Tau-binding compounds

Abstract

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

Description

[0001] Related applications

[0002] 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 hereby incorporated by reference in their entirety.

[0003] Sequence Listing

[0004] This application contains a sequence listing that has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. The XML copy was created on August 23, 2023, is named V2071-3005PCT_SL.xml, and is 1,438,459 bytes in size. Technical Field

[0005] The present disclosure provides tau-binding compounds and adeno-associated virus (AAV) particles comprising the compounds. Background Art

[0006] Tauopathies are a group of neurodegenerative diseases characterized by the dysfunction and / or aggregation of the microtubule-associated protein tau. Tau is generally a soluble protein known to associate with microtubules based on its phosphorylation degree. In view of its unique and extended structure, tau is considered as an important component of the intracellular transport process, especially in neuronal cells. The hyperphosphorylation of tau suppresses its combination with microtubules and microtubule assembly activity. In addition, the hyperphosphorylation of tau makes it easy to misfold and aggregate. In tauopathies, tau becomes hyperphosphorylated, misfolded and aggregates into neurofibrillary tangles (NFTs) of paired helical filaments (PHFs), torsion bands or straight filaments. These NFTs are considered to indicate the impending neuronal cell death to a great extent and are considered to cause extensive neuronal cell loss, thereby causing various behaviors and cognitive defects.

[0007] Genetically defined tauopathies have been described, with mutations in the tau gene now being shown to cause an autosomal dominant tauopathy known as frontotemporal dementia and parkinsonism associated with chromosome 17 (FTDP-17). This provides evidence that changes in tau can lead to neurodegenerative changes in the brain. These molecules are considered more likely to cause amyloid deposition, meaning they are more likely to become hyperphosphorylated and more likely to aggregate into NFTs (Hutton, M. et al., 1998, Nature 393(6686):702-5).

[0008] A variety of approaches have been proposed to therapeutically interfere with the progression of tauopathy and prevent subsequent molecular and cellular consequences. Given that NFTs consist of hyperphosphorylated, misfolded, and aggregated forms of tau, interference at each of these stages provides a purposable target. The introduction of agents that limit phosphorylation, block misfolding, or prevent aggregation is a promising strategy. It has also been proposed that the introduction of anti-tau antibodies could prevent the transneuronal spread of tauopathy.

[0009] There remains a need for anti-tau antibodies for use in tauopathy treatment, diagnosis, and other applications. The present disclosure addresses this need with the related compounds and methods described herein. Summary of the Invention

[0010] The present disclosure relates, at least in part, to compositions and methods for regulating the level of tau (e.g., aggregation and or distribution of tau) and / or the delivery (e.g., vectorized delivery) of antibodies that bind to tau (e.g., anti-tau antibodies, e.g., anti-tau antibodies described herein). In some embodiments, the level of tau (e.g., aggregation or distribution) is reduced or inhibited using anti-tau antibodies described herein or separation (e.g., recombinant) AAV particles comprising viral genomes encoding anti-tau antibodies (e.g., anti-tau antibodies described herein). In some embodiments, the degradation of tau is increased using anti-tau antibodies described herein or separation (e.g., recombinant) AAV particles comprising viral genomes encoding anti-tau antibodies (e.g., anti-tau antibodies described herein). This inhibition and / or degradation may be applicable to the treatment of disorders and / or neurological disorders associated with the expression of tau, such as tauopathy.

[0011] Thus, in one aspect, the present disclosure provides an isolated (e.g., recombinant) antibody that binds to tau, comprising a heavy chain variable region (VH) comprising one, two or three of the heavy chain complementary determining region 1 (HC CDR1), heavy chain complementary determining region 2 (HC CDR2) and / or heavy chain complementary determining region 3 (HC CDR3) of any one of the HC CDR sequences of Table 1 or 4; and / or a light chain variable region (VL) comprising one, two or three of the light chain complementary determining region 1 (LC CDR1), light chain complementary determining region 2 (LC CDR2) and / or light chain complementary determining region 3 (LC CDR3) of any one of the LC CDR sequences of Table 1 or 4.

[0012] In another aspect, the present disclosure provides an antibody that binds to human tau, comprising a heavy chain variable region (VH) comprising a heavy chain complementary determining region 1 (HC CDR1), a heavy chain complementary determining region 2 (HC CDR2), and a heavy chain complementary determining region 3 (HC CDR3) and / or a light chain variable region (VL) comprising a light chain complementary determining region 1 (LC CDR1), a light chain complementary determining region 2 (LC CDR2), and a light chain complementary determining region 3 (LC CDR3), wherein (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; (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: 1144, 1145, 410, 1146, 529, and 571, respectively; (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.

[0013] In another aspect, the present disclosure provides an antibody that binds to human tau, comprising a heavy chain variable region (VH) comprising a heavy chain complementary determining region 1 (HC CDR1), a heavy chain complementary determining region 2 (HC CDR2), and a heavy chain complementary determining region 3 (HC CDR3) and / or a light chain variable region (VL) comprising a light chain complementary determining region 1 (LC CDR1), a light chain complementary determining region 2 (LC CDR2), and a light chain complementary determining region 3 (LC CDR3), wherein: (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; (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; NO: 1144, 1145, 410, 1146, 529 and 571; (c) HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2 and LC CDR3 comprise the amino acid 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; or (d) HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2 and LC CDR3 comprise the amino acid sequences of SEQ ID NO: 314, 341, 410, 1154, 529 and 571, respectively; and wherein: (i) VH comprises an amino acid sequence comprising one, two, three, four, five, six, seven, eight, nine or all of the following: NO:21, wherein the amino acid is an amino acid 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) VL comprises an amino acid sequence comprising one, two or all of the following: an amino acid other than D at position 17, Q at position 18, and / or G at position 68, as numbered according to SEQ ID NO:93.

[0014] In another aspect, the present disclosure provides an antibody that binds to human tau, comprising a heavy chain variable region (VH) comprising a heavy chain complementary determining region 1 (HC CDR1), a heavy chain complementary determining region 2 (HC CDR2), and a heavy chain complementary determining region 3 (HC CDR3) and / or a light chain variable region (VL) comprising a light chain complementary determining region 1 (LC CDR1), a light chain complementary determining region 2 (LC CDR2), and a light chain complementary determining region 3 (LC CDR3), wherein: (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; (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; NO:1144, 1145, 410, 1146, 529 and 571; (c) HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2 and LC CDR3 comprise the amino acid 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; or (d) HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2 and LC CDR3 comprise the amino acid sequences of SEQ ID NO:314, 341, 410, 1154, 529 and 571, respectively; and wherein: (i) VH comprises an amino acid sequence comprising 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; and / or (ii) VL comprises an amino acid sequence comprising one, two or all of the following: 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.

[0015] In another aspect, the present disclosure provides an antibody that binds to human tau, comprising a heavy chain variable region (VH) comprising a heavy chain complementary determining region 1 (HC CDR1), a heavy chain complementary determining region 2 (HC CDR2), and a heavy chain complementary determining region 3 (HC CDR3) and / or a light chain variable region (VL) comprising a light chain complementary determining region 1 (LC CDR1), a light chain complementary determining region 2 (LC CDR2), and a light chain complementary determining region 3 (LC CDR3), wherein: (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; (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; NO: 1144, 1145, 410, 1146, 529 and 571; (c) HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2 and LC CDR3 comprise the amino acid 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; or (d) HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2 and LC CDR3 comprise the amino acid sequences of SEQ ID NO: 314, 341, 410, 1154, 529 and 571, respectively; and wherein: (i) VH comprises the amino acid sequence of SEQ ID NO: 1144, 1145, 410, 1146, 529 and 571, respectively; NO:67-71; and / or (ii) VL 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 NO:67-71; 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 NO:72-76.

[0016] In another aspect, the present disclosure provides an antibody that binds to human tau, comprising a heavy chain variable region (VH) comprising a heavy chain complementary determining region 1 (HC CDR1), a heavy chain complementary determining region 2 (HC CDR2), and a heavy chain complementary determining region 3 (HC CDR3) and / or a light chain variable region (VL) comprising a light chain complementary determining region 1 (LC CDR1), a light chain complementary determining region 2 (LC CDR2), and a light chain complementary determining region 3 (LC CDR3), wherein: (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; (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; NO: 1144, 1145, 410, 1146, 529 and 571; (c) HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2 and LC CDR3 comprise the amino acid 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; or (d) HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2 and LC CDR3 comprise the amino acid sequences of SEQ ID NO: 1144, 1145, 410, 1146, 529 and 571, respectively. NO:314, 341, 410, 1154, 529 and 571 amino acid sequence; and wherein: (i) VH comprises 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: according to SEQ at position 5, numbered according to SEQ ID NO: 21; V at position 7; S at position 9; A at position 11; V at position 12; K at position 14; S 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) VL comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or all of the following: I at position 2, numbered according to SEQ ID NO: 93; 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. ;

[0017] In another aspect, the present disclosure provides an antibody that binds to human tau, comprising a heavy chain variable region (VH) comprising a heavy chain complementary determining region 1 (HC CDR1), a heavy chain complementary determining region 2 (HC CDR2), and a heavy chain complementary determining region 3 (HC CDR3) and / or a light chain variable region (VL) comprising a light chain complementary determining region 1 (LC CDR1), a light chain complementary determining region 2 (LC CDR2), and a light chain complementary determining region 3 (LC CDR3), wherein: (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; (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; NO: 1144, 1145, 410, 1146, 529 and 571; (c) HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2 and LC CDR3 comprise the amino acid 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; or (d) HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2 and LC CDR3 comprise the amino acid sequences of SEQ ID NO: 314, 341, 410, 1154, 529 and 571, respectively; and wherein: (i) VH comprises the amino acid sequence of SEQ ID NO: 69 or is identical to SEQ ID NO: 69. NO:69; and / or (ii) 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 an amino acid sequence of SEQ ID NO:73.

[0018] In another aspect, the present 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.

[0019] In another aspect, the present 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.

[0020] In another aspect, the disclosure provides a nucleic acid encoding an antibody that binds to tau (e.g., an anti-tau antibody described herein).

[0021] In another aspect, the disclosure provides a vector encoding an antibody that binds to tau (e.g., an anti-tau antibody described herein).

[0022] In another aspect, the present disclosure provides a host cell comprising an antibody that binds to tau (e.g., an anti-tau antibody described herein) or a nucleic acid encoding an antibody that binds to 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.

[0023] In another aspect, the present disclosure provides a method for producing an antibody that binds to tau (e.g., an anti-tau antibody described herein). In some embodiments, the method includes culturing a host cell comprising an anti-tau antibody described herein under conditions suitable for gene expression.

[0024] In another aspect, the present disclosure provides a viral genome comprising a promoter operably linked to a nucleic acid encoding an antibody that binds to tau (e.g., an anti-tau antibody described herein). In some embodiments, the viral genome further comprises an internal terminal repeat (ITR) sequence (e.g., an ITR region described herein), an enhancer (e.g., an enhancer described herein), an intron region (e.g., an intron region described herein) and / or an exon region (e.g., an exon region described herein), a poly A signal region (e.g., a poly A signal sequence described herein) and / or an encoded miR binding site.

[0025] In 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, such as a wild-type AAV capsid protein or a functional variant thereof. In some embodiments, the capsid protein comprises or is selected from AAV9 capsid protein, AAV5 capsid protein, VOY101 capsid protein, PHP.N capsid protein or PHP.B capsid protein or a functional variant thereof.

[0026] In another aspect, the disclosure provides a method for delivering an exogenous antibody (e.g., an anti-tau antibody as described herein) bound to tau to a subject. In some embodiments, the subject suffers from or is diagnosed as suffering from a neurological disorder, tauopathy, and / or a disease related to the expression of tau. In some embodiments, the disease related to tau expression, neurological disorder, or tauopathy include AD, FTDP-17, FTLD, FTD, CTE, PSP, Down syndrome, Pick's disease, CBD, corticobasal syndrome, ALS, Prion diseases, CJD, multiple system atrophy, mild cognitive impairment, only entangled dementia, or progressive subcortical gliosis.

[0027] In another aspect, the present disclosure provides a method for treating a subject suffering from or diagnosed with a neurological disorder, tauopathy and / or a disease associated with the expression of tau. 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 associated with tau expression, the neurological disorder or tauopathy includes 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, only entangled dementia or progressive subcortical gliosis.

[0028] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the embodiments listed below.

[0029] Listed implementation plans

[0030] 1. An antibody that binds to human tau, comprising:

[0031] (a) a heavy chain variable region (VH) comprising a heavy chain complementary determining region 1 (HC CDR1) comprising the amino acid sequence of SEQ ID NO: 64, a heavy chain complementary determining region 2 (HC CDR2) comprising the amino acid sequence of SEQ ID NO: 1145, and a heavy chain complementary 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 complementary determining region 1 (LC CDR1) comprising the amino acid sequence of SEQ ID NO: 1146, a light chain complementary determining region 2 (LC CDR2) comprising the amino acid sequence of SEQ ID NO: 529, and a light chain complementary determining region 3 (LC CDR3) comprising the amino acid sequence of SEQ ID NO: 571;

[0032] (b) a VH comprising a HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1144, a HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1145, and a HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410; and a VL comprising a LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1146, a LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571;

[0033] (c) a VH comprising a HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1165, a HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1166, and a HC CDR3 comprising the amino acid sequence of SEQ ID NO: 1167; and a VL comprising a LC CDR1 comprising the amino acid sequence of SEQ ID NO: 473, a LC CDR2 comprising the amino acid sequence of RVS, and a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; or

[0034] (d) a VH comprising a HC CDR1 comprising the amino acid sequence of SEQ ID NO: 314, a HC CDR2 comprising the amino acid sequence of SEQ ID NO: 341, and a HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410; and a VL comprising a LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1154, a LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571;

[0035] Optionally, the antibody is a humanized antibody.

[0036] 2. An antibody that binds to human tau, comprising:

[0037] (a) a heavy chain variable region (VH) comprising a heavy chain complementary determining region 1 (HC CDR1) comprising the amino acid sequence of SEQ ID NO: 64, a heavy chain complementary determining region 2 (HC CDR2) comprising the amino acid sequence of SEQ ID NO: 1145, and a heavy chain complementary 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 complementary determining region 1 (LC CDR1) comprising the amino acid sequence of SEQ ID NO: 1146, a light chain complementary determining region 2 (LC CDR2) comprising the amino acid sequence of SEQ ID NO: 529, and a light chain complementary determining region 3 (LC CDR3) comprising the amino acid sequence of SEQ ID NO: 571;

[0038] (b) a VH comprising a HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1144, a HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1145, and a HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410; and a VL comprising a LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1146, a LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571;

[0039] (c) a VH comprising a HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1165, a HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1166, and a HC CDR3 comprising the amino acid sequence of SEQ ID NO: 1167; and a VL comprising a LC CDR1 comprising the amino acid sequence of SEQ ID NO: 473, a LC CDR2 comprising the amino acid sequence of RVS, and a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; or

[0040] (d) a VH comprising a HC CDR1 comprising the amino acid sequence of SEQ ID NO: 314, a HC CDR2 comprising the amino acid sequence of SEQ ID NO: 341, and a HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410; and a VL comprising a LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1154, a LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; and

[0041] in:

[0042] (i) the VH comprises an amino acid sequence comprising one, two, three, four, five, six, seven, eight, nine or all of the following: an amino acid other than Q at position 5, other than P at position 7, other than T at position 9, other than L at position 11, other than V at position 12, other than N at position 19, other than L at position 20, other than K at position 67, other than A at position 68 and / or other than S at position 76, numbered according to SEQ ID NO: 21; and / or

[0043] (ii) the VL comprises an amino acid sequence comprising one, two or all of the following: an amino acid other than D at position 17, other than Q at position 18 and / or other than G at position 68, numbered according to SEQ ID NO: 93.

[0044] 3. An antibody that binds to human tau, comprising:

[0045] (a) a heavy chain variable region (VH) comprising a heavy chain complementary determining region 1 (HC CDR1) comprising the amino acid sequence of SEQ ID NO: 64, a heavy chain complementary determining region 2 (HC CDR2) comprising the amino acid sequence of SEQ ID NO: 1145, and a heavy chain complementary 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 complementary determining region 1 (LC CDR1) comprising the amino acid sequence of SEQ ID NO: 1146, a light chain complementary determining region 2 (LC CDR2) comprising the amino acid sequence of SEQ ID NO: 529, and a light chain complementary determining region 3 (LC CDR3) comprising the amino acid sequence of SEQ ID NO: 571;

[0046] (b) a VH comprising a HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1144, a HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1145, and a HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410; and a VL comprising a LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1146, a LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571;

[0047] (c) a VH comprising a HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1165, a HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1166, and a HC CDR3 comprising the amino acid sequence of SEQ ID NO: 1167; and a VL comprising a LC CDR1 comprising the amino acid sequence of SEQ ID NO: 473, a LC CDR2 comprising the amino acid sequence of RVS, and a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; or

[0048] (d) a VH comprising a HC CDR1 comprising the amino acid sequence of SEQ ID NO: 314, a HC CDR2 comprising the amino acid sequence of SEQ ID NO: 341, and a HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410; and a VL comprising a LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1154, a LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; and

[0049] in:

[0050] (i) the VH comprises an amino acid sequence comprising one, two, three, four, five, six, seven, eight or all of the following: 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, a K at position 19, a V at position 20, an R at position 67 and / or a V at position 68, numbered according to SEQ ID NO: 21; and / or

[0051] (ii) the VL comprises an amino acid sequence comprising one, two or all of the following: 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.

[0052] 4. An antibody that binds to human tau, comprising:

[0053] (a) a heavy chain variable region (VH) comprising a heavy chain complementary determining region 1 (HC CDR1) comprising the amino acid sequence of SEQ ID NO: 64, a heavy chain complementary determining region 2 (HC CDR2) comprising the amino acid sequence of SEQ ID NO: 1145, and a heavy chain complementary 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 complementary determining region 1 (LC CDR1) comprising the amino acid sequence of SEQ ID NO: 1146, a light chain complementary determining region 2 (LC CDR2) comprising the amino acid sequence of SEQ ID NO: 529, and a light chain complementary determining region 3 (LC CDR3) comprising the amino acid sequence of SEQ ID NO: 571;

[0054] (b) a VH comprising a HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1144, a HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1145, and a HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410; and a VL comprising a LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1146, a LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571;

[0055] (c) a VH comprising a HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1165, a HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1166, and a HC CDR3 comprising the amino acid sequence of SEQ ID NO: 1167; and a VL comprising a LC CDR1 comprising the amino acid sequence of SEQ ID NO: 473, a LC CDR2 comprising the amino acid sequence of RVS, and a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; or

[0056] (d) a VH comprising a HC CDR1 comprising the amino acid sequence of SEQ ID NO: 314, a HC CDR2 comprising the amino acid sequence of SEQ ID NO: 341, and a HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410; and a VL comprising a LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1154, a LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; and

[0057] in:

[0058] (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: 67-71; and / or

[0059] (ii) the 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: 72-76.

[0060] 5. The antibody of any one of embodiments 1-4, 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.

[0061] 6. The antibody of any one of embodiments 1-5, 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.

[0062] 7. The antibody of any one of embodiments 1-6, 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.

[0063] 8. The antibody of any one of embodiments 1-7, 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.

[0064] 9. The antibody of any one of embodiments 1-8, wherein the VH comprises an amino acid sequence comprising one, two, three, four, five, six, seven, eight, nine, or all of the following: an amino acid other than Q at position 5, other than P at position 7, other than T at position 9, other than L at position 11, other than V at position 12, other than N at position 19, other than L at position 20, other than K at position 67, other than A at position 68, and / or other than S at position 76, numbered according to SEQ ID NO: 21.

[0065] 10. The antibody of any one of embodiments 1-9, wherein the VH comprises:

[0066] (a) 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: an amino acid other than Q at position 5 numbered NO: 21; 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;

[0067] (b) 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or all of the following: an amino acid other than Q at position 5 numbered NO: 21; 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;

[0068] (c) 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: an amino acid other than Q at position 5 numbered NO: 21; 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; an amino acid other than K at position 67; 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;

[0069] (d) 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or all of the following: an amino acid at position 1 other than Q; an amino acid at position 5 other than Q; an amino acid at position 7 other than P; an amino acid at position 9 other than T; an amino acid at position 11 other than L; an amino acid at position 12 other than V; an amino acid at position 19 other than N; an amino acid at position 20 other than L; an amino acid at position 67 other than K; an amino acid at position 68 other than A; an amino acid at position 70 other than L; an amino acid at position 76 other than S; an amino acid at position 79 other than V; an amino acid at position 80 other than F; an amino acid at position 81 other than I; an amino acid at position 82 other than Q; an amino acid at position 85 other than S; an amino acid at position 89 other than E, an amino acid at position 113 other than S; and / or an amino acid at position 115 other than T; or

[0070] (e) 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or all of the following: an amino acid at position 5 other than Q; an amino acid at position 7 other than P; an amino acid at position 9 other than T; an amino acid at position 11 other than L; an amino acid at position 12 other than V; an amino acid at position 16 other than S; an amino acid at position 19 other than N; an amino acid at position 20 other than L; an amino acid at position 43 other than H; an amino acid at position 48 other than I; an amino acid at position 67 other than K; an amino acid at position 68 other than A; an amino acid at position 70 other than L; an amino acid at position 76 other than S; an amino acid at position 77 other than T; an amino acid at position 87 other than T; and / or an amino acid at position 91 other than S.

[0071] 11. The antibody of any one of embodiments 1-10, wherein the VH comprises 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: NO:21 numbered amino acid at position 5 other than Q; amino acid at position 7 other than P; amino acid at position 9 other than T; amino acid at position 11 other than L; amino acid at position 12 other than V; amino acid at position 14 other than P; amino acid at position 16 other than S; amino acid at position 19 other than N; amino acid at position 20 other than L; amino acid at position 38 other than K; amino acid at position 39 other than E; amino acid at position 40 other than R; amino acid at position 43 other than H; amino acid at position 67 other than K; amino acid at position 68 other than A; amino acid at position 71 other than T; amino acid at position 72 other than V; amino acid at position 73 other than H; amino acid at position 74 other than K; amino acid at position 76 other than S; amino acid at position 84 other than S; and / or amino acid at position 113 other than S.

[0072] 12. The antibody of any one of embodiments 1-10, wherein the VH comprises 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: NO:21 numbered amino acid at position 5 except Q; amino acid at position 6 except Q; amino acid at position 7 except P; amino acid at position 9 except T; amino acid at position 11 except L; amino acid at position 12 except V; amino acid at position 16 except S; amino acid at position 19 except N; amino acid at position 20 except L; amino acid at position 48 except I; amino acid at position 67 except K; amino acid at position 68 except A; amino acid at position 70 except L; amino acid at position 76 except S; amino acid at position 77 except T; amino acid at position 79 except V; amino acid at position 80 except F; amino acid at position 81 except I; amino acid at position 82 except Q; amino acid at position 87 except T; amino acid at position 91 except S; and / or amino acid at position 113 except S.

[0073] 13. The antibody of any one of embodiments 1-10, wherein the VH comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or all of the following: NO:21 numbered amino acid at position 1 except Q; amino acid at position 5 except Q; amino acid at position 7 except P; amino acid at position 9 except T; amino acid at position 11 except L; amino acid at position 12 except V; amino acid at position 19 except N; amino acid at position 20 except L; amino acid at position 67 except K; amino acid at position 68 except A; amino acid at position 70 except L; amino acid at position 76 except S; amino acid at position 79 except V; amino acid at position 80 except F; amino acid at position 81 except I; amino acid at position 82 except Q; amino acid at position 85 except S; amino acid at position 89 except E, amino acid at position 113 except S; and / or amino acid at position 115 except T.

[0074] 14. The antibody of any one of embodiments 1-10, wherein the VH comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or all of the following: an amino acid at position 5 other than Q; an amino acid at position 7 other than P; an amino acid at position 9 other than T; an amino acid at position 11 other than L; an amino acid at position 12 other than V; an amino acid at position 16 other than S; an amino acid at position 19 other than N; an amino acid at position 20 other than L; an amino acid at position 43 other than H; an amino acid at position 48 other than I; an amino acid at position 67 other than K; an amino acid at position 68 other than A; an amino acid at position 70 other than L; an amino acid at position 76 other than S; an amino acid at position 77 other than T; an amino acid at position 87 other than T; and / or an amino acid at position 91 other than S.

[0075] 15. The antibody of any one of embodiments 1-14, wherein the VH comprises an amino acid sequence comprising one, two, three, four, five, six, seven, eight, or all of the following: 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, a K at position 19, a V at position 20, an R at position 67, and / or a V at position 68, numbered according to SEQ ID NO: 21.

[0076] 16. The antibody of any one of embodiments 1-15, wherein the VH comprises:

[0077] (a) 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: 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;

[0078] (b) 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 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; 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;

[0079] (c) 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: 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;

[0080] (d) 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 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; or

[0081] (e) 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 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.

[0082] 17. The antibody of any one of embodiments 1-11, 15, or 16, wherein the VH comprises 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: 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 / or an L at position 113.

[0083] 18. The antibody of any one of embodiments 1-10, 12, 15, or 16, wherein the VH comprises 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: a V at position 5; an E at position 6; an S at position 7; an A at position 9; a V at position 11; a K at position 12; an A at position 16; a K at position 19; a V at position 20; an M at position 48; an R at position 67; a V at position 68; an I at position 70; an A at position 76; an S at position 77; an A at position 79; a Y at position 80; an M at position 81; an E at position 82; an R at position 87; a T at position 91; and / or a T at position 113.

[0084] 19. The antibody of any one of embodiments 1-10, 13, 15, or 16, wherein the VH comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or all of the following: an E at position 1; 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; a K at position 19; a V at position 20; an R at position 67; a V at position 68; an M at position 70; an I at position 76; an A at position 79; a Y at position 80; an M at position 81; an E at position 82; an R at position 85; a D at position 89, an L at position 113, and / or an S at position 115.

[0085] 20. The antibody of any one of embodiments 1-10 or 14-16, wherein the VH comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or all of the following: 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 A at position 16; a K at position 19; a V at position 20; a Q at position 43; an M at position 48; an R at position 67; a V at position 68; an M at position 70; a T at position 76; an S at position 77; an R at position 87; and / or a T at position 91

[0086] 21. The antibody of any one of embodiments 1-20, wherein the VL comprises an amino acid sequence comprising one, two, or all of the following: an amino acid other than D at position 17, other than Q at position 18, and / or other than G at position 68, numbered according to SEQ ID NO: 93.

[0087] 22. The antibody of any one of embodiments 1-21, wherein the VL comprises:

[0088] (a) 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or all of the following: an amino acid at position 7 other than T; an amino acid at position 14 other than S; an amino acid at position 17 other than D; an amino acid at position 18 other than Q; an amino acid at position 42 other than L; an amino acid at position 44 other than K; an amino acid at position 50 other than K; an amino acid at position 68 other than G; an amino acid at position 88 other than L; an amino acid at position 92 other than F; and / or an amino acid at position 105 other than G;

[0089] (b) 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or all of the following: an amino acid at position 2 other than V; an amino acid at position 7 other than T; an amino acid at position 12 other than P; an amino acid at position 14 other than S; an amino acid at position 15 other than L; an amino acid at position 17 other than D; an amino acid at position 18 other than Q; an amino acid at position 50 other than K; an amino acid at position 68 other than G; an amino acid at position 88 other than L; an amino acid at position 92 other than F; an amino acid at position 105 other than G; and / or an amino acid at position 109 other than L;

[0090] (c) 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or all of the following: an amino acid at position 2 other than V; an amino acid at position 11 other than L; an amino acid at position 14 other than T; an amino acid at position 17 other than D; an amino acid at position 18 other than Q; an amino acid at position 42 other than L; an amino acid at position 44 other than K; an amino acid at position 48 other than S; an amino acid at position 50 other than K; an amino acid at position 68 other than G; an amino acid at position 72 other than S; an amino acid at position 81 other than S; an amino acid at position 88 other than L; and / or an amino acid at position 105 other than G;

[0091] (d) 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or all of the following: an amino acid at position 2 other than V; an amino acid at position 3 other than V; an amino acid at position 7 other than T; an amino acid at position 14 other than S; an amino acid at position 17 other than D; an amino acid at position 18 other than Q; an amino acid at position 42 other than L; an amino acid at position 44 other than K; an amino acid at position 50 other than K; an amino acid at position 51 other than L; an amino acid at position 68 other than G; and / or an amino acid at position 88 other than L; or

[0092] (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: NO:93 numbered amino acid at position 1 except D; amino acid at position 2 except V; amino acid at position 4 except M; amino acid at position 7 except T; amino acid at position 9 except L; amino acid at position 10 except S; amino acid at position 12 except P; amino acid at position 13 except V; amino acid at position 15 except L; amino acid at position 17 except D; amino acid at position 18 except Q; amino acid at position 20 except S; amino acid at position 21 except I; amino acid at position 48 except S; amino acid at position 63 except V; amino acid at position 68 except G; amino acid at position 72 except S; amino acid at position 79 except K; amino acid at position 82 except R; amino acid at position 83 except V; amino acid at position 85 except A; and / or amino acid at position 89 except G.

[0093] 23. The antibody of any one of embodiments 1-22, wherein the VL comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or all of the following: 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.

[0094] 24. The antibody of any one of embodiments 1-22, wherein the VL comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or all of the following: an amino acid other than T at position 7, numbered as in SEQ ID NO: 93; 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.

[0095] 25. The antibody of any one of embodiments 1-22, wherein the VL comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or all of the following: 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.

[0096] 26. The antibody of any one of embodiments 1-25, wherein the VL comprises an amino acid sequence comprising one, two, or all of the following: 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.

[0097] 27. The antibody of any one of embodiments 1-26, wherein the VL comprises:

[0098] (a) 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or all of the following: 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, as numbered according to SEQ ID NO: 93;

[0099] (b) 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 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;

[0100] (c) 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 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, as numbered according to SEQ ID NO: 93;

[0101] (d) 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or all of the following: 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; or

[0102] (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: 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.

[0103] 28. The antibody of any one of embodiments 1-23, 26, or 27, wherein VL comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or all of the following: an I at position 2; an S at position 7; an S at position 12; a T at position 14; a P at position 15; a Q at position 17; a P at position 18; a Q at position 50; an S at position 68; a V at position 88; a Y at position 92; a Q at position 105; and / or a V at position 109, numbered according to SEQ ID NO: 93.

[0104] 29. The antibody of any one of embodiments 1-22, 24, 26, or 27, wherein the VL comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or all of: an S at position 7; a T at position 14; a Q at position 17; a P at position 18; a Q at position 42; an R at position 44; an R at position 50; an S at position 68; a V at position 88; a Y at position 92; and / or a Q at position 105, numbered according to SEQ ID NO: 93.

[0105] 30. The antibody of any one of embodiments 1-22 or 24-27, wherein the VL comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or all of the following: an I at position 2; an S at position 11; a T at position 14; a Q at position 17; a P at position 18; a Q at position 42; an R at position 44; a P at position 48; an R at position 50; an S at position 68; an A at position 72; an N at position 81; a V at position 88; and / or a Q at position 105, numbered as per SEQ ID NO: 93.

[0106] 31. The antibody of any one of embodiments 1-30, wherein:

[0107] (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; optionally wherein the VH comprises FRH1-CDRH1-FRH2-CDRH2-FRH3-CDRH3-FRH4 from N-terminus to C-terminus; and / or

[0108] (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; optionally wherein the VL comprises FRL1-CDRL1-FRL2-CDRL2-FRL3-CDRL3-FRL4 from N-terminus to C-terminus.

[0109] 32. The antibody of embodiment 31, wherein:

[0110] (a)(i) the FRH1 corresponds to positions 1-25 of the heavy chain variable region numbered according to any one of SEQ ID NOs: 21 or 67-71; the FRH2 corresponds to positions 36-49 according to any one of SEQ ID NOs: 21 or 67-71; the FRH3 corresponds to positions 67-96 according to any one of SEQ ID NOs: 21 or 67-71; and / or the FRH4 corresponds to positions 108-118 according to any one of SEQ ID NOs: 21 or 67-71; or

[0111] (ii) the FRH1 corresponds to positions 1-30 of the heavy chain variable region numbered according to any one of SEQ ID NOs: 21 or 67-71; the FRH2 corresponds to positions 36-49 of the heavy chain variable region numbered according to any one of SEQ ID NOs: 21 or 67-71; the FRH3 corresponds to positions 67-98 of the heavy chain variable region numbered according to any one of SEQ ID NOs: 21 or 67-71; and / or the FRH4 corresponds to positions 108-118 of the heavy chain variable region numbered according to any one of SEQ ID NOs: 21 or 67-71; and / or

[0112] (b) the FRL1 corresponds to positions 1-23 of the light chain variable region numbered according to any one of SEQ ID NOs: 72-76 or 93; the FRL2 corresponds to positions 40-54 of the light chain variable region numbered according to any one of SEQ ID NOs: 72-76 or 93; the FRL3 corresponds to positions 62-93 of the light chain variable region numbered according to any one of SEQ ID NOs: 72-76 or 93; and / or the FRL4 corresponds to positions 103-112 of the light chain variable region numbered according to any one of SEQ ID NOs: 72-76 or 93.

[0113] 33. The antibody of any one of the preceding embodiments, wherein

[0114] (a) the VH comprises one, two, three or all of the following:

[0115] (i) FRH1 comprising amino acids 1-25 or 1-30 of any one of SEQ ID NOs: 67-71 (optionally any one of SEQ ID NOs: 67 or 69-72); 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 1-25 or 1-30 of any one of SEQ ID NOs: 67-71 (optionally any one of SEQ ID NOs: 67 or 69-72); or an amino acid sequence comprising one, two, three but not more than four different amino acids relative to amino acids 1-25 or 1-30 of any one of SEQ ID NOs: 67-71 (optionally any one of SEQ ID NOs: 67 or 69-72);

[0116] (ii) FRH2 comprising amino acids 36-49 of any one of SEQ ID NOs: 67-71 (optionally any one of SEQ ID NOs: 67 or 69-72); 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 36-49 of any one of SEQ ID NOs: 67-71 (optionally any one of SEQ ID NOs: 67 or 69-72); or an amino acid sequence comprising one, two, three but not more than four different amino acids relative to amino acids 36-49 of any one of SEQ ID NOs: 67-71 (optionally any one of SEQ ID NOs: 67 or 69-72);

[0117] (iii) FRH3 comprising amino acids 67-96 or 67-98 of any one of SEQ ID NOs: 67-71 (optionally any one of SEQ ID NOs: 67 or 69-72); 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 67-96 or 67-98 of any one of SEQ ID NOs: 67-71 (optionally any one of SEQ ID NOs: 67 or 69-72); or an amino acid sequence comprising one, two, three but not more than four different amino acids relative to amino acids 67-96 or 67-98 of any one of SEQ ID NOs: 67-71 (optionally any one of SEQ ID NOs: 67 or 69-72); and / or

[0118] (iv) FRH4 comprising amino acids 108-118 of any one of SEQ ID NOs: 67-71 (optionally any one of SEQ ID NOs: 67 or 69-72); 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 108-118 of any one of SEQ ID NOs: 67-71 (optionally any one of SEQ ID NOs: 67 or 69-72); or an amino acid sequence comprising one, two, three but not more than four different amino acids relative to amino acids 108-118 of any one of SEQ ID NOs: 67-71 (optionally any one of SEQ ID NOs: 67 or 69-72); and / or

[0119] (b) the VL comprises one, two, three or all of the following:

[0120] (i) FRL1 comprising amino acids 1-23 of any one of SEQ ID NOs: 72-76 (optionally any one of SEQ ID NOs: 72-74); 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 1-23 of any one of SEQ ID NOs: 72-76 (optionally any one of SEQ ID NOs: 72-74); or an amino acid sequence comprising one, two, three but not more than four different amino acids relative to amino acids 1-23 of any one of SEQ ID NOs: 72-76 (optionally any one of SEQ ID NOs: 72-74);

[0121] (ii) FRL2 comprising amino acids 40-54 of any one of SEQ ID NOs: 72-76 (optionally any one of SEQ ID NOs: 72-74); 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 40-54 of any one of SEQ ID NOs: 72-76 (optionally any one of SEQ ID NOs: 72-74); or an amino acid sequence comprising one, two, three but not more than four different amino acids relative to amino acids 40-54 of any one of SEQ ID NOs: 72-76 (optionally any one of SEQ ID NOs: 72-74);

[0122] (iii) FRL3 comprising amino acids 62-93 of any one of SEQ ID NOs: 72-76 (optionally any one of SEQ ID NOs: 72-74); 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 62-93 of any one of SEQ ID NOs: 72-76 (optionally any one of SEQ ID NOs: 72-74); or an amino acid sequence comprising one, two, three but not more than four different amino acids relative to amino acids 62-93 of any one of SEQ ID NOs: 72-76 (optionally any one of SEQ ID NOs: 72-74); and / or

[0123] (iv) FRL4 comprising amino acids 103-112 of any one of SEQ ID NOs: 72-76 (optionally any one of SEQ ID NOs: 72-74); 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 103-112 of any one of SEQ ID NOs: 72-76 (optionally any one of SEQ ID NOs: 72-74); or an amino acid sequence comprising one, two, three but not more than four different amino acids relative to amino acids 103-112 of any one of SEQ ID NOs: 72-76 (optionally any one of SEQ ID NOs: 72-74).

[0124] 34. The antibody of any one of embodiments 1-33, wherein:

[0125] (i) the VH does not comprise one, two, three or all of the following: FRH1 comprising amino acids 1-25 or 1-30 of SEQ ID NO: 21; FRH2 comprising amino acids 36-49 of SEQ ID NO: 21; FRH3 comprising amino acids 67-96 or 67-98 of SEQ ID NO: 21; and / or FRH4 comprising amino acids 108-118 of SEQ ID NO: 21; and / or

[0126] (ii) the VL does not comprise one, two, three or all of the following: FRL1 comprising amino acids 1-23 of SEQ ID NO: 93; FRL2 comprising amino acids 40-54 of SEQ ID NO: 93; FRL3 comprising amino acids 62-93 of SEQ ID NO: 93; and / or FRL4 comprising amino acids 103-112 of SEQ ID NO: 93.

[0127] 35. The antibody of any one of embodiments 1-34, wherein 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 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: 67-71.

[0128] 36. The antibody of any one of embodiments 1-35, wherein the VH comprises an amino acid sequence comprising 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 any one of SEQ ID NOs: 67-71.

[0129] 37. The antibody of any one of embodiments 1-36, wherein the VH comprises an amino acid sequence comprising at least one, two, three, four, or five but not more than 16 different amino acids relative to the amino acid sequence of any one of SEQ ID NOs: 67-71.

[0130] 38. The antibody of any one of embodiments 1-11, 15-17, or 21-37, wherein the VH comprises the amino acid sequence of SEQ ID NO: 69; 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 SEQ ID NO: 69.

[0131] 39. The antibody of any one of embodiments 1-11, 15-17, or 21-38, wherein the VH comprises an amino acid sequence comprising 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: 69.

[0132] 40. The antibody of any one of embodiments 1-11, 15-17, or 21-39, wherein the VH comprises an amino acid sequence comprising at least one, two, three, four, or five but not more than 16 different amino acids relative to the amino acid sequence of SEQ ID NO: 69.

[0133] 41. The antibody of any one of embodiments 1-10, 12, 15, 16, 18, or 21-37, wherein the VH comprises:

[0134] (i) the amino acid sequence of SEQ ID NO: 67; 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 SEQ ID NO: 67;

[0135] (ii) an amino acid sequence comprising 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

[0136] (iii) an amino acid sequence comprising at least one, two, three, four or five but not more than 16 different amino acids relative to the amino acid sequence of SEQ ID NO: 67.

[0137] 42. The antibody of any one of embodiments 1-10, 13, 15, 16, 19, or 21-37, wherein the VH comprises:

[0138] (i) the amino acid sequence of SEQ ID NO: 70; 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 SEQ ID NO: 70;

[0139] (ii) an amino acid sequence comprising 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

[0140] (iii) an amino acid sequence comprising at least one, two, three, four or five but not more than 16 different amino acids relative to the amino acid sequence of SEQ ID NO: 70.

[0141] 43. The antibody of any one of embodiments 1-10, 15, 16, or 20-37, wherein the VH comprises:

[0142] (i) the amino acid sequence of SEQ ID NO: 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 SEQ ID NO: 71;

[0143] (ii) an amino acid sequence comprising 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

[0144] (iii) an amino acid sequence comprising at least one, two, three, four or five but not more than 16 different amino acids relative to the amino acid sequence of SEQ ID NO: 71.

[0145] 44. The antibody of any one of embodiments 1-43, wherein the VL comprises the amino acid sequence of any one of SEQ ID NOs: 72-76; 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: 72-76.

[0146] 45. The antibody of any one of embodiments 1-44, wherein the VL comprises an amino acid sequence comprising 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 any one of SEQ ID NOs: 72-76.

[0147] 46. ​​The antibody of any one of embodiments 1-45, wherein the VL comprises an amino acid sequence comprising at least one, two, three, four, or five but not more than 10 different amino acids relative to the amino acid sequence of any one of SEQ ID NOs: 72-76.

[0148] 47. The antibody of any one of embodiments 1-23, 26-28, or 31-46, wherein the VL comprises the amino acid sequence of SEQ ID NO: 73; 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 SEQ ID NO: 73.

[0149] 48. The antibody of any one of embodiments 1-23, 26-28, or 31-47, wherein the VL comprises an amino acid sequence comprising 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.

[0150] 49. The antibody of any one of embodiments 1-23, 26-28, or 31-48, wherein the VL comprises an amino acid sequence comprising at least one, two, three, four, or five but not more than 10 different amino acids relative to the amino acid sequence of SEQ ID NO: 73.

[0151] 50. The antibody of any one of embodiments 1-22, 24, 26, 27, 29, or 31-46, wherein the VL comprises:

[0152] (i) the amino acid sequence of SEQ ID NO: 72; 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 SEQ ID NO: 72;

[0153] (ii) an amino acid sequence comprising 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;

[0154] (iii) an amino acid sequence comprising at least one, two, three, four or five but not more than ten different amino acids relative to the amino acid sequence of SEQ ID NO: 72.

[0155] 51. The antibody of any one of embodiments 1-22, 24-27, or 30-46, wherein the VL comprises:

[0156] (i) the amino acid sequence of SEQ ID NO: 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 SEQ ID NO: 74;

[0157] (ii) an amino acid sequence comprising 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;

[0158] (iii) an amino acid sequence comprising at least one, two, three, four or five but not more than ten different amino acids relative to the amino acid sequence of SEQ ID NO: 74.

[0159] 52. The antibody of any one of embodiments 1-51, wherein:

[0160] (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 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: 67-71; an amino acid sequence that comprises 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 any one of SEQ ID NOs: 67-71; or an amino acid sequence that comprises at least one, two, three, four, or five but not more than 16 different amino acids relative to the amino acid sequence of any one of SEQ ID NOs: 67-71; and

[0161] (b) the VL comprises the amino acid sequence of any one of SEQ ID NOs: 72-76; 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: 72-76; an amino acid sequence that comprises 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 any one of SEQ ID NOs: 72-76; or an amino acid sequence that comprises at least one, two, three, four, or five but not more than 10 different amino acids relative to the amino acid sequence of any one of SEQ ID NOs: 72-76.

[0162] 53. The antibody of any one of embodiments 1-52, wherein:

[0163] (a) the VH comprises the amino acid sequence of any one of SEQ ID NOs: 67 or 69-71, 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 69-71; an amino acid sequence that comprises 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 any one of SEQ ID NOs: 67 or 69-71; or an amino acid sequence that comprises at least one, two, three, four, or five but not more than 16 different amino acids relative to the amino acid sequence of any one of SEQ ID NOs: 67 or 69-71; and

[0164] (b) the VL comprises the amino acid sequence of any one of SEQ ID NOs: 72-74; 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: 72-74; an amino acid sequence that comprises 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 any one of SEQ ID NOs: 72-74; or an amino acid sequence that comprises at least one, two, three, four, or five but not more than 10 different amino acids relative to the amino acid sequence of any one of SEQ ID NOs: 72-74.

[0165] 54. The antibody of any one of embodiments 1-53, wherein:

[0166] (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 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of any one of SEQ ID NOs: 67-71; and

[0167] (b) the VL comprises the amino acid sequence of any one of SEQ ID NOs: 72-76; 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: 72-76.

[0168] 55. The antibody of any one of embodiments 1-54, wherein:

[0169] (a) the VH comprises the amino acid sequence of any one of SEQ ID NOs: 67 or 69-71, 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: 67 or 69-71; and

[0170] (b) the VL comprises the amino acid sequence of any one of SEQ ID NOs: 72-74; 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: 72-74.

[0171] 56. The antibody of any one of embodiments 1-58, wherein:

[0172] (i) the VH comprises the amino acid sequence of SEQ ID NO: 67, or an amino acid sequence that is 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 that is at least 91%, 93%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 72;

[0173] (ii) the VH comprises the amino acid sequence of SEQ ID NO: 67, or an amino acid sequence that is 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 that is at least 91%, 93%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 73;

[0174] (iii) the VH comprises the amino acid sequence of SEQ ID NO: 67, or an amino acid sequence that is 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 that is at least 91%, 93%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 74;

[0175] (iv) the VH comprises the amino acid sequence of SEQ ID NO:67, or an amino acid sequence that is 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 that is at least 91%, 93%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:75;

[0176] (v) the VH comprises the amino acid sequence of SEQ ID NO: 67, or an amino acid sequence that is 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 that is at least 91%, 93%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 76;

[0177] (vi) the VH comprises the amino acid sequence of SEQ ID NO:68, or an amino acid sequence that is 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 that is at least 91%, 93%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:72;

[0178] (vii) the VH comprises the amino acid sequence of SEQ ID NO:68, or an amino acid sequence that is 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 that is at least 91%, 93%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:73;

[0179] (viii) the VH comprises the amino acid sequence of SEQ ID NO:68, or an amino acid sequence that is 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 that is at least 91%, 93%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:74;

[0180] (ix) the VH comprises the amino acid sequence of SEQ ID NO:68, or an amino acid sequence that is 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 that is at least 91%, 93%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:75;

[0181] (x) the VH comprises the amino acid sequence of SEQ ID NO:68, or an amino acid sequence that is 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 that is at least 91%, 93%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:76;

[0182] (xi) the VH comprises the amino acid sequence of SEQ ID NO:69, or an amino acid sequence that is 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 that is at least 91%, 93%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:72;

[0183] (xii) the VH comprises the amino acid sequence of SEQ ID NO:69, or an amino acid sequence that is 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 that is at least 91%, 93%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:73;

[0184] (xiii) the VH comprises the amino acid sequence of SEQ ID NO:69, or an amino acid sequence that is 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 that is at least 91%, 93%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:74;

[0185] (xiv) the VH comprises the amino acid sequence of SEQ ID NO:69, or an amino acid sequence that is 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 that is at least 91%, 93%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:75;

[0186] (xv) the VH comprises the amino acid sequence of SEQ ID NO:69, or an amino acid sequence that is 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 that is at least 91%, 93%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:76;

[0187] (xvi) the VH comprises the amino acid sequence of SEQ ID NO:70, or an amino acid sequence that is 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 that is at least 91%, 93%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:72;

[0188] (xvii) the VH comprises the amino acid sequence of SEQ ID NO:70, or an amino acid sequence that is 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 that is at least 91%, 93%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:73;

[0189] (xviii) the VH comprises the amino acid sequence of SEQ ID NO:70, or an amino acid sequence that is 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 that is at least 91%, 93%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:74;

[0190] (xix) the VH comprises the amino acid sequence of SEQ ID NO:70, or an amino acid sequence that is 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 that is at least 91%, 93%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:75;

[0191] (xx) the VH comprises the amino acid sequence of SEQ ID NO:70, or an amino acid sequence that is 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 that is at least 91%, 93%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:76;

[0192] (xxi) the VH comprises the amino acid sequence of SEQ ID NO:71, or an amino acid sequence that is 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 that is at least 91%, 93%, 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:72;

[0193] (xxii) the VH comprises the amino acid sequence of SEQ ID NO:71, or an amino acid sequence that is 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 that is at least 91%, 93%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:73;

[0194] (xxiii) the VH comprises the amino acid sequence of SEQ ID NO:71, or an amino acid sequence that is 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 that is at least 91%, 93%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:74;

[0195] (xxiv) the VH comprises the amino acid sequence of SEQ ID NO:71, or an amino acid sequence that is 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 that is at least 91%, 93%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:75; or

[0196] (xv) the VH comprises the amino acid sequence of SEQ ID NO:71, or an amino acid sequence that is 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 that is at least 91%, 93%, 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:76.

[0197] 57. The antibody of any one of embodiments 1-11, 15-17, 21-23, 26-28, 31-38, 44-49, or 52-56, wherein:

[0198] (i) the VH comprises the amino acid sequence of SEQ ID NO: 69, or an amino acid sequence that is 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 comprises 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: 69; or an amino acid sequence that comprises at least one, two, three, four or five but not more than 16 different amino acids relative to the amino acid sequence of any one of SEQ ID NO: 69; and

[0199] (ii) the VL comprises the amino acid sequence of SEQ ID NO: 73, or an amino acid sequence that is 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 comprises 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 comprises at least one, two, three, four or five but not more than 16 different amino acids relative to the amino acid sequence of any one of SEQ ID NO: 73.

[0200] 58. The antibody of any one of embodiments 1-11, 15-17, 21-23, 26-28, 31-38, 44-49, or 52-57, 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.

[0201] 59. 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, or 52-56, wherein:

[0202] (i) the VH comprises the amino acid sequence of SEQ ID NO: 67, or an amino acid sequence that is 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 comprises 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: 67; or an amino acid sequence that comprises at least one, two, three, four or five but not more than 16 different amino acids relative to the amino acid sequence of any one of SEQ ID NO: 67; and

[0203] (ii) the VL comprises the amino acid sequence of SEQ ID NO: 72, or an amino acid sequence that is 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 comprises 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 comprises at least one, two, three, four or five but not more than 16 different amino acids relative to the amino acid sequence of any one of SEQ ID NO: 72.

[0204] 60. 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, or 52-56, wherein:

[0205] (i) the VH comprises the amino acid sequence of SEQ ID NO: 70, or an amino acid sequence that is 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 comprises 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: 70; or an amino acid sequence that comprises at least one, two, three, four or five but not more than 16 different amino acids relative to the amino acid sequence of any one of SEQ ID NO: 70; and

[0206] (ii) the VL comprises the amino acid sequence of SEQ ID NO: 72, or an amino acid sequence that is 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 comprises 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 comprises at least one, two, three, four or five but not more than 16 different amino acids relative to the amino acid sequence of any one of SEQ ID NO: 72.

[0207] 61. The antibody of any one of embodiments 1-10, 14-16, 20-23, 31-37, 43-49, or 52-56, wherein:

[0208] (i) the VH comprises the amino acid sequence of SEQ ID NO: 71, or an amino acid sequence that is 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 comprises 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: 71; or an amino acid sequence that comprises at least one, two, three, four or five but not more than 16 different amino acids relative to the amino acid sequence of any one of SEQ ID NO: 71; and

[0209] (ii) the VL comprises the amino acid sequence of SEQ ID NO: 73, or an amino acid sequence that is 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 comprises 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 comprises at least one, two, three, four or five but not more than 16 different amino acids relative to the amino acid sequence of any one of SEQ ID NO: 73.

[0210] 62. The antibody of any one of embodiments 1-10, 14-16, 20-22, 25-27, 30-37, 43-46, or 51-56, wherein:

[0211] (i) the VH comprises the amino acid sequence of SEQ ID NO: 71, or an amino acid sequence that is 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 comprises 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: 71; or an amino acid sequence that comprises at least one, two, three, four or five but not more than 16 different amino acids relative to the amino acid sequence of any one of SEQ ID NO: 71; and

[0212] (ii) the VL comprises the amino acid sequence of SEQ ID NO: 74, or an amino acid sequence that is 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 comprises 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 comprises at least one, two, three, four or five but not more than 16 different amino acids relative to the amino acid sequence of any one of SEQ ID NO: 74.

[0213] 63. The antibody of any one of embodiments 1-62, wherein:

[0214] (i) the nucleotide sequence encoding the VH comprises the nucleotide sequence of any one of SEQ ID NOs: 156-160, or a nucleotide sequence that is at least 80% (e.g., at least 85%, 87%, 90%, 91%, 95%, 96%, 97%, 98% or 99%) identical thereto; and / or

[0215] (ii) the nucleotide sequence encoding the VL comprises the nucleotide sequence of any one of SEQ ID NOs: 161-165, or a nucleotide sequence that is at least 80% (e.g., at least 85%, 87%, 90%, 91%, 95%, 96%, 97%, 98% or 99%) identical thereto.

[0216] 64. The antibody of any one of embodiments 1-63, wherein:

[0217] (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 that is at least 80% (e.g., at least 85%, 87%, 90%, 91%, 95%, 96%, 97%, 98% or 99%) identical thereto; and / or

[0218] (ii) the nucleotide sequence encoding the VL comprises the nucleotide sequence of any one of SEQ ID NOs: 161-163, or a nucleotide sequence that is at least 80% (e.g., at least 85%, 87%, 90%, 91%, 95%, 96%, 97%, 98% or 99%) identical thereto.

[0219] 65. The antibody of any one of embodiments 1-11, 15-17, 21-23, 26-28, 31-38, 44-49, 52-58, 63, or 64, wherein:

[0220] (i) the nucleotide sequence encoding the VH comprises the nucleotide sequence of SEQ ID NO: 158, or a nucleotide sequence that is at least 80% (e.g., at least 85%, 87%, 90%, 91%, 95%, 96%, 97%, 98% or 99%) identical thereto; and / or

[0221] (ii) the nucleotide sequence encoding the VL comprises the nucleotide sequence of any one of SEQ ID NO: 162, or a nucleotide sequence that is at least 80% (e.g., at least 85%, 87%, 90%, 91%, 95%, 96%, 97%, 98% or 99%) identical thereto.

[0222] 66. 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, or 64, wherein:

[0223] (i) the nucleotide sequence encoding the VH comprises the nucleotide sequence of SEQ ID NO: 156, or a nucleotide sequence that is at least 80% (e.g., at least 85%, 87%, 90%, 91%, 95%, 96%, 97%, 98% or 99%) identical thereto; and / or

[0224] (ii) the nucleotide sequence encoding the VL comprises the nucleotide sequence of any one of SEQ ID NO: 161, or a nucleotide sequence that is at least 80% (e.g., at least 85%, 87%, 90%, 91%, 95%, 96%, 97%, 98% or 99%) identical thereto.

[0225] 67. 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, or 64, wherein:

[0226] (i) the nucleotide sequence encoding the VH comprises the nucleotide sequence of SEQ ID NO: 159, or a nucleotide sequence that is at least 80% (e.g., at least 85%, 87%, 90%, 91%, 95%, 96%, 97%, 98% or 99%) identical thereto; and / or

[0227] (ii) the nucleotide sequence encoding the VL comprises the nucleotide sequence of any one of SEQ ID NO: 161, or a nucleotide sequence that is at least 80% (e.g., at least 85%, 87%, 90%, 91%, 95%, 96%, 97%, 98% or 99%) identical thereto.

[0228] 68. The antibody of any one of embodiments 1-10, 14-16, 20-23, 25-27, 30-37, 43-49, 51-56, 61-64, wherein:

[0229] (i) the nucleotide sequence encoding the VH comprises the nucleotide sequence of SEQ ID NO: 160, or a nucleotide sequence that is at least 80% (e.g., at least 85%, 87%, 90%, 91%, 95%, 96%, 97%, 98% or 99%) identical thereto; and / or

[0230] (ii) the nucleotide sequence encoding the VL comprises the nucleotide sequence of any one of SEQ ID NO: 162 or 163, or a nucleotide sequence that is at least 80% (e.g., at least 85%, 87%, 90%, 91%, 95%, 96%, 97%, 98% or 99%) identical thereto.

[0231] 69. 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.

[0232] 70. An antibody that binds to human tau, comprising:

[0233] (a) a heavy chain variable region (VH) comprising a heavy chain complementary determining region 1 (HC CDR1) comprising the amino acid sequence of SEQ ID NO: 64, a heavy chain complementary determining region 2 (HC CDR2) comprising the amino acid sequence of SEQ ID NO: 1145, and a heavy chain complementary 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 complementary determining region 1 (LC CDR1) comprising the amino acid sequence of SEQ ID NO: 1146, a light chain complementary determining region 2 (LC CDR2) comprising the amino acid sequence of SEQ ID NO: 529, and a light chain complementary determining region 3 (LC CDR3) comprising the amino acid sequence of SEQ ID NO: 571;

[0234] (b) a VH comprising a HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1144, a HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1145, and a HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410; and a VL comprising a LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1146, a LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571;

[0235] (c) a VH comprising a HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1165, a HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1166, and a HC CDR3 comprising the amino acid sequence of SEQ ID NO: 1167; and a VL comprising a LC CDR1 comprising the amino acid sequence of SEQ ID NO: 473, a LC CDR2 comprising the amino acid sequence of RVS, and a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; or

[0236] (d) a VH comprising a HC CDR1 comprising the amino acid sequence of SEQ ID NO: 314, a HC CDR2 comprising the amino acid sequence of SEQ ID NO: 341, and a HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410; and a VL comprising a LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1154, a LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; and

[0237] in:

[0238] (i) the VH comprises 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: 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 / or an L at position 113; and

[0239] (ii) the VL comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or all of the following: an I at position 2, an S at position 7, an S at position 12, a T at position 14, a P at position 15, a Q at position 17, a P at position 18, a Q at position 50, an S at position 68, a V at position 88, a Y at position 92, a Q at position 105, and / or a V at position 109.

[0240] 71. An antibody that binds to human tau, comprising:

[0241] (a) a heavy chain variable region (VH) comprising a heavy chain complementary determining region 1 (HC CDR1) comprising the amino acid sequence of SEQ ID NO: 64, a heavy chain complementary determining region 2 (HC CDR2) comprising the amino acid sequence of SEQ ID NO: 1145, and a heavy chain complementary 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 complementary determining region 1 (LC CDR1) comprising the amino acid sequence of SEQ ID NO: 1146, a light chain complementary determining region 2 (LC CDR2) comprising the amino acid sequence of SEQ ID NO: 529, and a light chain complementary determining region 3 (LC CDR3) comprising the amino acid sequence of SEQ ID NO: 571;

[0242] (b) a VH comprising a HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1144, a HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1145, and a HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410; and a VL comprising a LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1146, a LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571;

[0243] (c) a VH comprising a HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1165, a HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1166, and a HC CDR3 comprising the amino acid sequence of SEQ ID NO: 1167; and a VL comprising a LC CDR1 comprising the amino acid sequence of SEQ ID NO: 473, a LC CDR2 comprising the amino acid sequence of RVS, and a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; or

[0244] (d) a VH comprising a HC CDR1 comprising the amino acid sequence of SEQ ID NO: 314, a HC CDR2 comprising the amino acid sequence of SEQ ID NO: 341, and a HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410; and a VL comprising a LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1154, a LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; and

[0245] in:

[0246] (i) the VH comprises the amino acid sequence of SEQ ID NO: 69, 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 SEQ ID NO: 69; and / or

[0247] (ii) the VL comprises the amino acid sequence of SEQ ID NO: 73, 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 SEQ ID NO: 73.

[0248] 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.

[0249] 73. An antibody that binds to human tau, comprising:

[0250] (a) a heavy chain variable region (VH) comprising a heavy chain complementary determining region 1 (HC CDR1) comprising the amino acid sequence of SEQ ID NO: 64, a heavy chain complementary determining region 2 (HC CDR2) comprising the amino acid sequence of SEQ ID NO: 1145, and a heavy chain complementary 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 complementary determining region 1 (LC CDR1) comprising the amino acid sequence of SEQ ID NO: 1146, a light chain complementary determining region 2 (LC CDR2) comprising the amino acid sequence of SEQ ID NO: 529, and a light chain complementary determining region 3 (LC CDR3) comprising the amino acid sequence of SEQ ID NO: 571;

[0251] (b) a VH comprising a HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1144, a HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1145, and a HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410; and a VL comprising a LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1146, a LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571;

[0252] (c) a VH comprising a HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1165, a HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1166, and a HC CDR3 comprising the amino acid sequence of SEQ ID NO: 1167; and a VL comprising a LC CDR1 comprising the amino acid sequence of SEQ ID NO: 473, a LC CDR2 comprising the amino acid sequence of RVS, and a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; or

[0253] (d) a VH comprising a HC CDR1 comprising the amino acid sequence of SEQ ID NO: 314, a HC CDR2 comprising the amino acid sequence of SEQ ID NO: 341, and a HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410; and a VL comprising a LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1154, a LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; and

[0254] in:

[0255] (i) the VH comprises 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: a V at position 5; an E at position 6; an S at position 7; an A at position 9; a V at position 11; a K at position 12; an A at position 16; a K at position 19; a V at position 20; an M at position 48; an R at position 67; a V at position 68; an I at position 70; an A at position 76; an S at position 77; an A at position 79; a Y at position 80; an M at position 81; an E at position 82; an R at position 87; a T at position 91; and / or a T at position 113; and

[0256] (ii) the VL comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or all of the following: S at position 7, numbered according to SEQ ID NO: 93; 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.

[0257] 74. An antibody that binds to human tau, comprising:

[0258] (a) a heavy chain variable region (VH) comprising a heavy chain complementary determining region 1 (HC CDR1) comprising the amino acid sequence of SEQ ID NO: 64, a heavy chain complementary determining region 2 (HC CDR2) comprising the amino acid sequence of SEQ ID NO: 1145, and a heavy chain complementary 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 complementary determining region 1 (LC CDR1) comprising the amino acid sequence of SEQ ID NO: 1146, a light chain complementary determining region 2 (LC CDR2) comprising the amino acid sequence of SEQ ID NO: 529, and a light chain complementary determining region 3 (LC CDR3) comprising the amino acid sequence of SEQ ID NO: 571;

[0259] (b) a VH comprising a HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1144, a HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1145, and a HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410; and a VL comprising a LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1146, a LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571;

[0260] (c) a VH comprising a HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1165, a HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1166, and a HC CDR3 comprising the amino acid sequence of SEQ ID NO: 1167; and a VL comprising a LC CDR1 comprising the amino acid sequence of SEQ ID NO: 473, a LC CDR2 comprising the amino acid sequence of RVS, and a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; or

[0261] (d) a VH comprising a HC CDR1 comprising the amino acid sequence of SEQ ID NO: 314, a HC CDR2 comprising the amino acid sequence of SEQ ID NO: 341, and a HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410; and a VL comprising a LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1154, a LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; and

[0262] in:

[0263] (i) the VH comprises the amino acid sequence of SEQ ID NO: 67, 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 SEQ ID NO: 67; and / or

[0264] (ii) the VL comprises the amino acid sequence of SEQ ID NO: 72, 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 SEQ ID NO: 72.

[0265] 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.

[0266] 76. An antibody that binds to human tau, comprising:

[0267] (a) a heavy chain variable region (VH) comprising a heavy chain complementary determining region 1 (HC CDR1) comprising the amino acid sequence of SEQ ID NO: 64, a heavy chain complementary determining region 2 (HC CDR2) comprising the amino acid sequence of SEQ ID NO: 1145, and a heavy chain complementary 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 complementary determining region 1 (LC CDR1) comprising the amino acid sequence of SEQ ID NO: 1146, a light chain complementary determining region 2 (LC CDR2) comprising the amino acid sequence of SEQ ID NO: 529, and a light chain complementary determining region 3 (LC CDR3) comprising the amino acid sequence of SEQ ID NO: 571;

[0268] (b) a VH comprising a HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1144, a HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1145, and a HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410; and a VL comprising a LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1146, a LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571;

[0269] (c) a VH comprising a HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1165, a HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1166, and a HC CDR3 comprising the amino acid sequence of SEQ ID NO: 1167; and a VL comprising a LC CDR1 comprising the amino acid sequence of SEQ ID NO: 473, a LC CDR2 comprising the amino acid sequence of RVS, and a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; or

[0270] (d) a VH comprising a HC CDR1 comprising the amino acid sequence of SEQ ID NO: 314, a HC CDR2 comprising the amino acid sequence of SEQ ID NO: 341, and a HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410; and a VL comprising a LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1154, a LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; and

[0271] in:

[0272] (i) the VH comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 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; and

[0273] (ii) the VL comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or all of the following: S at position 7, numbered according to SEQ ID NO: 93; 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.

[0274] 77. An antibody that binds to human tau, comprising:

[0275] (a) a heavy chain variable region (VH) comprising a heavy chain complementary determining region 1 (HC CDR1) comprising the amino acid sequence of SEQ ID NO: 64, a heavy chain complementary determining region 2 (HC CDR2) comprising the amino acid sequence of SEQ ID NO: 1145, and a heavy chain complementary 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 complementary determining region 1 (LC CDR1) comprising the amino acid sequence of SEQ ID NO: 1146, a light chain complementary determining region 2 (LC CDR2) comprising the amino acid sequence of SEQ ID NO: 529, and a light chain complementary determining region 3 (LC CDR3) comprising the amino acid sequence of SEQ ID NO: 571;

[0276] (b) a VH comprising a HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1144, a HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1145, and a HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410; and a VL comprising a LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1146, a LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571;

[0277] (c) a VH comprising a HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1165, a HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1166, and a HC CDR3 comprising the amino acid sequence of SEQ ID NO: 1167; and a VL comprising a LC CDR1 comprising the amino acid sequence of SEQ ID NO: 473, a LC CDR2 comprising the amino acid sequence of RVS, and a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; or

[0278] (d) a VH comprising a HC CDR1 comprising the amino acid sequence of SEQ ID NO: 314, a HC CDR2 comprising the amino acid sequence of SEQ ID NO: 341, and a HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410; and a VL comprising a LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1154, a LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; and

[0279] in:

[0280] (i) the VH comprises the amino acid sequence of SEQ ID NO: 70, 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 SEQ ID NO: 70; and / or

[0281] (ii) the VL comprises the amino acid sequence of SEQ ID NO: 72, 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 SEQ ID NO: 72.

[0282] 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.

[0283] 79. An antibody that binds to human tau, comprising:

[0284] (a) a heavy chain variable region (VH) comprising a heavy chain complementary determining region 1 (HC CDR1) comprising the amino acid sequence of SEQ ID NO: 64, a heavy chain complementary determining region 2 (HC CDR2) comprising the amino acid sequence of SEQ ID NO: 1145, and a heavy chain complementary 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 complementary determining region 1 (LC CDR1) comprising the amino acid sequence of SEQ ID NO: 1146, a light chain complementary determining region 2 (LC CDR2) comprising the amino acid sequence of SEQ ID NO: 529, and a light chain complementary determining region 3 (LC CDR3) comprising the amino acid sequence of SEQ ID NO: 571;

[0285] (b) a VH comprising a HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1144, a HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1145, and a HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410; and a VL comprising a LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1146, a LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571;

[0286] (c) a VH comprising a HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1165, a HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1166, and a HC CDR3 comprising the amino acid sequence of SEQ ID NO: 1167; and a VL comprising a LC CDR1 comprising the amino acid sequence of SEQ ID NO: 473, a LC CDR2 comprising the amino acid sequence of RVS, and a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; or

[0287] (d) a VH comprising a HC CDR1 comprising the amino acid sequence of SEQ ID NO: 314, a HC CDR2 comprising the amino acid sequence of SEQ ID NO: 341, and a HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410; and a VL comprising a LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1154, a LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; and

[0288] in:

[0289] (i) the VH comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or all of the following: 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 A at position 16; a K at position 19; a V at position 20; a Q at position 43; an M at position 48; an R at position 67; a V at position 68; an M at position 70; a T at position 76; an S at position 77; an R at position 87; and / or a T at position 91; and

[0290] (ii) the VL comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or all of the following: an I at position 2, an S at position 7, an S at position 12, a T at position 14, a P at position 15, a Q at position 17, a P at position 18, a Q at position 50, an S at position 68, a V at position 88, a Y at position 92, a Q at position 105, and / or a V at position 109.

[0291] 80. An antibody that binds to human tau, comprising:

[0292] (a) a heavy chain variable region (VH) comprising a heavy chain complementary determining region 1 (HC CDR1) comprising the amino acid sequence of SEQ ID NO: 64, a heavy chain complementary determining region 2 (HC CDR2) comprising the amino acid sequence of SEQ ID NO: 1145, and a heavy chain complementary 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 complementary determining region 1 (LC CDR1) comprising the amino acid sequence of SEQ ID NO: 1146, a light chain complementary determining region 2 (LC CDR2) comprising the amino acid sequence of SEQ ID NO: 529, and a light chain complementary determining region 3 (LC CDR3) comprising the amino acid sequence of SEQ ID NO: 571;

[0293] (b) a VH comprising a HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1144, a HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1145, and a HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410; and a VL comprising a LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1146, a LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571;

[0294] (c) a VH comprising a HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1165, a HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1166, and a HC CDR3 comprising the amino acid sequence of SEQ ID NO: 1167; and a VL comprising a LC CDR1 comprising the amino acid sequence of SEQ ID NO: 473, a LC CDR2 comprising the amino acid sequence of RVS, and a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; or

[0295] (d) a VH comprising a HC CDR1 comprising the amino acid sequence of SEQ ID NO: 314, a HC CDR2 comprising the amino acid sequence of SEQ ID NO: 341, and a HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410; and a VL comprising a LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1154, a LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; and

[0296] in:

[0297] (i) the VH comprises the amino acid sequence of SEQ ID NO: 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 SEQ ID NO: 71; and / or

[0298] (ii) the VL comprises the amino acid sequence of SEQ ID NO: 73, 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 SEQ ID NO: 73.

[0299] 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.

[0300] 82. An antibody that binds to human tau, comprising:

[0301] (a) a heavy chain variable region (VH) comprising a heavy chain complementary determining region 1 (HC CDR1) comprising the amino acid sequence of SEQ ID NO: 64, a heavy chain complementary determining region 2 (HC CDR2) comprising the amino acid sequence of SEQ ID NO: 1145, and a heavy chain complementary 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 complementary determining region 1 (LC CDR1) comprising the amino acid sequence of SEQ ID NO: 1146, a light chain complementary determining region 2 (LC CDR2) comprising the amino acid sequence of SEQ ID NO: 529, and a light chain complementary determining region 3 (LC CDR3) comprising the amino acid sequence of SEQ ID NO: 571;

[0302] (b) a VH comprising a HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1144, a HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1145, and a HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410; and a VL comprising a LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1146, a LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571;

[0303] (c) a VH comprising a HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1165, a HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1166, and a HC CDR3 comprising the amino acid sequence of SEQ ID NO: 1167; and a VL comprising a LC CDR1 comprising the amino acid sequence of SEQ ID NO: 473, a LC CDR2 comprising the amino acid sequence of RVS, and a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; or

[0304] (d) a VH comprising a HC CDR1 comprising the amino acid sequence of SEQ ID NO: 314, a HC CDR2 comprising the amino acid sequence of SEQ ID NO: 341, and a HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410; and a VL comprising a LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1154, a LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; and

[0305] in:

[0306] (i) the VH comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or all of the following: 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 A at position 16; a K at position 19; a V at position 20; a Q at position 43; an M at position 48; an R at position 67; a V at position 68; an M at position 70; a T at position 76; an S at position 77; an R at position 87; and / or a T at position 91; and

[0307] (ii) the VL comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 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.

[0308] 83. An antibody that binds to human tau, comprising:

[0309] (a) a heavy chain variable region (VH) comprising a heavy chain complementary determining region 1 (HC CDR1) comprising the amino acid sequence of SEQ ID NO: 64, a heavy chain complementary determining region 2 (HC CDR2) comprising the amino acid sequence of SEQ ID NO: 1145, and a heavy chain complementary 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 complementary determining region 1 (LC CDR1) comprising the amino acid sequence of SEQ ID NO: 1146, a light chain complementary determining region 2 (LC CDR2) comprising the amino acid sequence of SEQ ID NO: 529, and a light chain complementary determining region 3 (LC CDR3) comprising the amino acid sequence of SEQ ID NO: 571;

[0310] (b) a VH comprising a HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1144, a HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1145, and a HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410; and a VL comprising a LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1146, a LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571;

[0311] (c) a VH comprising a HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1165, a HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1166, and a HC CDR3 comprising the amino acid sequence of SEQ ID NO: 1167; and a VL comprising a LC CDR1 comprising the amino acid sequence of SEQ ID NO: 473, a LC CDR2 comprising the amino acid sequence of RVS, and a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; or

[0312] (d) a VH comprising a HC CDR1 comprising the amino acid sequence of SEQ ID NO: 314, a HC CDR2 comprising the amino acid sequence of SEQ ID NO: 341, and a HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410; and a VL comprising a LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1154, a LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; and

[0313] in:

[0314] (i) the VH comprises the amino acid sequence of SEQ ID NO: 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 SEQ ID NO: 71; and / or

[0315] (ii) the VL comprises the amino acid sequence of SEQ ID NO: 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 SEQ ID NO: 74.

[0316] 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.

[0317] 85. The antibody of any one of the preceding embodiments, wherein the antibody is a humanized antibody.

[0318] 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, a Fv, or a single-chain Fv fragment (scFv).

[0319] 87. 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.

[0320] 88. The antibody of any one of the preceding embodiments, comprising a heavy chain constant region of IgG4 and a light chain constant region of kappa.

[0321] 89. The antibody of any one of the preceding embodiments, wherein:

[0322] (i) the antibody comprises a human IgG4 constant region comprising an amino acid other than serine at position 228 according to EU numbering;

[0323] (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;

[0324] (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 that is at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 194; and / or

[0325] (iv) the antibody comprises a heavy chain constant region (e.g., a human IgG4 constant region), wherein the nucleotide sequence encoding the heavy chain constant region comprises the nucleotide sequence of any one of SEQ ID NO: 195, 196, 198 or 199, or a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO: 195, 196, 198 or 199.

[0326] 90. The antibody of any one of embodiments 1-35, wherein the antibody comprises a light chain constant region (e.g., a kappa light chain constant region), wherein:

[0327] (i) the light chain constant region comprises the amino acid sequence of SEQ ID NO: 200, or an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 200; and / or

[0328] (ii) the nucleotide sequence encoding the light chain constant region comprises the nucleotide sequence of SEQ ID NO: 201 or 202, or a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 201 or 202.

[0329] 91. The antibody of any one of embodiments 1-90, wherein the antibody comprises a heavy chain comprising an amino acid sequence of any one of SEQ ID NOs: 170-174, or an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 170-174.

[0330] 92. The antibody of any one of embodiments 1-91, wherein the antibody comprises a light chain comprising an amino acid sequence of any one of SEQ ID NOs: 175-179, or an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 175-179.

[0331] 93. The antibody of any one of embodiments 1-92, wherein the antibody comprises:

[0332] (i) a heavy chain comprising the amino acid sequence of any one of SEQ ID NOs: 170-174, or an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 170-174; and

[0333] (ii) a light chain comprising the amino acid sequence of any one of SEQ ID NOs: 175-179, or an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 175-179.

[0334] 94. The antibody of any one of embodiments 1-93, wherein the antibody comprises:

[0335] (i) a heavy chain comprising the amino acid sequence of any one of SEQ ID NOs: 170 or 172-174, or an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 170 or 172-174; and

[0336] (ii) a light chain comprising the amino acid sequence of any one of SEQ ID NOs: 175-177, or an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 175-177.

[0337] 95. The antibody of any one of the preceding embodiments, comprising:

[0338] (i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 170, or an amino acid sequence that is 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 that is at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 175;

[0339] (ii) a heavy chain comprising the amino acid sequence of SEQ ID NO: 170, or an amino acid sequence that is 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 that is at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 176;

[0340] (iii) a heavy chain comprising the amino acid sequence of SEQ ID NO: 170, or an amino acid sequence that is 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 that is at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 177;

[0341] (iv) a heavy chain comprising the amino acid sequence of SEQ ID NO: 170, or an amino acid sequence that is 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 that is at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 178;

[0342] (v) a heavy chain comprising the amino acid sequence of SEQ ID NO: 170, or an amino acid sequence that is 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 that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 179;

[0343] (vi) a heavy chain comprising the amino acid sequence of SEQ ID NO: 171, or an amino acid sequence that is 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 that is at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 175;

[0344] (vii) a heavy chain comprising the amino acid sequence of SEQ ID NO: 171, or an amino acid sequence that is 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 that is at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 176;

[0345] (viii) a heavy chain comprising the amino acid sequence of SEQ ID NO: 171, or an amino acid sequence that is 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 that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 177;

[0346] (ix) a heavy chain comprising the amino acid sequence of SEQ ID NO: 171, or an amino acid sequence that is 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 that is at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 178;

[0347] (x) a heavy chain comprising the amino acid sequence of SEQ ID NO: 171, or an amino acid sequence that is 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 that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 179;

[0348] (xi) a heavy chain comprising the amino acid sequence of SEQ ID NO: 172, or an amino acid sequence that is 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 that is at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 175;

[0349] (xii) a heavy chain comprising the amino acid sequence of SEQ ID NO: 172, or an amino acid sequence that is 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 that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 176;

[0350] (xiii) a heavy chain comprising the amino acid sequence of SEQ ID NO: 172, or an amino acid sequence that is 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 that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 177;

[0351] (xiv) a heavy chain comprising the amino acid sequence of SEQ ID NO: 172, or an amino acid sequence that is 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 that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 178;

[0352] (xv) a heavy chain comprising the amino acid sequence of SEQ ID NO: 172, or an amino acid sequence that is 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 that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 179;

[0353] (xvi) a heavy chain comprising the amino acid sequence of SEQ ID NO: 173, or an amino acid sequence that is 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 that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 175;

[0354] (xvii) a heavy chain comprising the amino acid sequence of SEQ ID NO: 173, or an amino acid sequence that is 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 that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 176;

[0355] (xviii) a heavy chain comprising the amino acid sequence of SEQ ID NO: 173, or an amino acid sequence that is 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 that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 177;

[0356] (xix) a heavy chain comprising the amino acid sequence of SEQ ID NO: 173, or an amino acid sequence that is 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 that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 178;

[0357] (xx) a heavy chain comprising the amino acid sequence of SEQ ID NO: 173, or an amino acid sequence that is 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 that is at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 179;

[0358] (xxi) 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: 175, or an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 175;

[0359] (xxii) 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;

[0360] (xxiii) 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;

[0361] (xxiv) 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: 178, or an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 178; or

[0362] (xxv) 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: 179, or an amino acid sequence that is at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 179.

[0363] 96. 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.

[0364] 97. The antibody of any one of embodiments 1-11, 15-17, 21-23, 26-28, 31-38, 44-49, 52-58, 63-65, 69-72, or 85-96, 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.

[0365] 98. 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.

[0366] 99. 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.

[0367] 100. The antibody of any one of embodiments 1-10, 14-16, 20-23, 31-37, 43-49, 52-56, 51, 63, 64, 68, 69, 79-81, 85-95, comprising 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.

[0368] 101. The antibody of any one of embodiments 1-10, 14-16, 20-22, 25-27, 30-37, 43-46, 51-56, 62-64, 68, 69, 82-95, comprising 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.

[0369] 102. The antibody of any one of the preceding embodiments, comprising:

[0370] (i) a heavy chain, wherein the nucleotide sequence encoding the heavy chain comprises the nucleotide sequence of any one of SEQ ID NOs: 180-184, or a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 180-184; and / or

[0371] (ii) a light chain, wherein the nucleotide sequence encoding the light chain comprises the nucleotide sequence of any one of SEQ ID NOs: 185-189, or a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 185-189.

[0372] 103. The antibody of any one of the preceding embodiments, comprising:

[0373] (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 that is at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 180 or 182-184; and / or

[0374] (ii) a light chain, wherein the nucleotide sequence encoding the light chain comprises the nucleotide sequence of any one of SEQ ID NOs: 185-187, or a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 185-187.

[0375] 104. 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, 85-98, 102, or 103, comprising:

[0376] (i) a heavy chain, wherein the nucleotide sequence encoding the heavy chain comprises the nucleotide sequence of SEQ ID NO: 182, or a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 182; and / or

[0377] (ii) a light chain, wherein the nucleotide sequence encoding the light chain comprises the nucleotide sequence of SEQ ID NO: 186, or a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 186.

[0378] 105. 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, 85-95, 98, 102, or 103, comprising:

[0379] (i) a heavy chain, wherein the nucleotide sequence encoding the heavy chain comprises the nucleotide sequence of SEQ ID NO: 180, or a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 180; and / or

[0380] (ii) a light chain, wherein the nucleotide sequence encoding the light chain comprises the nucleotide sequence of SEQ ID NO: 185, or a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 185.

[0381] 106. 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, 85-95, 99, 102, or 103, comprising:

[0382] (i) a heavy chain, wherein the nucleotide sequence encoding the heavy chain comprises the nucleotide sequence of SEQ ID NO: 183, or a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 183; and / or

[0383] (ii) a light chain, wherein the nucleotide sequence encoding the light chain comprises the nucleotide sequence of SEQ ID NO: 185, or a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 185.

[0384] 107. The antibody of any one of embodiments 1-10, 14-16, 20-23, 25-27, 30-37, 43-49, 51-56, 51, 62-65, 68, 69, 79-95, or 100-103, comprising:

[0385] (i) a heavy chain, wherein the nucleotide sequence encoding the heavy chain comprises the nucleotide sequence of SEQ ID NO: 184, or a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 184; and / or

[0386] (ii) a light chain, wherein the nucleotide sequence encoding the light chain comprises the nucleotide sequence of SEQ ID NO: 186 or 187, or a nucleotide sequence that is at least 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 186 or 187.

[0387] 108. The antibody of any of the preceding embodiments, wherein the antibody binds to the C-terminus of tau protein, eg, residues 409-436 numbered according to SEQ ID NO:920.

[0388] 109. The antibody of any of the preceding embodiments, wherein the antibody binds to phosphorylated residues of tau protein.

[0389] 110. The antibody of any one of the preceding embodiments, wherein the antibody binds to phosphorylated serine at position 422 (eg, pS422) numbered according to SEQ ID NO: 920.

[0390] 111. The antibody of any of the preceding embodiments, wherein the antibody preferentially binds 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 as described in Example 1 or Example 8.

[0391] 112. The antibody of any one of the preceding embodiments, which reduces, eg, inhibits, aggregation of tau.

[0392] 113. The antibody of any of the preceding embodiments, which binds to an epitope comprising a region formed by a complex of at least two tau proteins, such as a tau dimer.

[0393] 114. The antibody of any one of the preceding embodiments, which has one, two, three, four, five or all of the following properties:

[0394] (i) is capable of binding to iPHFs 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., when measured by an assay (e.g., an SPR or Biacore assay) (e.g., an assay as described in Example 8);

[0395] (ii) is capable of binding to phosphorylated serine at position 422 of human tau numbered according to SEQ ID NO:920 (e.g., a peptide comprising the amino acid sequence of SEQ ID NO:33) (e.g., pS422), e.g., when measured by an assay (e.g., an SPR or Biacore assay) (e.g., an assay as described in Example 8);

[0396] (iii) is capable of binding to ePHF with an affinity of at least about 0.08-0.2 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., when measured by an assay (e.g., an ELISA assay) (e.g., an assay as described in Example 8);

[0397] (iv) exhibits low polyspecificity, e.g., a BVP score of at least about 1.6-6 (e.g., a BVP score 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., when measured by an assay (e.g., a BVP ELISA assay) (e.g., an assay as described in Example 8);

[0398] (v) capable of binding pathological tau, e.g., as measured by an assay (e.g., an IHC assay, e.g., an assay as described in Example 8); and / or

[0399] (vi) the antibody preferentially binds 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 as described in Example 8).

[0400] 115. The antibody of any of the preceding embodiments, wherein the antibody exhibits a low immunogenicity risk (e.g., having a response rate of no more than about 55% (e.g., no more than about 50%, 46%, 48%, 30%, 24% or 20%) in a donor (e.g., in PBMC cells isolated from the donor), e.g., as measured by an assay (e.g., a T cell proliferation assay, e.g., an assay as described in Example 8).

[0401] 116. An antibody that competes for binding to tau with the antibody of any of the preceding embodiments.

[0402] 117. An antibody that binds to the same epitope, substantially the same epitope, or an overlapping epitope as the antibody of any one of the preceding embodiments.

[0403] 118. A nucleic acid encoding the antibody of any preceding claim.

[0404] 119. The nucleic acid of embodiment 118, encoding:

[0405] (i) VH, wherein the nucleotide sequence encoding the VH comprises the nucleotide sequence of any one of SEQ ID NOs: 156-160, or a nucleotide sequence that is at least 86% (e.g., at least 87%, 90%, 95%, 96%, 97%, 98% or 99%) identical thereto; and / or

[0406] (ii) VL, wherein the nucleotide sequence encoding the VL comprises the nucleotide sequence of any one of SEQ ID NOs: 161-165, or a nucleotide sequence that is at least 86% (e.g., at least 91%, 95%, 96%, 97%, 98% or 99%) identical thereto.

[0407] 120. The nucleic acid of embodiment 118 or 119, encoding:

[0408] (i) VH, wherein 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 that is at least 86% (e.g., at least 87%, 90%, 95%, 96%, 97%, 98% or 99%) identical thereto; and / or

[0409] (ii) VL, wherein the nucleotide sequence encoding the VL comprises the nucleotide sequence of any one of SEQ ID NOs: 161-163, or a nucleotide sequence that is at least 86% (e.g., at least 91%, 95%, 96%, 97%, 98% or 99%) identical thereto.

[0410] 121. The nucleic acid of any one of embodiments 118-120, encoding:

[0411] (i) a heavy chain, wherein the nucleotide sequence encoding the heavy chain comprises the nucleotide sequence of any one of SEQ ID NOs: 180-184, or a nucleotide sequence that is at least 86% (e.g., at least 87%, 90%, 95%, 96%, 97%, 98% or 99%) identical thereto; and / or

[0412] (ii) a light chain, wherein the nucleotide sequence encoding the light chain comprises the nucleotide sequence of any one of SEQ ID NOs: 185-189, or a nucleotide sequence that is at least 86% (e.g., at least 91%, 95%, 96%, 97%, 98% or 99%) identical thereto.

[0413] 122. The nucleic acid of any one of embodiments 118-121, encoding:

[0414] (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 that is at least 86% (e.g., at least 87%, 90%, 95%, 96%, 97%, 98% or 99%) identical thereto; and / or

[0415] (ii) a light chain, wherein the nucleotide sequence encoding the light chain comprises the nucleotide sequence of any one of SEQ ID NOs: 185-187, or a nucleotide sequence that is at least 86% (e.g., at least 91%, 95%, 96%, 97%, 98% or 99%) identical thereto.

[0416] 123. The nucleic acid of any one of embodiments 118-122, encoding:

[0417] (i) VH, wherein the nucleotide sequence encoding said 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 VL, wherein the nucleotide sequence encoding 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

[0418] (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.

[0419] 124. The nucleic acid of any one of embodiments 118-123, which is codon-optimized.

[0420] 125. An antibody encoded by the nucleic acid of any one of embodiments 118-124.

[0421] 126. The antibody of any one of embodiments 1-117 or 125 or the nucleic acid of any one of embodiments 118-124, which is isolated, e.g., recombinant.

[0422] 127. A vector comprising the nucleic acid of any one of embodiments 118-124 or 126, or a nucleic acid encoding the antibody of any one of embodiments 1-117, 125 or 126.

[0423] 128. A host cell comprising the nucleic acid of any one of embodiments 118-124 or 126, a nucleic acid encoding the antibody of any one of embodiments 1-117, 125 or 126, the antibody of any one of embodiments 1-117, 125 or 126, or the vector of embodiment 127.

[0424] 129. The host cell of embodiment 128, wherein the host cell is an insect cell, a bacterial cell, or a mammalian cell.

[0425] 130. A method of producing an antibody, the method comprising culturing the host cell of embodiment 128 or 129 under conditions suitable for gene expression.

[0426] 131. An isolated nucleic acid encoding a payload, wherein the encoded payload comprises the antibody of any one of embodiments 1-117, 125, or 126.

[0427] 132. The nucleic acid of embodiment 131, further encoding a signal sequence, optionally wherein the nucleotide sequence encoding the signal sequence comprises the nucleotide sequence of any one of the signal sequences listed in Table 14, or a nucleotide sequence having at least 95% sequence identity thereto.

[0428] 133. The nucleic acid of embodiment 131 or 132, further encoding a second signal sequence, optionally wherein the nucleotide sequence encoding the signal sequence comprises the nucleotide sequence of any one of the signal sequences listed in Table 14, or a nucleotide sequence having at least 95% sequence identity thereto.

[0429] 134. The nucleic acid of any one of embodiments 131-133, wherein:

[0430] (i) the nucleotide sequence encoding the signal sequence is located 5' relative to the nucleotide sequence encoding the VH; and / or

[0431] (ii) the nucleotide sequence encoding the signal sequence is located 5' relative to the nucleotide sequence encoding the VL.

[0432] 135. The nucleic acid of any one of embodiments 131-134, wherein the encoded VH and VL sequences are directly linked, e.g., without a linker.

[0433] 136. The nucleic acid of any one of embodiments 131-135, wherein the encoded VH and VL sequences are connected via a linker.

[0434] 137. The nucleic acid of embodiment 136, wherein the linker comprises a nucleotide sequence of any one of the linker sequences provided in Table 15, or a nucleotide sequence having at least 95% sequence identity thereto.

[0435] 138. The nucleic acid of any one of embodiments 131-137, 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).

[0436] 139. A viral genome comprising a promoter operably linked to a nucleic acid encoding a payload comprising the antibody of any one of embodiments 1-117, 125, or 126; or a nucleic acid of any one of embodiments 131-138.

[0437] 140. The viral genome of embodiment 139, wherein the promoter:

[0438] (i) selected from the group consisting of human elongation factor 1α-subunit (EF1α), cytomegalovirus (CMV) immediate early enhancer and / or promoter, chicken β-actin (CBA) and its derivative CAG, β-glucuronidase (GUSB) or ubiquitin C (UBC), neuron-specific enolase (NSE), platelet-derived growth factor (PDGF), platelet-derived growth factor B chain (PDGF-β), intercellular adhesion molecule 2 (ICAM-2), synaptophysin (Syn), methyl-CpG junction Ca2+ / calmodulin-dependent protein kinase II (CaMKII), metabotropic glutamate receptor 2 (mGluR2), neurofilament light chain (NFL) or heavy chain (NFH), β-globin minigene nβ2, preproenkephalin (PPE), enkephalin (Enk) and excitatory amino acid transporter 2 (EAAT2), glial fibrillary acidic protein (GFAP), myelin basic protein (MBP) or fragments thereof, such as truncated fragments, or functional variants; and / or

[0439] (ii) a nucleotide sequence comprising any one of the promoter sequences provided in Table 11, or a nucleotide sequence that is at least 95% identical thereto.

[0440] 141. The viral genome of embodiment 139 or 140, further comprising an enhancer, optionally wherein the enhancer is a CMV immediate-early (CMVie) enhancer.

[0441] 142. The viral genome of any one of embodiments 139-141, further comprising a polyadenylation (polyA) signal region.

[0442] 143. The viral genome of embodiment 142, wherein the polyA signal region comprises the nucleotide sequence of any one of SEQ ID NOs: 1134-1136, or a nucleotide sequence at least 95% identical thereto.

[0443] 144. The viral genome of any one of embodiments 139-143, further comprising an inverted terminal repeat (ITR) sequence.

[0444] 145. The viral genome of embodiment 144, wherein:

[0445] (i) the ITR sequence is located 5' relative to the encoded payload; and / or

[0446] (ii) The ITR sequence is located 3' relative to the encoded payload.

[0447] 146. The viral genome of any one of embodiments 139-145, comprising an ITR sequence located 5' to the encoded payload and an ITR sequence located 3' to the encoded payload.

[0448] 147. The viral genome of any one of embodiments 139-146, wherein the ITR sequence comprises the nucleotide sequence of any one of SEQ ID NOs: 1035-1038, or a nucleotide sequence having at least 80%, 85%, 90% or 95% sequence identity thereto.

[0449] 148. The viral genome of any one of embodiments 139-147, further comprising an intron region.

[0450] 149. The viral genome of embodiment 148, wherein the intron region comprises the nucleotide sequence of any one of the intron regions listed in Table 13, or a nucleotide sequence that is at least 95% identical thereto.

[0451] 150. The viral genome of any one of embodiments 139-149, comprising at least one, two, or three intron regions.

[0452] 151. The viral genome of any one of embodiments 139-150, further comprising an exon region.

[0453] 152. The viral genome of embodiment 151, wherein the exon region comprises a nucleotide sequence of any one of the exon sequences in Table 12, or a nucleotide sequence having at least 95% identity thereto.

[0454] 153. The viral genome of any one of embodiments 139-152, comprising at least one, two, or three exon regions.

[0455] 154. The viral genome of any one of embodiments 139-153, further comprising a Kozak sequence, optionally wherein the Kozak sequence comprises a nucleotide sequence of GCCGCCACCATG (SEQ ID NO: 1079) or GAGGAGCCACC (SEQ ID NO: 1089).

[0456] 155. The viral genome of any one of embodiments 139-154, further comprising a nucleotide sequence encoding a miR binding site, e.g., a miR binding site that modulates (e.g., reduces) expression of the payload encoded by the viral genome in cells or tissues expressing the corresponding miRNA.

[0457] 156. The viral genome of embodiment 155, comprising at least 1-5 copies of an encoded miR binding site, such as at least 1, 2, 3, 4, or 5 copies.

[0458] 157. The viral genome of any one of embodiments 139-156, comprising at least 3 copies of an encoded miR binding site, optionally wherein all three copies comprise the same miR binding site, or at least one, two, or all of the copies comprise different miR binding sites.

[0459] 158. The viral genome of any one of embodiments 139-157, comprising at least 4 copies of an encoded miR binding site, optionally wherein all four copies comprise the same miR binding site, or at least one, two, three, or all of the copies comprise different miR binding sites.

[0460] 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, miR-142-3p, or a combination thereof, optionally wherein:

[0461] (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 one, two, three, four, five, six or seven modifications but not more than ten modifications of SEQ ID NO: 1029;

[0462] (ii) the encoded miR183 binding site comprises a nucleotide sequence of SEQ ID NO: 1032, or a nucleotide sequence substantially identical thereto (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98% or 99% sequence identity); or a nucleotide sequence having at least one, two, three, four, five, six or seven modifications but not more than ten modifications of SEQ ID NO: 1032; and / or

[0463] (iii) the encoded miR-142-3p binding site comprises a nucleotide sequence of SEQ ID NO: 1031, or a nucleotide sequence substantially identical thereto (e.g., having at least 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98% or 99% sequence identity); or a nucleotide sequence having at least one, two, three, four, five, six or seven modifications but not more than ten modifications of SEQ ID NO: 1031.

[0464] 160. The viral genome of any one of embodiments 139-159, which is single-stranded or self-complementary.

[0465] 161. The viral genome of any one of embodiments 139-160, further comprising:

[0466] (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

[0467] (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.

[0468] 162. The viral genome of embodiment 161, wherein the Rep78 protein, Rep68 protein, Rep52 protein and / or Rep40 protein are encoded by at least one Rep gene.

[0469] 163. The viral genome of any one of embodiments 139-162, further comprising:

[0470] (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

[0471] (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.

[0472] 164. The viral genome of embodiment 163, wherein the VP1 polypeptide, VP2 polypeptide and / or VP3 polypeptide in the copy are encoded by at least one Cap gene.

[0473] 165. A vector comprising the viral genome of any one of embodiments 139-164.

[0474] 166. An isolated (e.g., recombinant) AAV particle comprising:

[0475] (i) capsid protein, and

[0476] (ii) the nucleic acid of any one of embodiments 131-138 or the viral genome of any one of embodiments 139-164.

[0477] 167. The isolated AAV particle of embodiment 166, wherein:

[0478] (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;

[0479] (ii) the capsid protein comprises an amino acid sequence having at least one, two or three modifications but not more than 30, 20 or 10 modifications of the amino acid sequence of SEQ ID NO: 1003;

[0480] (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;

[0481] (iv) the capsid protein comprises an amino acid sequence having at least one, two or three modifications but not more than 30, 20 or 10 modifications of the amino acid sequence of SEQ ID NO: 1011;

[0482] (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

[0483] (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.

[0484] 168. The isolated AAV particle of embodiment 166 or 167, wherein the capsid protein comprises:

[0485] (i) an amino acid substitution at position K449 numbered according to SEQ ID NO: 1003, e.g., a K449R substitution;

[0486] (ii) an insert comprising the amino acid sequence of TLAVPFK (SEQ ID NO: 1151), optionally wherein the insert is present immediately after position 588 relative to the reference sequence numbered according to SEQ ID NO: 1003;

[0487] (iii) an amino acid other than "A" at position 587 and / or an amino acid other than "Q" at position 588 according to SEQ ID NO: 1003; and / or

[0488] (iv) amino acid substitutions of A587D and / or Q588G numbered according to SEQ ID NO: 1003.

[0489] 169. The AAV particle of any one of embodiments 166-168, 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 wherein the insert is present immediately after position 588 of SEQ ID NO: 1003.

[0490] 170. The AAV particle of any one of embodiments 166-169, wherein the capsid protein comprises (i) an amino acid substitution of K449R as numbered by SEQ ID NO: 1003; (ii) an insert comprising the amino acid sequence of TLAVPFK (SEQ ID NO: 1151), optionally wherein the insert is present immediately after position 588 relative to the reference sequence numbered by SEQ ID NO: 1003; and (iii) amino acid substitutions of A587D and Q588G as numbered by SEQ ID NO: 1003.

[0491] 171. The AAV particle of any one of embodiments 166-169, wherein the capsid protein comprises (i) an insert comprising the amino acid sequence of TLAVPFK (SEQ ID NO: 1151), optionally wherein the insert is present immediately 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.

[0492] 172. An AAV particle as described in any of embodiments 166-171, wherein the capsid protein comprises VOY101, VOY201, AAVPHP.B (PHP.B), AAVPHP.A (PHP.A), AAVG2B-26, AAVG2B-13, AAVTH1.1-32, AAVTH1.1-35, AAVPHP.B2 (PHP.B2), AAVPHP.B3 (PHP.B3), AAVPHP.N / PHP.B-DGT, AAVPHP.B-EST, AAVPHP.B-GGT, AAVPHP.B-ATP, AAVPHP.B-ATT-T, AAVPHP.B-DGT-T, AAVPHP.B-GGT-T, AAVPHP.B-SGS, AAVPHP.B-AQP, AAVPHP.B-QQP, AAVPHP.B-SNP(3), AAVPHP.B-SN P, AAVPHP.B-QGT, AAVPHP.B-NQT, AAVPHP.B-EGS, AAVPHP.B-SGN, AAVPHP.B-EGT, AAVPHP.B-DST, AAV PHP.B-DST, AAVPHP.B-STP, AAVPHP.B-PQP, AAVPHP.B-SQP, AAVPHP.B-QLP, AAVPHP.B-TMP, AAVPHP.B- TTP, AAVPHP.S / G2A12, AAVG2A15 / G2A3 (G2A3), AAVG2B4 (G2B4), AAVG2B5 (G2B5), AAVPHP.N (PHP.N), PHP.S, AAV1, AAV2, AAV2 variant, AAV2 / 3 variant, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9.47, AAV9 (hu14), AAV9, AAV9 K449R, AAV10, AAV11, AAV12, AAVrh8, AAVrh10, AAVDJ, AAVDJ8 or AAV2G9 capsid protein or its functional variant.

[0493] 173. The AAV particle of any one of embodiments 166-172, wherein the capsid protein comprises an AAV5 capsid protein or a variant thereof or an AAV9 capsid protein or a variant thereof.

[0494] 174. The AAV particle of any one of embodiments 166-173, wherein the capsid protein comprises:

[0495] (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);

[0496] (ii) an amino acid sequence comprising at least one, two or three modifications but not more than 30, 20 or 10 modifications, e.g., substitutions, relative to the amino acid sequence of SEQ ID NO: 1023; or

[0497] (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).

[0498] 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).

[0499] 176. A host cell comprising the nucleic acid of any one of embodiments 131-138, the viral genome of any one of embodiments 139-164, or the AAV particle of any one of embodiments 166-175, optionally wherein the host cell is an insect cell, a bacterial cell, or a mammalian cell.

[0500] 177. A nucleic acid encoding a viral genome as described in any of embodiments 139-164, and a backbone region suitable for replicating the viral genome in a cell, such as a bacterial cell (e.g., wherein the backbone region comprises one or both of a bacterial origin of replication and a selectable marker).

[0501] 178. A method for producing a viral genome, the method comprising:

[0502] (i) providing a nucleic acid molecule comprising the viral genome of any one of embodiments 139-164; and

[0503] (ii) cleaving the viral genome from the backbone region, for example by cleaving nucleic acid molecules upstream and downstream of the viral genome.

[0504] 179. A method for producing isolated (e.g., recombinant) AAV particles, the method comprising

[0505] (i) providing a host cell comprising the viral genome of embodiment 176; and

[0506] (ii) incubating the host cell under conditions suitable for enclosing the viral genome in capsid protein;

[0507] The isolated AAV particles are thus produced.

[0508] 180. The method of embodiment 179, further comprising, prior to step (i), introducing a first nucleic acid molecule comprising the viral genome into the host cell.

[0509] 181. The method of any one of embodiments 178-180, wherein the host cell comprises a second nucleic acid encoding the capsid protein.

[0510] 182. The method of embodiment 181, wherein the second nucleic acid molecule is introduced into the host cell before, simultaneously with, or after the first nucleic acid molecule.

[0511] 183. A pharmaceutical composition comprising the antibody of any one of embodiments 1-117, 125, or 126, the AAV particle of any one of embodiments 166-175, or the AAV particle comprising the viral genome of any one of embodiments 139-164, or the isolated nucleic acid of any one of embodiments 131-138, and a pharmaceutically acceptable excipient.

[0512] 184. A method of delivering an exogenous antibody that binds to tau to a subject, comprising administering an effective amount of the pharmaceutical composition of embodiment 183, the antibody of any of embodiments 1-117, 125, or 126, the AAV particle of any of embodiments 166-175, or the AAV particle comprising the viral genome of any of embodiments 139-164, or the isolated nucleic acid of any of embodiments 131-138.

[0513] 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, e.g., abnormal tau expression.

[0514] 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).

[0515] 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.

[0516] 188. A method of treating a subject having or diagnosed as having a disease associated with tau expression, comprising administering to the subject an effective amount of the pharmaceutical composition of embodiment 183, the antibody of any of embodiments 1-117, 125, or 126, the AAV particle of any of embodiments 166-175, or the AAV particle comprising the viral genome of any of embodiments 139-164, or the isolated nucleic acid of any of embodiments 131-138.

[0517] 189. A method of treating a subject having or diagnosed as having a neurological disorder, e.g., 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 1-117, 125, or 126, the AAV particle of any one of embodiments 166-175, or the AAV particle comprising the viral genome of any one of embodiments 139-164, or the isolated nucleic acid of any one of embodiments 131-138.

[0518] 190. A method of treating a subject having or diagnosed as having a tauopathy, comprising administering to the subject an effective amount of the pharmaceutical composition of embodiment 183, the antibody of any of embodiments 1-117, 125, or 126, the AAV particle of any of embodiments 166-175, or the AAV particle comprising the viral genome of any of embodiments 139-164, or the isolated nucleic acid of any of embodiments 131-138.

[0519] 191. The method of any one of embodiments 185-190, wherein the disease associated with tau expression, the neurological disorder, or the tauopathy 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, dementia tau-only, or progressive subcortical gliosis.

[0520] 192. The method of any one of embodiments 188-191, wherein treating comprises preventing progression of the disease in the subject.

[0521] 193. The method of any one of embodiments 184-192, wherein the subject is human.

[0522] 194. The method of any one of embodiments 184-193, wherein the antibody or the AAV particle is administered to the subject intravenously, intramuscularly, via intraparenchymal administration, intracerebroventricularly, via intracisterna magna (ICM) injection, intrathecally, via focused ultrasound (FUS), e.g., intravenous administration combined with microbubbles (FUS-MB) or MRI-guided FUS combined with intravenous administration.

[0523] 195. The method of any one of embodiments 184-194, wherein the antibody or the AAV particle is administered intravenously to the subject.

[0524] 196. The method of any one of embodiments 184-194, wherein the antibody or the AAV particle is administered to the subject via intracisterna magna injection (ICM).

[0525] 197. The method of any one of embodiments 184-196, further comprising assessing (e.g., measuring) the level of antibodies produced in the subject (e.g., in cells or tissues of the subject).

[0526] 198. The method of any one of embodiments 184-197, wherein the administration results in production of an antibody in the subject, eg, in a cell or tissue of the subject, eg, 0.001 μg / mL to 100 mg / mL of the antibody.

[0527] 199. The method of embodiment 198, wherein the cell is a neuronal cell.

[0528] 200. The method of embodiment 198, wherein the tissue is central nervous system tissue, such as brain tissue.

[0529] 201. The method of any one of embodiments 184-200, further comprising performing a blood test, an imaging test (e.g., a PET scan or a combination of a PET scan and a biomarker, such as serum biomarker staining), a CNS biopsy sample, or an aqueous cerebrospinal fluid biopsy.

[0530] 202. The method of any one of embodiments 197-201, wherein measuring the level of the antibody is performed before, during, or after treatment with the antibody or the AAV particle.

[0531] 203. The method of any one of embodiments 184-202, wherein the subject has an antibody level greater than a reference level, e.g., a subject who has not received treatment with the antibody or the AAV particle, e.g., has not been administered the antibody or the AAV particle.

[0532] 204. The method of any one of embodiments 184-203, further comprising administering an additional therapeutic agent and / or therapy useful for treating or preventing a disorder associated with tau expression, a neurological disorder, such as a neurodegenerative disorder.

[0533] 205. The method of embodiment 204, wherein the additional therapeutic agent and / or therapy comprises a cholinesterase inhibitor (e.g., donepezil, rivastigmine, and / or galantamine), an N-methyl D-aspartate (NMDA) antagonist (e.g., memantine), an antipsychotic, an anxiolytic, an anticonvulsant, a dopamine agonist (e.g., pramipexole, ropinirole, rotigotine, and / or apomorphine), an MAO B inhibitors (e.g., selegiline, rasagiline, and / or safinamide), catechol O-methyltransferase (COMT) inhibitors (entacapone, opicapone, and / or tolcapone), anticholinergics (e.g., benztropine and / or trihexyphenidyl), amantadine, carbidopa-levodopa, deep brain stimulation (DBS), or a combination thereof.

[0534] 206. The antibody of any one of embodiments 1-117, 125, or 126, the pharmaceutical composition of embodiment 183, or the AAV particle of any one of embodiments 166-175, for use in the manufacture of a medicament.

[0535] 207. The antibody of any one of embodiments 1-117, 125, or 126, the pharmaceutical composition of embodiment 183, or the AAV particle of any one of embodiments 166-175, for use in treating a disease associated with tau expression.

[0536] 208. The antibody of any one of embodiments 1-117, 125, or 126, the pharmaceutical composition of embodiment 183, or the AAV particle of any one of embodiments 166-175, for use in treating a neurological disorder, such as a neurodegenerative disorder or traumatic brain injury (TBI).

[0537] 209. The antibody of any one of embodiments 1-117, 125, or 126, the pharmaceutical composition of embodiment 183, or the AAV particle of any one of embodiments 166-175 for use in treating tauopathy.

[0538] 210. Use of an effective amount of the antibody of any one of embodiments 1-117, 125, or 126, the pharmaceutical composition of embodiment 183, or the AAV particle of any one of embodiments 166-175 in the manufacture of a medicament.

[0539] 211. Use of the antibody of any one of embodiments 1-117, 125, or 126, the pharmaceutical composition of embodiment 183, or the AAV particle of any one of embodiments 166-175 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).

[0540] 212. An AAV viral genome comprising a nucleotide sequence encoding an antibody, fragment or variant thereof that binds to tau, wherein the AAV viral genome comprises, in 5' to 3' order:

[0541] (i) a 5' adeno-associated (AAV) ITR, optionally wherein the 5' AAV ITR comprises the nucleotide sequence of SEQ ID NO: 1035, or a nucleotide sequence that is at least 70%, 75%, 80%, 85%, 90%, 95% or 99% identical thereto;

[0542] (ii) an enhancer, optionally wherein the enhancer comprises the nucleotide sequence of 1050, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95% or 99% identical thereto;

[0543] (iii) a promoter (e.g., a CBA promoter or a variant thereof), optionally wherein the promoter comprises the nucleotide sequence of SEQ ID NO: 1042, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95% or 99% identical thereto;

[0544] (iv) an intron, optionally wherein the intron comprises the nucleotide sequence of SEQ ID NO: 1067, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95% or 99% identical thereto;

[0545] (v) a nucleotide sequence encoding a first signal sequence, optionally wherein:

[0546] (a) the first encoded signal sequence comprises the amino acid sequence of SEQ ID NO: 1; an amino acid sequence comprising one, two, three but not more than four different amino acids relative to SEQ ID NO: 1; or an amino acid sequence comprising one, two, three but not more than four modifications, e.g., substitutions, e.g., conservative substitutions, relative to SEQ ID NO: 1; and / or

[0547] (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;

[0548] (vi) a nucleotide sequence encoding a heavy chain variable region, wherein:

[0549] (a) the encoded heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 21, or an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95% or 99% identical thereto; and / or

[0550] (b) the nucleotide sequence encoding the heavy chain variable region comprises the nucleotide sequence of SEQ ID NO: 7, or a nucleotide sequence that is at least 70%, 75%, 80%, 85%, 90%, 95% or 99% identical thereto;

[0551] (v) a nucleotide sequence encoding a heavy chain constant region, optionally wherein:

[0552] (a) the encoded heavy chain constant region comprises the amino acid sequence of SEQ ID NO: 16, or an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95% or 99% identical thereto; and / or

[0553] (b) the nucleotide sequence encoding the heavy chain constant region comprises the nucleotide sequence of SEQ ID NO: 805, or a nucleotide sequence that is at least 70%, 75%, 80%, 85%, 90%, 95% or 99% identical thereto;

[0554] (vi) a first linker, optionally wherein the first linker comprises the nucleotide sequence of SEQ ID NO: 1724; a nucleotide sequence comprising one, two, three but not more than four different nucleotides relative to the nucleotide sequence of SEQ ID NO: 1724; a nucleotide sequence comprising one, two, three but not more than four modifications, e.g., substitutions, relative to SEQ ID NO: 1724;

[0555] (vii) a second linker, optionally wherein the second linker comprises the nucleotide sequence of SEQ ID NO: 1726; a nucleotide sequence comprising one, two, three but not more than four different nucleotides relative to the nucleotide sequence of SEQ ID NO: 1726; a nucleotide sequence comprising one, two, three but not more than four modifications, e.g., substitutions, relative to SEQ ID NO: 1726;

[0556] (viii) a nucleotide sequence encoding a second signal sequence, optionally wherein:

[0557] (a) the first encoded signal sequence comprises the amino acid sequence of SEQ ID NO: 2; an amino acid sequence comprising one, two, three but not more than four different amino acids relative to SEQ ID NO: 2; or an amino acid sequence comprising one, two, three but not more than four modifications, e.g., substitutions, e.g., conservative substitutions, relative to SEQ ID NO: 2; and / or

[0558] (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;

[0559] (ix) a nucleotide sequence encoding a light chain variable region, wherein:

[0560] (a) the encoded light chain variable region comprises the amino acid sequence of SEQ ID NO: 93, or an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95% or 99% identical thereto; and / or

[0561] (b) the nucleotide sequence encoding the light chain variable region comprises the nucleotide sequence of SEQ ID NO: 11, or a nucleotide sequence that is at least 70%, 75%, 80%, 85%, 90%, 95% or 99% identical thereto;

[0562] (x) a nucleotide sequence encoding a light chain constant region, optionally wherein:

[0563] (a) the encoded light chain constant region comprises the amino acid sequence of SEQ ID NO: 18, or an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95% or 99% identical thereto; and / or

[0564] (b) the nucleotide sequence encoding the light chain constant region comprises the nucleotide sequence of SEQ ID NO: 17, or a nucleotide sequence that is at least 70%, 75%, 80%, 85%, 90%, 95% or 99% identical thereto;

[0565] (xi) a polyA signal sequence, optionally wherein the polyA signal sequence comprises the nucleotide sequence of SEQ ID NO: 1134, or a nucleotide sequence at least 70%, 75%, 80%, 85%, 90%, 95% or 99% identical thereto; and

[0566] (xii) a 3' AAV ITR, optionally wherein the 3' AAV ITR comprises the nucleotide sequence of SEQ ID NO: 1037, or a nucleotide sequence that is at least 70%, 75%, 80%, 85%, 90%, 95% or 99% identical thereto.

[0567] 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.

[0568] 214. The viral genome of any one of embodiments 139-164 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 DESCRIPTION OF THE DRAWINGS

[0569] Figure 1 To depict the stimulation index (ratio of the number of proliferating T cells of a blank sample) of each antibody after incubation with PBMC cells from 50 healthy donors representing the total population, based on HLA-DRB1 expression, as a measure of relative immunogenicity risk. The tested antibodies include Herceptin control, Ab2, Ab1, Ab3, Ab4, and Ab5 from left to right on the X-axis. A stimulation index greater than or equal to 2.0 is considered a positive reaction. DETAILED DESCRIPTION

[0570] I. Composition

[0571] In some embodiments, the present disclosure provides compositions that interact with 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 present in a neurodegenerative disease of a type known as tauopathy. Tau hyperphosphorylation causes aggregation and inhibition of tau-dependent microtubule assembly. In tauopathy, tau aggregates form paired helical filaments (PHFs) present in neurofibrillary tangles (NFTs). These aggregates cause neuronal loss and cognitive decline. Anti-tau antibodies of the present disclosure may be applicable to treatment and / or diagnosis of tauopathy, as well as other applications described herein.

[0572] Antibody

[0573] In some embodiments, the compounds of the present disclosure (e.g., anti-tau antibodies) and compositions comprise antibodies or fragments thereof. In some embodiments, the antibodies described herein bind to tau. For example, the antibody binds to an epitope on tau, such as a conformational epitope, a phosphorylation epitope, or a linear epitope, for example, as described herein.

[0574] As used herein, the term "antibody" refers to the broadest sense and specifically encompasses various embodiments including, but not limited to, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies formed from at least two intact antibodies), single-chain Fv (scFv) formats, and antibody fragments (such as Fab, F(ab'), F(ab')2, Fv, etc.), as long as they exhibit the desired function or biological activity. Antibodies are primarily amino acid-based molecules, but may also include one or more modifications (including, but not limited to, the addition of sugar moieties, fluorescent moieties, chemical tags, etc.).

[0575] The antibodies of the present disclosure (including antigen-binding fragments thereof) may include, but are not limited to, polyclonal antibodies, monoclonal antibodies, multispecific antibodies, bispecific antibodies, trispecific antibodies, human antibodies, humanized antibodies, chimeric antibodies, single-chain antibodies, diabodies, linear antibodies, Fab fragments, F(ab') fragments, F(ab')2 fragments, Fv fragments, fragments produced by a Fab expression library, variable domains, anti-idiotypic (anti-Id) antibodies (including, for example, anti-Id antibodies to antibodies of the invention), antibodies produced intracellularly (i.e., intrabodies), codon-optimized antibodies, scFv fragments, tandem scFv antibodies, bispecific T-cell engagers, mAb2 antibodies, chimeric antigen receptors (CARs), tetravalent bispecific antibodies, biosynthetic antibodies, natural antibodies, miniaturized antibodies, monobodies, large antibodies, and epitope-binding fragments of any of the above.

[0576] In some embodiments, the antibody comprises at least one immunoglobulin variable domain sequence.Antibodies may include, for example, full-length, mature antibodies and antigen-binding fragments of antibodies.For example, antibodies may include a heavy (H) chain variable domain sequence (abbreviated herein as VH) and a light (L) chain variable domain sequence (abbreviated herein as VL). In another example, the antibody 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 (such as scFv), single variable domain antibodies, double antibodies (Dab) (divalent and bispecific) and chimeric (for example, humanized) antibodies, which can be produced by modifying the entire antibody or synthesized de novo using recombinant DNA technology. These functional antibody fragments maintain the ability to selectively bind to their corresponding antigens or receptors. Antibodies and antibody fragments can be from antibodies of any class including but not limited to IgG, IgA, IgM, IgD and IgE, and antibodies of any subclass (e.g., human IgG1, IgG2, IgG3 and IgG4, and mouse IgG1, IgG2a, IgG2b, IgG2c and IgG3). The antibodies of the present disclosure can be monoclonal antibodies or polyclonal antibodies. The antibodies can also be human antibodies, humanized antibodies, CDR-grafted antibodies or in vitro generated antibodies. The antibodies can have a heavy chain constant region selected from, for example, IgG1, IgG2, IgG3 or IgG4. The antibodies can also have a light chain selected from, for example, κ or λ.

[0577] In some embodiments, the antibodies of the present disclosure comprise functional fragments or variants thereof. The constant region of an antibody can be altered (e.g., mutated) to modify the properties of the antibody (e.g., to increase or decrease one or more of the following: Fc receptor binding, antibody glycosylation, the number of cysteine ​​residues, effector cell function, or complement function).

[0578] As used herein, the term "antibody fragment" refers to a portion of an intact antibody or a fusion protein thereof, which in some cases includes at least one antigen binding region. Examples of antigen-binding fragments include: (i) a Fab fragment, which is a monovalent fragment consisting of the VL, VH, CL, and CH1 domains; (ii) a F(ab')2 fragment, which is a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) an Fd fragment, which consists of the VH and CH1 domains; (iv) an Fv fragment, which consists of the VL and VH domains of a single arm of an antibody, (v) a diabody (dAb) fragment, which consists of a VH domain; (vi) camelid or camelized variable domains; (vii) single-chain Fv (scFv), see, e.g., Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883); and (viii) single-domain antibodies. These antibody fragments are obtained using conventional techniques known to those skilled in the art, and the practicality of the fragment is screened in the same manner as complete antibodies. Antibody fragments can also be incorporated into single-domain antibodies, large antibodies, small antibodies, nanobodies, intracellular antibodies, double antibodies, three antibodies, four antibodies, v-NAR and double-scFv (see, for example, Hollinger and Hudson, Nature Biotechnology 23:1126-1136,2005). In some embodiments, papain digestion of antibody produces two identical antigen-binding fragments each having a single antigen-binding site, which are referred to as "Fab" fragments. Residual "Fc" fragments are also produced, and their name reflects their ability to crystallize easily. Pepsin treatment produces F (ab') 2 fragments with two antigen-binding sites and still capable of cross-linking antigens. Antibodies of the present disclosure may include one or more of these fragments and can be produced, for example, by enzymatic digestion of complete antibodies or by recombinant expression.

[0579] In some embodiments, the antibody can be a single domain antibody. A single domain antibody may include an antibody whose complementary determining region is a part of a single domain polypeptide. Examples include, but are not limited to, heavy chain antibodies, antibodies naturally lacking light chains, single domain antibodies derived from conventional 4-chain antibodies, engineered antibodies, and single domain scaffolds other than those derived from antibodies. A single domain antibody can be any of those in the art, or any future single domain antibodies. Single domain antibodies can be derived from any species, including but not limited to mice, humans, camels, llamas, fish, sharks, goats, rabbits, and cattle. According to another aspect of the invention, a single domain antibody is a naturally occurring single domain antibody referred to as a heavy chain antibody lacking light chains. Such single domain antibodies are disclosed, for example, in WO 9404678. For clarity, this variable domain derived from a heavy chain antibody naturally lacking light chains is referred to herein as a VHH or nanobody to distinguish it from the conventional VH of a four-chain immunoglobulin. Such VHH molecules may be derived from antibodies produced in species of the Camelidae family, such as camels, llamas, dromedaries, alpacas and llamas. Species other than Camelidae may produce heavy chain antibodies that naturally lack light chains; such VHHs are within the scope of the present invention.

[0580] "Native antibodies" are typically heterotetrameric glycoproteins of about 150,000 daltons consisting of two identical light (L) chains and two identical heavy (H) chains. The genes encoding the heavy and light chains of antibodies are known and the segments that make up each gene have been fully 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 connected to the heavy chain by one covalent disulfide bond, while the number of disulfide bonds varies between the heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide bridges. Each heavy chain has a variable domain (V H ), followed by multiple constant domains. Each light chain has a variable domain at one end (V L ) and a constant domain at its other end; the constant domain of the light chain is aligned with the first constant domain of the heavy chain, and the light chain variable domain is aligned with the variable domain of the heavy chain.

[0581] As used herein, the term "variable domain" refers to a specific antibody domain present on both the heavy and light chains of an antibody, the sequence of which differs widely between antibodies and is used for the binding and specificity of each specific antibody for its specific antigen. In some embodiments, the VH and VL regions of the antibodies described herein can be subdivided into hypervariable regions known as complementarity determining regions (CDRs) interspersed with more conserved regions known as framework regions (FRs).

[0582] As used herein, the term "hypervariable region" refers to the region within the variable domain that contains the amino acid residues responsible for antigen binding. The amino acids present in the hypervariable region determine the structure of the complementarity determining region (CDR), which is part of the antigen binding site of an antibody.

[0583] As used herein, the term "CDR" refers to the region of an antibody comprising a 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 referred to as "framework regions" (FRs). The antigen binding site (also referred to as the antigen combining site or paratope) comprises the amino acid residues necessary for interacting with a specific antigen. The precise residues that constitute the antigen binding site can be determined by CDR analysis.

[0584] As used herein, the term "CDR analysis" refers to any process used to determine which antibody variable domain residues constitute the CDRs. The extent of the framework regions and CDRs is precisely defined by a number of methods (see Kabat, EA, et al. (1991) Sequences of Proteins of Immunological Interest, 5th ed., US Department of Health and Human Services, NIH Publication No. 91-3242; Chothia, C. et al. (1987) J. Mol. Biol. 196:901-917; and the AbM definition used by Oxford Molecular's AbM antibody modeling software. See generally, for example, Protein Sequence and Structure Analysis of Antibody Variable Domains. In: Antibody Engineering Lab Manual (Duebel, S. and Kontermann, R., Springer-Verlag, Heidelberg, eds.). CDR analysis can be performed by co-crystallization with bound antigen. In some embodiments, CDR analysis can include computational evaluation based on comparison with other antibodies (Strohl, WR Therapeutic Antibody Engineering. Woodhead Publishing, Philadelphia). PA. 2012. Chapter 3, pp. 47-54, the contents of which are incorporated herein by reference in their entirety).CDR analysis and / or precise amino acid sequence boundaries may include the use of numbering schemes including, but not limited to, those taught 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, the CDRs defined according to the Chothia numbering scheme are sometimes also referred to as hypervariable loops.

[0585] For example, according to Kabat, the CDR amino acid residues in the heavy chain variable domain (VH) are numbered 31-35 (HCDR1), 50-65 (HCDR2), and 95-102 (HCDR3); and the CDR amino acid residues in the light chain variable domain (VL) are numbered 24-34 (LCDR1), 50-56 (LCDR2), and 89-97 (LCDR3).

[0586] For example, according to Chothia, the CDR amino acids in VH are numbered 26-32 (HCDR1), 52-56 (HCDR2), and 95-102 (HCDR3); and the amino acid residues in VL are numbered 26-32 (LCDR1), 50-52 (LCDR2), and 91-96 (LCDR3).

[0587] For example, by combining the CDR definitions of 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.

[0588] In general, each VH and VL domain has three CDRs. The VL CDRs are referred to herein as LC CDR1, LC CDR2, and LC CDR3, in the order in which they appear along the variable domain polypeptide as they move from the N-terminus to the C-terminus. The VH CDRs are referred to herein as HC CDR1, HC CDR2, and HC CDR3, in the order in which they appear along the variable domain polypeptide as they move from the N-terminus to the C-terminus. Each of the CDRs, with the exception of the HC CDR3, has a favorable canonical structure, comprising an amino acid sequence whose sequence and length can be highly variable between antibodies, thereby generating a variety of three-dimensional structures in the antigen-binding domain (Nikoloudis, D. et al., 2014. Peer J. 2: e456). In some cases, CDRH3s can be analyzed across a panel of related antibodies to assess antibody diversity. Various methods for 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. Chapter 3, pp. 47-54, the contents of which are herein incorporated by reference in their entirety).

[0589] In some embodiments, the antigen binding domain of an antibody of the present disclosure is a portion of an antibody comprising a determinant that forms an interface that binds to a tau polypeptide or an epitope thereof. Relative to a protein (or protein mimetic), an antigen binding site typically comprises one or more loops (having at least four amino acids or amino acid mimics) that form an interface that binds to a tau polypeptide. Typically, an antibody's antigen binding site comprises at least one or two CDRs and / or hypervariable loops, or more typically at least three, four, five, or six CDRs and / or hypervariable loops.

[0590] In other embodiments, the antibody has a heavy chain constant region selected from, for example, IgG1, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgD, and IgE; in particular, a heavy chain constant region selected from, for example, human heavy chain constant regions of IgG1, IgG2, IgG3, and IgG4, or a heavy chain constant region of murine heavy chain constant regions of IgG1, IgG2a, IgG2b, IgG2c, and IgG3. In another embodiment, the antibody has a light chain constant region selected from, for example, a light chain constant region of a (e.g., mouse or human) light chain constant region of κ or λ.

[0591] The constant region can be changed (e.g., mutated) to modify the properties of the antibody (e.g., to increase or decrease one or more of the following: Fc receptor binding, antibody glycosylation, the number of cysteine ​​residues, effector cell function, and / or complement function). In some embodiments, the antibody has: effector function; and can fix complement. In other embodiments, the antibody does not recruit effector cells; or fix complement. In other embodiments, the antibody has reduced or no ability to bind to Fc receptors. For example, it is an isotype or subtype, fragment, or other mutant that does not support binding to an Fc receptor, for example, it has a mutagenized or deleted Fc receptor binding region.

[0592] Methods for changing the constant region of an antibody are known in the art. The function of the change, for example, an antibody having a changed affinity for an effector ligand, such as an FcR on a cell or the C1 component of complement, can be produced by replacing at least one amino acid residue in the constant portion of the antibody with a different residue (see, for example, EP 388,151A1, U.S. Patent No. 5,624,821 and U.S. Patent No. 5,648,260, the contents of all patents are hereby incorporated by reference). Similar types of changes can be described that, if applied to mouse or other species immunoglobulins, reduce or eliminate these functions.

[0593] As used herein, the term "Fv" refers to an antibody fragment comprising the smallest fragment on the antibody required to form a complete antigen binding site. These regions are composed of a dimer of a heavy chain variable domain and a light chain variable domain that are tightly, non-covalently associated. Fv fragments can be produced by protein cleavage, but are substantially unstable. Generally, a flexible linker is inserted between the light chain variable domain and the heavy chain variable domain (to form a single-chain Fv (scFv)) or a recombinant method for producing a stable Fv fragment by introducing a disulfide bridge between the heavy chain variable domain and the light chain variable domain is known in the art (Strohl, WR Therapeutic Antibody Engineering. Woodhead Publishing, Philadelphia PA. 2012. Chapter 3, pages 46-47, the contents of which are incorporated herein by reference in their entirety).

[0594] The "light chains" of antibodies 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 domains. Antibodies can be assigned to different classes depending on the amino acid sequence of the constant domain of their heavy chains.

[0595] As used herein, the term "single-chain Fv" or "scFv" refers to a fusion protein of VH and VL antibody domains, wherein these domains are linked together into a single polypeptide chain by a flexible peptide linker. In some embodiments, the Fv polypeptide linker enables scFv to form the desired structure for antigen binding. In some embodiments, scFv is used in conjunction with phage display, yeast display or other display methods, wherein it can be expressed in conjunction with surface members (e.g., phage coat proteins) and used to identify high-affinity peptides for a given antigen. In some embodiments, the antibodies of the present disclosure are prepared as scFvFc antibodies. The term "scFvFc" refers to an antibody form comprising a fusion of one or more scFv and an antibody Fc domain.

[0596] The term "chimeric antibody" refers to an antibody having a portion derived from two or more sources. A chimeric antibody may comprise portions derived from different species. For example, a chimeric antibody may comprise an antibody having a mouse variable domain and a human constant domain. Further examples of chimeric antibodies and methods for producing same include any of 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, the contents of each of which are incorporated herein by reference in their entirety.

[0597] The term "diabody" refers to small antibody fragments with two antigen-binding sites, which fragments include a light chain variable domain V linked to a light chain variable domain V on the same polypeptide chain. L The heavy chain variable domain V HBy using a linker that is too short to allow pairing between the two domains on the same chain, the domains are forced to pair with the complementary domains of another chain and create two antigen-binding sites. Diabodies are more fully described in, for example, EP 404,097; WO 93 / 11161; and Hollinger et al., Proc. Natl. Acad. Sci. USA, 90:6444-6448 (1993), the contents of each of which are incorporated herein by reference in their entirety.

[0598] The term "intrabody" refers to a form of antibody that is not secreted by the cells that produce it, but is targeted to one or more intracellular proteins. Intrabody can be used to achieve many cellular processes, including but not limited to intracellular transport, transcription, translation, metabolic processes, proliferation signaling and cell division. In some embodiments, the method of the present invention may include a therapy based on intrabody. In some such embodiments, the variable domain sequences and / or CDR sequences disclosed herein may be incorporated into one or more constructs for a therapy based on intrabody. In some cases, the intrabody of the present invention can target one or more glycosylated intracellular proteins or can regulate the interaction between one or more glycosylated intracellular proteins and an alternative protein.

[0599] As used herein, the term "chimeric antigen receptor (chimeric antigen receptor)" or "CAR" refers to an artificial receptor that is engineered to be expressed on the surface of an immune effector cell, resulting in such immune effector cells being specifically targeted to the cells expressing an entity, which is bound to the artificial receptor with high affinity. CAR can be designed to comprise one or more segments, antibody variable domains and / or antibody CDRs of an antibody, so that when such CAR is expressed on an immune effector cell, the immune effector cell binds to and removes any cell identified by the antibody portion of the CAR. In some cases, CAR is designed to specifically bind to cancer cells, resulting in the removal of immune regulation of cancer cells.

[0600] The antibodies of the present invention may be monoclonal antibodies or polyclonal antibodies. As used herein, the term "monoclonal antibody" refers to an antibody obtained from a population of substantially uniform cells (or clones), e.g., the individual antibodies comprising the population are identical and / or bind to the same epitope, except for possible variants that may occur during the production of the monoclonal antibody, such variants typically being present in small amounts. In contrast to polyclonal antibody preparations that typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen.

[0601] 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.

[0602] In some embodiments, the antibody comprises the following amino acid sequence of an antibody, wherein the variable region or a portion thereof (e.g., CDR) is produced in a non-human organism such as a rat or mouse. Antibodies comprising chimeric, CDR-grafted, and humanized antibodies are within the present invention. Antibodies comprising antibody sequences produced in a non-human organism such as a rat or mouse and then modified, for example, in the variable framework or constant region to reduce antigenicity in humans are within the present invention.

[0603] The monoclonal antibodies herein include "chimeric" antibodies (immunoglobulins) in which a portion of the heavy and / or light chain is identical or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain is identical or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies.

[0604] The antibodies of the present disclosure can be from any animal origin, including mammals, birds, reptiles and insects. Mammalian antibodies can be, for example, human, murine (e.g., mouse or rat), donkey, sheep, rabbit, goat, guinea pig, camel, cow or horse origin.

[0605] In some embodiments, the antibody of the present disclosure can be an antibody mimetic.Term " antibody mimetic (antibody mimetic) " refers to any molecule that simulates the function or effect of an antibody and is specifically and with high affinity bound to its molecular target.In some embodiments, antibody mimetic can be a single antibody, which is designed to be incorporated into the fibronectin type III domain (Fn3) as a protein scaffold (US 6,673,901; US ​​6,348,584).In some embodiments, antibody mimetic can be those known in the art, including but not limited to affibody (affibody) molecule, affilin, affitin, anticalin, avimer, DARPin, Fynomer and Kunitz and domain peptides.In other embodiments, antibody mimetic can include one or more non-peptide regions.

[0606] As used herein, the term "antibody variant" refers to a biological molecule that is similar to an antibody in structure, sequence and / or function, but includes some differences in its amino acid sequence, composition or structure compared to another antibody or a natural antibody.

[0607] Multispecific antibodies

[0608] In some embodiments, the antibody is a multispecific antibody, for example, it comprises a plurality of immunoglobulin variable domain sequences, wherein the first immunoglobulin variable domain sequence in the plurality has binding specificity to the first epitope and the second immunoglobulin variable domain sequence in the plurality has binding specificity to the second epitope. In some embodiments, the first epitope and the second epitope are on the same antigen, for example, the same protein (or a subunit of a multimeric protein). In some embodiments, the first epitope and the second epitope overlap. In some embodiments, the first epitope and the second epitope do not overlap. In some embodiments, the first epitope and the second epitope are on different antigens, for example, 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.

[0609] In some embodiments, multispecific antibodies are bispecific antibodies. Bispecific antibodies have specificity for no more than two antigens. Bispecific antibodies are characterized by having a first immunoglobulin variable domain sequence with binding specificity to a first epitope and a second immunoglobulin variable domain sequence with binding specificity to a second epitope. In some embodiments, the first epitope and the second epitope are on the same antigen, such as the same protein (or subunit of a multimeric protein). In some embodiments, the first epitope and the second epitope overlap. In some embodiments, the first epitope and the second epitope do not overlap. In some embodiments, the first epitope and the second epitope are on different antigens, such as different proteins (or different subunits of a multimeric protein). In some embodiments, the bispecific antibody comprises a heavy chain variable domain sequence and a light chain variable domain sequence with binding specificity to the first epitope and a heavy chain variable domain sequence and a light chain variable domain sequence with binding specificity to the second epitope. In some embodiments, the bispecific antibody comprises a half antibody with binding specificity to the first epitope and a half antibody with binding specificity to the 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 a scFv or fragment thereof having binding specificity for a first epitope and a scFv or fragment thereof having binding specificity for a second epitope. In some embodiments, the anti-tau antibody is a bispecific antibody.

[0610] In some embodiments, the sequences of the antibodies of the present disclosure can be generated from bispecific or heterodimeric antibodies generated using protocols known in the art; including, but not limited to, the "knob-in-hole" approach described, for example, in US5731168; electrostatic manipulation of Fc pairing as described, for example, in WO 09 / 089004, WO 06 / 106905, and WO 2010 / 129304; strand exchange engineered domain (SEED) heterodimer formation as 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; dual antibody conjugates of bispecific structure, for example, by antibody cross-linking, using heterobifunctional reagents having amine-reactive groups and thiol-reactive groups, as described, for example, in US4433059; and the like. 4444878, bispecific antibody determinants produced by recombining half antibodies (heavy chain-light chain pairs or Fabs) from different antibodies by cycles of reduction and oxidation of the disulfide bond between the two heavy chains; trifunctional antibodies, such as three Fab' fragments cross-linked by sulfhydryl-reactive groups, as described in, for example, US5273743; biosynthetic binding proteins, such as a pair of scFvs cross-linked by C-terminal tails, preferably by disulfide- or amine-reactive chemical cross-linking, as described in, for example, US5534254; bifunctional antibodies, such as Fab fragments with different binding specificities dimerized by replacing leucine zippers (e.g., c-fos and c-jun) of the constant domains, as described in, for example, US5582996; bispecific and oligospecific monovalent and oligovalent receptors, such as the VH-VH domains of two antibodies connected by a polypeptide spacer between the CH1 region of one antibody and the VH region of another antibody, as described in, for example, US5591828. CH1 region (two Fab fragments), which typically have associated light chains; bispecific DNA-antibody conjugates, e.g., by cross-linking of antibodies or Fab fragments of double-stranded DNA segments, as described in, e.g., US5635602; bispecific fusion proteins, e.g., expression constructs containing two scFvs and a complete constant region with a hydrophilic helical peptide linker therebetween, as described in, e.g., US5637481; multivalent and multispecific binding proteins, e.g., dimers of polypeptides having a first domain with a binding region having an Ig heavy chain variable region and a second domain with a binding region having an Ig light chain variable region, generally referred to as diabodies, as described in, e.g., US5837242 (higher order structures generating bispecific, trispecific, or tetraspecific molecules are also disclosed); miniantibody constructs having linked VL and VH chains further linked to an antibody hinge and CH3 region with a peptide spacer, which can be dimerized to form bispecific / multivalent molecules, as described in, e.g., US5837821;As described in, for example, US5844094, VH domains and VL domains are linked with a short peptide linker (e.g., 5 or 10 amino acids) or with no linker at all in either orientation, which can form dimers to form bispecific diabodies, trimers, and tetramers; as described in, for example, US5864019, strings of VH domains (or VL domains in family members) linked to a cross-linkable group at the C-terminus by a peptide bond, which further associate with a VL domain to form a series of FVs (or scFvs); and as described in, for example, US5869620, single-chain binding polypeptides having VH domains and VL domains linked by a peptide linker are combined into multivalent structures by non-covalent or chemical cross-linking to form, for example, homobivalent, heterobivalent, trivalent, and tetravalent structures using scFV or diabody-type formats.;

[0611] Intracellular antibodies

[0612] In some embodiments, the payload can encode intracellular antibodies. Intracellular antibodies are not secreted by the cells that produce them, but are in the form of antibodies that target one or more intracellular proteins. Intracellular antibodies are expressed and work in cells and can be used to achieve many cellular processes, including but not limited to intracellular transport, transcription, translation, metabolic processes, proliferation signaling and cell division. In some embodiments, the methods described herein include intracellular antibody-based therapies. In some such embodiments, the variable domain sequences and / or CDR sequences disclosed herein are incorporated into one or more constructs for intracellular antibody-based therapies. For example, intracellular antibodies can target one or more glycosylated intracellular proteins or can regulate the interaction between one or more glycosylated intracellular proteins and alternative proteins.

[0613] More than 20 years ago, intracellular antibodies (Biocca, Neuberger and Cattaneo EMBO J.9: 101-108, 1990) for intracellular targets were first described. The intracellular expression of intracellular antibodies in different compartments of mammalian cells allows the function of endogenous molecules to be blocked or regulated (Biocca et al., EMBO J.9: 101-108, 1990; Colby et al., Proc. Natl. Acad. Sci. USA 101: 17616-21, 2004). Intracellular antibodies can change protein folding, protein-protein, protein-DNA, protein-RNA interactions and protein modifications. It can induce phenotypic knockout and act as a neutralizing agent by directly binding to the target antigen, by transferring its intracellular transport or by suppressing its association with a binding partner. It is mainly used as a research tool and appears as a therapeutic molecule for treating human diseases such as viral pathology, cancer and misfolding diseases. The rapidly growing recombinant antibody biomarket offers intrabodies with enhanced binding specificity, stability, and solubility, as well as lower immunogenicity that facilitates their use in therapy (Biocca, abstract in Antibody Expression and Production Cell Engineering, vol. 7, 2011, pp. 179-195).

[0614] In some embodiments, intrabodies have advantages over interfering RNA (iRNA); for example, iRNA has been shown to exert a variety of non-specific effects, while intrabodies have been shown to have higher specificity and affinity for targeting antigens. In addition, as proteins, intrabodies have a much longer active half-life than iRNA. Therefore, when the active half-life of the intracellular target molecule is long, gene silencing by iRNA may produce an effect more slowly, while the effect of intrabody expression can be almost instantaneous. Finally, intrabodies can be designed to block certain binding interactions of specific target molecules while avoiding disruption of other interactions.

[0615] Intrabodies are typically single-chain variable fragments (scFv) expressed by recombinant nucleic acid molecules and engineered to remain within the cell (e.g., in the cytoplasm, endoplasmic reticulum, or periplasm). Intrabodies can be used, for example, to eliminate the function of the protein to which the intrabody binds. The expression of intrabodies can also be regulated by using an inducible promoter in a nucleic acid expression vector comprising the intrabody.Intrabodies for use in viral genomes can be generated using methods known in the art, such as those disclosed and reviewed in the following references: (Marasco et al., 1993 Proc. Natl. Acad. Sci. USA, 90:7889-7893; Chen et al., 1994, Hum. Gene Ther. 5:595-601; Chen et 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; Rondon 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., 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., 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). Specifically, CCR5 intrabodies were generated by Steinberger et al., 2000, Proc. Natl. Acad. Sci. USA 97:805-810).See generally Marasco, WA, 1998, “Intrabodies: Basic Research and Clinical Gene Therapy Applications” Springer: New York; and 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.

[0616] Sequences from donor antibodies can be used to develop intracellular antibodies. Intracellular antibodies are usually recombinantly expressed in cells as single domain fragments such as separation of VH domains and VL domains or expressed as single chain variable fragments (scFv) antibodies. For example, intracellular antibodies are usually expressed as single polypeptides to form single chain antibodies comprising the variable domains of the heavy chain and light chain connected by a flexible linker polypeptide. Intracellular antibodies usually lack disulfide bonds and can regulate the expression or activity of target genes by their specific binding activity. Single chain antibodies can also be expressed as single chain variable region fragments connected to the constant region of the light chain.

[0617] As known in the art, intrabody can be engineered into recombinant polynucleotide vector to encode subcellular transport signal at its N-terminal or C-terminal, thereby allowing to express with high concentration in the subcellular compartment where the target protein is located. For example, the intrabody targeting endoplasmic reticulum (ER) is engineered to mix leader peptide and optionally C-terminal ER to keep signal, such as KDEL amino acid motif (SEQ ID NO:4545). It is intended that the intrabody that plays active role in nucleus is engineered to comprise nuclear localization signal. Lipid moiety is connected to intrabody to tether intrabody to the cytosol side of plasma membrane. Also targeting intrabody can play function in cytosol. For example, cytosol intrabody is used for isolating factor in cytosol, prevents it from being transferred to its natural cell destination thus.

[0618] There are certain technical challenges associated with intracellular antibody expression. Specifically, the protein conformational folding and structural stability of newly synthesized intracellular antibodies are affected by the reducing conditions of the intracellular environment.

[0619] Due to its practically unlimited ability to specifically recognize different conformations of proteins including pathological isoforms, and because it can target potential aggregation sites (intracellular and extracellular sites), intracellular antibodies can be promising therapeutic agents for treating misfolding diseases, including tau diseases, prion diseases, Alzheimer's disease, Parkinson's disease, and Huntington's disease. These molecules can act as neutralizers for the protein by preventing the protein from aggregating and / or by transporting the protein from its possible aggregation site along a new route, thereby acting as molecular diverters for intracellular transport (Cardinale and Biocca, Curr. Mol. Med. 2008, 8: 2-11).

[0620] Antibody development

[0621] Antibodies according to the present disclosure can be developed using standard methods in the art. Two major antibody preparation technologies are immunization and antibody display technology. In either case, the desired antibody is identified from a larger pool of candidates based on affinity for a specific target or epitope. An immune response is characterized by the reaction of cells, tissues, and / or organs of an organism to the presence of a foreign entity. This immune response typically results in the production of one or more antibodies by the organism against a foreign entity, such as an antigen or a portion of an antigen.

[0622] antigen

[0623] For example, using any naturally occurring or synthetic antigen, antibodies can be developed (e.g., by immunization) or selected (e.g., from a candidate pool). As used herein, "antigen" is an entity that induces or causes an immune response in an organism and may also refer to an antibody binding partner. The immune response is characterized by the response of the cells, tissues, and / or organs of an organism to the presence of a foreign entity. This immune response typically results in the organism producing one or more antibodies against the foreign entity. In some embodiments, the antigen comprises tau protein.

[0624] As used herein, the term "tau protein" refers to a protein or protein complex comprising the microtubule-associated protein tau or a peptide fragment thereof. Tau protein may include an enriched paired helical filament tau protein (ePHF) also known as "sarkosyl-insoluble tau" or a fragment thereof. Tau protein may comprise one or more phosphorylated residues. Such phosphorylated residues may correspond to disease-associated tau protein (also referred to herein as "pathological tau").

[0625] Immunization

[0626] In some embodiments, antibodies can be prepared by immunizing a host with an antigen of interest. Host animals (e.g., mice, rabbits, goats, or llamas) can be immunized with antigenic proteins to cause lymphocytes that specifically bind to the antigen. Lymphocytes can be collected and fused with immortalized cell lines to produce hybridomas, which can be cultured in suitable culture media to promote growth (e.g., see Kohler, G. et al., Continuous cultures of fused cells secreting antibody of predefined specificity. Nature. 1975 Aug 7; 256 (5517): 495-7, the contents of which are incorporated herein by reference in their entirety). Alternatively, lymphocytes can be immunized in vitro.

[0627] Lymphocytes can be fused with immortalized cell lines using a suitable fusing agent (e.g., polyethylene glycol) to form hybridoma cells (e.g., see 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 can be a transformed mammalian cell, particularly a myeloma cell of rodent, rabbit, bovine or human origin. In some embodiments, rat or mouse myeloma cell lines are used. Hybridoma cells can 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, parent cells lacking hypoxanthine guanine phosphoribosyl transferase (HGPRT or HPRT) can be used and the culture medium for the resulting hybridoma cells can be supplemented with hypoxanthine, aminopterin and thymidine ("HAT medium") to prevent the growth of HGPRT-deficient (unfused) cells.

[0628] The desirable properties of the immortalized cell line may include, but are not limited to, efficient fusion, high-level antibody expression supporting selected antibody-producing cells, and sensitivity to unfused cell inhibitory culture media (e.g., HAT culture media). In some embodiments, the immortalized cell line is a murine myeloma line. Such cell lines are available from, for example, the Salk Institute Cell Distribution Center (Salk Institute Cell Distribution Center, San Diego, CA) or the American Type Culture Collection (American Type Culture Collection, Manassas, VA). Human myeloma and mouse-human heteromyeloma cell lines can also be used to produce human monoclonal antibodies (e.g., see Kozbor, D. et al., A human hybrid myeloma for production of human monoclonal antibodies. J Immunol. 1984 Dec; 133 (6): 3001-5 and Brodeur, B. et al., Monoclonal Antibody Production Techniques and Applications. Marcel Dekker, Inc., New York. 1987; 33: 51-63, the contents of each of which are incorporated herein by reference in their entirety).

[0629] Hybridoma cell culture medium can be assayed for the presence of monoclonal antibodies with the desired binding specificity. Assays may 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 (ELISAs). 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).

[0630] The antibodies produced by the cultured hybridomas can be analyzed to determine the binding specificity to the target antigen. Once an antibody with desirable characteristics is identified, the corresponding hybridoma can be subcloned by limiting dilution procedures and grown by standard methods. The antibodies produced by the hybridomas can be separated and purified using standard immunoglobulin purification procedures such as protein A sepharose, hydroxyapatite chromatography, gel electrophoresis, dialysis or affinity chromatography. Alternatively, hybridoma cells can be grown in mammals as ascites in vivo. In some embodiments, the antibodies can be separated directly from the serum of the immunized host.

[0631] In some embodiments, recombinant antibodies produced by immunization can be prepared. Such antibodies can be prepared using the genomic antibody sequence from a selected hybridoma. The hybridoma genomic antibody sequence can be obtained by extracting RNA molecules from antibody-producing hybridoma cells and producing cDNA by reverse transcriptase polymerase chain reaction (PCR). PCR can be used to amplify cDNA using primers specific for antibody heavy and light chains. The PCR product can then be subcloned into a plasmid for sequence analysis. Antibodies can be produced by inserting the resulting antibody sequence into an expression vector. Some recombinant antibodies can be prepared using a synthetic nucleic acid construct encoding an amino acid sequence corresponding to the amino acid sequence obtained from separating hybridoma antibodies.

[0632] Antibody display

[0633] In some embodiments, antibodies can be developed using antibody display technology. "Display technology" refers to a system and method for expressing amino acid-based candidate compounds in a certain format, in which the compound is connected to the nucleic acid encoding it and can approach a target or ligand. In most systems, candidate compounds are expressed on the surface of a host capsid or cell, however, there are some host-free systems (e.g., ribosome display). Display technology can be used to produce a display "library" comprising several groups of candidate compound library members. A display library having 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 using an antibody display library to screen target antigens. An antibody display library can include millions to billions of members, each member expressing a unique antibody domain. The displayed antibody fragment can be a scFv antibody fragment, which is a V or V fragment connected by a flexible linker. H and V LFusion proteins of antibody domains. Display libraries can include antibody fragments with different levels of diversity between the variable domain framework region and the CDR. Display library antibody fragment CDRs can include unique variable loop lengths and / or sequences. The antibody variable domains or CDRs selected from the display library can be directly incorporated into the antibody sequence for recombinant antibody production or mutated and used for further optimization by in vitro affinity maturation.

[0634] Antibody display libraries may include antibody phage display libraries. Antibody phage display libraries utilize phage virus particles with millions to billions of members as hosts, each member expressing a unique antibody domain. Such libraries can provide a rich and diverse source of potential hundreds of antibody fragments that can be used to select different affinity levels 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 of which are incorporated herein by reference in their entirety). The displayed antibody fragments may be scFv antibody fragments. Phage display library members can be expressed as fusion proteins connected to viral coat proteins (e.g., the N-terminus of viral pIII coat proteins). V L The chains can be expressed separately to associate with V in the periplasm before the complex is incorporated into the viral coat. H The precipitated library members can be sequenced from the bound phage to obtain cDNA encoding the desired antibody domain.

[0635] In some embodiments, antibody display libraries can be produced 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 may include antibody variable domains expressed on the surface of Saccharomyces cerevisiae cells. Yeast display libraries can be developed by displaying the antibody fragments of interest as fusion proteins with yeast surface proteins (e.g., Aga2p proteins). Yeast cells displaying antibodies or antibody fragments with affinity for a specific target can be separated according to standard methods. Such methods may include, but are not limited to, magnetic separation and flow cytometry.

[0636] Recombinant synthesis

[0637] The antibodies of the present disclosure can be prepared using recombinant DNA technology and related processes. The construct (e.g., DNA expression plasmid) encoding the antibody can be prepared and used to synthesize a complete antibody or part thereof. In some embodiments, the DNA sequence encoding the antibody variable domains of the present disclosure can be inserted into an expression vector (e.g., a mammalian expression vector) encoding other antibody domains and used to prepare antibodies with inserted variable domains. The DNA sequence encoding the antibody variable domains can be inserted into the downstream of the upstream expression vector region with a promoter / enhancer element and / or encoding an immunoglobulin signal sequence. The DNA sequence encoding the antibody variable domains can be inserted into the upstream of the downstream expression vector region encoding an immunoglobulin constant domain. The encoded constant domain can be from any class (e.g., IgG, IgA, IgD, IgE, and IgM) or species (e.g., humans, mice, rabbits, rats, and non-human primates). In some embodiments, the encoded constant domains encode human IgG (e.g., IgG1, IgG2, IgG3, or IgG4) constant domains. In some embodiments, the encoded constant domain encodes a mouse IgG (eg, IgG1, IgG2a, IgG2b, IgG2c, or IgG3) constant domain.

[0638] Expression vectors encoding the antibodies of the present disclosure can be used to transfect cells for antibody production. Such cells can be mammalian cells. Stably transfected cell lines with the antibody expression vector can be prepared and used to establish stable cell lines. Antibody-producing cell lines can be expanded to express antibodies that can be isolated or purified from cell culture medium.

[0639] Antibody characterization

[0640] In some embodiments, antibodies of the present disclosure may be identified, selected, or excluded based on different characteristics. Such characteristics may include, but are not limited to, physical characteristics and functional characteristics. Physical characteristics may include characteristics of the antibody structure [e.g., amino acid sequence or residues; secondary, tertiary, or quaternary protein structure; post-translational modifications (e.g., glycosylation); chemical bonds and stability]. Functional characteristics may include, but are not limited to, antibody affinity (i.e., for a specific epitope and / or antigen) and antibody activity (e.g., the ability of the antibody to activate or inhibit a target, process, or pathway).

[0641] Antibody binding and affinity

[0642] In some embodiments, antibodies of the present disclosure can be identified, selected, or excluded based on binding and / or affinity levels for specific epitopes and / or antigens. Antibody binding and / or affinity levels 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). Anti-tau antibody in vitro testing can be performed using brain samples or portions. Such samples or portions can be obtained from subjects with AD (e.g., human AD patients). In some embodiments, brain samples or portions can 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 portions used for antibody affinity testing may be derived from the TG4510 / P301S mouse strain. Antibody affinity can be compared with a control sample lacking the specific antigen for which affinity is being analyzed. In some embodiments, control samples used for anti-tau antibody testing may include brain samples or portions from non-diseased human subjects. In some embodiments, brain samples or portions from wild-type and / or tau knockout mouse strains can be used as control samples.

[0643] In vitro affinity testing can be performed using recombinant or isolated protein antigens (e.g., by ELISA). For example, recombinant or isolated ePHF can be used for anti-tau antibody affinity testing. In some embodiments, when assessed by ELISA, the anti-tau antibodies 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. In some embodiments, the EC50 exhibited 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, when assessed by ELISA, the anti-tau antibodies of the present disclosure may exhibit an EC50 of about 0.01 nM to about 100 nM for binding to any of the antigens listed in Table 8, or comprising any of the antigens or epitopes included therein (including but not limited to conformational epitopes). In some embodiments, the EC50 exhibited may be less than about 50 nM, less than about 20 nM, less than about 10 nM, or less than about 1 nM.

[0644] In some embodiments, the anti-tau antibodies of the present disclosure bind to pathological tau but not to non-pathological tau. Such antibodies may be referred to herein as being "selective" for pathological forms of tau. In some embodiments, the anti-tau antibodies of the present disclosure bind to tau tangles.

[0645] 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 more than one epitope or antigen. In some embodiments, multispecific antibodies can be identified, selected or excluded based on the relative affinity for each epitope or antigen recognized. For example, a multispecific antibody can be selected for use or further development based on a higher affinity for one epitope or antigen compared to a second epitope or antigen to which the multispecific antibody exhibits affinity.

[0646] In some embodiments, anti-tau antibodies can be tested for competition with other anti-tau antibodies. This testing can be performed to provide information about the specific epitope recognized by the antibody and can generate information related to the level of affinity for the epitope compared to competing antibodies. In some embodiments, the anti-tau antibodies used for antibody binding and / or affinity analysis may include anti-tau antibody PT3 as described in U.S. Patent No. 9,371,376; anti-tau antibody C10.2 as described in U.S. Patent No. 10,196,439 (referred to therein as antibody "C10-2"); anti-tau antibody IPN002 as described in U.S. Patent No. 10,040,847; anti-tau antibody AT8 (ThermoFisher, Waltham, MA); anti-tau antibody AT100 (ThermoFisher, Waltham, MA); anti-tau antibody AT120 as described in U.S. Patent No. 5,843,779; or anti-tau antibody PT76 as described in Vandermeeren, M. et al., J Alzheimers Dis. 2018; 65(1):265-281.

[0647] Antibody activity

[0648] In some embodiments, antibodies of the present disclosure can be identified, selected, or excluded based on their ability to promote or reduce certain activities. 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 their activity.

[0649] Anti-tau antibodies can be characterized by their ability to inhibit tau aggregation. Inhibition can be based on physical interference with tau aggregation or can be based on anti-tau antibody-dependent depletion (immune depletion) of tau protein. Characterization based on tau aggregation inhibition can be assessed using one or more tau aggregation assays. In some embodiments, anti-tau antibodies can be characterized by tau seeding assays. The tau seeding assay typically includes initiating tau aggregation in vitro and assessing the aggregation inhibition of the tested candidate compound. The tau seeding assay can be performed using tau aggregation biosensor cells. The tau aggregation biosensor cells produce 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 samples from high tau brain tissue or fluid (to promote tau aggregation) and treated with or without candidate compounds to assess tau aggregation inhibition. In some embodiments, before incubation with biosensor cells, anti-tau antibodies can be used to deplete tau from the culture medium. The aggregation level using depleted culture medium can be compared with the aggregation level using non-depleted culture medium to assess the anti-tau antibody inhibitory function. Tau aggregation biosensor cells may include, but are not limited to, tau RD biosensor cells. In some embodiments, neurons expressing human tau may be used.

[0650] In some embodiments, the anti-tau antibodies of the present disclosure can inhibit tau aggregation at a half-maximal inhibitory concentration (IC50) of about 1 nM to about 30 nM, as determined by an immunodepletion assay (e.g., using tau RD biosensor cells).

[0651] Antibody modification

[0652] Antibodies can be modified to obtain variants with one or more altered properties. Such properties may include or relate to antibody structure, function, affinity, specificity, protein folding, stability, manufacturing, expression and / or immunogenicity (i.e., the immune response in subjects treated with such antibodies). In some embodiments, antibody fragments or variants can be used to modify another antibody or can be incorporated into an antibody.

[0653] Antibody modification may include amino acid sequence modification. Such modifications may include, but are not limited to, amino acid deletions, additions and / or substitutions. Modifications may provide information by amino acid sequence analysis. This analysis may include comparing 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 compared antibodies may include those that are bound to the same epitope. The compared antibodies may be bound to different epitopes (alone or overlapping) of the same protein or target (e.g., to identify residues or regions that confer specificity for a particular epitope). The comparison may include light chain and / or heavy chain sequence difference analysis, CDR sequence difference analysis, germline sequence analysis and / or framework sequence analysis. The information obtained from this analysis may be used to identify amino acid residues, amino acid segments, amino acid side chains, CDR lengths and / or other features or properties that are conserved or variable between antibodies that are bound to the same or different epitopes.

[0654] In some embodiments, modified versions of the anti-tau antibodies described above can be prepared by adding, deleting, or substituting one or more CDR amino acid residues.

[0655] In some embodiments, an anti-tau antibody can be modified by aligning the amino acid sequences of antibodies that bind to similar targets and, based on analysis of the aligned sequences, preparing modified antibodies with one or more amino acid deletions, substitutions, or insertions.

[0656] For example, as described in Table 1, the disclosure includes amino acid consensus sequences of CDR region sequences indicating specific amino acids that may be modified or amino acid residue positions (indicated using the variable "X") that may be more commonly substituted in antibody amino acid sequences.

[0657] Table 1: Consensus CDRs of exemplary anti-tau antibodies V0022, V0023, and V0024

[0658]

[0659]

[0660] Functional modification

[0661] In some embodiments, the 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, the ability to mobilize or immobilize a target, and the ability to activate or inhibit a target, process, or pathway. In some embodiments, the functional properties include or relate to the ability to modulate protein-protein interactions, protein aggregation, enzyme activity, receptor-ligand interactions, cell signaling pathways, protein degradation cascades, and / or biological or physiological responses.

[0662] Antibody modification can optimize antibodies by adjusting epitope affinity. Such modifications can be performed by affinity maturation. Affinity maturation techniques are used to identify sequences encoding CDRs with the highest affinity for the target antigen. In some embodiments, antibody display technology (e.g., phage or yeast) can be used. Such methods can include mutating the nucleotide sequence encoding the optimized parent antibody. The nucleotide sequence can generally be randomly mutated or changed in expression at specific amino acid residues to produce millions to billions of variants. Sites or residues can be selected for mutation based on the sequence or amino acid frequency observed in natural human antibody repertoires. Variants can be subjected to repeated rounds of affinity screening for target antigen binding (e.g., using display library screening technology, surface plasmon resonance technology, fluorescence-associated cell sorting (FACS) analysis, enzyme-linked immunosorbent assay (ELISA) etc.). Repeated 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 the antibody sequence for generation. In some cases, the goal of affinity maturation is to increase the affinity of the antibody 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 less than the desired affinity, the process can be repeated.

[0663] In some embodiments, antibody 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 can be performed using brain samples or portions. Such samples or portions can be obtained from subjects with AD (e.g., human AD patients). In some embodiments, brain samples or portions 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 portions used for antibody affinity testing can be derived from TG4510 / P301S mouse strains. Antibody affinity can be compared with control samples lacking the specific antigens being analyzed for affinity. In some embodiments, control samples can include brain samples or portions from non-diseased human subjects. In some embodiments, brain samples or portions from wild-type and / or tau knockout mouse strains can be used as control samples. In vitro affinity testing can 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 can be used.

[0664] In some embodiments, antibody affinity analysis can be used to adjust antibody multispecificity (e.g., reduce or enhance antibody multispecificity). This adjustment can include adjusting the relative affinity for two or more epitopes or antigens. For example, an antibody can be optimized to obtain a higher affinity for one epitope or antigen compared to a second epitope or antigen.

[0665] Antibodies can be modified to optimize antibody functional properties. Such functional properties can be evaluated or engineered based on analytical assay results related to one or more antibody functional properties. Assays can be used to screen multiple antibodies based on functional criteria to identify or grade antibodies. Anti-tau antibodies can be modified to optimize tau aggregation inhibition. This inhibition can be based on physical interference with tau aggregation or can be based on the ability of anti-tau antibodies to deplete tau protein from assay samples. Optimization based on tau aggregation inhibition can be evaluated using one or more tau aggregation assays (e.g., by tau seeding assays).

[0666] Produce modification

[0667] 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 features that adversely affect production. Such features may include, but are not limited to, unpaired cysteines or irregular disulfides; glycosylation sites (e.g., N-linked NXS / T sites); acid cleavage sites, amino acid oxidation sites, and consistency with mouse germline sequences; asparagine deamidation sites; aspartate isomerization sites; N-terminal pyroglutamate formation sites; and amino acid sequence regions that are prone to aggregation (e.g., within CDR sequences).

[0668] In some embodiments, the antibodies of the present disclosure can be prepared using recombinant DNA technology (e.g., referring to U.S. Patent No. 4,816,567, which is hereby incorporated by reference in its entirety). Antibody encoding DNA can be separated and sequenced using conventional procedures (e.g., by using oligonucleotide probes that can specifically bind to the genes encoding the heavy and light chains of mouse antibodies). In some embodiments, hybridoma cells can be used as preferred DNA sources. Once separated, DNA can be placed in an expression vector and then transfected into a host cell. Host cells may include but are not limited to HEK293 cells, HEK293T cells, monkey COS cells, Chinese hamster ovary (CHO) cells, and myeloma cells that do not produce immunoglobulins in other cases, to obtain the synthesis of monoclonal antibodies in recombinant host cells. DNA can also be modified, for example, by replacing the coding sequence of human heavy and light chain constant domains with homologous mouse sequences (U.S. Patent No. 4,816,567) or by covalently linking all or part of the coding sequence of non-immunoglobulin polypeptides to immunoglobulin coding sequences.

[0669] Antibody humanization

[0670] In some embodiments, the anti-tau antibodies of the present disclosure can be prepared as humanized antibodies. "Humanized" antibodies are chimeric antibodies containing minimal sequences (e.g., variable domains or CDRs) derived from non-human immunoglobulins (e.g., mouse immunoglobulins). Humanized antibodies can be prepared from human (recipient) immunoglobulins, wherein residues from hypervariable regions are replaced with hypervariable region residues from one or more non-human "donor" antibodies (e.g., mouse, rat, rabbit, or non-human primate). Donor antibodies can be selected based on desired specificity, affinity, and / or ability. Humanized antibodies may include one or more back mutations, including restoring one or more amino acids to amino acids present in donor antibodies. Conversely, residues from donor antibodies contained in humanized antibodies may be mutated to match residues present in human receptor antibodies. Back mutations can be introduced to reduce human immune responses to humanized antibodies. In some embodiments, back mutations are introduced to avoid problems with antibody production (e.g., protein aggregation or post-translational modification).

[0671] For the expression plasmid of the fully humanized antibody with human constant region of construction coding, the DNA sequence encoding antibody variable region can be inserted in expression vector (for example, mammalian expression vector) between upstream promoter / enhancer and immunoglobulin signal sequence and downstream immunoglobulin constant region gene.Then, DNA sample can be transfected into the mammalian cell for antibody production.The constant domain of human antibody from any class can be used.There are five kinds of complete human antibodies of main classes: IgA, IgD, IgE, IgG and IgM, and a plurality of in these classifications can be further divided into subclass (isotype), for example 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).

[0672] Stably transfected cell lines with DNA encoding humanized antibodies can be prepared and used to establish stable cell lines. Humanized antibody-producing cell lines can be expanded to express humanized antibodies that can be harvested and purified from the cell culture medium.

[0673] In some embodiments, the humanized antibodies of the present disclosure may have cross-reactivity with non-human species. Species cross-reactivity can allow antibodies to be used in different animals for various purposes. For example, cross-reactive antibodies can be used in preclinical animal studies to provide information about antibody efficacy and / or toxicity. 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).

[0674] Antibody conjugates

[0675] In some embodiments, the antibodies of the present disclosure can be or are prepared as antibody conjugates. As used herein, the term "conjugate / conjugate" refers to any agent, cargo or chemical moiety attached to a receptor entity or the process of attaching this agent, cargo or chemical moiety. As used herein, the term "antibody conjugate" refers to any antibody with an attached agent, cargo or chemical moiety. The conjugate used to prepare an antibody conjugate may include a therapeutic agent. Such therapeutic agents may include drugs. Antibody conjugates including conjugated drugs are referred to herein as "antibody drug conjugates." Based on the affinity of the associated antibody for proteins or epitopes associated with such targets, antibody drug conjugates can be used to guide the conjugated drug to a specific target. Such antibody drug conjugates can be used to localize the biological activity associated with such conjugated drugs to target cells, tissues, organs or other targeted entities. In some embodiments, the conjugate used to prepare an antibody conjugate includes a detectable label. The antibody can be conjugated to a detectable label for detection purposes. Such detectable labels can include, but are not limited to, radioisotopes, fluorophores, chromophores, chemiluminescent compounds, enzymes, enzyme cofactors, dyes, metal ions, ligands, biotin, avidin, streptavidin, haptens, quantum dots, or any other detectable label known in the art or described herein.

[0676] The conjugate can be attached to the antibody directly or via a joint. Direct attachment can be by covalent bonding or by non-covalent association (e.g., ionic bond, hydrostatic bond, hydrophobic bond, hydrogen bond, hybridization, etc.). The joint used for conjugate attachment may include any chemical structure capable of connecting the antibody to the conjugate. In some embodiments, the joint includes a polymer molecule (e.g., nucleic acid, polypeptide, polyethylene glycol, carbohydrate, lipid, or a combination thereof). The antibody conjugate joint can be cleavable (e.g., by contact with an enzyme, pH change, or temperature change).

[0677] Exemplary anti-tau antibodies

[0678] In some embodiments, the anti-tau antibody comprises at least one antigen binding domain, e.g., a variable region, or an antigen binding fragment thereof, from an antibody described herein, e.g., from V0004, V0009, V0022, V0023, V0024, or V0052, e.g., as described in Tables 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 an antigen binding fragment thereof, from an antibody described in WO 2021 / 211753 (the contents of which are hereby incorporated by reference in their entirety), 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 WO 2021 / 211753.

[0679] 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, 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 having at least one, two, or three modifications (e.g., substitutions, e.g., conservative substitutions) but not more than 30, 20, or 10 modifications (e.g., substitutions, e.g., conservative substitutions) of an amino acid sequence of a heavy chain variable region provided in Table 4.

[0680] In some embodiments, the nucleotide sequence encoding the anti-tau antibody comprises a nucleotide sequence from the heavy chain variable region of an antibody described herein, e.g., selected from V0004, V0009, V0022, V0023, V0024, or V0052, e.g., as described in Table 4, or a nucleotide sequence substantially identical (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences.

[0681] 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 having at least one, two, or three modifications (e.g., substitutions, e.g., conservative substitutions) but not more than 30, 20, or 10 modifications (e.g., substitutions, e.g., conservative substitutions) of an amino acid sequence of a light chain variable region provided in Table 4.

[0682] In some embodiments, the nucleotide sequence encoding the anti-tau antibody comprises a nucleotide sequence from a light chain variable region of an antibody described herein, e.g., selected from V0004, V0009, V0022, V0023, V0024, or V0052, e.g., as described in Table 4, or a nucleotide sequence substantially identical (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences.

[0683] In some embodiments, an anti-tau antibody comprises a heavy chain variable region and 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 anti-tau antibody comprises a heavy chain variable region comprising an amino acid sequence having at least one, two or three modifications (e.g., substitutions, e.g., conservative substitutions) but not more than 30, 20 or 10 modifications (e.g., substitutions, e.g., conservative substitutions) of an amino acid sequence of a heavy chain variable region provided in Table 4; and a light chain variable region comprising an amino acid sequence having at least one, two or three modifications (e.g., substitutions, e.g., conservative substitutions) but not more than 30, 20 or 10 modifications (e.g., substitutions, e.g., conservative substitutions) of an amino acid sequence of a light chain variable region provided in Table 4.

[0684] In some embodiments, the anti-tau antibody comprises a heavy chain constant region, such as a human IgG1, IgG2, IgG3 or IgG4 constant region, or a mouse IgG1, IgG2A, IgG2B, IgG2C or IgG3 constant region. In some embodiments, the heavy chain constant comprises an amino acid sequence set forth in Table 5, or a sequence substantially identical to any of the foregoing sequences (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98% or 99% sequence identity). 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 to any of the foregoing sequences (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98% or 99% sequence identity).

[0685] In some embodiments, the anti-tau antibody comprises a light chain constant region, such as a kappa light chain constant region, such as 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 to any of the foregoing sequences (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98% or 99% sequence identity). 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 to any of the foregoing sequences (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98% or 99% sequence identity).

[0686] 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).

[0687] In some embodiments, an anti-tau antibody comprises a heavy chain variable region and a constant region, a light chain variable region and a constant region, or both, comprising an amino acid sequence for a variable region of Table 4 and an amino acid sequence for a constant region of Table 5; or 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.

[0688] In some embodiments, the anti-tau antibody comprises at least one, two, or three complementarity determining regions (CDRs) from a heavy chain variable region comprising an amino acid sequence in Table 4, or encoded by a nucleic acid sequence in Table 4; or a sequence substantially identical to any of the foregoing sequences (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity). In some embodiments, one, two, three, four, five, or all of the CDRs have one, two, three, four, five, or more changes, such as amino acid substitutions, insertions, or deletions, relative to the amino acid sequence shown in Table 4 or the amino acid sequence encoded by the nucleotide sequence shown in Table 4. In some embodiments, the encoded anti-tau antibody comprises a substitution in a heavy chain CDR, such as one or more substitutions in CDR1, CDR2, and / or CDR3 of the heavy chain.

[0689] In some embodiments, the anti-tau antibody comprises at least one, two, or three complementarity determining regions (CDRs) from a light chain variable region comprising an amino acid sequence in Table 4, or encoded by a nucleic acid sequence in Table 4; or a sequence substantially identical to any of the foregoing sequences (e.g., having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity). In some embodiments, one, two, three, four, five, or all of the CDRs have one, two, three, four, five, or more changes, such as amino acid substitutions, insertions, or deletions, relative to the amino acid sequence shown in Table 4 or the amino acid sequence encoded by the nucleotide sequence shown in Table 4. In some embodiments, the anti-tau antibody comprises a substitution in a light chain CDR, such as one or more substitutions in CDR1, CDR2, and / or CDR3 of the light chain.

[0690] In some embodiments, the anti-tau antibodies comprise at least one, two, three, four, five, or six CDRs (or collectively all CDRs) from the 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 CDRs) have one, two, three, four, five, six, or more changes, e.g., amino acid substitutions, insertions, or deletions, relative to the CDRs shown in Table 4 or encoded by the nucleotide sequences shown in Table 4.

[0691] In some embodiments, the anti-tau antibody comprises all three CDRs from the heavy chain variable region, all three CDRs from the light chain variable region, or both (e.g., all six CDRs from the heavy chain variable region and the light chain variable region), which comprises the amino acid sequence shown in Table 4, or is encoded by the nucleotide sequence shown in Table 4.

[0692] In some embodiments, the anti-tau antibodies of the present disclosure may include CDRs identified by CDR analysis of the variable domain sequences provided herein via co-crystallization with bound antigen; by computational evaluation based on comparison with other antibodies (e.g., see Strohl, WR Therapeutic Antibody Engineering. Woodhead Publishing, Philadelphia PA. 2012. Chapter 3, pp. 47-54); or the Kabat, Chothia, Al-Lazikani, Lefranc, or Honegger numbering schemes as previously described.

[0693] Table 4. Exemplary anti-tau antibodies

[0694]

[0695]

[0696]

[0697]

[0698]

[0699]

[0700]

[0701]

[0702]

[0703]

[0704]

[0705]

[0706]

[0707]

[0708]

[0709] Table 4A. Exemplary humanized heavy chain variable regions and heavy chains of V0022

[0710]

[0711]

[0712]

[0713]

[0714]

[0715]

[0716]

[0717]

[0718]

[0719] Table 4B. Exemplary humanized light chain variable regions and light chains of V0022

[0720]

[0721]

[0722]

[0723]

[0724]

[0725] Table 4C. Exemplary anti-tau humanized V0022 antibodies

[0726]

[0727]

[0728]

[0729]

[0730] Table 5. Constant regions of heavy and light chains

[0731]

[0732]

[0733]

[0734]

[0735]

[0736]

[0737]

[0738]

[0739]

[0740]

[0741] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of the heavy chain complementary 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 the 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 comprise the sequences of SEQ ID NOs: 299, 343, 395, 460, 518, and 557, respectively. In some embodiments, one or more of the CDRs (or collectively all 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 NOs: 299, 343, 395, 460, 518, or 557.

[0742] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of the heavy chain complementary 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 the 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 comprise the sequences of SEQ ID NOs: 1140, 1141, 395, 460, 518, and 557, respectively. In some embodiments, one or more of the CDRs (or collectively all 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 NOs: 1140, 1141, 395, 460, 518, and 557.

[0743] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of the heavy chain complementary 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 the 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 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: 1155, SEQ ID NO: 1156, SEQ ID NO: 1157, SEQ ID NO: 1158, NAK, and SEQ ID NO: 557.

[0744] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of the heavy chain complementary 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 the 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 comprise the sequences of SEQ ID NOs: 304, 347, 400, 464, 523, and 562, respectively. In some embodiments, one or more of the CDRs (or collectively all 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 NOs: 304, 347, 400, 464, 523, and 562.

[0745] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of the heavy chain complementary 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 the 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 comprise the sequences of SEQ ID NOs: 1142, 1143, 400, 464, 523, and 562, respectively. In some embodiments, one or more of the CDRs (or collectively all 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 NOs: 1142, 1143, 400, 464, 523, and 562.

[0746] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of the heavy chain complementary 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 the 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 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: 1160, SEQ ID NO: 1161, SEQ ID NO: 1162, SEQ ID NO: 1163, WAS, and SEQ ID NO: 562.

[0747] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of the heavy chain complementary 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 the 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 comprise the sequences of SEQ ID NOs: 314, 341, 410, 1154, 529, and 571, respectively. In some embodiments, one or more of the CDRs (or collectively all 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 NOs: 314, 341, 410, 1154, 529, and 571.

[0748] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of the heavy chain complementary 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 the 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 comprise the sequences of SEQ ID NOs: 1144, 1145, 410, 1146, 529, and 571, respectively. In some embodiments, one or more of the CDRs (or collectively all 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 NOs: 1144, 1145, 410, 1146, 529, and 571.

[0749] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of the heavy chain complementary 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 the LC CDR1, LC CDR2, and / or LC CDR3, wherein the LC CDR1, LC CDR2, and LC CDR3 sequences comprise the sequences of SEQ ID NOs: 473, 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 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.

[0750] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of the heavy chain complementary 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 the 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 one of SEQ ID NOs: 64, 1145, 1167, 1146, 529, and 571.

[0751] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of the heavy chain complementary 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 the 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 comprise the sequences of SEQ ID NOs: 315, 341, 410, 474, 529, and 571, respectively. In some embodiments, one or more of the CDRs (or collectively all 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 NOs: 315, 341, 410, 474, 529, and 571.

[0752] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of the heavy chain complementary 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 the 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 comprise the sequences of SEQ ID NOs: 1147, 1148, 410, 474, 529, and 571, respectively. In some embodiments, one or more of the CDRs (or collectively all 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 NOs: 1147, 1148, 410, 474, 529, and 571.

[0753] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of the heavy chain complementary 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 the 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 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: 1168, SEQ ID NO: 1169, SEQ ID NO: 1167, SEQ ID NO: 1170, RVS, and SEQ ID NO: 571.

[0754] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of the heavy chain complementary 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 the 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 comprise the sequences of SEQ ID NOs: 316, 341, 410, 475, 530, and 571, respectively. In some embodiments, one or more of the CDRs (or collectively all 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 NOs: 316, 341, 410, 475, 530, and 571.

[0755] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of the heavy chain complementary 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 the 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 comprise the sequences of SEQ ID NOs: 1149, 1150, 410, 475, 530, and 571, respectively. In some embodiments, one or more of the CDRs (or collectively all 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 NOs: 1149, 1150, 410, 475, 530, and 571.

[0756] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of the heavy chain complementary 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 the 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 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: 1171, SEQ ID NO: 1166, SEQ ID NO: 1167, SEQ ID NO: 1172, RVS, and SEQ ID NO: 571.

[0757] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of the heavy chain complementary 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 the 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 comprise the sequences of SEQ ID NOs: 325, 362, 435, 495, 540, and 587, respectively. In some embodiments, one or more of the CDRs (or collectively all 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 NOs: 325, 362, 435, 495, 540, and 587.

[0758] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of the heavy chain complementary 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 the 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 comprise the sequences of SEQ ID NOs: 1152, 1153, 435, 495, 540, and 587, respectively. In some embodiments, one or more of the CDRs (or collectively all 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 NOs: 1152, 1153, 435, 495, 540, and 587.

[0759] In some embodiments, the anti-tau antibody comprises at least one, two, three, or all of the heavy chain complementary 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 the 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 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: 1173, SEQ ID NO: 1174, SEQ ID NO: 1175, SEQ ID NO: 1176, YAS, and SEQ ID NO: 587.

[0760] 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 to any of the foregoing sequences (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity). In some embodiments, the anti-tau antibody comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 78; or encoded by the nucleotide sequence of SEQ ID NO: 224; or a sequence substantially identical to any of the foregoing sequences (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity). In some embodiments, the anti-tau antibody comprises a heavy chain variable region and a light chain variable region comprising the amino acid sequences of SEQ ID NOs: 4 and 78, respectively; or encoded by the nucleotide sequences of SEQ ID NOs: 150 and 224, respectively; or a sequence substantially identical (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity) to any of the foregoing sequences. In some embodiments, the nucleotide sequence encoding the heavy chain variable region of the anti-tau antibody comprises the nucleotide sequence of SEQ ID NO: 150, or a sequence substantially identical (e.g., having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity); and / or the nucleotide sequence encoding the light chain variable region comprises the nucleotide sequence of SEQ ID NO: 224, or a sequence substantially identical (e.g., having at least about 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity).

[0761] In some embodiments, the anti-tau antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 9; or encoded by the nucleotide sequence of SEQ ID NO: 155; or a sequence substantially identical to any of the foregoing sequences (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity). In some embodiments, the anti-tau antibody comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 83; or encoded by the nucleotide sequence of SEQ ID NO: 229; or a sequence substantially identical to any of the foregoing sequences (e.g., having at least about 70%, 75%, 80%, 85%, 90%, 92%, 95%, 97%, 98%, or 99% sequence identity). In some embodiments, the anti-tau antibody comprises a heavy chain variable region and a light chain variable region comprising the amino acid sequences of SEQ ID NOs: 9 and 83, respectively; or encoded...

Claims

1. An antibody that binds to human tau, comprising: (a) a heavy chain variable region (VH) comprising a heavy chain complementary determining region 1 (HC CDR1) comprising the amino acid sequence of SEQ ID NO: 64, a heavy chain complementary determining region 2 (HC CDR2) comprising the amino acid sequence of SEQ ID NO: 1145, and a heavy chain complementary 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 complementary determining region 1 (LC CDR1) comprising the amino acid sequence of SEQ ID NO: 1146, a light chain complementary determining region 2 (LC CDR2) comprising the amino acid sequence of SEQ ID NO: 529, and a light chain complementary determining region 3 (LC CDR3) comprising the amino acid sequence of SEQ ID NO: 571; (b) a VH comprising a HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1144, a HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1145, and a HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410; and a VL comprising a LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1146, a LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; (c) a VH comprising a HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1165, a HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1166, and a HC CDR3 comprising the amino acid sequence of SEQ ID NO: 1167; and a VL comprising a LC CDR1 comprising the amino acid sequence of SEQ ID NO: 473, a LC CDR2 comprising the amino acid sequence of RVS, and a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; or (d) a VH comprising a HC CDR1 comprising the amino acid sequence of SEQ ID NO: 314, a HC CDR2 comprising the amino acid sequence of SEQ ID NO: 341, and a HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410; and a VL comprising a LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1154, a LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; and in: (i) the VH comprises an amino acid sequence comprising 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; and (ii) the VL comprises an amino acid sequence comprising one, two or all of the following: Q or E at position 17, P or R at position 18 and / or S at position 68 according to SEQ ID NO:

93.

2. An antibody that binds to human tau, comprising: (a) a heavy chain variable region (VH) comprising a heavy chain complementary determining region 1 (HC CDR1) comprising the amino acid sequence of SEQ ID NO: 64, a heavy chain complementary determining region 2 (HC CDR2) comprising the amino acid sequence of SEQ ID NO: 1145, and a heavy chain complementary 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 complementary determining region 1 (LC CDR1) comprising the amino acid sequence of SEQ ID NO: 1146, a light chain complementary determining region 2 (LC CDR2) comprising the amino acid sequence of SEQ ID NO: 529, and a light chain complementary determining region 3 (LC CDR3) comprising the amino acid sequence of SEQ ID NO: 571; (b) a VH comprising a HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1144, a HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1145, and a HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410; and a VL comprising a LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1146, a LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; (c) a VH comprising a HC CDR1 comprising the amino acid sequence of SEQ ID NO: 1165, a HC CDR2 comprising the amino acid sequence of SEQ ID NO: 1166, and a HC CDR3 comprising the amino acid sequence of SEQ ID NO: 1167; and a VL comprising a LC CDR1 comprising the amino acid sequence of SEQ ID NO: 473, a LC CDR2 comprising the amino acid sequence of RVS, and a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; or (d) a VH comprising a HC CDR1 comprising the amino acid sequence of SEQ ID NO: 314, a HC CDR2 comprising the amino acid sequence of SEQ ID NO: 341, and a HC CDR3 comprising the amino acid sequence of SEQ ID NO: 410; and a VL comprising a LC CDR1 comprising the amino acid sequence of SEQ ID NO: 1154, a LC CDR2 comprising the amino acid sequence of SEQ ID NO: 529, and a LC CDR3 comprising the amino acid sequence of SEQ ID NO: 571; and in: (i) the VH comprises 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 NO: 69, 67, 68, 70 or 71; and (ii) the VL comprises an amino acid sequence that is 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.

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 comprising 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 of any one of claims 1 to 4, wherein the VH comprises: (a) 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: 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) 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 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; 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) 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: 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 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; or (e) 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 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.

6. An antibody as described in any one of claims 2-5, wherein the VL comprises an amino acid sequence comprising one, two or all of the following: Q or E at position 17, P or R at position 18 and / or S at position 68 according to SEQ ID NO:

93.

7. The antibody of any one of claims 1-6, wherein the VL comprises: (a) 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or all of the following: 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, according to the numbering of SEQ ID NO:93; (b) 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 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; (c) 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 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; (d) 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or all of the following: 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; 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: 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.

8. The antibody of any one of claims 1 to 7, wherein: (i) the VH comprises 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; and (ii) the VL comprises an I at position 2; an S at position 7; an S at position 12; a T at position 14; a P at position 15; a Q at position 17; a P at position 18; a Q at position 50; an S at position 68; a V at position 88; a Y at position 92; a Q at position 105; and a V at position 109, numbered according to SEQ ID NO: 93 or 73.

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

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

11. An antibody as claimed in any one of the preceding claims, wherein (a) the VH comprises one, two, three or all of the following: (i) FRH1 comprising amino acids 1-25 or 1-30 of any one of SEQ ID NOs: 67-71; 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 1-25 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 comprising 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 comprising 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 comprising 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 comprises one, two, three or all of the following: (i) FRL1 comprising amino acids 1-23 of any one of SEQ ID NOs: 72-76; 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 1-23 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 comprising 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 comprising 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 comprising one, two, three but not more than four modifications (eg, substitutions, eg, conservative substitutions) relative to amino acids 103-112 of any one of SEQ ID NOs: 72-76.

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

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

74.

14. The antibody of any one of claims 1-13, 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 of any one of claims 1 to 14, wherein: (i) the nucleotide sequence encoding the VH comprises the nucleotide sequence of any one of SEQ ID NOs: 156-160, or a nucleotide sequence that is 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 that is at least 90%, 92%, 95%, 96%, 97%, 98% or 99% identical thereto.

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

17. The antibody of any one of the preceding claims, which is a full length antibody, a bispecific antibody, a Fab, a F(ab')2, a Fv or a single chain Fv fragment (scFv).

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

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

20. The antibody of any one of the preceding claims, wherein: (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 that is 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), wherein the nucleotide sequence encoding the heavy chain constant region comprises the nucleotide sequence of any one of SEQ ID NO: 195, 196, 198 or 199, or a nucleotide sequence that is at least 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NO: 195, 196, 198 or 199.

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

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

23. The antibody of any one of claims 1-22, wherein the antibody comprises: (i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 172, or an amino acid sequence that is 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 that is 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 that is 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 that is 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 that is 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 that is 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 that is 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 that is at least 90%, 92%, 95%, 96%, 97%, 98% or 99% identical thereto.

24. The antibody of any one of claims 1-23, 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 of any one of claims 22-24, wherein: (i) the nucleotide sequence encoding the heavy chain comprises a nucleotide sequence of any one of SEQ ID NOs: 180-184, or a nucleotide sequence that is 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 sequence that is at least 90%, 92%, 95%, 96%, 97%, 98% or 99% identical to any one of SEQ ID NOs: 185-189.

26. The antibody of 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) according to the numbering of SEQ ID NO:920; (iv) 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 as described in Example 1 or 8; (v) reducing, for example, inhibiting, the aggregation of tau; and / or (vi) binds to an epitope comprising a region formed by a complex of at least two tau proteins, such as a tau dimer.

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

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

29. The nucleic acid of claim 28, wherein: (i) the nucleotide sequence encoding the VH comprises a nucleotide sequence of SEQ ID NO: 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 a nucleotide sequence of any one of SEQ ID NO: 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; (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; (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; (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.

30. The nucleic acid of claim 28 or 29, wherein: (i) the nucleotide sequence encoding the heavy chain comprises the nucleotide sequence of SEQ ID NO: 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 SEQ ID NO: 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; (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; (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; (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.

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

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

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

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

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

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

37. The viral genome of any one of claims 33-36, wherein the promoter is 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 derivative CAG, β-glucuronidase (GUSB) or ubiquitin C (UBC), neuron-specific enolase (NSE), platelet-derived growth factor (PDGF), platelet-derived growth factor B chain (PDGF-β), intercellular adhesion molecule 2 (ICAM-2), Synapsin (Syn), methyl-CpG binding protein 2 (MeCP2), Ca2+ / calmodulin-dependent protein kinase II (CaMKII), metabotropic glutamate receptor 2 (mGluR2), neurofilament light chain (NFL) or heavy chain (NFH), β-globin minigene nβ2, preproenkephalin (PPE), enkephalin (Enk) and excitatory amino acid transporter 2 (EAAT2), glial fibrillary acidic protein (GFAP), myelin basic protein (MBP) or fragments thereof, such as truncated fragments, or functional variants.

38. The viral genome of any one of claims 33-37, further comprising: (i) enhancers; (ii) polyadenylation (polyA) signal region; (ii) one or two ITR sequences; (iii) at least 1, 2 or 3 intronic regions; (iv) at least 1, 2 or 3 exon regions; and / or (v) Nucleotide sequences encoding microRNA (miR) binding sites.

39. The viral genome of claim 38, wherein the ITR sequence is located 5' relative to the nucleic acid encoding the antibody and / or the ITR sequence is located 3' relative to the nucleic acid encoding the antibody.

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

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

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

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

45. A pharmaceutical composition comprising the antibody of any one of claims 1-27 or 32 or the AAV particle of claim 41 or 42; and a pharmaceutically acceptable excipient.

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

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

48. The method of claim 46 or 47, wherein the neurological condition comprises: (i) tauopathy; (ii) TBI; and / or (iii) Alzheimer's disease (AD), frontotemporal dementia and Parkinson's disease linked to chromosome 17 (FTDP-17), frontotemporal 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, entanglement-only dementia, mild cognitive impairment, or progressive subcortical gliosis.

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

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

51. The method of any one of claims 46-50, further comprising administering an additional therapeutic agent and / or therapy useful for treating or preventing a neurological disorder or a neurodegenerative disorder, such as a tauopathy, optionally wherein the additional therapeutic agent and / or therapy comprises a cholinesterase inhibitor (e.g. donepezil, rivastigmine and / or galantamine), an N-methyl D-aspartate (NMDA) antagonist (e.g. memantine), an antipsychotic, 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, apicapone 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 as described in any one of claims 1-27 or 32, an AAV particle as described in claim 41 or 42, or a pharmaceutical composition as described in claim 45 for use as a medicament.

53. An antibody as described in any one of claims 1-27 or 32, an AAV particle as described in claim 41 or 42, or a pharmaceutical composition as described in claim 45, for use in treating a neurological disorder or a neurodegenerative disorder, a tauopathy, or a traumatic brain injury (TBI).

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

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