805-810). See generally Marasco, W.A., 1998, "Intrabodies: Basic Research and Clinical Gene Therapy Applications," Springer: New York. Also, for a review of scFvs, see Pluckthun in "The Pharmacology of Monoclonal Antibodies," 1994, vol. 113, Rosenburg and Moore eds. Springer-Verlag, New York, pp. 269-315.

[0276] Intrabodies may be developed using sequences derived from donor antibodies. Intrabodies are often recombinantly expressed intracellularly as single domain fragments, such as isolated VH and VL domains, or as single-chain variable fragment (scFv) antibodies. For example, intrabodies are often expressed as a single polypeptide to form single-chain antibodies comprising heavy and light chain variable domains connected by a flexible linker polypeptide. Intrabodies typically lack disulfide bonds and can modulate target gene expression or activity via their specific binding activity. Single-chain antibodies can also be expressed as a single-chain variable region fragment linked to a light chain constant region.

[0277] As is known in the art, intrabodies can be engineered into recombinant polynucleotide vectors to encode intracellular transport signals at their N- or C-termini, enabling high-level expression in the intracellular compartment where the target protein is located. For example, intrabodies targeted to the endoplasmic reticulum (ER) are engineered to incorporate a leader peptide and, optionally, a C-terminal ER retention signal, such as the KDEL amino acid motif (SEQ ID NO: 4545). Intrabodies intended to exert activity in the nucleus are engineered to contain a nuclear localization signal. A lipid moiety is attached to the intrabody to anchor it to the cytosolic side of the plasma membrane. Intrabodies can also be targeted to exert their function in the cytosol. For example, cytosolic intrabodies are used to sequester factors in the cytosol, thereby preventing them from being transported to their natural intracellular destination.

[0278] Expression of intrabodies presents certain technical challenges, in particular, the folding and structural stability of the protein conformation of newly synthesized intracellular intracellular proteins is affected by the reducing conditions of the intracellular environment.

[0279] Because intrabodies have a virtually limitless ability to specifically recognize different conformations of proteins, including pathological isoforms, and can be targeted to potential aggregation sites (both intracellular and extracellular), they may be promising therapeutic agents for the treatment of misfolded diseases, including tauopathies, prion diseases, Alzheimer's disease, Parkinson's disease, and Huntington's disease. These molecules can function as neutralizers of amyloidogenic proteins by preventing their aggregation and / or as molecular shunters of intracellular trafficking by rerouting the protein away from its potential aggregation site (Cardinale, and Biocca, Curr. Mol. Med. 2008, 8:2-11).

[0280] Antibody development Antibodies according to the present disclosure can be developed using standard methods in the art. Two primary antibody preparation techniques are immunization and antibody display. In both cases, the desired antibody is identified from a larger pool of candidates based on its affinity for a particular target or epitope. An immune response is characterized by the reaction of an organism's cells, tissues, and / or organs to the presence of a foreign substance. Such an immune response typically leads to the organism producing one or more antibodies against the foreign substance, such as an antigen or a portion of an antigen.

[0281] antigen Antibodies can be developed (e.g., via immunization) or selected (e.g., from a pool of candidates) using, for example, any naturally occurring or synthetic antigen. As used herein, an "antigen" is an entity that induces or elicits an immune response in an organism and may also refer to an antibody binding partner. An immune response is characterized by the reaction of an organism's cells, tissues, and / or organs to the presence of a foreign substance. Such an immune response typically leads to the organism producing one or more antibodies against the foreign substance. In some embodiments, the antigen comprises tau protein.

[0282] As used herein, the term "tau protein" refers to a protein or protein complex containing the microtubule-associated protein tau or a peptide fragment thereof. Tau proteins may include condensed paired helical fibrillar tau protein (ePHF), also known as "sarkosyl-insoluble tau," or fragments thereof. Tau proteins may contain one or more phosphorylated residues. Such phosphorylated residues may correspond to disease-associated tau proteins (also referred to herein as "pathological tau").

[0283] immunization In some embodiments, antibodies can be prepared by immunizing a host with an antigen of interest. Immunizing a host animal (e.g., a mouse, rabbit, goat, or llama) with an antigenic protein can induce lymphocytes that specifically bind to the antigen. The lymphocytes can be collected and fused with an immortalized cell line to generate hybridomas, which can be cultured in a suitable culture medium to promote growth (see, e.g., Kohler, G. et al., Continuous cultures of fused cells secreting antibody of predefined specificity. Nature. 1975 Aug 7;256(5517):495-7, the contents of which are incorporated herein by reference in their entirety). Alternatively, lymphocytes can be immunized in vitro.

[0284] Lymphocytes may be fused with an immortalized cell line using a suitable fusing agent (e.g., polyethylene glycol) to form hybridoma cells (see, e.g., Goding, JW, Monoclonal Antibodies: Principles and Practice. Academic Press. 1986; 59-1031, the contents of which are incorporated herein by reference in their entirety). The immortalized cell line may be transformed mammalian cells, particularly myeloma cells of rodent, rabbit, bovine, or human origin. In some embodiments, rat or mouse myeloma cell lines are used. The hybridoma cells may be cultured in a suitable culture medium that typically contains one or more substances that inhibit the growth or survival of unfused cells. For example, parental cells lacking the enzyme hypoxanthine guanine phosphoribosyltransferase (HGPRT or HPRT) may be used, and the culture medium for the resulting hybridoma cells may be supplemented with hypoxanthine, aminopterin, and thymidine ("HAT medium") to prevent growth of HGPRT-deficient (unfused) cells.

[0285] Desirable properties of immortalized cell lines include, but are not limited to, efficient fusion, support of high levels of antibody expression by the selected antibody-producing cells, and sensitivity to a medium that inhibits unfused cells (e.g., HAT medium). In some embodiments, the immortalized cell line is a mouse myeloma line. Such cell lines can be obtained, for example, from the Salk Institute Cell Distribution Center (San Diego, CA) or the American Type Culture Collection (Manassas, VA). Human myeloma and mouse-human heteromyeloma cell lines can also be used to produce human monoclonal antibodies (see, e.g., Kozbor, D. et al., A human hybrid myeloma for production of human monoclonal antibodies. J Immunol. 1984 December;133(6):3001-5 and Brodeur, B. et al., Monoclonal Antibody Production Techniques and Applications. Marcel Dekker, Inc., New York. 1987;33:51-63, the contents of each of which are incorporated herein by reference in their entirety).

[0286] Hybridoma cell culture medium can be assayed for the presence of monoclonal antibodies with the desired binding specificity. Assays can include, but are not limited to, immunoprecipitation assays, in vitro binding assays, radioimmunoassays (RIA), surface plasmon resonance (SPR) assays, and / or enzyme-linked immunosorbent assays (ELISA). In some embodiments, the binding specificity of a monoclonal antibody can be determined by Scatchard analysis (Munson, PJ et al., Ligand: a versatile computerized approach for characterization of ligand-binding systems. Anal Biochem. 1980 Sep 1;107(1):220-39, the contents of which are incorporated herein by reference in their entirety).

[0287] Antibodies produced by cultured hybridomas may be analyzed to determine their binding specificity for the target antigen. Once antibodies with desirable characteristics are identified, the corresponding hybridomas may be subcloned by limiting dilution procedures and grown by standard methods. Antibodies produced by hybridomas may be isolated and purified using standard immunoglobulin purification procedures, such as, for example, protein A-Sepharose, hydroxyapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography. Alternatively, hybridoma cells may be grown in vivo as ascites in a mammal. In some embodiments, antibodies may be isolated directly from the serum of an immunized host.

[0288] In some embodiments, recombinant versions of antibodies generated by immunization may be prepared. Such antibodies may be prepared using genomic antibody sequences from selected hybridomas. The genomic antibody sequence of a hybridoma may be obtained by extracting RNA molecules from antibody-producing hybridoma cells and producing cDNA by reverse transcriptase polymerase chain reaction (PCR). PCR may be used to amplify the cDNA using primers specific for the antibody heavy and light chains. The PCR product may then be subcloned into a plasmid for sequence analysis. Antibodies may be produced by inserting the resulting antibody sequence into an expression vector. Some recombinant antibodies may be prepared using synthetic nucleic acid constructs encoding amino acid sequences corresponding to those obtained from isolated hybridoma antibodies.

[0289] antibody display In some embodiments, antibodies can be developed using antibody display technology. "Display technology" refers to systems and methods for expressing amino acid-based candidate compounds in a format accessible to a target or ligand, where the compounds are linked to a nucleic acid encoding the compound. In most systems, candidate compounds are expressed on the surface of a host capsid or cell, although some host-free systems exist (e.g., ribosome display). Display technology can be used to generate a display "library" containing a set of candidate compound library members. A display library that includes antibodies (or variants or fragments thereof) as library members is referred to herein as an "antibody display library." Antibodies can be designed, selected, or optimized by screening target antigens using an antibody display library. An antibody display library can contain millions to billions of members, each expressing a unique antibody domain. The displayed antibody fragments can be expressed as V H and V L The antibody variable domains or CDRs obtained from display library selection may be directly incorporated into antibody sequences for recombinant antibody production or may be mutated and utilized for further optimization via in vitro affinity maturation.

[0290] Antibody display libraries can include antibody phage display libraries. Antibody phage display libraries utilize phage virus particles as hosts, with millions to billions of members, each expressing a unique antibody domain. Such libraries can provide a diverse source that can be used to select potentially hundreds of antibody fragments with varying levels of affinity for one or more antigens of interest (McCafferty, et al., 1990. Nature. 348:552-4; Edwards, BM et al., 2003. JMB. 334:103-18; Schofield, D. et al., 2007. Genome Biol. 8, R254; and Pershad, K. et al., 2010. Protein Engineering Design and Selection. 23:279-88; the contents of each are incorporated herein by reference in their entirety). The displayed antibody fragments can be scFv antibody fragments. Phage display library members can be expressed as fusion proteins linked to a viral coat protein (e.g., the N-terminus of the viral pIII coat protein). L The V chains are expressed separately and expressed in the periplasm. H After assembly with the chain, the complex may be incorporated into a viral coat. The precipitated library members may be sequenced from the bound phage to obtain cDNAs encoding the desired antibody domains.

[0291] In some embodiments, antibody display libraries can be generated using yeast surface display technology. Antibody yeast display libraries are composed of yeast cells with surface-displayed antibodies or antibody fragments. Antibody yeast display libraries can contain antibody variable domains expressed on the surface of Saccharomyces cerevisiae cells. Yeast display libraries can be expanded by displaying antibody fragments of interest as fusion proteins with yeast surface proteins (e.g., Aga2p protein). Yeast cells displaying antibodies or antibody fragments with affinity for a particular target can be isolated according to standard methods. Such methods can include, but are not limited to, magnetic separation and flow cytometry.

[0292] Recombinant synthesis Antibodies of the present disclosure can be prepared using recombinant DNA technology and related processes. Constructs (e.g., DNA expression plasmids) encoding antibodies can be prepared and used to synthesize complete antibodies or portions thereof. In some embodiments, DNA sequences encoding antibody variable domains of the present disclosure can be inserted into expression vectors (e.g., mammalian expression vectors) encoding other antibody domains and used to prepare antibodies with the inserted variable domains. DNA sequences encoding antibody variable domains can be inserted downstream of an upstream expression vector region having a promoter / enhancer element and / or encoding an immunoglobulin signal sequence. DNA sequences encoding antibody variable domains can be inserted upstream of a downstream expression vector region encoding an immunoglobulin constant domain. The encoded constant domain can be derived from any class (e.g., IgG, IgA, IgD, IgE, and IgM) or species (e.g., human, mouse, rabbit, rat, and non-human primate). In some embodiments, the encoded constant domain encodes the constant domain of human IgG (e.g., IgG1, IgG2, IgG3, or IgG4). In some embodiments, the encoded constant domain encodes the constant domain of a mouse IgG (eg, IgG1, IgG2a, IgG2b, IgG2c, or IgG3).

[0293] An expression vector encoding an antibody of the present disclosure can be used to transfect cells for antibody production. Such cells can be mammalian cells. Cell lines stably transfected with the antibody expression vector can be prepared and used to establish stable cell lines. The antibody-producing cell line can be expanded to express the antibody, which can be isolated or purified from the cell culture medium.

[0294] Antibody characterization In some embodiments, antibodies of the present disclosure can be identified, selected, or excluded based on different characteristics. Such characteristics can include, but are not limited to, physical and functional characteristics. Physical characteristics can include antibody structural properties (e.g., amino acid sequence or residues; secondary, tertiary, or quaternary protein structure; post-translational modifications (e.g., glycosylation); chemical bonds, and stability). Functional characteristics can include, but are not limited to, antibody affinity (i.e., for a particular epitope and / or antigen) and antibody activity (e.g., the ability of an antibody to activate or inhibit a target, process, or pathway).

[0295] Antibody Binding and Affinity In some embodiments, antibodies of the present disclosure can be identified, selected, or excluded based on the level of binding and / or affinity for a particular epitope and / or antigen. The level of antibody binding and / or affinity can be assessed using different antigen formats. In some embodiments, antibody affinity for different antigen formats can be tested in vitro (e.g., by ELISA). In vitro testing of anti-tau antibodies can be performed using brain samples or fragments. Such samples or fragments can be obtained from subjects with AD (e.g., human AD patients). In some embodiments, brain samples or fragments can be obtained from non-human subjects. Such non-human subjects can include non-human animals (e.g., mice, rats, and primates) used in AD disease model studies. In some embodiments, brain samples or fragments used in antibody affinity testing can be derived from the TG4510 / P301S mouse strain. Antibody affinity can be compared to a control sample lacking the particular antigen for which affinity is being analyzed. In some embodiments, the control sample used in anti-tau antibody testing can include a brain sample or fragment from a non-diseased human subject. In some embodiments, brain samples or sections from wild-type and / or tau knockout mouse strains may be used as control samples.

[0296] In vitro affinity testing may be performed using recombinant or isolated protein antigens (e.g., by ELISA). For example, recombinant or isolated ePHF may be used for anti-tau antibody affinity testing. In some embodiments, an anti-tau antibody of the present disclosure may exhibit a half-maximal effective concentration (EC50) of about 0.01 nM to about 100 nM for binding to ePHF as assessed by ELISA. In some embodiments, the exhibited EC50 may be less than about 50 nM, less than about 20 nM, less than about 10 nM, or less than about 1 nM. In some embodiments, an anti-tau antibody of the present disclosure may exhibit an EC50 of about 0.01 nM to about 100 nM for binding to any of the antigens listed in Table 8, or an epitope (including, but not limited to, a conformational epitope) comprising or contained in any of the antigens, as assessed by ELISA. In some embodiments, the exhibited EC50 may be less than about 50 nM, less than about 20 nM, less than about 10 nM, or less than about 1 nM.

[0297] In some embodiments, the anti-tau antibodies of the present disclosure bind to pathological tau but not to non-pathological tau. Such antibodies are sometimes referred to herein as being "selective" for pathological forms of tau. In some embodiments, the anti-tau antibodies of the present disclosure bind to tau tangles.

[0298] In some embodiments, antibody affinity analysis can be used to identify, select, or exclude multispecific antibodies. As used herein, the term "multispecific antibody" refers to an antibody that has affinity for multiple epitopes or antigens. In some embodiments, multispecific antibodies can be identified, selected, or excluded based on the relative affinity for each recognized epitope or antigen. For example, a multispecific antibody can be selected for use or further development based on its higher affinity for one epitope or antigen to which it exhibits affinity compared to a second epitope or antigen.

[0299] In some embodiments, anti-tau antibodies may be tested for competition with other anti-tau antibodies. Such testing can be performed to provide information about the specific epitope recognized by the antibody and can yield information related to the level of epitope affinity compared to competing antibodies. In some embodiments, the anti-tau antibody used in antibody binding and / or affinity analyses may include the anti-tau antibody PT3 described in U.S. Pat. No. 9,371,376, the anti-tau antibody C10.2 described in U.S. Pat. No. 10,196,439 (referred to therein as antibody "C10-2"), the anti-tau antibody IPN002 described in U.S. Pat. No. 10,040,847, the anti-tau antibody AT8 (ThermoFisher, Waltham, MA), the anti-tau antibody AT100 (ThermoFisher, Waltham, MA), the anti-tau antibody AT120 described in U.S. Pat. No. 5,843,779, or the anti-tau antibody PT76 described in Vandermeeren, M. et al., J Alzheimers Dis. 2018;65(1):265-281.

[0300] antibody activity In some embodiments, antibodies of the present disclosure can be identified, selected, or excluded based on their ability to promote or reduce a particular activity. Antibody activity can be assessed using analytical assays. Such assays can be selected or designed to detect, screen, measure, and / or rank antibodies based on such antibody activity.

[0301] Anti-tau antibodies can be characterized by their ability to inhibit tau aggregation. Inhibition can be based on physical disruption of tau aggregates or on anti-tau antibody-dependent depletion (immunodepletion) of tau protein. Characterization based on tau aggregation inhibition can be evaluated using one or more assays of tau aggregation. In some embodiments, anti-tau antibodies can be characterized by a tau seeding assay. A tau seeding assay typically involves initiating tau aggregation in vitro and evaluating aggregation inhibition by a candidate compound being tested. The tau seeding assay can be performed using tau aggregation biosensor cells. The tau aggregation biosensor cells generate a detectable signal (e.g., a fluorescent signal) in response to tau aggregation. The tau aggregation biosensor cells can be cultured with recombinant or isolated tau, or with a sample from tau-rich brain tissue or fluid (to promote tau aggregation), and treated with or without a candidate compound to evaluate tau aggregation inhibition. In some embodiments, anti-tau antibodies can be used to deplete tau from the culture medium prior to incubation with biosensor cells. The level of aggregation in the depleted medium can be compared to the level of aggregation in the non-depleted medium to assess the inhibitory function of the anti-tau antibody. Tau aggregation biosensor cells can include, but are not limited to, tau RD biosensor cells. In some embodiments, neurons expressing human tau can be used.

[0302] In some embodiments, anti-tau antibodies of the present disclosure may inhibit tau aggregation with a half-maximal inhibitory concentration (IC50) of about 1 nM to about 30 nM, as determined by an immunodepletion assay (e.g., using TauRD biosensor cells).

[0303] Antibody Modification Antibodies can be modified to produce variants with one or more altered properties. Such properties may include or relate to the antibody's structure, function, affinity, specificity, protein folding, stability, production, expression, and / or immunogenicity (i.e., immune response in a subject treated with such an antibody). In some embodiments, antibody fragments or variants may be used to modify another antibody or incorporated into a synthetic antibody.

[0304] Antibody modifications may include amino acid sequence modifications. Such modifications may include, but are not limited to, amino acid deletions, additions, and / or substitutions. Modification information may be obtained by amino acid sequence analysis. Such analysis may include alignment of amino acid sequences between different antibodies or antibody variants. Two or more antibodies may be compared to identify residues or regions suitable for modification. The antibodies compared may include those that bind to the same epitope. The antibodies compared may also bind to different (distinct or overlapping) epitopes of the same protein or target (e.g., to identify residues or regions that confer specificity for a particular epitope). Comparison may include analysis of light and / or heavy chain sequence variation, analysis of CDR sequence variation, analysis of germline sequences, and / or analysis of framework sequences. Information obtained from such analysis can be used to identify amino acid residues, amino acid segments, amino acid side chains, CDR lengths, and / or other properties or characteristics that are conserved or variable between antibodies that bind the same or different epitopes.

[0305] In some embodiments, modified versions of the above-described anti-tau antibodies may be prepared by adding, deleting, or substituting one or more CDR amino acid residues. In some embodiments, anti-tau antibodies may be modified by aligning the amino acid sequences of antibodies that bind to similar targets and preparing modified antibodies with one or more amino acid deletions, substitutions, or insertions based on analysis of the aligned sequences.

[0306] The present disclosure includes amino acid consensus sequences for CDR region sequences and indicates specific amino acids that may be modified, or more generally, amino acid residue positions (indicated using the variable "X") that may be substituted, in antibody amino acid sequences, e.g., as set forth in Table 1.

[0307] [Table 1-1]

[0308] [Table 1-2]

[0309] Functional modification In some embodiments, antibodies of the present disclosure may be modified to optimize one or more functional properties (e.g., antibody affinity or activity). Non-limiting examples of antibody functional properties include epitope or antigen affinity, ability to recruit or immobilize a target, and ability to activate or inhibit a target, process, or pathway. In some embodiments, functional properties include or relate to protein-protein interactions, protein aggregation, enzymatic activity, receptor-ligand interactions, cell signaling pathways, proteolytic cascades, and / or the ability to modulate a biological or physiological response.

[0310] Antibody modification can optimize antibodies by adjusting epitope affinity. Such modifications can be performed by affinity maturation. Affinity maturation techniques are used to identify CDR-encoding sequences with the highest affinity for the target antigen. In some embodiments, antibody display technologies (e.g., phage or yeast) can be used. Such methods can involve mutating the nucleotide sequence encoding the parent antibody to be optimized. The nucleotide sequence can be mutated entirely randomly or at specific amino acid residues to alter expression, generating millions to billions of variants. Sites or residues can be selected for mutation based on the frequency of the sequence or amino acid observed in the natural human antibody repertoire. Variants can be subjected to multiple rounds of affinity screening for target antigen binding (e.g., using display library screening techniques, surface plasmon resonance techniques, fluorescence-associated cell sorting (FACS) analysis, enzyme-linked immunosorbent assay (ELISA), etc.). Multiple rounds of selection, mutation, and expression can be performed to identify antibody fragment sequences with the highest affinity for the target antigen. Such sequences can be directly incorporated into antibody sequences for production. In some cases, the goal of affinity maturation is to increase antibody affinity by at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 7-fold, at least 8-fold, at least 9-fold, at least 10-fold, at least 20-fold, at least 30-fold, at least 40-fold, at least 50-fold, at least 100-fold, at least 500-fold, at least 1,000-fold, or more than 1,000-fold compared to the affinity of the original or starting antibody. If the affinity is lower than desired, the process can be repeated.

[0311] In some embodiments, antibody affinity may be assessed using different antigen formats. In some embodiments, antibody affinity to different antigen formats may be tested in vitro (e.g., by ELISA). In vitro testing may be performed using brain samples or fragments. Such samples or fragments may be obtained from subjects with AD (e.g., human AD patients). In some embodiments, brain samples or fragments may be obtained from non-human subjects. Such non-human subjects may include non-human animals (e.g., mice, rats, and primates) used in AD disease model studies. In some embodiments, brain samples or fragments used in antibody affinity testing may be derived from the TG4510 / P301S mouse strain. Antibody affinity may be compared to a control sample lacking the specific antigen for which affinity is being analyzed. In some embodiments, the control sample may include a brain sample or fragment from a non-diseased human subject. In some embodiments, brain samples or fragments from wild-type and / or tau knockout mouse strains may be used as control samples. In vitro affinity testing may be performed using recombinant or isolated protein antigens (e.g., by ELISA). In some embodiments, recombinant or isolated ePHFs are used for antibody affinity testing. In some embodiments, the antigens listed in Table 8 may be used.

[0312] In some embodiments, antibody affinity analysis can be used to adjust the multispecificity of an antibody (e.g., to reduce or increase the multispecificity of an antibody). Such adjustment can include adjusting the relative affinity for two or more epitopes or antigens. For example, an antibody can be optimized to have higher affinity for one epitope or antigen compared to a second epitope or antigen.

[0313] Antibodies can be modified to optimize the functional properties of the antibody. Such functional properties can be evaluated or engineered based on analytical assay results related to one or more functional properties of the antibody. Assays can be used to screen multiple antibodies and identify or rank antibodies based on functional criteria. Anti-tau antibodies can be modified to optimize tau aggregation inhibition. Such inhibition can be based on the physical disruption of tau aggregates or the ability of the anti-tau antibody to deplete tau protein from the assay sample. Optimization based on tau aggregation inhibition can be assessed using one or more assays of tau aggregation (e.g., by tau seeding assays).

[0314] Modification of production In some embodiments, modifications may be made to optimize antibody production. Such modifications may include or relate to one or more of protein folding, stability, expression, and / or immunogenicity. Modifications may be made to address one or more antibody characteristics that adversely affect production. Such characteristics may include, but are not limited to, unpaired cysteines or irregular disulfides; glycosylation sites (e.g., N-linked NXS / T sites); acid cleavage sites, amino acid oxidation sites, compatibility with mouse germline sequences; asparagine deamidation sites; aspartic acid isomerization sites; N-terminal pyroglutamate formation sites; and aggregation-prone amino acid sequence regions (e.g., within CDR sequences).

[0315] In some embodiments, antibodies of the present disclosure can be prepared using recombinant DNA technology (see, e.g., U.S. Pat. No. 4,816,567, incorporated herein by reference in its entirety). DNA encoding the antibody can be isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes capable of specifically binding to genes encoding the heavy and light chains of a murine antibody). In some embodiments, hybridoma cells can be used as a preferred source of DNA. Once isolated, the DNA can be placed into an expression vector, which is then transfected into host cells. Host cells can include, but are not limited to, HEK293 cells, HEK293T cells, monkey COS cells, Chinese hamster ovary (CHO) cells, and myeloma cells, which do not otherwise produce immunoglobulin proteins, for the synthesis of monoclonal antibodies in recombinant host cells. The DNA can also be modified, for example, by substituting the coding sequence for human heavy and light chain constant domains for the homologous murine sequences (U.S. Pat. No. 4,816,567), or by covalently linking all or part of the coding sequence for a non-immunoglobulin polypeptide to the immunoglobulin coding sequence.

[0316] Antibody humanization In some embodiments, the anti-tau antibodies of the present disclosure may be prepared as humanized antibodies. A "humanized" antibody is a chimeric antibody that contains minimal sequence (e.g., variable domain or CDR) derived from a non-human immunoglobulin (e.g., a murine immunoglobulin). A humanized antibody may be prepared from a human (recipient) immunoglobulin in which hypervariable region residues are substituted by hypervariable region residues derived from one or more non-human "donor" antibodies (e.g., a mouse, rat, rabbit, or non-human primate). The donor antibody may be selected based on the desired specificity, affinity, and / or potency. A humanized antibody may contain one or more back mutations, including the restoration of one or more amino acids to those found in the donor antibody. Conversely, donor antibody residues in a humanized antibody may be mutated to match those present in the human recipient antibody. Back mutations may be introduced to reduce the human immune response to the humanized antibody. In some embodiments, back mutations are introduced to avoid problems with antibody manufacturing (e.g., protein aggregation or post-translational modifications).

[0317] To construct an expression plasmid encoding a fully humanized antibody with a human constant region, DNA sequences encoding the antibody variable region can be inserted into an expression vector (e.g., a mammalian expression vector) between an upstream promoter / enhancer and immunoglobulin signal sequence and a downstream immunoglobulin constant region gene. The DNA sample can then be transfected into mammalian cells for antibody production. Constant domains from any class of human antibody can be used. There are five major classes of intact human antibodies: IgA, IgD, IgE, IgG, and IgM, some of which can be further divided into subclasses (isotypes), e.g., IgG1 (human and mouse), IgG2 (human), IgG2a (mouse), IgG2b (mouse), IgG2c (mouse), IgG3 (human and mouse), IgG4 (human), IgA (mouse), IgA1 (human), and IgA2 (human).

[0318] Cell lines stably transfected with DNA encoding the humanized antibody may be prepared and used to establish stable cell lines. The humanized antibody-producing cell lines may be expanded to express the humanized antibody, which may be harvested and purified from the cell culture medium.

[0319] In some embodiments, the humanized antibodies of the present disclosure may have cross-reactivity with non-human species. Species cross-reactivity may allow the antibody to be used in different animals for various purposes. For example, cross-reactive antibodies may be used in preclinical animal studies to provide information about the efficacy and / or toxicity of the antibody. Non-human species may include, but are not limited to, mice, rats, rabbits, dogs, pigs, goats, sheep, and non-human primates (e.g., cynomolgus monkeys).

[0320] antibody conjugates In some embodiments, the antibodies of the present disclosure may be or may be prepared as antibody conjugates. As used herein, the term "conjugate" refers to any agent, cargo, or chemical moiety attached to a receptor entity, or the process of attaching such an agent, cargo, or chemical moiety. As used herein, the term "antibody conjugate" refers to any antibody having an attached agent, cargo, or chemical moiety. Conjugates used to prepare antibody conjugates may include a therapeutic agent. Such therapeutic agents may include drugs. Antibody conjugates containing a conjugated drug are referred to herein as "antibody-drug conjugates." Antibody-drug conjugates may be used to target a conjugated drug to a particular target based on the affinity of the associated antibody for a protein or epitope associated with such a target. Such antibody-drug conjugates may be used to localize the biological activity associated with such a conjugated drug to a target cell, tissue, organ, or other targeting entity. In some embodiments, the conjugates used to prepare antibody conjugates include a detectable label. The antibody can be conjugated with a detectable label for detection purposes. Such detectable labels can include, but are not limited to, radioisotopes, fluorophores, chromophores, chemiluminescent compounds, enzymes, enzyme cofactors, dyes, metal ions, ligands, biotin, avidin, streptavidin, haptens, quantum dots, or any other detectable labels known in the art or described herein.

[0321] The conjugate may be attached to the antibody directly or via a linker. Direct attachment may be by covalent bonding or by non-covalent association (e.g., ionic, electrostatic, hydrophobic, hydrogen bonding, hybridization, etc.). The linker used to attach the conjugate may comprise any chemical structure capable of connecting the antibody to the conjugate. In some embodiments, the linker comprises a polymer (e.g., a nucleic acid, a polypeptide, polyethylene glycol, a carbohydrate, a lipid, or a combination thereof). The antibody conjugate linker may be cleavable (e.g., via contact with an enzyme, a change in pH, or a change in temperature).

[0322] Exemplary Anti-Tau Antibodies In some embodiments, the anti-tau antibody comprises at least one antigen-binding domain, e.g., a variable region or antigen-binding fragment thereof, from an antibody described herein, e.g., from V0004, V0009, V0022, V0023, V0024, or V0052, as described in Table 1 or 4, or a sequence substantially identical (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences. In some embodiments, the anti-tau antibody comprises at least one antigen-binding domain, e.g., a variable region or antigen-binding fragment thereof, from an antibody described in WO2021 / 211753, the entire contents of which are incorporated herein by reference, 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 antibody sequences disclosed in WO2021 / 211753.

[0323] In some embodiments, the anti-tau antibody comprises a heavy chain variable region from an antibody described herein, e.g., selected from V0004, V0009, V0022, V0023, V0024, or V0052, e.g., as described in Table 4, or a sequence substantially identical (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences. In some embodiments, the heavy chain variable region comprises an amino acid sequence that has at least one, two, or three modifications (e.g., substitutions, e.g., conservative substitutions) of the amino acid sequence of a heavy chain variable region presented in Table 4, but no more than 30, no more than 20, or no more than 10 modifications (e.g., substitutions, e.g., conservative substitutions).

[0324] In some embodiments, the nucleotide sequence encoding the anti-tau antibody comprises the nucleotide sequence of a heavy chain variable region from an antibody described herein, e.g., as described in Table 4, e.g., selected from V0004, V0009, V0022, V0023, V0024, or V0052, or a nucleotide sequence substantially identical (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences.

[0325] In some embodiments, the anti-tau antibody comprises a light chain variable region from an antibody described herein, e.g., selected from V0004, V0009, V0022, V0023, V0024, or V0052, e.g., as described in Table 4, or a sequence substantially identical (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences. In some embodiments, the light chain variable region comprises an amino acid sequence that has at least one, two, or three modifications (e.g., substitutions, e.g., conservative substitutions) of the amino acid sequence of a light chain variable region presented in Table 4, but no more than 30, no more than 20, or no more than 10 modifications (e.g., substitutions, e.g., conservative substitutions).

[0326] In some embodiments, the nucleotide sequence encoding the anti-tau antibody comprises the nucleotide sequence of a light chain variable region from an antibody described herein, e.g., as described in Table 4, e.g., selected from V0004, V0009, V0022, V0023, V0024, or V0052, or a nucleotide sequence substantially identical (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences.

[0327] In some embodiments, the anti-tau antibody comprises a heavy chain variable region and a light chain variable region from an antibody described herein, e.g., as described in Table 4, e.g., selected from V0004, V0009, V0022, V0023, V0024, or V0052, or a sequence substantially identical (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences. In some embodiments, the anti-tau antibody comprises a heavy chain variable region comprising an amino acid sequence having at least one, two, or three modifications (e.g., substitutions, e.g., conservative substitutions) of the heavy chain variable region amino acid sequence presented in Table 4, but no more than 30, no more than 20, or no more than 10 modifications (e.g., substitutions, e.g., conservative substitutions); and a light chain variable region comprising an amino acid sequence having at least one, two, or three modifications (e.g., substitutions, e.g., conservative substitutions) of the light chain variable region amino acid sequence presented in Table 4, but no more than 30, no more than 20, or no more than 10 modifications (e.g., substitutions, e.g., conservative substitutions).

[0328] In some embodiments, the anti-tau antibody comprises a heavy chain constant region, e.g., a human IgG1, IgG2, IgG3, or IgG4 constant region, or a murine IgG1, IgG2A, IgG2B, IgG2C, or IgG3 constant region. In some embodiments, the heavy chain constant comprises an amino acid sequence set forth in Table 5, or a sequence substantially identical (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences. In some embodiments, the nucleic acid encoding the heavy chain constant region comprises a nucleotide sequence set forth in Table 5, or a nucleotide sequence substantially identical (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences.

[0329] In some embodiments, the anti-tau antibody comprises a light chain constant region, e.g., a kappa light chain constant region, e.g., a human kappa or lambda light chain constant region, or a mouse kappa or lambda light chain constant region. In some embodiments, the light chain constant comprises an amino acid sequence set forth in Table 5, or a sequence substantially identical (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences. In some embodiments, the nucleic acid encoding the light chain constant region comprises a nucleotide sequence set forth in Table 5, or a nucleotide sequence substantially identical (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences.

[0330] In some embodiments, the anti-tau antibody comprises a heavy chain constant region and a light chain constant region. In some embodiments, the heavy chain constant region and the light chain constant region comprise an amino acid sequence set forth in Table 5, or a sequence substantially identical thereto (e.g., having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity). In some embodiments, the nucleotide sequence encoding the anti-tau antibody comprises a nucleotide sequence of a heavy chain constant region and a nucleotide sequence of a kappa or lambda light chain constant region. In some embodiments, the nucleotide sequence encoding the heavy chain constant region and the light chain constant region comprises a nucleotide sequence set forth in Table 5, or a nucleotide sequence substantially identical thereto (e.g., having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity).

[0331] In some embodiments, the anti-tau antibody comprises a heavy chain variable and constant region, a light chain variable and constant region, or both, that comprises an amino acid sequence of Table 4 for the variable region and an amino acid sequence of Table 5 for the constant region, or that is encoded by a nucleic acid sequence of Tables 4 and 5, 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.

[0332] In some embodiments, the anti-tau antibody comprises at least one, two, or three complementarity determining regions (CDRs) from a heavy chain variable region comprising an amino acid sequence of Table 4, or encoded by a nucleic acid sequence of Table 4, or a sequence substantially identical (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences. In some embodiments, one, two, three, four, five, or all of the CDRs have one, two, three, four, five, or more changes, e.g., amino acid substitutions, insertions, or deletions, relative to the amino acid sequence shown in Table 4 or encoded by the nucleotide sequence shown in Table 4. In some embodiments, the encoded anti-tau antibody comprises substitutions in the heavy chain CDRs, e.g., one or more substitutions in CDR1, CDR2, and / or CDR3 of the heavy chain.

[0333] In some embodiments, the anti-tau antibody comprises at least one, two, or three complementarity determining regions (CDRs) from a light chain variable region comprising an amino acid sequence of Table 4, or encoded by a nucleic acid sequence of Table 4, or a sequence substantially identical (e.g., having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences. In some embodiments, one, two, three, four, five, or all of the CDRs have one, two, three, four, five, or more changes, e.g., amino acid substitutions, insertions, or deletions, relative to the amino acid sequence shown in Table 4 or encoded by the nucleotide sequence 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.

[0334] In some embodiments, the anti-tau antibody comprises at least one, two, three, four, five, or six CDRs (or collectively all of the CDRs) from heavy and light chain variable regions comprising the amino acid sequences shown in Table 4, or encoded by the nucleotide sequences shown in Table 4. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, six, or more alterations, e.g., amino acid substitutions, insertions, or deletions, relative to the CDRs shown in Table 4 or encoded by the nucleotide sequences shown in Table 4.

[0335] In some embodiments, the anti-tau antibody comprises all three CDRs from a heavy chain variable region, all three CDRs from a light chain variable region, or both (e.g., all six CDRs from the heavy and light chain variable regions) comprising the amino acid sequence shown in Table 4 or encoded by the nucleotide sequence shown in Table 4.

[0336] In some embodiments, anti-tau antibodies of the present disclosure may comprise CDRs identified by CDR analysis of the variable domain sequences presented herein via co-crystal structure analysis with bound antigen, by computational evaluation based on comparison with other antibodies (see, e.g., Strohl, WR Therapeutic Antibody Engineering. Woodhead Publishing, Philadelphia PA. 2012. Ch. 3, p47-54), or by the Kabat, Chothia, Al-Lazikani, Lefranc, or Honegger numbering schemes, as previously described.

[0337] [Table 2-1]

[0338] [Table 2-2]

[0339]

Table 2-3

[0340]

Table 2-4

[0341]

Table 2-5

[0342]

Table 2-6

[0343]

Table 2-7

[0344]

Table 2-8

[0345]

Table 2-9

[0346]

Table 2-10

[0347]

Table 2-11

[0348]

Table 2-12

[0349]

Table 3-1

[0350]

Table 3-2

[0351]

Table 3-3

[0352]

Table 3-4

[0353]

Table 3-5

[0354]

Table 3-6

[0355]

Table 3-7

[0356]

Table 4-1

[0357]

Table 4-2

[0358]

Table 4-3

[0359]

Table 4-4

[0360]

Table 5-1

[0361]

Table 5-2

[0362]

Table 5-3

[0363]

Table 6-1

[0364]

Table 6-2

[0365]

Table 6-3

[0366]

Table 6-4

[0367]

Table 6-5

[0368]

Table 6-6

[0369]

Table 6-7

[0370] [Table 6-8]

[0371] [Table 6-9]

[0372] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of heavy chain complementarity determining region 1 (HC CDR1), HC CDR2, and / or HC CDR3, wherein the HC CDR1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NOs: 299, 343, and 395, respectively. In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of LC CDR1, LC CDR2, and / or LC CDR3, wherein the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NOs: 460, 518, and 557, respectively. In some embodiments, the anti-tau antibody comprises HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3, wherein the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences respectively comprise the sequences of SEQ ID NOs: 299, 343, 395, 460, 518, and 557. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, or more changes, e.g., amino acid substitutions, insertions, or deletions, relative to the amino acid sequence of any of SEQ ID NOs: 299, 343, 395, 460, 518, or 557.

[0373] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of heavy chain complementarity determining region 1 (HC CDR1), HC CDR2, and / or HC CDR3, wherein the HC CDR1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NOs: 1140, 1141, and 395, respectively. In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of LC CDR1, LC CDR2, and / or LC CDR3, wherein the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NOs: 460, 518, and 557, respectively. In some embodiments, the anti-tau antibody comprises HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3, wherein the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences respectively comprise the sequences of SEQ ID NOs: 1140, 1141, 395, 460, 518, and 557. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, or more changes, e.g., amino acid substitutions, insertions, or deletions, relative to the amino acid sequence of any of SEQ ID NOs: 1140, 1141, 395, 460, 518, and 557.

[0374] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of heavy chain complementarity determining region 1 (HC CDR1), HC CDR2, and / or HC CDR3, wherein the HC CDR1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NOs: 1155, 1156, and 1157, respectively. In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of LC CDR1, LC CDR2, and / or LC CDR3, wherein the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NOs: 1158, NAK, and SEQ ID NO: 557, respectively. In some embodiments, the anti-tau antibody comprises HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3, wherein the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NO: 1155, SEQ ID NO: 1156, SEQ ID NO: 1157, SEQ ID NO: 1158, NAK, and SEQ ID NO: 557, respectively. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, or more changes, e.g., amino acid substitutions, insertions, or deletions, relative to the amino acid sequence of any of SEQ ID NO: 1155, SEQ ID NO: 1156, SEQ ID NO: 1157, SEQ ID NO: 1158, NAK, and SEQ ID NO: 557.

[0375] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of heavy chain complementarity determining region 1 (HC CDR1), HC CDR2, and / or HC CDR3, wherein the HC CDR1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NOs: 304, 347, and 400, respectively. In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of LC CDR1, LC CDR2, and / or LC CDR3, wherein the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NOs: 464, 523, and 562, respectively. In some embodiments, the anti-tau antibody comprises HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3, wherein the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences respectively comprise the sequences of SEQ ID NOs: 304, 347, 400, 464, 523, and 562. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, or more changes, e.g., amino acid substitutions, insertions, or deletions, relative to the amino acid sequence of any of SEQ ID NOs: 304, 347, 400, 464, 523, and 562.

[0376] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of heavy chain complementarity determining region 1 (HC CDR1), HC CDR2, and / or HC CDR3, wherein the HC CDR1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NOs: 1142, 1143, and 400, respectively. In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of LC CDR1, LC CDR2, and / or LC CDR3, wherein the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NOs: 464, 523, and 562, respectively. In some embodiments, the anti-tau antibody comprises HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3, wherein the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences respectively comprise the sequences of SEQ ID NOs: 1142, 1143, 400, 464, 523, and 562. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, or more changes, e.g., amino acid substitutions, insertions, or deletions, relative to the amino acid sequence of any of SEQ ID NOs: 1142, 1143, 400, 464, 523, and 562.

[0377] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of heavy chain complementarity determining region 1 (HC CDR1), HC CDR2, and / or HC CDR3, wherein the HC CDR1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NOs: 1160, 1161, and 1162, respectively. In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of LC CDR1, LC CDR2, and / or LC CDR3, wherein the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NOs: 1163, WAS, and SEQ ID NO: 562, respectively. In some embodiments, the anti-tau antibody comprises HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3, wherein the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NO: 1160, SEQ ID NO: 1161, SEQ ID NO: 1162, SEQ ID NO: 1163, WAS, and SEQ ID NO: 562, respectively. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, or more changes, e.g., amino acid substitutions, insertions, or deletions, relative to the amino acid sequence of any of SEQ ID NO: 1160, SEQ ID NO: 1161, SEQ ID NO: 1162, SEQ ID NO: 1163, WAS, and SEQ ID NO: 562.

[0378] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of heavy chain complementarity determining region 1 (HC CDR1), HC CDR2, and / or HC CDR3, wherein the HC CDR1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NOs: 314, 341, and 410, respectively. In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of LC CDR1, LC CDR2, and / or LC CDR3, wherein the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NOs: 1154, 529, and 571, respectively. In some embodiments, the anti-tau antibody comprises HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3, wherein the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences respectively comprise the sequences of SEQ ID NOs: 314, 341, 410, 1154, 529, and 571. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, or more changes, e.g., amino acid substitutions, insertions, or deletions, relative to the amino acid sequence of any of SEQ ID NOs: 314, 341, 410, 1154, 529, and 571.

[0379] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of heavy chain complementarity determining region 1 (HC CDR1), HC CDR2, and / or HC CDR3, wherein the HC CDR1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NOs: 1144, 1145, and 410, respectively. In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of LC CDR1, LC CDR2, and / or LC CDR3, wherein the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NOs: 1146, 529, and 571, respectively. In some embodiments, the anti-tau antibody comprises HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3, wherein the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences respectively comprise the sequences of SEQ ID NOs: 1144, 1145, 410, 1146, 529, and 571. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, or more changes, e.g., amino acid substitutions, insertions, or deletions, relative to the amino acid sequence of any of SEQ ID NOs: 1144, 1145, 410, 1146, 529, and 571.

[0380] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of heavy chain complementarity determining region 1 (HC CDR1), HC CDR2, and / or HC CDR3, wherein the HC CDR1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NOs: 1165, 1166, and 1167, respectively. In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of LC CDR1, LC CDR2, and / or LC CDR3, wherein the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NO: 473, RVS, and SEQ ID NO: 571, respectively. In some embodiments, the anti-tau antibody comprises HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3, wherein the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NO: 1165, SEQ ID NO: 1166, SEQ ID NO: 1167, SEQ ID NO: 473, RVS, and SEQ ID NO: 571, respectively. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, or more changes, e.g., amino acid substitutions, insertions, or deletions, relative to the amino acid sequence of any one of SEQ ID NO: 1165, SEQ ID NO: 1166, SEQ ID NO: 1167, SEQ ID NO: 473, RVS, and SEQ ID NO: 571.

[0381] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of heavy chain complementarity determining region 1 (HC CDR1), HC CDR2, and / or HC CDR3, wherein the HC CDR1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NOs: 64, 1145, and 1167, respectively. In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of LC CDR1, LC CDR2, and / or LC CDR3, wherein the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NOs: 1146, 529, and 571, respectively. In some embodiments, the anti-tau antibody comprises HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3, wherein the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences respectively comprise the sequences of SEQ ID NOs: 64, 1145, 1167, 1146, 529, and 571. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, or more changes, e.g., amino acid substitutions, insertions, or deletions, relative to the amino acid sequence of any of SEQ ID NOs: 64, 1145, 1167, 1146, 529, and 571.

[0382] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of heavy chain complementarity determining region 1 (HC CDR1), HC CDR2, and / or HC CDR3, wherein the HC CDR1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NOs: 315, 341, and 410, respectively. In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of LC CDR1, LC CDR2, and / or LC CDR3, wherein the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NOs: 474, 529, and 571, respectively. In some embodiments, the anti-tau antibody comprises HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3, wherein the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences respectively comprise the sequences of SEQ ID NOs: 315, 341, 410, 474, 529, and 571. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, or more changes, e.g., amino acid substitutions, insertions, or deletions, relative to the amino acid sequence of any of SEQ ID NOs: 315, 341, 410, 474, 529, and 571.

[0383] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of heavy chain complementarity determining region 1 (HC CDR1), HC CDR2, and / or HC CDR3, wherein the HC CDR1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NOs: 1147, 1148, and 410, respectively. In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of LC CDR1, LC CDR2, and / or LC CDR3, wherein the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NOs: 474, 529, and 571, respectively. In some embodiments, the anti-tau antibody comprises HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3, wherein the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences respectively comprise the sequences of SEQ ID NOs: 1147, 1148, 410, 474, 529, and 571. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, or more changes, e.g., amino acid substitutions, insertions, or deletions, relative to the amino acid sequence of any of SEQ ID NOs: 1147, 1148, 410, 474, 529, and 571.

[0384] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of heavy chain complementarity determining region 1 (HC CDR1), HC CDR2, and / or HC CDR3, wherein the HC CDR1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NOs: 1168, 1169, and 1167, respectively. In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of LC CDR1, LC CDR2, and / or LC CDR3, wherein the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NOs: 1170, RVS, and SEQ ID NO: 571, respectively. In some embodiments, the anti-tau antibody comprises HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3, wherein the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NO: 1168, SEQ ID NO: 1169, SEQ ID NO: 1167, SEQ ID NO: 1170, RVS, and SEQ ID NO: 571, respectively. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, or more changes, e.g., amino acid substitutions, insertions, or deletions, relative to the amino acid sequence of any of SEQ ID NO: 1168, SEQ ID NO: 1169, SEQ ID NO: 1167, SEQ ID NO: 1170, RVS, and SEQ ID NO: 571.

[0385] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of heavy chain complementarity determining region 1 (HC CDR1), HC CDR2, and / or HC CDR3, wherein the HC CDR1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NOs: 316, 341, and 410, respectively. In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of LC CDR1, LC CDR2, and / or LC CDR3, wherein the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NOs: 475, 530, and 571, respectively. In some embodiments, the anti-tau antibody comprises HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3, wherein the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences respectively comprise the sequences of SEQ ID NOs: 316, 341, 410, 475, 530, and 571. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, or more changes, e.g., amino acid substitutions, insertions, or deletions, relative to the amino acid sequence of any of SEQ ID NOs: 316, 341, 410, 475, 530, and 571.

[0386] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of heavy chain complementarity determining region 1 (HC CDR1), HC CDR2, and / or HC CDR3, wherein the HC CDR1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NOs: 1149, 1150, and 410, respectively. In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of LC CDR1, LC CDR2, and / or LC CDR3, wherein the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NOs: 475, 530, and 571, respectively. In some embodiments, the anti-tau antibody comprises HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3, wherein the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences respectively comprise the sequences of SEQ ID NOs: 1149, 1150, 410, 475, 530, and 571. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, or more changes, e.g., amino acid substitutions, insertions, or deletions, relative to the amino acid sequence of any of SEQ ID NOs: 1149, 1150, 410, 475, 530, and 571.

[0387] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of heavy chain complementarity determining region 1 (HC CDR1), HC CDR2, and / or HC CDR3, wherein the HC CDR1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NOs: 1171, 1166, and 1167, respectively. In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of LC CDR1, LC CDR2, and / or LC CDR3, wherein the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NOs: 1172, RVS, and SEQ ID NO: 571, respectively. In some embodiments, the anti-tau antibody comprises HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3, wherein the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NO:1171, SEQ ID NO:1166, SEQ ID NO:1167, SEQ ID NO:1172, RVS, and SEQ ID NO:571, respectively. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, or more changes, e.g., amino acid substitutions, insertions, or deletions, relative to the amino acid sequence of any of SEQ ID NO:1171, SEQ ID NO:1166, SEQ ID NO:1167, SEQ ID NO:1172, RVS, and SEQ ID NO:571.

[0388] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of heavy chain complementarity determining region 1 (HC CDR1), HC CDR2, and / or HC CDR3, wherein the HC CDR1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NOs: 325, 362, and 435, respectively. In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of LC CDR1, LC CDR2, and / or LC CDR3, wherein the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NOs: 495, 540, and 587, respectively. In some embodiments, the anti-tau antibody comprises HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3, wherein the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences respectively comprise the sequences of SEQ ID NOs: 325, 362, 435, 495, 540, and 587. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, or more changes, e.g., amino acid substitutions, insertions, or deletions, relative to the amino acid sequence of any of SEQ ID NOs: 325, 362, 435, 495, 540, and 587.

[0389] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of heavy chain complementarity determining region 1 (HC CDR1), HC CDR2, and / or HC CDR3, wherein the HC CDR1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NOs: 1152, 1153, and 435, respectively. In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of LC CDR1, LC CDR2, and / or LC CDR3, wherein the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NOs: 495, 540, and 587, respectively. In some embodiments, the anti-tau antibody comprises HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3, wherein the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences respectively comprise the sequences of SEQ ID NOs: 1152, 1153, 435, 495, 540, and 587. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, or more changes, e.g., amino acid substitutions, insertions, or deletions, relative to the amino acid sequence of any of SEQ ID NOs: 1152, 1153, 435, 495, 540, and 587.

[0390] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of heavy chain complementarity determining region 1 (HC CDR1), HC CDR2, and / or HC CDR3, wherein the HC CDR1, HC CDR2, and HC CDR3 sequences comprise the sequences of SEQ ID NOs: 1173, 1174, and 1175, respectively. In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of LC CDR1, LC CDR2, and / or LC CDR3, wherein the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NOs: 1176, YAS, and SEQ ID NO: 587, respectively. In some embodiments, the anti-tau antibody comprises HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3, wherein the HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NO: 1173, SEQ ID NO: 1174, SEQ ID NO: 1175, SEQ ID NO: 1176, YAS, and SEQ ID NO: 587, respectively. In some embodiments, one or more of the CDRs (or collectively all of the CDRs) have one, two, three, four, five, or more changes, e.g., amino acid substitutions, insertions, or deletions, relative to the amino acid sequence of any of SEQ ID NO: 1173, SEQ ID NO: 1174, SEQ ID NO: 1175, SEQ ID NO: 1176, YAS, and SEQ ID NO: 587.

[0391] In some embodiments, the anti-tau antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:4, or encoded by the nucleotide sequence of SEQ ID NO:150, or a sequence substantially identical (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences. In some embodiments, the anti-tau antibody comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:78, or encoded by ...

Claims

1. An antibody that binds to human tau, (a) a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (HC CDR1) comprising the amino acid sequence of SEQ ID NO: 64, a heavy chain complementarity determining region 2 (HC CDR2) comprising the amino acid sequence of SEQ ID NO: 1145, and a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of SEQ ID NO: 1167; and a light chain variable region (VL) comprising a light chain complementarity determining region 1 (LC CDR1) comprising the amino acid sequence of SEQ ID NO: 1146, a light chain complementarity determining region 2 (LC CDR2) comprising the amino acid sequence of SEQ ID NO: 529, and a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of SEQ ID NO: 571; (b) a VH comprising an HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1144, an HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1145, and an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410; and a VL comprising an LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1146, an LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; (c) a VH comprising an HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1165, an HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1166, and an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 1167, and a VL comprising an LC CDR1 comprising the amino acid sequence of SEQ ID NO: 473, an LC CDR2 comprising the amino acid sequence of RVS, and an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; or (d) a VH comprising an HC CDR1 comprising the amino acid sequence of SEQ ID NO: 314, an HC CDR2 comprising the amino acid sequence of SEQ ID NO: 341, and an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410, and a VL comprising an LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1154, an LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; and (i) the VH comprises an amino acid sequence including one, two, three, four, five, six, seven, eight, or all of V at position 5, S at position 7, A at position 9, V at position 11, K at position 12, K at position 19, V at position 20, R at position 67, and / or V at position 68, numbered according to SEQ ID NO: 21; (ii) the VL comprises an amino acid sequence numbered according to SEQ ID NO: 93, including one, two, or all of Q or E at position 17, P or R at position 18, and / or S at position 68; The antibody.

2. An antibody that binds to human tau, (a) a heavy chain variable region (VH) comprising a heavy chain complementarity determining region 1 (HC CDR1) comprising the amino acid sequence of SEQ ID NO: 64, a heavy chain complementarity determining region 2 (HC CDR2) comprising the amino acid sequence of SEQ ID NO: 1145, and a heavy chain complementarity determining region 3 (HC CDR3) comprising the amino acid sequence of SEQ ID NO: 1167; and a light chain variable region (VL) comprising a light chain complementarity determining region 1 (LC CDR1) comprising the amino acid sequence of SEQ ID NO: 1146, a light chain complementarity determining region 2 (LC CDR2) comprising the amino acid sequence of SEQ ID NO: 529, and a light chain complementarity determining region 3 (LC CDR3) comprising the amino acid sequence of SEQ ID NO: 571; (b) a VH comprising an HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1144, an HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1145, and an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410; and a VL comprising an LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1146, an LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; (c) a VH comprising an HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1165, an HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1166, and an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 1167, and a VL comprising an LC CDR1 comprising the amino acid sequence of SEQ ID NO: 473, an LC CDR2 comprising the amino acid sequence of RVS, and an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; or (d) a VH comprising an HC CDR1 comprising the amino acid sequence of SEQ ID NO: 314, an HC CDR2 comprising the amino acid sequence of SEQ ID NO: 341, and an HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410, and a VL comprising an LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1154, an LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and an LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; and (i) the VH comprises an amino acid sequence at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NOs: 69, 67, 68, 70, or 71; (ii) the VL comprises an amino acid sequence at least 92%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NOs: 73, 72, or 74-76; The antibody.

3. 3. The antibody of claim 1 or 2, wherein the HC CDR1 comprises the amino acid sequence of SEQ ID NO: 1144, the HC CDR2 comprises the amino acid sequence of SEQ ID NO: 1145, the HC CDR3 comprises the amino acid sequence of SEQ ID NO: 410, the LC CDR1 comprises the amino acid sequence of SEQ ID NO: 1146, the LC CDR2 comprises the amino acid sequence of SEQ ID NO: 529, and the LC CDR3 comprises the amino acid sequence of SEQ ID NO:

571.

4. The antibody of claim 2 or 3, wherein the VH comprises an amino acid sequence including one, two, three, four, five, six, seven, eight, or all of the following: V at position 5, S at position 7, A at position 9, V at position 11, K at position 12, K at position 19, V at position 20, R at position 67, and / or V at position 68, numbered according to SEQ ID NO:

21.

5. The antibody according to any one of claims 1 to 4, wherein the VH is (a) one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, or all of the following, numbered according to SEQ ID NO:21: V at position 5, E at position 6, S at position 7, A at position 9, V at position 11, K at position 12, A at position 16, K at position 19, V at position 20, M at position 48, R at position 67, V at position 68, I at position 70, A at position 76, S at position 77, A at position 79, Y at position 80, M at position 81, E at position 82, R at position 87, T at position 91, and / or T at position 113; (b) one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, or all of the following, numbered according to SEQ ID NO: 21: V at position 5, S at position 7, A at position 9, V at position 11, K at position 12, A at position 16, K at position 19, V at position 20, R at position 38, R at position 67, V at position 68, M at position 70, I at position 76, S at position 77, A at position 79, Y at position 80, M at position 81, E at position 82, R at position 87, D at position 89, and / or L at position 113; (c) one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, or all of the following, numbered according to SEQ ID NO: 21: V at position 5, S at position 7, A at position 9, V at position 11, K at position 12, S at position 14, A at position 16, K at position 19, V at position 20, R at position 38, Q at position 39, A at position 40, Q at position 43, R at position 67, V at position 68, I at position 71, R at position 72, D at position 73, T at position 74, T at position 76, T at position 84, and / or L at position 113; (d) 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or all of E at position 1, V at position 5, S at position 7, A at position 9, V at position 11, K at position 12, K at position 19, V at position 20, R at position 67, V at position 68, M at position 70, I at position 76, A at position 79, Y at position 80, M at position 81, E at position 82, R at position 85, D at position 89, L at position 113, and / or S at position 115, numbered according to SEQ ID NO: 21; or (e) one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, or all of the following, numbered according to SEQ ID NO:21: V at position 5, S at position 7, A at position 9, V at position 11, K at position 12, A at position 16, K at position 19, V at position 20, Q at position 43, M at position 48, R at position 67, V at position 68, M at position 70, T at position 76, S at position 77, R at position 87, and / or T at position 91 The antibody comprising:

6. The antibody of any one of claims 2 to 5, wherein the VL comprises an amino acid sequence including one, two, or all of Q or E at position 17, P or R at position 18, and / or S at position 68, numbered according to SEQ ID NO:

93.

7. The antibody according to any one of claims 1 to 6, wherein the VL is (a) one, two, three, four, five, six, seven, eight, nine, ten, or all of S at position 7, T at position 14, Q at position 17, P at position 18, Q at position 42, R at position 44, R at position 50, S at position 68, V at position 88, Y at position 92, and / or Q at position 105, numbered according to SEQ ID NO: 93; (b) one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, or all of: I at position 2, S at position 7, S at position 12, T at position 14, P at position 15, Q at position 17, P at position 18, Q at position 50, S at position 68, V at position 88, Y at position 92, Q at position 105, and / or V at position 109, numbered according to SEQ ID NO: 93; (c) 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or all of I at position 2, S at position 11, T at position 14, Q at position 17, P at position 18, Q at position 42, R at position 44, P at position 48, R at position 50, S at position 68, A at position 72, N at position 81, V at position 88, and / or Q at position 105; (d) one, two, three, four, five, six, seven, eight, nine, ten, eleven, or all of: I at position 2, E at position 3, S at position 7, T at position 14, Q at position 17, P at position 18, Q at position 42, R at position 44, R at position 50, R at position 51, S at position 68, and / or V at position 88, numbered according to SEQ ID NO: 93; or (e) one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, or all of the following, numbered according to SEQ ID NO:93: E at position 1, I at position 2, L at position 4, S at position 7, A at position 9, T at position 10, S at position 12, L at position 13, P at position 15, E at position 17, R at position 18, T at position 20, L at position 21, A at position 48, I at position 63, S at position 68, P at position 72, T at position 79, S at position 82, L at position 83, P at position 85, and / or A at position 89 The antibody comprising:

8. The antibody according to any one of claims 1 to 7, (i) the VH comprises, numbered according to SEQ ID NO: 21 or 69, a V at position 5, an S at position 7, an A at position 9, a V at position 11, a K at position 12, an S at position 14, an A at position 16, a K at position 19, a V at position 20, an R at position 38, a Q at position 39, an A at position 40, a Q at position 43, an R at position 67, a V at position 68, an I at position 71, an R at position 72, a D at position 73, a T at position 74, a T at position 76, a T at position 84, and an L at position 113; (ii) the VL comprises, numbered according to SEQ ID NO: 93 or 73, I at position 2, S at position 7, S at position 12, T at position 14, P at position 15, Q at position 17, P at position 18, Q at position 50, S at position 68, V at position 88, Y at position 92, Q at position 105, and V at position 109; The antibody.

9. The antibody according to any one of claims 1 to 8, (i) the VH comprises one, two, three, or four framework regions, e.g., one, two, three, or all of FRH1, FRH2, FRH3, and / or FRH4, and optionally the VH comprises, from N-terminus to C-terminus, FRH1-HC CDR1-FRH2-HC CDR2-FRH3-HC CDR3-FRH4; and / or (ii) the VL comprises one, two, three, or four framework regions, e.g., one, two, three, or all of FRL1, FRL2, FRL3, and / or FRL4, and optionally the VL comprises, from N-terminus to C-terminus, FRL1-LC CDR1-FRL2-LC CDR2-FRL3-LC CDR3-FRL4; The antibody.

10. 10. The antibody of claim 9, (a)(i) the FRH1 corresponds to positions 1 to 25 of the heavy chain variable region when numbered according to SEQ ID NOs: 21 or any one of 67 to 71; the FRH2 corresponds to positions 36 to 49 when numbered according to SEQ ID NOs: 21 or any one of 67 to 71; the FRH3 corresponds to positions 67 to 96 when numbered according to SEQ ID NOs: 21 or any one of 67 to 71; and / or the FRH4 corresponds to positions 108 to 118 when numbered according to SEQ ID NOs: 21 or any one of 67 to 71. (ii) said FRH1 corresponds to positions 1 to 30 of the heavy chain variable region according to the numbering scheme of SEQ ID NOs: 21 or any one of 67 to 71; said FRH2 corresponds to positions 36 to 49 of the heavy chain variable region according to the numbering scheme of SEQ ID NOs: 21 or any one of 67 to 71; said FRH3 corresponds to positions 67 to 98 of the heavy chain variable region according to the numbering scheme of SEQ ID NOs: 21 or any one of 67 to 71; and / or said FRH4 corresponds to positions 108 to 118 of the heavy chain variable region according to the numbering scheme of SEQ ID NOs: 21 or any one of 67 to 71; and / or (b) the FRL1 corresponds to positions 1 to 23 of the light chain variable region according to the numbering scheme of any one of SEQ ID NOs: 72-76 or 93; the FRL2 corresponds to positions 40 to 54 of the light chain variable region according to the numbering scheme of any one of SEQ ID NOs: 72-76 or 93; the FRL3 corresponds to positions 62 to 93 of the light chain variable region according to the numbering scheme of any one of SEQ ID NOs: 72-76 or 93; and / or the FRL4 corresponds to positions 103 to 112 of the light chain variable region according to the numbering scheme of any one of SEQ ID NOs: 72-76 or 93. The antibody.

11. 10. The antibody according to any one of the preceding claims, (a) the VH is (i) FRH1 comprising amino acids 1-25 or 1-30 of any one of SEQ ID NOs: 67-71; an amino acid sequence containing one, two, three, but not more than four modifications (e.g., substitutions, e.g., conservative substitutions) relative to amino acids 1-25 or 1-30 of any one of SEQ ID NOs: 67-71; (ii) FRH2 comprising amino acids 36-49 of any one of SEQ ID NOs: 67-71; an amino acid sequence containing one, two, three, but not more than four modifications (e.g., substitutions, e.g., conservative substitutions) relative to amino acids 36-49 of any one of SEQ ID NOs: 67-71; (iii) FRH3 comprising amino acids 67-96 or 67-98 of any one of SEQ ID NOs: 67-71; an amino acid sequence containing one, two, three, but not more than four modifications (e.g., substitutions, e.g., conservative substitutions) relative to amino acids 67-96 or 67-98 of any one of SEQ ID NOs: 67-71; and / or (iv) FRH4, comprising amino acids 108-118 of any one of SEQ ID NOs: 67-71; an amino acid sequence containing one, two, three, but not more than four modifications (e.g., substitutions, e.g., conservative substitutions) relative to amino acids 108-118 of any one of SEQ ID NOs: 67-71. and / or (b) the VL is (i) FRL1 comprising amino acids 1-23 of any one of SEQ ID NOs: 72-76; an amino acid sequence containing one, two, three, but not more than four modifications (e.g., substitutions, e.g., conservative substitutions) relative to amino acids 1-23 of any one of SEQ ID NOs: 72-76; (ii) FRL2 comprising amino acids 40-54 of any one of SEQ ID NOs: 72-76; an amino acid sequence containing one, two, three, but not more than four modifications (e.g., substitutions, e.g., conservative substitutions) relative to amino acids 40-54 of any one of SEQ ID NOs: 72-76; (iii) FRL3 comprising amino acids 62-93 of any one of SEQ ID NOs: 72-76; an amino acid sequence containing one, two, three, but not more than four modifications (e.g., substitutions, e.g., conservative substitutions) relative to amino acids 62-93 of any one of SEQ ID NOs: 72-76; and / or (iv) FRL4, comprising amino acids 103-112 of any one of SEQ ID NOs: 72-76; an amino acid sequence containing one, two, three, but not more than four modifications (e.g., substitutions, e.g., conservative substitutions) relative to amino acids 103-112 of any one of SEQ ID NOs: 72-76. The antibody comprising one, two, three, or all of:

12. The antibody according to any one of claims 1 to 11, (a) the VH comprises the amino acid sequence of any one of SEQ ID NOs: 67-71; or an amino acid sequence that is at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NOs: 67-71; or an amino acid sequence that contains at least one, two, three, four, or five, but not more than ten, modifications, e.g., substitutions (e.g., conservative substitutions), relative to the amino acid sequence of any one of SEQ ID NOs: 67-71; and / or (b) the VL comprises the amino acid sequence of any one of SEQ ID NOs: 72-76; or an amino acid sequence at least 92%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of any one of SEQ ID NOs: 72-76; or an amino acid sequence that contains at least 1, 2, 3, 4, or 5, but not more than 10, modifications, e.g., substitutions (e.g., conservative substitutions), relative to the amino acid sequence of any one of SEQ ID NOs: 72-76. The antibody.

13. The antibody according to any one of claims 1 to 12, (i) the VH comprises the amino acid sequence of SEQ ID NO: 69, or an amino acid sequence at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 69, and the VL comprises the amino acid sequence of SEQ ID NO: 73, or an amino acid sequence at least 92%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 73; or (ii) the VH comprises the amino acid sequence of SEQ ID NO: 70 or an amino acid sequence at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 70, and the VL comprises the amino acid sequence of SEQ ID NO: 72 or an amino acid sequence at least 92%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 72; or (iii) the VH comprises the amino acid sequence of SEQ ID NO: 67 or an amino acid sequence at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 67, and the VL comprises the amino acid sequence of SEQ ID NO: 72 or an amino acid sequence at least 92%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 72; or (iv) the VH comprises the amino acid sequence of SEQ ID NO: 71 or an amino acid sequence at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 71, and the VL comprises the amino acid sequence of SEQ ID NO: 73 or an amino acid sequence at least 92%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 73; or (v) the VH comprises the amino acid sequence of SEQ ID NO: 71 or an amino acid sequence at least 90%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 71, and the VL comprises the amino acid sequence of SEQ ID NO: 74 or an amino acid sequence at least 92%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 74; The antibody.

14. The antibody of any one of claims 1 to 13, wherein the VH comprises the amino acid sequence of SEQ ID NO: 69 and the VL comprises the amino acid sequence of SEQ ID NO:

73.

15. The antibody according to any one of claims 1 to 14, (i) the nucleotide sequence encoding the VH comprises the nucleotide sequence of any one of SEQ ID NOs: 156-160, or a nucleotide sequence at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; and / or (ii) the nucleotide sequence encoding the VL comprises the nucleotide sequence of any one of SEQ ID NOs: 161-165, or a nucleotide sequence at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; The antibody.

16. The antibody of any one of the preceding claims, wherein the antibody is a humanized antibody.

17. Full length antibody, bispecific antibody, Fab, F(ab') ２ , Fv, or a single chain Fv fragment (scFv).

18. 10. The antibody of any one of the preceding claims, comprising a heavy chain constant region selected from IgG1, IgG2, IgG3, IgG4, and / or a kappa or lambda light chain constant region.

19. 10. The antibody of any one of the preceding claims, comprising an IgG4 heavy chain constant region and a kappa light chain constant region.

20. 10. The antibody according to any one of the preceding claims, (i) the antibody comprises a human IgG4 constant region comprising an amino acid other than serine at position 228 according to EU numbering; (ii) the antibody comprises a human IgG4 constant region comprising a serine to proline substitution at position 228 according to EU numbering; (iii) the antibody comprises a heavy chain constant region (e.g., a human IgG4 constant region) comprising the amino acid sequence of SEQ ID NO: 194, or an amino acid sequence at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 194; and / or (iv) the antibody comprises a heavy chain constant region (e.g., a human IgG4 constant region), and the nucleotide sequence encoding the heavy chain constant region comprises the nucleotide sequence of any one of SEQ ID NOs: 195, 196, 198, or 199, or a nucleotide sequence at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 195, 196, 198, or 199; The antibody.

21. 21. The antibody of any one of claims 1 to 20, wherein the antibody comprises a light chain constant region (e.g., a kappa light chain constant region); (i) the light chain constant region comprises the amino acid sequence of SEQ ID NO: 200, or an amino acid sequence at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 200; and / or (ii) the nucleotide sequence encoding the light chain constant region comprises SEQ ID NO: 201 or 202, or a nucleotide sequence at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 201 or 202; The antibody.

22. The antibody according to any one of claims 1 to 21, wherein the antibody (i) a heavy chain comprising the amino acid sequence of any one of SEQ ID NOs: 170-174, or an amino acid sequence at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 170-174; and / or (ii) a light chain comprising the amino acid sequence of any one of SEQ ID NOs: 175-179, or an amino acid sequence at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 175-179. The antibody comprising:

23. The antibody according to any one of claims 1 to 22, wherein the antibody (i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 172, or an amino acid sequence at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto, and a light chain comprising the amino acid sequence of SEQ ID NO: 176, or an amino acid sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto; (ii) a heavy chain comprising the amino acid sequence of SEQ ID NO: 173, or an amino acid sequence at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto, and a light chain comprising the amino acid sequence of SEQ ID NO: 175, or an amino acid sequence at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; (iii) a heavy chain comprising the amino acid sequence of SEQ ID NO: 170, or an amino acid sequence at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto, and a light chain comprising the amino acid sequence of SEQ ID NO: 175, or an amino acid sequence at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; (iv) a heavy chain comprising the amino acid sequence of SEQ ID NO: 174, or an amino acid sequence at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto, and a light chain comprising the amino acid sequence of SEQ ID NO: 176, or an amino acid sequence at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; or (v) a heavy chain comprising the amino acid sequence of SEQ ID NO: 174, or an amino acid sequence at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto, and a light chain comprising the amino acid sequence of SEQ ID NO: 177, or an amino acid sequence at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto. The antibody comprising:

24. The antibody of any one of claims 1 to 23, comprising a heavy chain comprising the amino acid sequence of SEQ ID NO: 172 and a light chain comprising the amino acid sequence of SEQ ID NO:

176.

25. The antibody according to any one of claims 22 to 24, (i) the nucleotide sequence encoding the heavy chain comprises the nucleotide sequence of any one of SEQ ID NOs: 180-184, or a nucleotide sequence at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 180-184; and / or (ii) the nucleotide sequence encoding the light chain comprises the nucleotide sequence of any one of SEQ ID NOs: 185-189, or a nucleotide acid sequence at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 185-189; The antibody.

26. 10. The antibody according to any one of the preceding claims, wherein the antibody (i) binds to the C-terminus of tau protein, e.g., residues 409-436 numbered according to SEQ ID NO: 920; (ii) binds to phosphorylated residues of tau protein; (iii) binds to the phosphorylated serine at position 422 (e.g., pS422) numbered according to SEQ ID NO: 920; (iv) preferentially binds to pathological tau (e.g., PHF tau or ePHF) relative to wild-type tau, e.g., as measured by an assay, e.g., an ELISA assay, an SPR assay, or a Biacore assay, e.g., an assay described in Example 1 or 8; (v) reducing, e.g., inhibiting, tau aggregation, and / or (vi) binds to an epitope that includes a region formed by a complex of at least two tau proteins, e.g., a tau dimer; The antibody.

27. An antibody that competes for binding to tau with an antibody of any one of the preceding claims or that binds to the same epitope as, substantially the same epitope as, or an overlapping epitope with, an epitope of an antibody of any one of the preceding claims.

28. A nucleic acid encoding the antibody of any one of claims 1 to 27.

29. 29. The nucleic acid of claim 28, (i) the nucleotide sequence encoding the VH comprises the nucleotide sequence of SEQ ID NOs: 156-160, or a nucleotide sequence at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto, and / or the nucleotide sequence encoding the VL comprises the nucleotide sequence of any one of SEQ ID NOs: 161-165, or a nucleotide sequence at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; (ii) the nucleotide sequence encoding the VH comprises the nucleotide sequence of SEQ ID NO: 158, or a nucleotide sequence at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto, and the nucleotide sequence encoding the VL comprises the nucleotide sequence of SEQ ID NO: 162, or a nucleotide sequence at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; or (iii) the nucleotide sequence encoding the VH comprises the nucleotide sequence of SEQ ID NO: 159, or a nucleotide sequence at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto, and the nucleotide sequence encoding the VL comprises the nucleotide sequence of SEQ ID NO: 161, or a nucleotide sequence at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical thereto; or (iv) the nucleotide sequence encoding the VH comprises the nucleotide sequence of SEQ ID NO: 156, or a nucleotide sequence at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto, and the nucleotide sequence encoding the VL comprises the nucleotide sequence of SEQ ID NO: 161, or a nucleotide sequence at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; or (v) the nucleotide sequence encoding the VH comprises the nucleotide sequence of SEQ ID NO: 160, or a nucleotide sequence at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto, and the nucleotide sequence encoding the VL comprises the nucleotide sequence of SEQ ID NO: 162, or a nucleotide sequence at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; or (vi) the nucleotide sequence encoding the VH comprises the nucleotide sequence of SEQ ID NO: 160, or a nucleotide sequence at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto, and the nucleotide sequence encoding the VL comprises the nucleotide sequence of SEQ ID NO: 163, or a nucleotide sequence at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; The nucleic acid.

30. 30. The nucleic acid of claim 28 or 29, (i) the nucleotide sequence encoding the heavy chain comprises the nucleotide sequence of 180-184, or a nucleotide sequence at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto, and / or the nucleotide sequence encoding the light chain comprises the nucleotide sequence of any one of SEQ ID NOs: 185-189, or a nucleotide sequence at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; (ii) the nucleotide sequence encoding the heavy chain comprises the nucleotide sequence of SEQ ID NO: 182, or a nucleotide sequence at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto, and the nucleotide sequence encoding the light chain comprises the nucleotide sequence of SEQ ID NO: 186, or a nucleotide sequence at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; or (iii) the nucleotide sequence encoding the heavy chain comprises the nucleotide sequence of SEQ ID NO: 183, or a nucleotide sequence at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto, and the nucleotide sequence encoding the light chain comprises the nucleotide sequence of SEQ ID NO: 185, or a nucleotide sequence at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; or (iv) the nucleotide sequence encoding the heavy chain comprises the nucleotide sequence of SEQ ID NO: 180, or a nucleotide sequence at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto, and the nucleotide sequence encoding the light chain comprises the nucleotide sequence of SEQ ID NO: 185, or a nucleotide sequence at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; or (iv) the nucleotide sequence encoding the heavy chain comprises the nucleotide sequence of SEQ ID NO: 184, or a nucleotide sequence at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto, and the nucleotide sequence encoding the light chain comprises the nucleotide sequence of SEQ ID NO: 186, or a nucleotide sequence at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; or (vi) the nucleotide sequence encoding the heavy chain comprises the nucleotide sequence of SEQ ID NO: 184, or a nucleotide sequence at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto, and the nucleotide sequence encoding the light chain comprises the nucleotide sequence of SEQ ID NO: 187, or a nucleotide sequence at least 90%, 92%, 95%, 96%, 97%, 98%, or 99% identical thereto; The nucleic acid.

31. The nucleotide sequence of any one of claims 28 to 30, which is codon-optimized.

32. An antibody encoded by the nucleic acid of any one of claims 28 to 31.

33. A viral genome comprising a promoter operably linked to a nucleic acid encoding the antibody of any one of claims 1 to 27 or 32.

34. The viral genome of claim 33, wherein the encoded VH and VL sequences are directly connected.

35. The viral genome of claim 33, wherein the encoded VH and VL sequences are connected via a linker.

36. 36. The viral genome of claim 35, wherein the linker comprises the nucleotide sequence of any of the linker sequences presented in Table 15, or a nucleotide sequence at least 95% identical thereto.

37. The promoter may be selected from the group consisting of human elongation factor 1 α-subunit (EF1α), cytomegalovirus (CMV) immediate early enhancer and / or promoter, chicken β-actin (CBA) and its derivatives CAG, β-glucuronidase (GUSB), or ubiquitin C (UBC), neuron-specific enolase (NSE), platelet-derived growth factor (PDGF), platelet-derived growth factor B chain (PDGF-β), intercellular adhesion molecule 2 (ICAM-2), synapsin (Syn), methyl-CpG binding protein 2 (MeCP2), Ca2+ / calmodulin-dependent protein 37. The viral genome of any one of claims 33 to 36, wherein the viral genome is selected from protein kinase II (CaMKII), metabotropic glutamate receptor 2 (mGluR2), neurofilament light chain (NFL) or neurofilament heavy chain (NFH), β-globin minigene nβ2, preproenkephalin (PPE), enkephalin (Enk) and excitatory amino acid transporter 2 (EAAT2), glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), or a fragment, e.g., truncation, or functional variant thereof.

38. The viral genome according to any one of claims 33 to 37, (i) an enhancer, (ii) a polyadenylation (polyA) signal region; (ii) one or two ITR sequences; (iii) at least one, two, or three intron regions; (iv) at least one, two, or three exon regions, and / or (v) a nucleotide sequence encoding a microRNA (miR) binding site; The viral genome further comprises:

39. 39. The viral genome of claim 38, wherein the ITR sequences are positioned 5' to the nucleic acid encoding the antibody and / or the ITR sequences are positioned 3' to the nucleic acid encoding the antibody.

40. A vector comprising a nucleotide sequence encoding a nucleic acid according to any one of claims 28 to 31, a viral genome according to any one of claims 33 to 39, or an antibody according to any one of claims 1 to 27 or 32.

41. An adeno-associated virus (AAV) particle comprising a capsid protein and a viral genome according to any one of claims 33 to 39.

42. 42. The AAV particle of claim 41 , wherein the capsid protein comprises an AAV5 capsid protein or a variant thereof, or an AAV9 capsid protein or a variant thereof.

43. 42. A host cell comprising a nucleic acid according to any one of claims 28 to 31, an antibody according to any one of claims 1 to 27 or 32, a vector according to claim 40, or an AAV particle according to claim 41 or 42, wherein the host cell is optionally an insect cell, a bacterial cell, or a mammalian cell.

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

45. A pharmaceutical composition comprising an antibody according to any one of claims 1 to 27 or 32 or an AAV particle according to claim 41 or 42, and a pharmaceutically acceptable excipient.

46. 1. A method for delivering an exogenous antibody that binds to tau to a subject, comprising administering an effective amount of an antibody of any one of claims 1 to 27 or 32, an AAV particle of claim 41 or 42, or a pharmaceutical composition of claim 45, and optionally (i) the subject has, has been diagnosed with, or is at risk of having a disease associated with tau expression; (ii) the subject has, has been diagnosed with, or is at risk of having a neurological disorder, e.g., a neurodegenerative disorder, and / or (iii) the subject has, has been diagnosed with, or is at risk of having a tauopathy; The method.

47. 46. ​​A method of treating a subject having or diagnosed as having a neurological or neurodegenerative disorder, a tauopathy, or traumatic brain injury (TBI), comprising administering to the subject an effective amount of an antibody of any one of claims 1 to 27 or 32, an AAV particle of claim 41 or 42, or a pharmaceutical composition of claim 45, thereby treating the subject having or diagnosed as having a neurological or neurodegenerative disorder, a tauopathy, or traumatic brain injury (TBI).

48. 48. The method of claim 46 or 47, wherein the neuropathy is: (i) tauopathy, (ii) TBI, and / or (iii) Alzheimer's disease (AD), frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), frontotemporal lobe dementia (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 senile dementia, mild cognitive impairment, or progressive subcortical gliosis The method comprising:

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

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

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

52. An antibody according to any one of claims 1 to 27 or 32, an AAV particle according to claim 41 or 42, or a pharmaceutical composition according to claim 45, for use as a medicament.

53. 46. ​​The antibody of any one of claims 1 to 27 or 32, the AAV particle of claim 41 or 42, or the pharmaceutical composition of claim 45, for use in the treatment of a neurological or neurodegenerative disorder, a tauopathy, or traumatic brain injury (TBI).

54. Use of an effective amount of an antibody of any one of claims 1 to 27 or 32, an AAV particle of claim 41 or 42, or a pharmaceutical composition of claim 45 in the manufacture of a medicament for treating a neurological or neurodegenerative disorder, a tauopathy, or traumatic brain injury.

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