WO2019094576A1 - Anticorps bispécifiques bace-tau - Google Patents

Anticorps bispécifiques bace-tau Download PDF

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Publication number
WO2019094576A1
WO2019094576A1 PCT/US2018/059801 US2018059801W WO2019094576A1 WO 2019094576 A1 WO2019094576 A1 WO 2019094576A1 US 2018059801 W US2018059801 W US 2018059801W WO 2019094576 A1 WO2019094576 A1 WO 2019094576A1
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seq
amino acid
acid sequence
cdr
variable region
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PCT/US2018/059801
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English (en)
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Mark S. Dennis
Lesley Ann KANE
Joseph W. LEWCOCK
Adam P. Silverman
Raymond Ka Hang TONG
Ryan J. Watts
Yin Zhang
Joy Yu Zuchero
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Denali Therapeutics Inc.
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Publication of WO2019094576A1 publication Critical patent/WO2019094576A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/40—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against enzymes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2881—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against CD71
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/71—Decreased effector function due to an Fc-modification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Definitions

  • Protein and peptide aggregation is a common feature in a number of neurodegenerative diseases, including Alzheimer' s disease and frontotemporal dementia.
  • Tau protein aggregation and neurofibrillary tangles are a primary marker of Alzheimer' s disease.
  • Tau protein is highly expressed in neurons and functions in stabilizing microtubules and aiding the assembly of tubulin in microtubules. Abnormal hyperphosphorylation of Tau can result in Tau aggregation. It is believed that after the initiation of Tau aggregation, the aggregates act as templates (or "seeds") for the misfolding of native Tau in the brain, resulting in the continued propagation of Tau aggregates and the formation of neurofibrillary tangles.
  • Amyloid beta ( ⁇ ) peptide aggregation into senile plaques is another primary marker of Alzheimer's disease.
  • ⁇ peptides are derived from amyloid precursor protein (APP), a transmembrane protein that is sequentially cleaved by proteases.
  • APP amyloid precursor protein
  • BACE1 beta-secretase 1
  • BACE1 beta-secretase 1
  • bispecific antibodies that specifically bind to a Tau protein and that specifically bind to a beta-secretase 1 (BACE1) protein are provided.
  • the Tau protein is a human Tau protein and the BACE1 protein is a human BACE1 protein.
  • the bispecific antibody comprises (a) a first antigen-binding portion comprising a first variable region that specifically binds to a Tau protein and (b) a second antigen-binding portion comprising a second variable region that specifically binds to a BACE1 protein.
  • the first antigen-binding portion comprises (i) a first heavy chain comprising a first Fc polypeptide and (ii) a first light chain.
  • the second antigen-binding portion comprises (i) a second heavy chain comprising a second Fc polypeptide and (ii) a second light chain.
  • the first Fc polypeptide is an unmodified Fc polypeptide.
  • the first Fc polypeptide is a modified Fc polypeptide.
  • the second Fc polypeptide is an unmodified Fc polypeptide.
  • the second Fc polypeptide is a modified Fc polypeptide.
  • the first Fc polypeptide is a modified Fc polypeptide and the second Fc polypeptide is a modified Fc polypeptide.
  • the bispecific antibody comprises:
  • a first antigen-binding portion comprising a first variable region that specifically binds to a Tau protein, wherein the first antigen-binding portion comprises (i) a first heavy chain comprising a first Fc polypeptide and (ii) a first light chain;
  • a second antigen-binding portion comprising a second variable region that specifically binds to a BACE1 protein, wherein the second antigen-binding portion comprises (i) a second heavy chain comprising a second Fc polypeptide and (ii) a second light chain;
  • first heavy chain and the second heavy chain form an Fc dimer
  • first Fc polypeptide is a modified Fc polypeptide and the second Fc polypeptide is a modified Fc polypeptide
  • first Fc polypeptide is a modified Fc polypeptide and the second Fc polypeptide is an unmodified Fc polypeptide
  • first Fc polypeptide is an unmodified Fc polypeptide and the second Fc polypeptide is a modified Fc polypeptide.
  • the first antigen-binding portion comprises a first variable region that specifically binds to a full-length human Tau protein of SEQ ID NO: l .
  • the first antigen-binding portion comprises a first variable region that recognizes an epitope within or comprising residues 111-125, an epitope within or comprising residues 186-205, an epitope within or comprising residues 251-270, and/or an epitope within or comprising residues 346-360 of a full-length human Tau protein of SEQ ID NO: l .
  • the first antigen-binding portion comprises a first variable region that specifically binds to two or more splice isoforms of human Tau protein.
  • the first antigen-binding portion comprises a first variable region that specifically binds to a phosphorylated human Tau protein and/or an unphosphorylated human Tau protein. In some embodiments, the first antigen-binding portion comprises a first variable region that specifically binds to a human Tau protein and exhibits cross-reactivity with a cynomolgus monkey Tau protein and/or a mouse Tau protein.
  • the first antigen-binding portion comprises one or more complementarity determining regions (CDRs) selected from the group consisting of:
  • CDR-H1 a heavy chain CDR1 (CDR-H1) having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs:2, 8, 11, 42, 49, 50, 51, 52, 53, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 555, 556, 1194, or 1 195, or having up to two amino acid substitutions relative to the amino acid sequence of any one of SEQ ID NOs:2, 8, 11, 42, 49, 50, 51, 52, 53, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 555, 556, 1194, or 1195;
  • CDR-H2 a heavy chain CDR2 having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs:3, 12, 43, 513, 514, 515, 516, 517,
  • CDR-H3 a heavy chain CDR3 having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 4, 9, 13, 17, 18, 44, 54, 1198, or
  • CDR-L1 light chain CDR1 having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 5, 14, 32, 46, 55, 56, 57, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 1200, or 1201, or having up to two amino acid substitutions relative to the amino acid sequence of any one of SEQ ID NOs: 5, 14, 32, 46, 55, 56, 57, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 1200, or 1201 ;
  • CDR-L2 a light chain CDR2 (CDR-L2) having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 6, 15, 33, 47, or 1202, or having up to two amino acid substitutions relative to the amino acid sequence of any one of SEQ ID NOs: 6, 15, 33, 47, or 1202;
  • CDR-L3 a light chain CDR3 (CDR-L3) having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs:7, 10, 16, 34, 35, 48, 58, 59, 60, 61, 535, 536, 537, 1203, or 1204, or having up to two amino acid substitutions relative to the amino acid sequence of any one of SEQ ID NOs:7, 10, 16, 34, 35, 48, 58, 59, 60, 61, 535, 536, 537, 1203, or 1204.
  • the first antigen-binding portion comprises one or more CDRs selected from the group consisting of:
  • a CDR-H1 comprising the amino acid sequence of any one of SEQ ID NOs:2, 8, 1 1, 42, 49, 50, 51, 52, 53, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 555, 556, 1194, or 1195;
  • a CDR-H2 comprising the amino acid sequence of any one of SEQ ID NOs: 3, 12, 43, 513, 514, 515, 516, 517, 518, 572, 1 196, or 1 197;
  • the first antigen-binding portion comprises: (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO:2, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:3, a CDR-H3 comprising the amino acid sequence of SEQ ID NO:4, a CDR-Ll comprising the amino acid sequence of SEQ ID NO:5, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:6, and a CDR- L3 comprising the amino acid sequence of SEQ ID NO:7; or
  • a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 8
  • a CDR-H2 comprising the amino acid sequence of SEQ ID NO:3, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 9
  • a CDR-Ll comprising the amino acid sequence of SEQ ID NO:5
  • a CDR-L2 comprising the amino acid sequence of SEQ ID NO:6
  • a CDR- L3 comprising the amino acid sequence of SEQ ID NO: 10;
  • a CDR-H1 comprising the amino acid sequence of SEQ ID NO:2, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:3, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 17, a CDR-Ll comprising the amino acid sequence of SEQ ID NO:5, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:6, and a CDR- L3 comprising the amino acid sequence of SEQ ID NO: 10; or
  • a CDR-H1 comprising the amino acid sequence of SEQ ID NO:2, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:3, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 18, a CDR-Ll comprising the amino acid sequence of SEQ ID NO:5, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:6, and a CDR- L3 comprising the amino acid sequence of SEQ ID NO: 10; or
  • a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 11, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 12, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 13, a CDR-Ll comprising the amino acid sequence of SEQ ID NO: 14, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 15, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 16;
  • a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 11, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 12, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 13, a CDR-Ll comprising the amino acid sequence of SEQ ID NO:32, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:33, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:34; or
  • a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 11, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 12, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 13, a CDR-Ll comprising the amino acid sequence of SEQ ID NO:32, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:33, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:35; or
  • a CDR-H1 comprising the amino acid sequence of SEQ ID NO:42, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:43, a CDR-H3 comprising the amino acid sequence of SEQ ID NO:44, a CDR-Ll comprising the amino acid sequence of SEQ ID NO:46, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:47, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:48; or
  • a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 11, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 12, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 13, a CDR-Ll comprising the amino acid sequence of SEQ ID NO:525, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 15, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 536; or
  • a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 11, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 12, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 13, a CDR-Ll comprising the amino acid sequence of SEQ ID NO:534, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 15, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 536; or
  • a CDR-H1 comprising the amino acid sequence of SEQ ID NO:555, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:572, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 13, a CDR-Ll comprising the amino acid sequence of SEQ ID NO:57, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 15, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 536; or
  • a CDR-H1 comprising the amino acid sequence of SEQ ID NO:555, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:572, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 13, a CDR-Ll comprising the amino acid sequence of SEQ ID NO:525, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 15, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 536; or
  • a CDR-H1 comprising the amino acid sequence of SEQ ID NO:556, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:572, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 13, a CDR-Ll comprising the amino acid sequence of SEQ ID NO:57, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 15, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 16; or
  • a CDR-H1 comprising the amino acid sequence of SEQ ID NO:556, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:572, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 13, a CDR-Ll comprising the amino acid sequence of SEQ ID NO:57, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 15, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 536; or
  • a CDR-H1 comprising the amino acid sequence of SEQ ID NO:556, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:572, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 13, a CDR-Ll comprising the amino acid sequence of SEQ ID NO:525, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 15, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 536.
  • the first antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to any one of SEQ ID NOs: 19, 21, 23, 25, 27, 29, 36, 37, 38, 39, 41, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, or 571.
  • sequence identity e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity
  • the first antigen-binding portion comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to any one of SEQ ID NOs:20, 22, 24, 26, 28, 30, 31, 40, 45, 538, 539, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, 583, 584, 585, or 586.
  • sequence identity e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity
  • the first antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to any one of SEQ ID NOs: 19, 21, 23, 25, 27, 29, 36, 37, 38, 39, 41, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, or 571 and comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to any one of SEQ ID NOs:20, 22, 24, 26, 28, 30, 31, 40, 45, 538
  • a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO:36 and a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO:40; or (i) a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO:37 and a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO:40; or
  • a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO:41 and a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO:45; or
  • the second antigen-binding portion comprises a second variable region that specifically binds to a full-length human BACE1 protein of SEQ ID NO: 65. In some embodiments, the second antigen-binding portion comprises a second variable region that recognizes an epitope within residues 314-460 of a full-length human BACE1 protein of SEQ ID NO:64. In some embodiments, the second antigen-binding portion comprises a second variable region that recognizes a conformational epitope.
  • the second antigen-binding portion comprises one or more CDRs selected from the group consisting of:
  • a CDR-H1 having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs:70, 1 10, 111, 112, 113, 1 14, 1 15, 116, 117, 118, 1 19, 120, 121, 122, 123, 124, 125, 126, 127, 128, 243, 244, 245, 719, 720, 721, 722, 723, 1140, 1141, 1142, 1 143, 1144, 1 145, 1146, or 1 147, or having up to two amino acid substitutions relative to the amino acid sequence of any one of SEQ ID NOs:70, 110, 111, 112, 1 13, 1 14, 115, 116, 1 17, 1 18, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 243, 244, 245, 719, 720, 721, 722, 723, 1140, 1141, 1142, 1 143, 1144, 1145, 1146, or 1147;
  • a CDR-H2 having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs:71, 72, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 246, 247, 248, 249, 250, 540, 541, 724, 725, 726, 843, 1148, 1149, 1150, 1151, 1152, 1153, 1154, 1155, 1156, or 1157, or having up to two amino acid substitutions relative to the amino acid sequence of any one of SEQ ID NOs:71, 72, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 246, 247, 248,
  • a CDR-H3 having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs:73, 151, 152, 153, 154, 155, 156, 157, 158, 159, 170, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 251, 542, 543, 544, 545, 546, 547, 548, 549, 915, 1158, 1159, 1160, 1161, 1162, 1163, or 1164, or having up to two amino acid substitutions relative to the amino acid sequence of any one of SEQ ID NOs:73, 151, 152, 153, 154, 155, 156, 157, 158, 159, 170, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 251, 542, 543, 544, 545, 546, 547, 548, 5
  • a CDR-H1 comprising the amino acid sequence of any one of SEQ ID NOs:70, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 243, 244, 245, 719, 720, 721, 722, 723, 1 140, 1 141, 1142, 1143, 1 144, 1145, 1146, or 1 147;
  • a CDR-H2 comprising the amino acid sequence of any one of SEQ ID NOs:71, 72, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 246, 247, 248, 249, 250, 540, 541, 724, 725, 726, 843, 1148, 1149, 1150, 1151, 1 152, 1153, 1154, 1155, 1 156, or 1 157;
  • a CDR-H3 comprising the amino acid sequence of any one of SEQ ID NOs:73, 151, 152, 153, 154, 155, 156, 157, 158, 159, 170, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 251, 542, 543, 544, 545, 546, 547, 548, 549, or 915, 1 158, 1159, 1160, 1161, 1162, 1 163, or 1 164;
  • a CDR-L2 comprising the amino acid sequence of any one of SEQ ID NOs:75, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 259, or 1015, 1123, 1124, 1125, 1126, 1 127, 1128, 1129, 1130, 1 131, or 1 132; and
  • a CDR-L3 comprising the amino acid sequence of any one of SEQ ID NOs: 16, 35, 76, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 260, 550, 551, 552, 553, 554, 727, 728, 729, 730, 731, 732, 1112, 1 133, 1134, 1135, 1136, 1137, 1 138, or 1 139.
  • the second antigen-binding portion comprises:
  • a CDR-H1 comprising the amino acid sequence of SEQ ID NO:70 or 719, a CDR-H2 comprising the amino acid sequence of any one of SEQ ID NOs:71, 72, or 540, a CDR-H3 comprising the amino acid sequence of SEQ ID NO:73, a CDR-L1 comprising the amino acid sequence of SEQ ID NO:74, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:75, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:76 or 550; or (b) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 110, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 129, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 151, a CDR-Ll comprising the amino acid sequence of SEQ ID NO: 195, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:
  • a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 111, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 130, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 152, a CDR-Ll comprising the amino acid sequence of SEQ ID NO: 196, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:210, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:222; or
  • a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 112, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 131, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 153, a CDR-Ll comprising the amino acid sequence of SEQ ID NO: 197, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:211, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:224; or
  • a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 113, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 132, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 154, a CDR-Ll comprising the amino acid sequence of SEQ ID NO: 198, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:212, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:224; or
  • a CDR-H1 comprising the amino acid sequence of SEQ ID NO: l 14, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 133, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 155, a CDR-Ll comprising the amino acid sequence of SEQ ID NO: 199, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:211, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:225; or
  • a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 115, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 134, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 156, a CDR-Ll comprising the amino acid sequence of SEQ ID NO:200, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:213, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:226; or
  • a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 116, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 135, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 157, a CDR-Ll comprising the amino acid sequence of SEQ ID NO:201, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:212, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:227; or
  • a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 117, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 136, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 158, a CDR-Ll comprising the amino acid sequence of SEQ ID NO:202, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:214, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:228; or
  • a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 118, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 137, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 159, a CDR-Ll comprising the amino acid sequence of SEQ ID NO:203, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:215, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:222; or
  • a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 117, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 139, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 161, a CDR-Ll comprising the amino acid sequence of SEQ ID NO:32, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:214, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:230; or
  • a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 120, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 140, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 162, a CDR-Ll comprising the amino acid sequence of SEQ ID NO:32, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:216, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:35; or
  • a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 121, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 141, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 163, a CDR-Ll comprising the amino acid sequence of SEQ ID NO:32, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:217, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:231; or
  • a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 122, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 142, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 164, a CDR-Ll comprising the amino acid sequence of SEQ ID NO:32, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:216, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 16; or
  • a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 123, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 143, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 165, a CDR-Ll comprising the amino acid sequence of SEQ ID NO:204, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:212, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:232; or
  • a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 124, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 145, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 167, a CDR-Ll comprising the amino acid sequence of SEQ ID NO:205, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:218, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:234; or
  • a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 125
  • a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 146
  • a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 168
  • a CDR-Ll comprising the amino acid sequence of SEQ ID NO:206
  • a CDR-L2 comprising the amino acid sequence of SEQ ID NO:219
  • a CDR-L3 comprising the amino acid sequence of SEQ ID NO:235;
  • a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 126, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 147, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 169, a CDR-Ll comprising the amino acid sequence of SEQ ID NO:207, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:220, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:236; or
  • a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 126, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 148, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 170, a CDR-Ll comprising the amino acid sequence of SEQ ID NO:32, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:216, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:35; or (v) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 127, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 149, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 171, a CDR-Ll comprising the amino acid sequence of SEQ ID NO:32, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:216, and a CDR-L3 comprising the amino acid
  • a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 126, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 149, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 171, a CDR-Ll comprising the amino acid sequence of SEQ ID NO:32, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:216, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 16; or
  • a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 128, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 150, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 172, a CDR-Ll comprising the amino acid sequence of SEQ ID NO:208, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:210, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:222; or
  • a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 128, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 1149, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 1 160, a CDR-Ll comprising the amino acid sequence of SEQ ID NO:208, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 1123, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 1135; or
  • a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 128, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 1149, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 1 160, a CDR-Ll comprising the amino acid sequence of SEQ ID NO:208, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 1123, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: l 135.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity to any one of SEQ ID NOs:66, 77, 78, 79, 80, 81, 82, 83, 84, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 238, 239, 240, 241, 242, 261, 262, 263, 264, 265, 266, 733, 734, 735, 736, 1 176, 1 177, 1178, 1179, 1 180, 1181, 1182, 1183, 1184, 1185, 1186, 1187, 1188, 1189, 1190, 1192, or 1193.
  • a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity to any one of SEQ ID NOs:67, 85, 86, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 252, 253, 254, 255, 256, 257, 267, 268, 269, 270, or 271, 737, 738, 739, 1 165, 1166, 1 167, 1168, 1169, 1170, 1171, 1172, 1173, 1 174, 1175, or 1191.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity to any one of SEQ ID NOs:66, 77, 78, 79, 80, 81, 82, 83, 84, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 238, 239, 240, 241, 242, 261, 262, 263, 264, 265, 266, 733, 734, 735, 736, 1 176, 1177, 1178, 1179, 1180, 1 181, 1182, 1183, 1 184, 1 185, 1186, 1187, 1 188, 1189, 1190, 1 192, or 1 193 and comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity to any one of SEQ ID NOs:66,
  • the second antigen-binding portion comprises: (a) a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO: 66 and a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO: 67; or
  • a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO: 79 and a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO:86; or
  • a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO: 80 and a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO: 86; or (n) a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO:81 and a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO: 86; or
  • a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO: 99 and a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO: 185; or (ee) a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO: 100 and a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO: 186; or
  • (nn) a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO: 109 and a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO: 194; or
  • (tt) a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO: 1 193 and a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO: 1191.
  • the second antigen-binding portion is produced by a hybridoma cell line selected from the group consisting of: (a) Accession Number LMBP 6871CB as deposited under the provisions of the Budapest Treaty with the Belgian Coordinated Collections of Micro-organisms, Zwijnaarde, Belgium, on May 13, 2009;
  • a bispecific antibody comprises:
  • a first antigen-binding portion comprising: a CDR-H1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 1 1 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 1 1, a CDR-H2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 12 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 12, a CDR-H3 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 13 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 13, a CDR-L1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 14 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 14, a CDR-L2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 15 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 15, and a
  • a second antigen-binding portion comprising: a CDR-H1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:70 or 719 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO:70 or 719, a CDR-H2 having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs:71, 72, or 540 or having up to two amino acid substitutions relative to the amino acid sequence of any one of SEQ ID NOs:71, 72, or 540, a CDR-H3 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO 73 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 73, a CDR-L1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 74 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 74, a CDR-L2 having at least 90% sequence identity to the amino acid sequence of
  • the first antigen-binding portion comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: l l, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 12, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 13, a CDR-Ll comprising the amino acid sequence of SEQ ID NO: 14, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 15, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 16; and the second antigen-binding portion comprises a CDR- Hl comprising the amino acid sequence of SEQ ID NO:70, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:71, a CDR-H3 comprising the amino acid sequence of SEQ ID NO:73, a CDR-Ll comprising the amino acid sequence of SEQ ID NO:74, a CDR-L2 comprising the amino acid sequence of SEQ ID
  • the bispecific antibody comprises:
  • a first antigen-binding portion comprising: a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID
  • a second antigen-binding portion comprising: a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity to any one of SEQ ID NOs:66, 77, 78, 79, 80, 81, 82, 83, or 84 and a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity to any one of SEQ ID NOs:67, 85, or 86.
  • the first antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:23 and comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:24; and the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 80 and comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 86.
  • a bispecific antibody comprises a first antigen-binding portion that comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:62 and/or a light chain comprising the amino acid sequence of SEQ ID NO:63.
  • a bispecific antibody comprises a second antigen-binding portion that comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:68 and/or a light chain comprising the amino acid sequence of SEQ ID NO: 69.
  • a bispecific antibody comprises: (a) a first antigen-binding portion that comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 62 and a light chain comprising the amino acid sequence of SEQ ID NO: 63; and (b) a second antigen-binding portion that comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:68 and a light chain comprising the amino acid sequence of SEQ ID NO:69.
  • a bispecific antibody comprises: (a) a first antigen-binding portion comprising: a CDR-H1 having at least
  • a second antigen-binding portion comprising: a CDR-H1 having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 128, 243, 244, or 245 or having up to two amino acid substitutions relative to the amino acid sequence of any one of SEQ ID NOs: 128, 243, 244, or 245, a CDR-H2 having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 150, 246, 247, 248, 249, or 250 or having up to two amino acid substitutions relative to the amino acid sequence of any one of SEQ ID NOs: 150, 246, 247, 248, 249, or 250, a CDR-H3 having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 172 or 251 or having up to two amino acid substitutions relative to the amino acid sequence of any one of SEQ ID NOs: 172 or 251, a CDR-L1 having at least 90% sequence identity to the amino acid sequence of any one of
  • the bispecific antibody comprises:
  • a first antigen-binding portion comprising: a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO:23 and a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO:24;
  • a second antigen-binding portion comprising: a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity to any one of SEQ ID NOs: 109, 238, 239, 240, 241, 242, 261, 262, 263, 264, 265, or 266 and a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity to any one of SEQ ID NOs: 194, 252, 253, 254, 255, 256, 257, 267, 268, 269, 270, or 271.
  • the bispecific antibody comprises:
  • a first antigen-binding portion comprising a heavy chain variable region having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:586 and a light chain variable region having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 570;
  • a second antigen-binding portion comprising a heavy chain variable region having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 1192 or SEQ ID NO: 1193 and a light chain variable region having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 1191.
  • the bispecific antibody comprises:
  • a first antigen-binding portion comprising a heavy chain variable region comprising to the amino acid sequence of SEQ ID NO:586 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:570; and a second antigen- binding portion comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1192 and a light chain variable region comprising the amino acid sequence of SEQ ID NO : 1191 ;
  • a first antigen-binding portion comprising a heavy chain variable region comprising to the amino acid sequence of SEQ ID NO:586 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:570; and a second antigen- binding portion comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1193 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 1191.
  • the first antigen-binding portion and/or the second antigen- binding portion is chimeric. In some embodiments, the first antigen-binding portion and/or the second antigen-binding portion is humanized. In some embodiments, the first antigen- binding portion and/or the second antigen-binding portion is fully human. In some embodiments, the first antigen-binding portion and/or the second antigen-binding portion is a Fab, a F(ab' )2, or a scFv.
  • the first Fc polypeptide and the second Fc polypeptide each contain modifications that promote heterodimerization.
  • one of the Fc polypeptides has a T366W substitution and other Fc polypeptide has T366S, L368A, and Y407V substitutions, according to EU numbering
  • the first Fc polypeptide contains the T366S, L368A, and Y407V substitutions and the second Fc polypeptide contains the T366W substitution.
  • the first Fc polypeptide contains the T366W substitution and the second Fc polypeptide contains the T366S, L368A, and Y407V substitutions.
  • the first Fc polypeptide and/or the second Fc polypeptide comprises a native FcRn binding site. In some embodiments, the first Fc polypeptide and/or the second Fc polypeptide comprises a modification that alters FcRn binding. [0034] In some embodiments, the first Fc polypeptide and the second Fc polypeptide do not have effector function. In some embodiments, the first Fc polypeptide and/or the second Fc polypeptide comprises a modification that reduces effector function. In some embodiments, the modification that reduces effector function is a substitution of Ala at position 234 and Ala at position 235, according to EU numbering.
  • the first Fc polypeptide and/or the second Fc polypeptide comprises amino acid changes relative to the native Fc sequence that extend serum stability or serum half-life.
  • the amino acid changes comprise substitutions of Tyr at position 252, Thr at position 254, and Glu at position 256, according to EU numbering.
  • the amino acid changes comprise substitutions of Leu at position 428 and Ser at position 434, according to EU numbering.
  • the amino acid changes comprise a substitution of Ser or Ala at position 434, according to EU numbering.
  • the first Fc polypeptide and/or the second Fc polypeptide specifically binds to a transferrin receptor.
  • the first Fc polypeptide and/or the second Fc polypeptide comprises at least two substitutions at positions selected from the group consisting of 384, 386, 387, 388, 389, 390, 413, 416, and 421, according to EU numbering.
  • the first Fc polypeptide and/or the second Fc polypeptide includes substitutions for at least three, four, five, six, seven, eight, or nine of the positions.
  • the first Fc polypeptide and/or the second Fc polypeptide further comprises one, two, three, or four substitutions at positions comprising 380, 391, 392, and 415, according to EU numbering. In some embodiments, the first Fc polypeptide and/or the second Fc polypeptide further comprises one, two, or three substitutions at positions comprising 414, 424, and 426, according to EU numbering.
  • the first Fc polypeptide and/or the second Fc polypeptide comprises Tip at position 388. In some embodiments, the first Fc polypeptide and/or the second Fc polypeptide comprises an aromatic amino acid at position 421. In some embodiments, the aromatic amino acid at position 421 is Tip or Phe.
  • the first Fc polypeptide and/or the second Fc polypeptide comprises at least one position selected from the following: position 380 is Trp, Leu, or Glu; position 384 is Tyr or Phe; position 386 is Thr; position 387 is Glu; position 388 is Trp; position 389 is Ser, Ala, Val, or Asn; position 390 is Ser or Asn; position 413 is Thr or Ser; position 415 is Glu or Ser; position 416 is Glu; and position 421 is Phe.
  • the first Fc polypeptide and/or the second Fc polypeptide comprises 2, 3, 4, 5, 6, 7, 8, 9, 10, or 1 1 positions selected from the following: position 380 is Trp, Leu, or Glu; position 384 is Tyr or Phe; position 386 is Thr; position 387 is Glu; position 388 is Trp; position 389 is Ser, Ala, Val, or Asn; position 390 is Ser or Asn; position 413 is Thr or Ser; position 415 is Glu or Ser; position 416 is Glu; and position 421 is Phe.
  • the first Fc polypeptide and/or the second Fc polypeptide comprises 1 1 positions as follows: position 380 is Trp, Leu, or Glu; position 384 is Tyr or Phe; position 386 is Thr; position 387 is Glu; position 388 is Trp; position 389 is Ser, Ala, Val, or Asn; position 390 is Ser or Asn; position 413 is Thr or Ser; position 415 is Glu or Ser; position 416 is Glu; and position 421 is Phe.
  • the first Fc polypeptide and/or the second Fc polypeptide has a CH3 portion with at least 85% identity, at least 90% identity, or at least 95% identity to amino acids 1 11-217 of any one of SEQ ID NOs:306-310, 330, 332-362, 409-480, and 587- 593.
  • the residues at at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 of the positions corresponding to EU index positions 380, 384, 386, 387, 388, 389, 390, 391, 392, 413, 414, 415, 416, 421, 424 and 426 of any one of SEQ ID NOs:306-310, 330, 332- 362, 409-480, and 587-593 are not deleted or substituted.
  • the first Fc polypeptide and/or the second Fc polypeptide comprises the amino acid sequence of any one of SEQ ID NOs:306-310, 330, 332-362, 409-480, and 587-593.
  • the bispecific antibody comprises a first Fc polypeptide having the sequence of any one of SEQ ID NOs:375-378 and 713-715 and/or a second Fc polypeptide having the sequence of any one of SEQ ID NOs:371 -374 and 716-718. In some embodiments, the bispecific antibody comprises a first Fc polypeptide having the sequence of any one of SEQ ID NOs:371-374 and 716-718 and/or a second Fc polypeptide having the sequence of any one of SEQ ID NOs:375-378 and 713-715.
  • each of the first antigen-binding portion and the second antigen-binding portion comprises an Fc polypeptide selected from the group consisting of SEQ ID NOs:363-378.
  • the first antigen-binding portion comprises an Fc polypeptide selected from the group consisting of SEQ ID NOs:363, 364, 365, 366, 375, 376, 377, and 378 and the second antigen-binding portion comprises an Fc polypeptide selected from the group consisting of SEQ ID NOs:367, 368, 369, 370, 371, 372, 373, and 374.
  • the first antigen-binding portion comprises an Fc polypeptide selected from the group consisting of SEQ ID NOs:367, 368, 369, 370, 371, 372, 373, and 374 and the second antigen-binding portion comprises an Fc polypeptide selected from the group consisting of SEQ ID NOs:363, 364, 365, 366, 375, 376, 377, and 378.
  • a bispecific antibody as described herein e.g., a bispecific antibody comprising a first antigen-binding portion comprising a first variable region that specifically binds to a Tau protein and a second antigen-binding portion comprising a second variable region that specifically binds to a BACEl protein, or a bispecific antibody comprising a first antigen-binding portion comprising a first variable region that specifically binds to a BACEl protein and a second antigen-binding portion comprising a second variable region that specifically binds to a Tau protein
  • the first Fc polypeptide and/or the second Fc polypeptide binds to the apical domain of the transferrin receptor. In some embodiments, the binding of the bispecific antibody to the transferrin receptor does not substantially inhibit binding of transferrin to the transferrin receptor.
  • the first Fc polypeptide and/or the second Fc polypeptide has an amino acid sequence identity of at least 75%, or at least 80%, 85%, 90%, 92%, or 95%, as compared to the corresponding wild-type Fc polypeptide (e.g., a wild-type Fc polypeptide that is a human IgGl, IgG2, IgG3, or IgG4 Fc polypeptide).
  • wild-type Fc polypeptide e.g., a wild-type Fc polypeptide that is a human IgGl, IgG2, IgG3, or IgG4 Fc polypeptide.
  • uptake of the bispecific antibody or antigen-binding portion thereof into the brain is greater than the uptake of the bispecific antibody or antigen-binding portion thereof without the modifications in the first Fc polypeptide and/or the second Fc polypeptide that result in transferrin receptor binding.
  • uptake of the bispecific antibody or antigen-binding portion thereof into the brain is at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100-fold greater as compared to the uptake of the bispecific antibody or antigen-binding portion thereof without the modifications in the first Fc polypeptide and/or the second Fc polypeptide that result in transferrin receptor binding.
  • the first Fc polypeptide is not modified to bind to a blood- brain barrier receptor and the second Fc polypeptide is modified to specifically bind to a transferrin receptor. In some embodiments, the first Fc polypeptide is modified to specifically bind to a transferrin receptor and the second Fc polypeptide is not modified to bind to a blood-brain barrier receptor.
  • the bispecific antibody prevents or reduces Tau seeding. In some embodiments, the bispecific antibody inhibits the production of an amyloid- ⁇ ( ⁇ ) peptide.
  • antigen-binding fragments comprise a first antigen-binding portion comprising a first variable region that specifically binds to a Tau protein and a second antigen-binding portion comprising a second variable region that specifically binds to a BACE1 protein.
  • the antigen-binding fragment further comprises an Fc polypeptide.
  • the Fc polypeptide is a modified Fc polypeptide.
  • the first Fc polypeptide and/or the second Fc polypeptide contains one or more of the modifications described herein, e.g., to promote heterodimerization, reduce effector function, extend serum half-life, and/or bind to a transferrin receptor.
  • first antigen-binding portion and the second antigen-binding portion further comprises an Fc polypeptide.
  • first antigen-binding portion further comprises a first Fc polypeptide and the second antigen-binding portion further comprises a second Fc polypeptide.
  • the first Fc polypeptide and/or the second Fc polypeptide is a modified Fc polypeptide.
  • the first Fc polypeptide and/or the second Fc polypeptide contains one or more of the modifications described herein, e.g., to promote heterodimerization, reduce effector function, extend serum half-life, and/or bind to a transferrin receptor.
  • the antigen-binding fragment may include a Fab fragment that comprises the first antigen-binding portion and further comprises an Fc polypeptide (e.g., a Fab-Fc fusion) and/or a Fab fragment that comprises the second antigen- binding portion and further comprises an Fc polypeptide.
  • the antigen- binding fragment may include a first Fab fragment that comprises the first antigen-binding portion and further comprises a first Fc polypeptide and a second Fab fragment that comprises the second antigen-binding portion and further comprises a second Fc polypeptide.
  • the first Fc polypeptide and/or the second Fc polypeptide is a modified Fc polypeptide.
  • the first Fc polypeptide and/or the second Fc polypeptide contains one or more of the modifications described herein, e.g., to promote heterodimerization, reduce effector function, extend serum half-life, and/or bind to a transferrin receptor.
  • compositions are provided.
  • the pharmaceutical composition comprises a bispecific antibody that specifically binds to a Tau protein and that specifically binds to a BACE1 protein as described herein and further comprises one or more pharmaceutically acceptable excipients.
  • isolated polynucleotides are provided.
  • the isolated polynucleotide comprises a nucleotide sequence encoding a first antigen-binding portion comprising a first variable region that specifically binds to a Tau protein and/or a second antigen-binding portion comprising a second variable region that specifically binds to a BACE1 protein.
  • vectors and host cells comprising such an isolated polynucleotide are provided.
  • antibodies are provided that compete for specific binding to a Tau protein and to a BACE1 protein with an antibody as described herein.
  • isolated humanized antibodies or antigen-binding portions thereof that specifically binds to a BACE1 protein (e.g., a human BACE1 protein) are provided.
  • the humanized antibody or antigen-binding portion thereof comprises a variable region that specifically binds to a BACE1 protein (e.g., a human BACE1 protein).
  • the humanized antibody comprises:
  • a CDR-H1 having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs:70, 719, 720, 721, 722, 723, or 746-834, or having up to two amino acid substitutions relative to the amino acid sequence of any one of SEQ ID NOs:70, 719, 720, 721, 722, 723, or 746-834;
  • a CDR-FI2 having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs:72, 540, 541, 724, 725, 726, or 835-878, or having up to two amino acid substitutions relative to the amino acid sequence of any one of SEQ ID NOs:72, 540, 541, 724, 725, 726, or 835-878;
  • a CDR-H3 having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs:73, 542, 543, 544, 545, 546, 547, 548, 549, or 879-940, or having up to two amino acid substitutions relative to the amino acid sequence of any one of SEQ ID NOs:73, 542, 543, 544, 545, 546, 547, 548, 549, or 879-940;
  • a CDR-L2 having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs:75 or 968-1040, or having up to two amino acid substitutions relative to the amino acid sequence of any one of SEQ ID NOs:75 or 968-1040;
  • a CDR-L3 having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs:76, 550, 551, 552, 553, 554, 727, 728, 729, 730, 731, 732, or 1041-1118, or having up to two amino acid substitutions relative to the amino acid sequence of any one of SEQ ID NO:76, 550, 551, 552, 553, 554, 727, 728, 729, 730, 731, 732, or 1041-1 1 18.
  • the humanized antibody comprises: (a) a CDR-H1 comprising the amino acid sequence of any one of SEQ ID NO: (a) a CDR-H1 comprising the amino acid sequence of any one of SEQ ID NO: (a) a CDR-H1 comprising the amino acid sequence of any one of SEQ ID NO: (a) a CDR-H1 comprising the amino acid sequence of any one of SEQ ID NO: (a) a CDR-H1 comprising the amino acid sequence of any one of SEQ ID
  • a CDR-H2 comprising the amino acid sequence of any one of SEQ ID NOs:72, 540, 541, 724, 725, 726, or 835-878;
  • a CDR-H3 comprising the amino acid sequence of any one of SEQ ID NOs:73, 542, 543, 544, 545, 546, 547, 548, 549, or 879-940;
  • the humanized antibody comprises: (a) a heavy chain variable region comprising (i) an amino acid sequence that has at least 75% sequence identity to any one of SEQ ID NOs: 77, 78, 79, 80, 81, 82, 83, or 84 and (ii) a CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs:70, 72, and 73, respectively; and/or
  • a light chain variable region comprising (i) an amino acid sequence that has at least 75% sequence identity to any one of SEQ ID NOs:85 or 86 and (ii) a CDR- Ll, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs:74, 75, and 76, respectively.
  • the humanized antibody comprises a heavy chain variable region comprising (i) an amino acid sequence that has at least 75% sequence identity to any one of SEQ ID NOs:77, 78, 79, 80, 81, 82, 83, or 84 and (ii) a CDR-H1, CDR-H2, and CDR- H3 having the amino acid sequences of SEQ ID NOs: 70, 72, and 73, respectively; and comprises a light chain variable region comprising (i) an amino acid sequence that has at least 75% sequence identity to any one of SEQ ID NOs:85 or 86 and (ii) a CDR-L1, CDR- L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs:74, 75, and 76, respectively.
  • the humanized antibody comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to any one of SEQ ID NOs:77, 78, 79, 80, 81, 82, 83, 84, 733, 734, 735, or 736.
  • sequence identity e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity
  • the humanized antibody comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to any one of SEQ ID NOs:85, 86, 737, 738, or 739.
  • sequence identity e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity
  • the humanized antibody comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%), at least 97%, at least 98%, or at least 99% sequence identity) to any one of SEQ ID NOs:77, 78, 79, 80, 81, 82, 83, 84, 733, 734, 735, or 736 and comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to any one of SEQ ID NOs: 85, 86, 737, 738, or 739. [0059] In some embodiments, the humanized antibody comprises:
  • a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO: 84 and a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO:85; or (i) a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO: 77 and a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO: 86; or
  • a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO: 80 and a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO: 86; or
  • isolated antibodies or antigen-binding portions thereof that specifically bind to a human BACE1 protein are provided.
  • the antibody or antigen-binding portion thereof comprises:
  • the CDR-H1 comprises the formula: -G-Y-X1-X2-X3-X4-X5-G-
  • X6-X7- (I) (SEQ ID NO:740), wherein: Xi is T, A, D, E, K, L, N, P, Q, R, S, or V; X2 is F, I,
  • X 3 is T, A, E, I, K, P, Q, R, or S
  • X 4 is T, S, K, R, A, I, N, or L
  • X 5 is Y, H, or N
  • X 6 is M, I, L, or V
  • X7 is S, A, F, G, H, T, V, or Y;
  • the CDR-H2 comprises the formula: -W-X1-N-T-X2-X3-X4-X5-
  • X6-X7-Y-A-D-D-F-T-G- (II) (SEQ ID NO:741), wherein: Xi is I, M, or V; X2 is Y, F, or S;
  • X 3 is S, K, N, R, or T;
  • X 4 is G, A, R, H, or S;
  • X 5 is V, A, I, F, L, or M;
  • Xe is P, A, or S;
  • Xv is T, A, I, N, S, Y, or V;
  • the CDR-H3 comprises the formula: -A-R-R-X1-X2-X3-X4-X5- Xe-Xy-D-Xs (III) (SEQ ID NO:742), wherein: Xi is F, A, H, I, L, M, S, T, or Y; X 2 is T, A,
  • X3 is S, A, F, P, T, or W;
  • X 4 is V, F, G, I, M, or S;
  • Xs is I or V;
  • Xe is A, F, N,
  • the light chain variable region comprises a CDR-L1, a CDR- L2, and a CDR-L3, wherein:
  • the CDR-L1 comprises the formula: -K-A-S-X1-X2-X3-X4-X5- ⁇ 6 - ⁇ 7 - ⁇ - (IV) (SEQ ID NO:743), wherein: Xi is Q, D, G, H, K, P, R, S, or Y; X 2 is D, A, E, G, K, N, R, S, T, or Y; X 3 is V, A, E, G, I, M, or P; X 4 is R, K, L, W, or N; Xs is T, S, or A; ⁇ is A or G; and X7 is V, I, or L;
  • the CDR-L2 comprises the formula: -W-X1-X2-X3-X4-X5-X6- (V) (SEQ ID NO:744), wherein: Xi is A, G, S, N, R, T, Y, or V; X2 is S, A, F, G, L, R, T, W, or Y; X 3 is T, A, D, E, G, N, or S; X 4 is R, G, H, I, K, L, N, P, S, W or Y; X 5 is H, I, L, M, P, Q, R, S, or Y; and Xe is T, A, D, F, G, H, I, K, M, N, S, or Y; and
  • the CDR-L3 comprises the formula: -X1-X2-X3-X4-X5-X6-X7- F-T- (VI) (SEQ ID NO:745), wherein: Xi is Q, H, E, K, or N; X2 is Q, D, E, or N; X 3 is H or Q; X 4 is Y, F, L, or N; Xs is Y or F; Xe is T, A, F, G, I, K, M, N, P, Q, R, S, E, or V; and ⁇ is P, A, D, F, H, L, R, S, T, W, G, E, or Y.
  • the antibody or antigen-binding portion thereof inhibits BACEl activity. In some embodiments, the antibody or antigen-binding portion thereof inhibits the production of amyloid- ⁇ ( ⁇ ) peptide. In some embodiments, the antigen- binding portion is a Fab, a F(ab')2, an scFv, or a bivalent scFv.
  • compositions that comprise a humanized antibody that specifically binds to a BACEl protein (e.g., a human BACEl protein) as described herein and further comprise one or more pharmaceutically acceptable excipients.
  • a BACEl protein e.g., a human BACEl protein
  • isolated polynucleotides comprise a nucleotide sequence encoding a humanized antibody that specifically binds to a BACEl protein as described herein.
  • vectors and host cells comprising such an isolated polynucleotide are provided.
  • antibodies are provided that compete for specific binding to a BACEl protein with a humanized antibody as described herein.
  • methods of preventing or reducing pathological Tau seeding and/or spreading comprise administering to the subject a bispecific antibody that specifically binds to a Tau protein and that specifically binds to a BACEl protein as described herein or a pharmaceutical composition comprising the bispecific antibody.
  • the subject has a neurodegenerative disease such as a tauopathy (e.g., a neurodegenerative tauopathy).
  • methods of reducing or inhibiting production of amyloid-beta peptides in a brain of a subject are provided.
  • the method comprises administering to the subject a bispecific antibody that specifically binds to a Tau protein and that specifically binds to a BACEl protein as described herein, a humanized antibody that specifically binds to a human BACEl protein as described herein, or a pharmaceutical composition comprising the bispecific antibody or humanized antibody.
  • the subject has a neurodegenerative disease such as a tauopathy (e.g., a neurodegenerative tauopathy).
  • the method comprises administering to a subject having a neurodegenerative disease a bispecific antibody that specifically binds to a Tau protein and that specifically binds to a BACEl protein as described herein, a humanized antibody that specifically binds to a human BACEl protein as described herein, or a pharmaceutical composition comprising the bispecific antibody or humanized antibody.
  • the neurodegenerative disease is a tauopathy (e.g., a neurodegenerative tauopathy).
  • the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, primary age-related tauopathy, progressive supranuclear palsy (PSP), frontotemporal dementia, frontotemporal dementia with parkinsonism linked to chromosome 17, argyrophilic grain dementia, amyotrophic lateral sclerosis/parkinsonism- dementia complex of Guam, corticobasal degeneration, chronic traumatic encephalopathy, Creutzf el dt- Jakob disease, dementia pugilistica, diffuse neurofibrillary tangles with calcification, Down's syndrome, familial British dementia, familial Danish dementia, Gerstmann-Straussler-Scheinker disease, globular glial tauopathy, Guadeloupean parkinsonism with dementia, Guadelopean PSP, Hallevorden-Spatz disease, Huntington' s disease, inclusion-body myositis, multiple system atrophy, myotonic dystrophy, neurofibrill
  • a bispecific antibody that specifically binds to a Tau protein and that specifically binds to a BACEl protein as described herein, or a humanized antibody that specifically binds to a human BACEl protein as described herein, or a pharmaceutical composition comprising the bispecific antibody or humanized antibody, in the manufacture of a medicament for the reduction or inhibition of production of amyloid- beta peptides is provided.
  • a bispecific antibody that specifically binds to a Tau protein and that specifically binds to a BACEl protein as described herein, or a pharmaceutical composition comprising the bispecific antibody, in the manufacture of a medicament for the prevention, reduction, or inhibition of Tau aggregation is provided.
  • a bispecific antibody that specifically binds to a Tau protein and that specifically binds to a BACEl protein as described herein, or a pharmaceutical composition comprising the bispecific antibody, in the manufacture of a medicament for the prevention or reduction of pathological Tau seeding and/or spreading is provided.
  • a bispecific antibody that specifically binds to a Tau protein and that specifically binds to a BACEl protein as described herein, or a humanized antibody that specifically binds to a human BACEl protein as described herein, or a pharmaceutical composition comprising the bispecific antibody or humanized antibody, in the manufacture of a medicament for the treatment of a neurodegenerative disease as described herein is provided.
  • FIG. 1A-1C SPR analysis of 1A11/1C7/3C.35.21 binding. Representative sensorgrams of the 1A11/1C7/3C.35.21 binding to (A) human BACEl (2.9 nM), (B) human Tau (0.79 nM) and (C) human TfR apical domain (82 nM).
  • FIG. 2. 1A11/1C7/3C.35.21 is capable of binding to three antigens simultaneously. Biotin-BACEl is first bound to the Octet streptavidin sensor, and the sensor tips were then dipped into 1A11/1C7/3C.35.21, Tau and TfR solution sequentially. Representative sensorgrams show that 1A11/1C7/3C.35.21 binds to BACEl, Tau and TfR (A), BACEl and TfR (B), BACEl and Tau (C). No interaction is observed between BACEl and Tau or BACEl and TfR in the absence of 1A11/1C7/3C.35.21 (D) and neither Tau or TfR bind to sensor tips non-specifically (E).
  • Tau biosensor FRET cells demonstrated that Tau aggregation is seeded by incubation with human AD brain lysate, but not control lysate. This seeding was blocked by the addition of all anti-Tau antibodies: bivalent 1C7 (Tau 1C7 /Tau 1C7 ), monovalent 1C7 (Tau 1C7 BACEl Ab153 ) and 1A11/1C7/3C.35.21.
  • the Tau seeding was unaffected by the addition of either negative control (Neg Ctrl Abm ) or BACEl bivalent (BACEl 1A11 /BACE1 1AU ) antibodies.
  • FIG. 4 Extracellular Tau increases neuronal uptake of 1A11/1C7/3C.35.21 into human neurons. Presence of recombinant Tau-GFP (black) resulted increased neuronal uptake of antibodies (hulgGI) that bind Tau. No change in cellular uptake of antibodies that do not bind Tau was observed. [0077] FIG. 5A-5B. 1A11/1C7/3C.35.21 is not toxic and is capable of blocking ⁇ , ⁇ production in human neurons. (A) At the same concentration of antibody (33 nM), both the bivalent BACEl 1A11 BACE1 1A11 and the monovalent 1A11/1C7/3C.35.21 inhibited ⁇ 4 ⁇ production to a similar degree. Inhibition of BACEl was not affected by the addition of additional recombinant Tau-GFP (black bars). (B) None of the antibodies or Tau-GFP treatments were toxic to neurons as measured by LDH release into the media.
  • FIG. 6A-6B Sequence alignment of clone hulAll-12 with chimeric antibody 1A11.
  • A Alignment of murine 1A11 heavy chain sequence (SEQ ID NO:66) and hulAl lvl2 heavy chain sequence (SEQ ID NO:80).
  • B Alignment of murine 1A11 light chain sequence comprising SEQ ID NO:67 and hulAl lvl2 light chain sequence comprising SEQ ID NO: 86. Kabat numbers and CDR regions for the antibodies are indicated.
  • FIG. 7 Cell-based assay for chimeric 1A11 and humanized 1A11 antibodies.
  • FIG. 8A-8B Bivalent and monovalent anti-BACEl 2H8 reduces ⁇ in a cell- based assay.
  • FIG. 9A-9D Brain and plasma PK/PD in PS19/TfR ms/hu KI mice.
  • A-B Plasma (A) and brain (B) hulgGI concentrations in PS 19/TfR ms/hu KI mice at various time points following a single 50 mg/kg intravenous injection of control IgG, Clone35.23.4:2H8/2H8, or Clone35.23.4:Control IgG (anti-RSV)/2H8 antibody.
  • bispecific antibodies and antigen-binding fragments having the ability to specifically bind to both Tau protein and beta-secretase 1 (BACE1) protein are provided.
  • the bispecific antibody or antigen-binding fragment specifically binds to unphosphorylated Tau, phosphorylated Tau, oligomeric Tau, intracellular Tau, and/or extracellular Tau, and further binds to the ectodomain of BACE1.
  • the bispecific antibody or antigen-binding fragment prevents or reduces Tau seeding, Tau oligomerization, and/or Tau aggregation, and further inhibits the production of an amyloid- ⁇ ( ⁇ ) peptide and/or prevents or reduces the formation of amyloid plaques.
  • the bispecific antibody or antigen-binding fragment comprises a modified Fc polypeptide that specifically binds to a blood-brain barrier (BBB) receptor, e.g., a transferrin receptor.
  • BBB blood-brain barrier
  • the bispecific antibody or antigen-binding fragment is capable of being transported across the BBB.
  • the bispecific antibody or antigen-binding fragment comprises a first antigen-binding portion that specifically binds to a Tau protein and a second antigen-binding portion that specifically binds to a BACEl protein. In some embodiments, the bispecific antibody or antigen-binding fragment comprises a first antigen-binding portion that specifically binds to a BACEl protein and a second antigen-binding portion that specifically binds to a Tau protein.
  • the first antigen-binding portion is defined as being an antigen-binding portion that specifically binds to a Tau protein and the second antigen-binding portion is defined as being an antigen-binding portion that specifically binds to a BACEl protein
  • the converse is also possible ⁇ i.e., the first antigen-binding portion can be an antigen-binding portion that specifically binds to a BACEl protein and the second antigen-binding portion can an antigen-binding portion that specifically binds to a Tau protein).
  • a first antigen-binding portion comprises a first Fc polypeptide comprising a knob mutation and a second antigen- binding portion comprises a second Fc polypeptide comprising a hole mutation
  • the first antigen-binding portion can be an antigen-binding portion that specifically binds to a Tau protein and the second antigen-binding portion can be an antigen- binding portion that specifically binds to a BACEl protein (i.e., the antigen-binding portion that specifically binds to Tau comprises an Fc polypeptide comprising a knob mutation and the antigen-binding portion that specifically binds to BACEl comprises an Fc polypeptide comprising a hole mutation), or that the first antigen-binding portion can be an antigen- binding portion that specifically binds to a BACEl protein and the second antigen-binding portion can be an antigen-binding portion that specifically binds to a Tau protein (i.e., the antigen-binding portion
  • humanized antibodies of antigen-binding fragments thereof having the ability to specifically bind to human BACEl protein are provided.
  • the humanized anti-BACEl antibody or antigen-binding fragment binds to the ectodomain of BACEl .
  • the humanized anti-BACEl antibody or antigen-binding fragment inhibits BACEl activity.
  • the humanized anti-BACEl antibody or antigen-binding fragment inhibits the production of an amyloid- ⁇ ( ⁇ ) peptide and/or prevents or reduces the formation of amyloid plaques.
  • the terms "about” and “approximately,” when used to modify an amount specified in a numeric value or range indicate that the numeric value as well as reasonable deviations from the value known to the skilled person in the art, for example ⁇ 20%, ⁇ 10%, or ⁇ 5%, are within the intended meaning of the recited value.
  • Tau protein refers to a native (i.e., wild-type) Tau protein of any vertebrate, such as but not limited to human, non-human primates (e.g., cynomolgus monkey), rodents (e.g., mice), and other mammals.
  • non-human primates e.g., cynomolgus monkey
  • rodents e.g., mice
  • the sequence of human Tau is available under UniProt entry PI 0636.
  • Tau protein encompasses a full-length Tau protein having a length of 441 amino acids (SEQ ID NO: l) as well as other naturally occurring isoforms of Tau.
  • an anti-Tau antibody refers to an antibody that specifically binds to a Tau protein (e.g., unphosphorylated Tau, phosphorylated Tau, total Tau (phosphorylated and unphosphorylated Tau), or a Tau splice isoform).
  • a Tau protein e.g., unphosphorylated Tau, phosphorylated Tau, total Tau (phosphorylated and unphosphorylated Tau), or a Tau splice isoform.
  • an anti-Tau antibody is an antibody that specifically binds to multiple forms of Tau protein (e.g., multiple Tau splice isoforms, unphosphorylated Tau, and/or phosphorylated Tau).
  • an anti-Tau antibody is an antibody that specifically binds to all six human Tau splice isoforms and to unphosphorylated Tau.
  • BACE1 protein refers to beta-secretase 1 (EC 3.4.23.46), which is an enzyme involved in proteolytic processing of the amyloid precursor protein.
  • BACEl as used herein refers to a BACEl protein of any vertebrate, such as but not limited to human, non-human primates (e.g., cynomolgus monkey), rodents (e.g., mice), and other mammals. The sequence of human BACEl is available under UniProt entry P56817.
  • Isoform A (BACE-1A), having a length of 501 amino acids
  • Isoform B (BACE-1B), having a length of 476 amino acids
  • Isoform C (BACE-1C), having a length of 457 amino acids
  • Isoform D (BACE-1D) having a length of 432 amino acids
  • Isoform 5, having a length of 401 amino acids
  • Isoform 6, having a length of 376 amino acids.
  • BACEl protein encompasses a full-length BACEl protein having a length of 501 amino acids (SEQ ID NO:64) and other isoforms of BACEl, as well as proprotein forms of BACEl proteins (e.g., SEQ ID NO:272) and mature forms of BACEl proteins (e.g., SEQ ID NO:65).
  • an anti-BACEl antibody refers to an antibody that specifically binds to a BACEl protein (e.g., human BACEl).
  • an anti- BACEl antibody is an antibody that specifically binds to multiple forms of BACEl protein (e.g., multiple BACEl splice isoforms).
  • an anti-BACEl antibody is an antibody that specifically binds to a mature form of BACEl that lacks a signal peptide sequence and that has been proteolytically processed from a proprotein (e.g., SEQ ID NO:65) and/or that specifically binds to a proprotein form of BACEl (e.g., SEQ ID NO:272).
  • the term “antibody” refers to a protein with an immunoglobulin fold that specifically binds to an antigen via its variable regions.
  • the term encompasses intact polyclonal antibodies, intact monoclonal antibodies, single chain antibodies, multispecific antibodies such as bispecific antibodies, monospecific antibodies, monovalent antibodies, chimeric antibodies, humanized antibodies, and human antibodies.
  • the term "antibody,” as used herein, also includes antibody fragments that retain binding specificity via its variable regions, including but not limited to Fab, F(ab') 2 , Fv, scFv, and bivalent scFv.
  • Antibodies can contain light chains that are classified as either kappa or lambda.
  • Antibodies can contain heavy chains that are classified as gamma, mu, alpha, delta, or epsilon, which in turn define the immunoglobulin classes, IgG, IgM, IgA, IgD and IgE, respectively.
  • An exemplary immunoglobulin (antibody) structural unit comprises a tetramer. Each tetramer is composed of two identical pairs of polypeptide chains, each pair having one "light” (about 25 kD) and one "heavy” chain (about 50-70 kD). The N-terminus of each chain defines a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition.
  • the terms “variable light chain” (VL) and “variable heavy chain” (VH) refer to these light and heavy chains, respectively.
  • variable region refers to a domain in an antibody heavy chain or light chain that is derived from a germline Variable (V) gene, Diversity (D) gene, or Joining (J) gene (and not derived from a Constant ( ⁇ and C6) gene segment), and that gives an antibody its specificity for binding to an antigen.
  • V germline Variable
  • D Diversity
  • J Joining
  • an antibody variable region comprises four conserved “framework” regions interspersed with three hypervariable “complementarity determining regions.”
  • CDR complementarity determining region
  • the CDRs are primarily responsible for antibody binding to an epitope of an antigen.
  • the CDRs of each chain are typically referred to as CDRl, CDR2, and CDR3, numbered sequentially starting from the N-terminus, and are also typically identified by the chain in which the particular CDR is located.
  • VH CDR3 or CDR-H3 is located in the variable region of the heavy chain of the antibody in which it is found, whereas a VL CDRl or CDR-Ll is the CDRl from the variable region of the light chain of the antibody in which it is found.
  • framework regions or "FRs" of different light or heavy chains are relatively conserved within a species.
  • the framework region of an antibody that is the combined framework regions of the constituent light and heavy chains, serves to position and align the CDRs in three-dimensional space.
  • Framework sequences can be obtained from public DNA databases or published references that include germline antibody gene sequences. For example, germline DNA sequences for human heavy and light chain variable region genes can be found in the "VBASE2" germline variable gene sequence database for human and mouse sequences.
  • CDRs and framework regions can be determined using various well known definitions in the art, e.g., Kabat, Chothia, international ImMunoGeneTics database (EVIGT), AbM, and observed antigen contacts ("Contact”).
  • CDRs are determined according to the Contact definition. See, MacCallum et al, J. Mol. Biol, 262:132-1 AS (1996).
  • CDRs are determined by a combination of Kabat, Chothia, and/or Contact CDR definitions.
  • antigen-binding portion and “antigen-binding fragment” are used interchangeably herein and refer to one or more fragments of an antibody that retains the ability to specifically bind to an antigen ⁇ e.g., a Tau protein or a BACEl protein) via its variable region.
  • antigen e.g., a Tau protein or a BACEl protein
  • antigen-binding fragments include, but are not limited to, a Fab fragment (a monovalent fragment consisting of the VL, VH, CL and CHI domains), F(ab')2 fragment (a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region), single chain Fv (scFv), disulfide-linked Fv (dsFv), complementarity determining regions (CDRs), a VL (light chain variable region), and a VH (heavy chain variable region).
  • a Fab fragment a monovalent fragment consisting of the VL, VH, CL and CHI domains
  • F(ab')2 fragment a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region
  • scFv single chain Fv
  • dsFv disulfide-linked Fv
  • CDRs complementarity determining regions
  • VL light chain variable region
  • VH heavy chain variable region
  • epitope refers to the area or region of an antigen to which the CDRs of an antibody specifically bind and can include a few amino acids or portions of a few amino acids, e.g. , S or 6, or more, e.g., 20 or more amino acids, or portions of those amino acids.
  • the epitope can be comprised of consecutive amino acids (e.g. , a linear epitope), or amino acids from different parts of the protein that are brought into proximity by protein folding (e.g. , a discontinuous or conformational epitope).
  • an antibody specifically binds to two distinct regions of an antigen (e.g., a Tau protein or a BACEl protein) that are not brought into proximity by protein folding, referred to herein as a "dual epitope.”
  • the phrase "recognizes an epitope,” as used with reference to an antibody, means that the antibody CDRs interact with or specifically bind to the antigen (e.g., the Tau protein or BACEl protein) at that epitope or a portion of the antigen containing that epitope.
  • the antigen e.g., the Tau protein or BACEl protein
  • multispecific antibody refers to an antibody that comprises two or more different antigen-binding portions, in which each antigen-binding portion comprises a different variable region that recognizes a different antigen, or a fragment or portion of the antibody that binds to the two or more different antigens via its variable regions.
  • bispecific antibody refers to an antibody that comprises two different antigen-binding portions, in which each antigen-binding portion comprises a different variable region that recognizes a different antigen, or a fragment or portion of the antibody that binds to the two different antigens via its variable regions.
  • a bispecific antibody comprises a first antigen-binding portion comprising a first variable region that recognizes a Tau protein and a second antigen-binding portion comprising a second variable region that recognizes a BACE1 protein. In some embodiments, a bispecific antibody comprises a first antigen-binding portion comprising a first variable region that recognizes a BACE1 protein and a second antigen-binding portion comprising a second variable region that recognizes a Tau protein.
  • a "monoclonal antibody” refers to antibodies produced by a single clone of cells or a single cell line and consisting of or consisting essentially of antibody molecules that are identical in their primary amino acid sequence.
  • a "polyclonal antibody” refers to an antibody obtained from a heterogeneous population of antibodies in which different antibodies in the population bind to different epitopes of an antigen.
  • a "chimeric antibody” refers to an antibody molecule in which the constant region, or a portion thereof, is altered, replaced or exchanged so that the antigen binding site (i.e., variable region, CDR, or portion thereof) is linked to a constant region of a different or altered class, effector function and/or species, or in which the variable region, or a portion thereof, is altered, replaced or exchanged with a variable region having a different or altered antigen specificity (e.g., CDR and framework regions from different species).
  • a chimeric antibody is a monoclonal antibody comprising a variable region from one source or species (e.g., mouse) and a constant region derived from a second source or species (e.g., human). Methods for producing chimeric antibodies are described in the art.
  • a “humanized antibody” is a chimeric immunoglobulin derived from a non-human source (e.g., murine) that contains minimal sequences derived from the non-human immunoglobulin outside the CDRs.
  • a humanized antibody will comprise at least one (e.g., two) antigen-binding variable domain(s), in which the CDR regions substantially correspond to those of the non-human immunoglobulin and the framework regions substantially correspond to those of a human immunoglobulin sequence.
  • certain framework region residues of a human immunoglobulin can be replaced with the corresponding residues from a non-human species to, e.g., improve specificity, affinity, and/or serum stability or serum half-life.
  • the humanized antibody can also comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin sequence.
  • a “human antibody” or a “fully human antibody” is an antibody having human heavy chain and light chain sequences, typically derived from human germline genes.
  • the antibody is produced by a human cell, by a non-human animal that utilizes human antibody repertoires (e.g., transgenic mice that are genetically engineered to express human antibody sequences), or by phage display platforms.
  • the term "specifically binds" refers to a molecule (e.g., an antibody (or an antigen- binding portion thereof) or a modified Fc polypeptide (or a target-binding portion thereof) that binds to an epitope or target with greater affinity, greater avidity, and/or greater duration to that epitope or target in a sample than it binds to another epitope or non-target compound (e.g., a structurally different antigen).
  • a molecule e.g., an antibody (or an antigen- binding portion thereof) or a modified Fc polypeptide (or a target-binding portion thereof) that binds to an epitope or target with greater affinity, greater avidity, and/or greater duration to that epitope or target in a sample than it binds to another epitope or non-target compound (e.g., a structurally different antigen).
  • an antibody (or antigen-binding portion thereof) or a modified Fc polypeptide (or a target-binding portion thereof) that specifically binds to an epitope or target is an antibody (or antigen-binding portion) or a modified Fc polypeptide (or a target-binding portion thereof) that binds to the epitope or target with at least 5-fold greater affinity than other epitopes or non-target compounds, e.g., at least 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 25-fold, 50-fold, 100-fold, 1000-fold, 10,000-fold, or greater affinity.
  • telomere binding can be exhibited, for example, by a molecule having an equilibrium dissociation constant KD for the epitope or target to which it binds of, e.g., 10 "4 M or smaller, e.g., 10 "5 M, 10 "6 M, 10 “7 M, 10 “8 M, 10 "9 M, 10 "10 M, 10 "u M, or 10 "12 M.
  • binding affinity is used herein to refer to the strength of a non-covalent interaction between two molecules, e.g., between an antibody (or an antigen-binding portion thereof) and an antigen, or between a modified Fc polypeptide (or a target-binding portion thereof) and a target.
  • Binding affinity may be quantified by measuring an equilibrium dissociation constant (KD), which refers to the dissociation rate constant (kd, time "1 ) divided by the association rate constant (k a , time "1 M "1 ).
  • KD equilibrium dissociation constant
  • KD can be determined by measurement of the kinetics of complex formation and dissociation, e.g., using Surface Plasmon Resonance (SPR) methods, e.g., a BiacoreTM system; kinetic exclusion assays such as KinExA ® ; and BioLayer interferometry (e.g., using the ForteBio ® Octet platform).
  • SPR Surface Plasmon Resonance
  • Binding affinity includes not only formal binding affinities, such as those reflecting 1 : 1 interactions between an antibody (or an antigen-binding portion thereof) and an antigen or between a modified Fc polypeptide (or a target-binding portion thereof) and a target, but also apparent affinities for which KD' S are calculated that may reflect avid binding.
  • the human transferrin receptor 1 polypeptide sequence is set forth in SEQ ID NO:330. Transferrin receptor protein 1 sequences from other species are also known (e.g., chimpanzee, accession number XP_003310238.1 ; rhesus monkey, NP_001244232.1 ; dog, NP_001003111.1; cattle, NP_001 193506.1 ; mouse, NP_035768.1; rat, NP_073203.1; and chicken, NP_990587.1).
  • transferrin receptor also encompasses allelic variants of exemplary reference sequences, e.g., human sequences, that are encoded by a gene at a transferrin receptor protein 1 chromosomal locus.
  • Full-length transferrin receptor protein includes a short N-terminal intracellular region, a transmembrane region, and a large extracellular domain. The extracellular domain is characterized by three domains: a protease- like domain, a helical domain, and an apical domain.
  • Fc polypeptide refers to the C-terminal region of a naturally occurring immunoglobulin heavy chain polypeptide that is characterized by an Ig fold as a structural domain.
  • An Fc polypeptide contains constant region sequences including at least the CFI2 domain and/or the CH3 domain and may contain at least part of the hinge region. In general, an Fc polypeptide does not contain a variable region.
  • a "modified Fc polypeptide” refers to an Fc polypeptide that has at least one mutation, e.g., a substitution, deletion or insertion, as compared to a wild-type immunoglobulin heavy chain Fc polypeptide sequence, but retains the overall Ig fold or structure of the native Fc polypeptide.
  • FcRn refers to the neonatal Fc receptor. Binding of Fc polypeptides to FcRn reduces clearance and increases serum stability or serum half-life of the Fc polypeptide.
  • the human FcRn protein is a heterodimer that is composed of a protein of about 50 kDa in size that is similar to a major histocompatibility (MHC) class I protein and a of about 15 kDa in size.
  • MHC major histocompatibility
  • an "FcRn binding site” refers to the region of an Fc polypeptide that binds to FcRn.
  • the FcRn binding site as numbered using the EU index, includes T250, L251, M252, 1253, S254, R255, T256, T307, E380, M428, H433, N434, H435, and Y436. These positions correspond to positions 20 to 26, 77, 150, 198, and 203 to 206 of SEQ ID O:273.
  • a "native FcRn binding site” refers to a region of an Fc polypeptide that binds to FcRn and that has the same amino acid sequence as the region of a naturally occurring Fc polypeptide that binds to FcRn.
  • CH3 domain and CH2 domain refer to immunoglobulin constant region domain polypeptides.
  • a CH3 domain polypeptide refers to the segment of amino acids from about position 341 to about position 447 as numbered according to the EU numbering scheme
  • a CH2 domain polypeptide refers to the segment of amino acids from about position 231 to about position 340 as numbered according to the EU numbering scheme and does not include hinge region sequences.
  • CH2 and CH3 domain polypeptides may also be numbered by the EVIGT (ImMunoGeneTics) numbering scheme in which the CH2 domain numbering is 1-1 10 and the CH3 domain numbering is 1-107, according to the IMGT Scientific chart numbering (EVIGT website).
  • CH2 and CH3 domains are part of the Fc region of an immunoglobulin.
  • An Fc region refers to the segment of amino acids from about position 231 to about position 447 as numbered according to the EU numbering scheme, but as used herein, can include at least a part of a hinge region of an antibody.
  • An illustrative hinge region sequence is the human IgGl hinge sequence EPKSCDKTHTCPPCP (SEQ ID NO:379).
  • mutant polypeptide or mutant polynucleotide is used interchangeably with “variant.”
  • a variant with respect to a given wild-type CH3 or CH2 domain reference sequence can include naturally occurring allelic variants.
  • non-naturally occurring CH3 or CH2 domain refers to a variant or mutant domain that is not present in a cell in nature and that is produced by genetic modification, e.g., using genetic engineering technology or mutagenesis techniques, of a native CH3 domain or CH2 domain polynucleotide or polypeptide.
  • variant includes any domain comprising at least one amino acid mutation with respect to wild-type. Mutations may include substitutions, insertions, and deletions.
  • cross-reacts refers to the ability of an antibody to bind to an antigen other than the antigen against which the antibody was raised.
  • cross-reactivity refers to the ability of an antibody to bind to an antigen from another species than the antigen against which the antibody was raised.
  • an anti-Tau antigen-binding portion as described herein that is raised against a human Tau protein can exhibit cross-reactivity with a Tau protein from a different species (e.g., mouse or monkey).
  • an anti-BACEl antigen-binding portion as described herein that is raised against a human BACE1 protein can exhibit cross- reactivity with a BACE1 protein from a different species ⁇ e.g., mouse or monkey).
  • nucleic acid or protein denotes that the nucleic acid or protein is essentially free of other cellular components with which it is associated in the natural state. Purity and homogeneity are typically determined using analytical chemistry techniques such as electrophoresis (e.g., polyacrylamide gel electrophoresis) or chromatography (e.g., high performance liquid chromatography). In some embodiments, an isolated nucleic acid or protein (e.g., antibody) is at least 85% pure, at least 90% pure, at least 95% pure, or at least 99% pure.
  • amino acid refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids. Naturally occurring are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, ⁇ -carboxyglutamate and O-phosphoserine.
  • Naturally occurring a-amino acids include, without limitation, alanine (Ala), cysteine (Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (He), arginine (Arg), lysine (Lys), leucine (Leu), methionine (Met), asparagine (Asn), proline (Pro), glutamine (Gin), serine (Ser), threonine (Thr), valine (Val), tryptophan (Trp), tyrosine (Tyr), and combinations thereof.
  • Stereoisomers of a naturally occurring a-amino acids include, without limitation, D-alanine (D-Ala), D-cysteine (D-Cys), D-aspartic acid (D-Asp), D-glutamic acid (D-Glu), D-phenylalanine (D-Phe), D- histidine (D-His), D-isoleucine (D-Ile), D-arginine (D-Arg), D-lysine (D-Lys), D-leucine (D- Leu), D-methionine (D-Met), D-asparagine (D-Asn), D-proline (D-Pro), D-glutamine (D- Gin), D-serine (D-Ser), D-threonine (D-Thr), D-valine (D-Val), D-tryptophan (D- ⁇ ), D- tyrosine (D-Tyr), and combinations thereof.
  • D-Ala D-alanine
  • amino acid analogs refers to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., an a carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs have modified R groups ⁇ e.g. , norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid.
  • Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-KJB Biochemical Nomenclature Commission.
  • polypeptide and “peptide” are used interchangeably herein to refer to a polymer of amino acid residues in a single chain.
  • the terms apply to amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymers.
  • Amino acid polymers may comprise entirely L-amino acids, entirely D-amino acids, or a mixture of L and D amino acids.
  • protein refers to either a polypeptide or a dimer (i.e, two) or multimer (i.e., three or more) of single chain polypeptides.
  • the single chain polypeptides of a protein may be joined by a covalent bond, e.g., a disulfide bond, or non-covalent interactions.
  • polynucleotide and “nucleic acid” interchangeably refer to chains of nucleotides of any length, and include DNA and RNA.
  • the nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and/or their analogs, or any substrate that can be incorporated into a chain by DNA or RNA polymerase.
  • a polynucleotide may comprise modified nucleotides, such as methylated nucleotides and their analogs. Examples of polynucleotides contemplated herein include single- and double- stranded DNA, single- and double-stranded RNA, and hybrid molecules having mixtures of single- and double-stranded DNA and RNA.
  • conservative amino acid groups refer to an alteration that results in the substitution of an amino acid with another amino acid that can be categorized as having a similar feature.
  • categories of conservative amino acid groups defined in this manner can include: a "charged/polar group” including Glu (Glutamic acid or E), Asp (Aspartic acid or D), Asn (Asparagine or N), Gin (Glutamine or Q), Lys (Lysine or K), Arg (Arginine or R), and His (Histidine or H); an "aromatic group” including Phe (Phenylalanine or F), Tyr (Tyrosine or Y), Tip (Tryptophan or W), and (Histidine or H); and an "aliphatic group” including Gly (Glycine or G), Ala (Alanine or A), Val (Valine or V), Leu (Leucine or L), He (Isoleucine or I), Met (Methionine or M), Ser
  • subgroups can also be identified.
  • the group of charged or polar amino acids can be sub-divided into sub-groups including: a "positively-charged sub-group” comprising Lys, Arg and His; a "negatively-charged sub-group” comprising Glu and Asp; and a "polar sub-group” comprising Asn and Gin.
  • the aromatic or cyclic group can be subdivided into sub-groups including: a "nitrogen ring sub-group” comprising Pro, His and Trp; and a "phenyl sub-group” comprising Phe and Tyr.
  • the aliphatic group can be sub-divided into sub-groups, e.g., an "aliphatic non-polar sub-group” comprising Val, Leu, Gly, and Ala; and an "aliphatic slightly-polar sub-group” comprising Met, Ser, Thr, and Cys.
  • Examples of categories of conservative mutations include amino acid substitutions of amino acids within the sub-groups above, such as, but not limited to: Lys for Arg or vice versa, such that a positive charge can be maintained; Glu for Asp or vice versa, such that a negative charge can be maintained; Ser for Thr or vice versa, such that a free -OH can be maintained; and Gin for Asn or vice versa, such that a free -NH2 can be maintained.
  • hydrophobic amino acids are substituted for naturally occurring hydrophobic amino acid, e.g., in the active site, to preserve hydrophobicity.
  • nucleic or percent “identity,” in the context of two or more polypeptide sequences, refer to two or more sequences or subsequences that are the same or have a specified percentage of amino acid residues, e.g., at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% or greater, that are identical over a specified region when compared and aligned for maximum correspondence over a comparison window or designated region as measured using a sequence comparison algorithm or by manual alignment and visual inspection.
  • sequence comparison of polypeptides typically one amino acid sequence acts as a reference sequence, to which a candidate sequence is compared. Alignment can be performed using various methods available to one of skill in the art, e.g., visual alignment or using publicly available software using known algorithms to achieve maximal alignment. Such programs include the BLAST programs, ALIGN, ALIGN-2 (Genentech, South San Francisco, Calif.) or Megalign (DNASTAR). The parameters employed for an alignment to achieve maximal alignment can be determined by one of skill in the art. For sequence comparison of polypeptide sequences for purposes of this application, the BLASTP algorithm standard protein BLAST for aligning two proteins sequence with the default parameters is used.
  • the terms “corresponding to,” “determined with reference to,” or “numbered with reference to” when used in the context of the identification of a given amino acid residue in a polypeptide sequence refers to the position of the residue of a specified reference sequence when the given amino acid sequence is maximally aligned and compared to the reference sequence.
  • an amino acid residue in a modified Fc polypeptide "corresponds to” an amino acid in SEQ ID NO:273, when the residue aligns with the amino acid in SEQ ID NO:273 when optimally aligned to SEQ ID NO:273.
  • the polypeptide that is aligned to the reference sequence need not be the same length as the reference sequence.
  • the terms "subject,” “individual,” and “patient,” as used interchangeably herein, refer to a mammal, including but not limited to humans, non-human primates, rodents (e.g., rats, mice, and guinea pigs), rabbits, cows, pigs, horses, and other mammalian species. In one embodiment, the patient is a human.
  • rodents e.g., rats, mice, and guinea pigs
  • rabbits cows, pigs, horses, and other mammalian species.
  • the patient is a human.
  • treatment treating
  • Treating” or “treatment” may refer to any indicia of success in the treatment or amelioration of a neurodegenerative disease ⁇ e.g., Alzheimer's disease or another neurodegenerative disease described herein), including any objective or subjective parameter such as abatement, remission, improvement in patient survival, increase in survival time or rate, diminishing of symptoms or making the disease more tolerable to the patient, slowing in the rate of degeneration or decline, or improving a patient's physical or mental well-being.
  • the treatment or amelioration of symptoms can be based on objective or subjective parameters.
  • the effect of treatment can be compared to an individual or pool of individuals not receiving the treatment, or to the same patient prior to treatment or at a different time during treatment.
  • pharmaceutically acceptable excipient refers to a non-active pharmaceutical ingredient that is biologically or pharmacologically compatible for use in humans or animals, such as, but not limited to a buffer, carrier, or preservative.
  • a “therapeutic amount” or “therapeutically effective amount” of an agent is an amount of the agent that treats, alleviates, abates, or reduces the severity of symptoms of a disease in a subject.
  • a “therapeutic amount” of an agent may improve patient survival, increase survival time or rate, diminish symptoms, make an injury, disease, or condition (e.g., a neurodegenerative disease) more tolerable, slow the rate of degeneration or decline, or improve a patient's physical or mental well-being.
  • administer refers to a method of delivering agents, compounds, or compositions to the desired site of biological action. These methods include, but are not limited to, topical delivery, parenteral delivery, intravenous delivery, intradermal delivery, intramuscular delivery, intrathecal delivery, colonic delivery, rectal delivery, or intraperitoneal delivery. In one embodiment, an antibody as described herein is administered intravenously.
  • bispecifrc antibodies having the ability to specifically bind to both Tau protein and BACE1 protein are provided.
  • the bispecifrc antibody comprises a first antigen-binding portion that specifically binds to a Tau protein (e.g., a human Tau protein); and a second antigen-binding portion that specifically binds to a BACE1 protein (e.g., a human BACE1 protein).
  • the first antigen-binding portion comprises a first variable region that specifically binds to a Tau protein.
  • the second antigen-binding portion comprises a second variable region that specifically binds to a BACE1 protein.
  • the first antigen-binding portion comprises a first heavy chain comprising a first Fc polypeptide and a first light chain.
  • the second antigen-binding portion comprises a second heavy chain comprising a second Fc polypeptide and a second light chain.
  • the bispecifrc antibody further comprises one or more modified Fc polypeptides.
  • the modified Fc polypeptide specifically binds to a blood-brain barrier (BBB) receptor, e.g., a transferrin receptor (TfR).
  • BBB blood-brain barrier
  • TfR transferrin receptor
  • the modified Fc polypeptide specifically binds to a transferrin receptor.
  • the bispecific antibody comprising the modified Fc polypeptide is capable of being transported across the BBB.
  • bispecific antibodies comprising: a first antigen-binding portion comprising a first variable region that specifically binds to a Tau protein, wherein the first antigen-binding portion comprises (i) a first heavy chain comprising a first Fc polypeptide and (ii) a first light chain; and
  • a second antigen-binding portion comprising a second variable region that specifically binds to a BACEl protein, wherein the second antigen-binding portion comprises (i) a second heavy chain comprising a second Fc polypeptide and (ii) a second light chain;
  • first Fc polypeptide and/or the second Fc polypeptide is a modified Fc polypeptide; and wherein the first heavy chain and the second heavy chain form an Fc dimer.
  • the first Fc polypeptide is a modified Fc polypeptide.
  • the second Fc polypeptide is a modified Fc polypeptide.
  • each of the first Fc polypeptide and the second Fc polypeptide is a modified Fc polypeptide.
  • a bispecific antibody that specifically binds to Tau protein e.g., human Tau
  • BACEl protein e.g., human BACEl
  • each antigen i.e., each of the Tau protein and the BACEl protein
  • the term "comparable affinity” means that the bispecific antibody has a binding affinity for an antigen (e.g., human Tau) that is within about a three-fold difference of the binding affinity of the monovalent antibody against the antigen, e.g., less than 3-fold, less than 2-fold, or less than 1.5-fold difference in binding affinity of the monovalent antibody against the antigen (e.g., a monovalent antibody against human Tau).
  • the binding affinity is measured by Biacore.
  • the binding affinity is measured using an ELISA assay.
  • the binding affinity is measured using a cell-based binding assay.
  • a bispecific antibody comprising a first antigen-binding portion comprising a first variable region that specifically binds to Tau protein (e.g., a first antigen-binding portion comprising the CDR, heavy chain, and/or light chain sequences of an anti-Tau 1C7 antibody as disclosed herein) and a second antigen- binding portion comprising a second variable region that specifically binds to BACEl protein (e.g., a second antigen-binding portion comprising the CDR, heavy chain, and/or light chain sequences of an anti-BACEl 1A11 antibody as disclosed herein) binds to the Tau protein with comparable affinity as a monovalent anti-Tau (e.g., 1C7) antibody antibody and binds to the BACE1 protein with comparable affinity as a monovalent anti-BACEl (e.g., 1A11) antibody.
  • the bispecific antibodies disclosed herein comprise a first antigen-binding portion comprising a first variable region that specifically binds to a Tau protein (e.g., a human Tau protein).
  • the first antigen-binding portion comprises a first variable region that specifically binds to one or more splice isoforms of human Tau protein (i.e., one or more of the splice isoforms 2N4R, 2N3R, 1N4R, 1N3R, 0N4R, and 0N3R).
  • the first antigen-binding portion comprises a first variable region that specifically binds to two or more splice isoforms of human Tau protein, e.g., to two, three, four, five, or all six of 2N4R, 2N3R, 1N4R, 1N3R, 0N4R, and 0N3R.
  • the first antigen-binding portion comprises a first variable region that specifically binds to unphosphorylated Tau and/or phosphorylated Tau, e.g., to an unphosphorylated form and/or a phosphorylated form of one, two, three, four, five, or all six of the splice isoforms 2N4R, 2N3R, 1N4R, 1N3R, 0N4R, and 0N3R.
  • the first antigen-binding portion comprises a first variable region that specifically binds to monomeric Tau.
  • the first antigen-binding portion comprises a first variable region that specifically binds to oligomeric Tau.
  • the first antigen-binding portion comprises a first variable region that specifically binds to intracellular Tau. In some embodiments, the first antigen-binding portion comprises a first variable region that specifically binds to extracellular Tau.
  • a bispecific antibody comprises a first antigen-binding portion comprising a first variable region that specifically binds to a human Tau protein with high affinity. In some embodiments, the first antigen-binding portion comprises a first variable region that specifically binds to a full-length human Tau protein (SEQ ID NO: l) with high affinity.
  • the first antigen-binding portion comprises a first variable region that has a binding affinity (KD) for SEQ ID NO: l of less than 50 nM, e.g., less than 40 nM, less than 30 nM, less than 20 nM, less than 10 nM, less than 1 nM, less than 500 pM, less than 250 pM, less than 150 pM, less than 100 pM, less than 50 pM, or less than about 10 pM.
  • KD binding affinity
  • the first antigen-binding portion comprises a first variable region that has a KD for SEQ ID NO: l in the range of about 1 pM to about 50 nM, e.g., about 1 pM to about 25 nM, about 1 pM to about 10 nM, about 1 pM to about 5 nM, about 1 pM to about 500 pM, about 5 pM to about 250 pM, or about 10 pM to about 100 pM.
  • a bispecific antibody comprises a first antigen-binding portion comprising a first variable region that specifically binds to a human Tau protein and that exhibits cross-reactivity with one or more other Tau proteins of other species.
  • the first antigen-binding portion comprising a first variable region that specifically binds to a human Tau protein exhibits cross-reactivity with a cynomolgus monkey ("cyno") Tau protein.
  • the first antigen-binding portion comprising a first variable region that specifically binds to a human Tau protein exhibits cross-reactivity with a mouse Tau protein.
  • the first antigen-binding portion comprising a first variable region specifically binds to a human Tau protein and exhibits cross-reactivity with both a cyno Tau protein and a mouse Tau protein.
  • ELISA assay solid-phase binding assays
  • immunoprecipitation e.g., surface plasmon resonance (e.g., Biacore TM (GE Healthcare, Piscataway, NJ)), kinetic exclusion assays (e.g., KinExA ® ), flow cytometry, fluorescence-activated cell sorting (FACS), BioLayer interferometry (e.g., Octet TM (ForteBio, Inc., Menlo Park, CA)), and western blot analysis.
  • ELISA is used to determine binding affinity and/or cross-reactivity. Methods for performing ELISA assays are known in the art, and are also described in the Examples section below.
  • SPR surface plasmon resonance
  • kinetic exclusion assays are used to determine binding affinity, binding kinetics, and/or cross-reactivity.
  • BioLayer interferometry assays are used to determine binding affinity, binding kinetics, and/or cross-reactivity.
  • the first antigen-binding portion comprises a first variable region that recognizes an epitope within or comprising residues 11 1-125, an epitope within or comprising residues 186-205, an epitope within or comprising residues 251-270, and/or an epitope within or comprising residues 346-360 of a full-length human Tau protein of SEQ ID NO: l .
  • the first antigen-binding portion comprises a first variable region that recognizes an epitope of human Tau comprising, within, or consisting of residues 111-125 of SEQ ID NO: 1.
  • the first antigen-binding portion comprises a first variable region that recognizes an epitope within residues 1 11-125 of SEQ ID NO: l . In some embodiments, the first antigen-binding portion comprises a first variable region that recognizes an epitope comprising at least 4, at least 5, at least 6, at least 7, at least 8, at least
  • the first antigen-binding portion comprises a first variable region that recognizes an epitope comprising 4-15, 4-12, 4-10, 4-8, 5-15, 5-12, 5-10, 5-8, 6-15, 6-12, 6-
  • the first antigen-binding portion comprises a first variable region that recognizes an epitope of human Tau comprising, within, or consisting of residues 186-205 of SEQ ID NO: l . In some embodiments, the first antigen-binding portion comprises a first variable region that recognizes an epitope within residues 186-205 of SEQ ID NO: l . In some embodiments, the first antigen-binding portion comprises a first variable region that recognizes an epitope comprising at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 contiguous amino acids within residues 186-205 of SEQ ID NO: l .
  • the first antigen-binding portion comprises a first variable region that recognizes an epitope comprising 4-15, 4-12, 4-10, 4-8, 5-15, 5-12, 5-10, 5-8, 6-15, 6-12, 6- 10, 6-8, 8-15, 8-12, 8-10, 10-15, 10-12, or 12-15 contiguous amino acids within residues 186- 205 of SEQ ID NO: 1.
  • the first antigen-binding portion comprises a first variable region that recognizes an epitope of human Tau comprising, within, or consisting of residues 251-270 of SEQ ID NO: l . In some embodiments, the first antigen-binding portion comprises a first variable region that recognizes an epitope within residues 251-270 of SEQ ID NO: l . In some embodiments, the first antigen-binding portion recognizes an epitope comprising at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 contiguous amino acids within residues 251-270 of SEQ ID NO: l .
  • the first antigen- binding portion comprises a first variable region that recognizes an epitope comprising 4-15, 4-12, 4-10, 4-8, 5-15, 5-12, 5-10, 5-8, 6-15, 6-12, 6-10, 6-8, 8-15, 8-12, 8-10, 10-15, 10-12, or 12-15 contiguous amino acids within residues 251-270 of SEQ ID NO: l .
  • the first antigen-binding portion comprises a first variable region that recognizes an epitope of human Tau comprising, within, or consisting of residues 346-360 of SEQ ID NO: 1.
  • the first antigen-binding portion comprises a first variable region that recognizes an epitope within residues 346-360 of SEQ ID NO: l . In some embodiments, the first antigen-binding portion comprises a first variable region that recognizes an epitope comprising at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, or at least 10 contiguous amino acids within residues 346-360 of SEQ ID NO: l .
  • the first antigen-binding portion comprises a first variable region that recognizes an epitope comprising 4-15, 4-12, 4-10, 4-8, 5-15, 5-12, 5-10, 5-8, 6-15, 6-12, 6- 10, 6-8, 8-15, 8-12, 8-10, 10-15, 10-12, or 12-15 contiguous amino acids within residues 346- 360 of SEQ ID NO: 1.
  • the first antigen-binding portion comprises a first variable region that has dual epitope specificity and recognizes both an epitope of human Tau comprising, within, or consisting of residues 251-270 of SEQ ID NO: l, and an epitope comprising, within, or consisting of residues 346-360 of SEQ ID NO: l .
  • the first antigen-binding portion comprises a first variable region that recognizes an epitope comprising, within, or consisting of a sequence corresponding to residues 256-270 of SEQ ID NO: l, and also recognizes an epitope comprising, within, or consisting of a sequence corresponding to residues 346-360 of SEQ ID NO: l .
  • the first antigen-binding portion comprises a first variable region that recognizes an epitope of human Tau within residues 251-270 of SEQ ID NO: l and also recognizes an epitope within residues 346-360 of SEQ ID NO: l . In some embodiments, the first antigen-binding portion comprises a first variable region that recognizes an epitope within residues 256-270 of SEQ ID NO: l and also recognizes an epitope within residues 346- 360 of SEQ ID NO: 1.
  • the first antigen-binding portion is chimeric. In some embodiments, the first antigen-binding portion is humanized. In some embodiments, the first antigen-binding portion is fully human.
  • a bispecific antibody comprises a first antigen-binding portion that comprises a heavy chain sequence, or a portion thereof, and/or a light chain sequence, or a portion thereof, derived from any of the following anti-Tau antibodies described herein: Clone 1A1, Clone 1A5, Clone 1D10, Clone 1G7, Clone 1C7, Clone 1H_G11, Clone 1H B12, Clone 17G2.A1, Clone hulC7.vl, Clone hulC7.v2, Clone hulC7.v2-l, Clone hulC7.v2-2, Clone hulC7.v3, and Clone hulC7.v4.
  • the amino acid sequences of the light chain variable region (VL) and heavy chain variable region (VH) of these anti-Tau antibodies are as follows: Clone 1A1 (e.g., SEQ ID NOs: 19 and 20), Clone 1A5 (e.g., SEQ ID NOs:21 and 22), Clone 1D10 (e.g., SEQ ID NOs:25 and 26), Clone 1G7 (e.g., SEQ ID NOs:27 and 28), Clone 1C7 (e.g., SEQ ID NOs:23 and 24), Clone 1H_G1 1 (e.g., SEQ ID NOs:29 and 30), Clone 1H B 12 (e.g., SEQ ID NOs:29 and 31), Clone 17G2.A1 (e.g., SEQ ID NOs:41 and 45), Clone hulC7.vl (e.g., SEQ ID NOs:36 and 40), Clone hulC7.v2 (e.g., SEQ ID
  • a bispecific antibody comprises a first antigen-binding portion that comprises one or more CDRs selected from the group consisting of: (a) a heavy chain CDR1 (CDR-H1) having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs:2, 8, 11, 42, 49, 50, 51, 52, 53, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 555, 556, 1194, or 1 195, or having up to two amino acid substitutions relative to the amino acid sequence of any one of SEQ ID Os:2, 8, 11, 42, 49, 50, 51, 52, 53, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 555, 556, 1194, or 1195;
  • CDR-H1 heavy chain C
  • CDR-H2 a heavy chain CDR2 (CDR-H2) having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 3, 12, 43, 513, 514, 515, 516, 517, 518, 572, 1196, or 1 197, or having up to two amino acid substitutions relative to the amino acid sequence of any one of SEQ ID NOs: 3, 12, 43, 513, 514, 515, 516, 517, 518, 572, 1196, or 1 197;
  • CDR-H3 a heavy chain CDR3 (CDR-H3) having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 4, 9, 13, 17, 18, 44, 54, 1198, or 1999, or having up to two amino acid substitutions relative to the amino acid sequence of any one of SEQ ID NOs: 4, 9, 13, 17, 18, 44, 54, 1198, or 1999;
  • CDR-L1 a light chain CDR1 (CDR-L1) having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 5, 14, 32, 46, 55, 56, 57, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 1200, or 1201, or having up to two amino acid substitutions relative to the amino acid sequence of any one of SEQ ID NOs: 5, 14, 32, 46, 55, 56, 57, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 1200, or 1201 ;
  • CDR-L2 a light chain CDR2 (CDR-L2) having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 6, 15, 33, 47, or 1202, or having up to two amino acid substitutions relative to the amino acid sequence of any one of SEQ ID NOs: 6, 15, 33, 47, or 1202;
  • CDR-L3 a light chain CDR3 having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 7, 10, 16, 34, 35, 48, 58, 59, 60, 61,
  • a bispecific antibody comprises a first antigen-binding portion that comprises one or more CDRs selected from the group consisting of:
  • a CDR-H1 comprising the amino acid sequence of any one of SEQ ID NOs:2, 8, 1 1, 42, 49, 50, 51, 52, 53, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505,
  • a CDR-H2 comprising the amino acid sequence of any one of SEQ ID NOs: 3, 12, 43, 513, 514, 515, 516, 517, 518, or 572, 1 196, or 1 197;
  • a CDR-L1 comprising the amino acid sequence of any one of SEQ ID NOs: 5, 14, 32, 46, 55, 56, 57, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 1200, or 1201 ;
  • a CDR-L3 comprising the amino acid sequence of any one of SEQ ID NOs: 7, 10, 16, 34, 35, 48, 58, 59, 60, 61, 535, 536, 537, 1203, or 1204.
  • the first antigen-binding portion comprises two, three, four, five, or all six of (a)-(f). In some embodiments, the first antigen-binding portion comprises the heavy chain CDRl of (a), the heavy chain CDR2 of (b), and the heavy chain CDR3 of (c). In some embodiments, the first antigen-binding portion comprises the light chain CDRl of (d), the light chain CDR2 of (e), and the light chain CDR3 of (f). In some embodiments, a CDR having up to two amino acid substitutions has one amino acid substitution relative to the reference sequence. In some embodiments, a CDR having up to two amino acid substitutions has two amino acid substitutions relative to the reference sequence. In some embodiments, the up to two amino acid substitutions are conservative substitutions.
  • the first antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to any one of SEQ ID NOs: 19, 21, 23,
  • the first antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of any one of SEQ ID NOs: 19, 21, 23, 25, 27, 29, 36, 37, 38, 39, 41, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, or 571.
  • the first antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of any one of SEQ ID NOs: 19, 21, 23, 25, 27, 29, 36, 37, 38, 39, 41, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, or 571.
  • a heavy chain variable region sequence having at least 90% sequence identity to a reference sequence contains one, two, three, four, five, six, seven, eight, nine, ten or more substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence but retains the ability to specifically bind to a human Tau protein.
  • the heavy chain variable region contains one, two, or three substitutions (e.g., conservative substitutions) in any one of SEQ ID NOs: 19, 21, 23, 25, 27, 29, 36, 37, 38, 39, 41, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, or 571.
  • substitutions e.g., conservative substitutions
  • the first antigen-binding portion comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to any one of SEQ ID NOs: 20, 22, 24, 26, 28, 30, 31, 40, 45, 538, 539, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, 583, 584, 585, or 586.
  • the first antigen-binding portion comprises a light chain variable region comprising the amino acid sequence of any one of SEQ ID NOs: 20, 22, 24,
  • a light chain variable region sequence having at least 90% sequence identity to a reference sequence contains one, two, three, four, five, six, seven, eight, nine, ten or more substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence but retains the ability to specifically bind to a human Tau protein.
  • the light chain variable region contains one, two, or three substitutions (e.g., conservative substitutions) in any one of SEQ ID NOs: 20, 22, 24, 26, 28, 30, 31, 40, 45, 538, 539, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, 583, 584, 585, or 586.
  • substitutions e.g., conservative substitutions
  • the first antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to any one of SEQ ID NOs: 19, 21, 23, 25, 27, 29, 36, 37, 38, 39, 41, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, or 571, and further comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to any one of SEQ ID NOs: 20, 22, 24, 26, 28, 30, 31, 40
  • the first antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of any one of SEQ ID NOs: 19, 21, 23, 25, 27, 29, 36, 37, 38, 39, 41, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, or 571 and further comprises a light chain variable region comprising the amino acid sequence of any one of SEQ ID NOs: 20, 22, 24, 26, 28, 30, 31, 40, 45, 538, 539, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, 583, 584, 585, or 586.
  • the first antigen-binding portion comprises:
  • a heavy chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to the heavy chain variable sequence of any one of Clone 1A1, Clone 1A5, Clone 1D10, Clone 1 G7, Clone 1C7, Clone 1H G11, Clone 1H B 12, Clone hulC7.vl, Clone hulC7.v2, Clone hulC7.v3, or Clone hulC7.v4, and (ii) a CDR-H1, CDR-H2, and CDR-H3 that is identical to the CDR-H1, CDR-H2, and CDR-H3, respectively, of the antibody clone; and/or
  • a light chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to the light chain variable sequence of any one of Clone 1A1, Clone 1A5, Clone 1D10, Clone 1 G7, Clone 1C7, Clone 1H G11, Clone 1H B 12, Clone hulC7.vl, Clone hulC7.v2, Clone hulC7.v2-l, Clone hulC7.v2-2, Clone hulC7.v3, or Clone hulC7.v4, and (ii) a CDR-L1, CDR-L2, and CDR-L3 that is identical to the CDR-L1, CDR-L2, and CDR- L3, respectively, of the antibody clo
  • the first antigen-binding portion comprises one or more CDR, heavy chain, and/or light chain sequences corresponding to anti-Tau antibody clone 1A1. In some embodiments, the first antigen-binding portion comprises an antibody or antigen-binding portion thereof that competes for binding with anti-Tau antibody clone 1 Al .
  • the first antigen-binding portion comprises a CDR-H1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:2 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO:2, a CDR-H2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 3 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO:3, a CDR-H3 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:4 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO:4, a CDR-L1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:5 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO:5, a CDR-L2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:6 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO:6, and
  • the first antigen-binding portion comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:2, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:3, a CDR-H3 comprising the amino acid sequence of SEQ ID NO:4, a CDR-L1 comprising the amino acid sequence of SEQ ID NO:5, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:6, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:7.
  • the first antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 19.
  • the first antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 19.
  • the first antigen-binding portion comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:20.
  • the first antigen-binding portion comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:20.
  • the first antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 19 and comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:20.
  • sequence identity e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity
  • the first antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 19 and comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:20. [0160] In some embodiments, the first antigen-binding portion comprises:
  • a heavy chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 19 and (ii) a CDR-H1, CDR-H2, and CDR-H3 that is identical to SEQ ID NOs:2, 3, and 4, respectively; and/or
  • a light chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:20 and (ii) a CDR-L1, CDR-L2, and CDR-L3 that is identical to SEQ ID NOs:5, 6, and 7, respectively.
  • sequence identity e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity
  • a bispecific antibody comprises (i) a first antigen-binding portion comprising anti-Tau antibody clone 1A1 or one or more CDR, heavy chain, and/or light chain sequences corresponding to anti-Tau antibody clone 1A1, and (ii) a second antigen-binding portion comprising an anti-BACEl antibody clone selected from the group consisting of Clone 1A11, Clone hulAl l .vl, Clone hulAl l .v2, Clone hulAl l .v3, Clone hulAl l .v4, Clone hulAl l .v5, Clone hulAl l .v6, Clone hulAl l .v7, Clone hulAl l .v8, Clone hulAl l .v9, Clone hulAl l .vlO, Clone hulAl
  • the first antigen-binding portion comprises one or more CDR, heavy chain, and/or light chain sequences corresponding to anti-Tau antibody clone 1A5. In some embodiments, the first antigen-binding portion comprises an antibody or antigen-binding portion thereof that competes for binding with anti-Tau antibody clone 1 A5.
  • the first antigen-binding portion comprises a CDR-H1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 8 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 8, a CDR-H2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 3 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO:3, a CDR-H3 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:9 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO:9, a CDR-L1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:5 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO:5, a CDR-L2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:6 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO:6, and
  • the first antigen-binding portion comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:8, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:3, a CDR-H3 comprising the amino acid sequence of SEQ ID NO:9, a CDR-L1 comprising the amino acid sequence of SEQ ID NO:5, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:6, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 10.
  • the first antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:21.
  • the first antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:21.
  • the first antigen-binding portion comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:22.
  • the first antigen-binding portion comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:22.
  • the first antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:21 and comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:22.
  • the first antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:21 and comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:22.
  • the first antigen-binding portion comprises:
  • a heavy chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least
  • a light chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least
  • a bispecific antibody comprises (i) a first antigen-binding portion comprising anti-Tau antibody clone 1A5 or one or more CDR, heavy chain, and/or light chain sequences corresponding to anti-Tau antibody clone 1A5, and (ii) a second antigen-binding portion comprising an anti-BACEl antibody clone selected from the group consisting of Clone 1A11, Clone hulAl l .vl, Clone hulAl l .v2, Clone hulAl l .v3, Clone hulAl l .v4, Clone hulAl l .v5, Clone hulAl l .v6, Clone hulAl l .v7, Clone hulAl l .v8, Clone hulAl l .v9, Clone hulAl l .vlO, Clone hulAl
  • the first antigen-binding portion comprises one or more CDR, heavy chain, and/or light chain sequences corresponding to anti-Tau antibody clone ID 10. In some embodiments, the first antigen-binding portion comprises an antibody or antigen-binding portion thereof that competes for binding with anti-Tau antibody clone ID 10.
  • the first antigen-binding portion comprises a CDR-H1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:2 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO:2, a CDR-H2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 3 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO:3, a CDR-H3 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 17 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 17, a CDR-L1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:5 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO:5, a CDR-L2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:6 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO:6, and
  • the first antigen-binding portion comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:2, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:3, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 17, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 5, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 6, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 10.
  • the first antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:25.
  • the first antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:25.
  • the first antigen-binding portion comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:26.
  • the first antigen-binding portion comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:26.
  • the first antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:25 and comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:26.
  • the first antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:25 and comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:26.
  • the first antigen-binding portion comprises:
  • a heavy chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:25 and (ii) a CDR-H1, CDR-H2, and CDR-H3 that is identical to SEQ ID NOs:2, 3, and 17, respectively; and/or
  • a light chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:26 and (ii) a CDR-L1, CDR-L2, and CDR-L3 that is identical to SEQ ID NOs:5, 6, and 10, respectively.
  • sequence identity e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity
  • a bispecific antibody comprises (i) a first antigen-binding portion comprising anti-Tau antibody clone 1D10 or one or more CDR, heavy chain, and/or light chain sequences corresponding to anti-Tau antibody clone ID 10, and (ii) a second antigen-binding portion comprising an anti-BACEl antibody clone selected from the group consisting of Clone 1A11, Clone hulAl l .vl, Clone hulAl l .v2, Clone hulAl l .v3, Clone hulAl l .v4, Clone hulAl l .v5, Clone hulAl l .v6, Clone hulAl l .v7, Clone hulAl l .v8, Clone hulAl l .v9, Clone hulAl l .vlO, Clone hulAl l l
  • the first antigen-binding portion comprises one or more CDR, heavy chain, and/or light chain sequences corresponding to anti-Tau antibody clone 1G7. In some embodiments, the first antigen-binding portion comprises an antibody or antigen-binding portion thereof that competes for binding with anti-Tau antibody clone 1G7.
  • the first antigen-binding portion comprises a CDR-H1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:2 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO:2, a CDR-H2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 3 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO:3, a CDR-H3 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 18 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 18, a CDR-L1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:5 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO:5, a CDR-L2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:6 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO:6, and
  • the first antigen-binding portion comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:2, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:3, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 18, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 5, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 6, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 10.
  • the first antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:27.
  • the first antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:27.
  • the first antigen-binding portion comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:28.
  • the first antigen-binding portion comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:28.
  • the first antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:27 and comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:28.
  • sequence identity e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity
  • the first antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:27 and comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:28. [0181] In some embodiments, the first antigen-binding portion comprises:
  • a heavy chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:27 and (ii) a CDR-H1, CDR-H2, and CDR-H3 that is identical to SEQ ID NOs:2, 3, and 18, respectively; and/or
  • a light chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:28 and (ii) a CDR-L1, CDR-L2, and CDR-L3 that is identical to SEQ ID NOs:5, 6, and 10, respectively.
  • sequence identity e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity
  • a bispecific antibody comprises (i) a first antigen-binding portion comprising anti-Tau antibody clone 1G7 or one or more CDR, heavy chain, and/or light chain sequences corresponding to anti-Tau antibody clone 1G7, and (ii) a second antigen-binding portion comprising an anti-BACEl antibody clone selected from the group consisting of Clone 1A11, Clone hulAl l .vl, Clone hulAl l .v2, Clone hulAl l .v3, Clone hulAl l .v4, Clone hulAl l .v5, Clone hulAl l .v6, Clone hulAl l .v7, Clone hulAl l .v8, Clone hulAl l .v9, Clone hulAl l .vlO, Clone hulAl
  • the first antigen-binding portion comprises one or more CDR, heavy chain, and/or light chain sequences corresponding to anti-Tau antibody clone 1C7. In some embodiments, the first antigen-binding portion comprises an antibody or antigen-binding portion thereof that competes for binding with anti-Tau antibody clone 1C7.
  • the first antigen-binding portion comprises a CDR-H1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 11 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 11, a CDR-H2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 12 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ED NO: 12, a CDR-H3 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 13 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 13, a CDR-L1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 14 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 14, a CDR-L2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 15 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 15, and
  • the first antigen-binding portion comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: l 1, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 12, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 13, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 14, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 15, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 16.
  • the first antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:23.
  • the first antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:23.
  • the first antigen-binding portion comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:24.
  • the first antigen-binding portion comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:24.
  • the first antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:23 and comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:24.
  • the first antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:23 and comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:24.
  • the first antigen-binding portion comprises:
  • a heavy chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:23 and (ii) a CDR-H1, CDR-H2, and CDR-H3 that is identical to SEQ ID NOs: l 1, 12, and 13, respectively; and/or
  • a light chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:24 and (ii) a CDR-L1, CDR-L2, and CDR-L3 that is identical to SEQ ID NOs: 14, 15, and 16, respectively.
  • sequence identity e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity
  • a bispecific antibody comprises (i) a first antigen-binding portion comprising anti-Tau antibody clone 1C7 or one or more CDR, heavy chain, and/or light chain sequences corresponding to anti-Tau antibody clone 1C7, and (ii) a second antigen-binding portion comprising an anti-BACEl antibody clone selected from the group consisting of Clone 1A11, Clone hulAl l .vl, Clone hulAl l .v2, Clone hulAl l .v3, Clone hulAl l .v4, Clone hulAl l .v5, Clone hulAl l .v6, Clone hulAl l .v7, Clone hulAl l .v8, Clone hulAl l .v9, Clone hulAl l .vlO, Clone hulAl
  • the first antigen-binding portion comprises one or more CDR, heavy chain, and/or light chain sequences corresponding to anti-Tau antibody clone 1H G11. In some embodiments, the first antigen-binding portion comprises an antibody or antigen-binding portion thereof that competes for binding with anti-Tau antibody clone 1H G11.
  • the first antigen-binding portion comprises a CDR-H1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 11 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 11, a CDR-H2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 12 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 12, a CDR-H3 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 13 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 13, a CDR-L1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:32 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO:32, a CDR-L2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:33 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO:33,
  • the first antigen-binding portion comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: l 1, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 12, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 13, a CDR-L1 comprising the amino acid sequence of SEQ ID NO:32, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:33, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:34.
  • the first antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:29.
  • the first antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:29.
  • the first antigen-binding portion comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:30.
  • the first antigen-binding portion comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:30.
  • the first antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:29 and comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:30.
  • the first antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:29 and comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:30.
  • the first antigen-binding portion comprises:
  • a heavy chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least
  • a light chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least
  • a bispecific antibody comprises (i) a first antigen-binding portion comprising anti-Tau antibody clone 1H Gi l or one or more CDR, heavy chain, and/or light chain sequences corresponding to anti-Tau antibody clone 1H G11, and (ii) a second antigen-binding portion comprising an anti-BACEl antibody clone selected from the group consisting of Clone 1A11, Clone hulAl l .vl, Clone hulAl l .v2, Clone hulAl l .v3, Clone hulAl l .v4, Clone hulAl l .v5, Clone hulAl l .v6, Clone hulAl l .v7, Clone hulAl l .v8, Clone hulAl l .v9, Clone hulAl l .vlO, Clone h
  • the first antigen-binding portion comprises one or more CDR, heavy chain, and/or light chain sequences corresponding to anti-Tau antibody clone 1H_B 12. In some embodiments, the first antigen-binding portion comprises an antibody or antigen-binding portion thereof that competes for binding with anti-Tau antibody clone 1H B 12.
  • the first antigen-binding portion comprises a CDR-H1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 11 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 11, a CDR-H2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 12 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 12, a CDR-H3 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 13 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 13, a CDR-L1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:32 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO:32, a CDR-L2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:33 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO:33,
  • the first antigen-binding portion comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: l 1, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 12, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 13, a CDR-L1 comprising the amino acid sequence of SEQ ID NO:32, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:33, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:35.
  • the first antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity ⁇ e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:29.
  • the first antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:29.
  • the first antigen-binding portion comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:31.
  • the first antigen-binding portion comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:31.
  • the first antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:29 and comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:31.
  • the first antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:29 and comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:31.
  • the first antigen-binding portion comprises: (a) a heavy chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:29 and (ii) a CDR-H1, CDR-H2, and CDR-H3 that is identical to SEQ ID NOs: l 1, 12, and 13, respectively; and/or
  • a light chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:31 and (ii) a CDR-L1, CDR-L2, and CDR-L3 that is identical to SEQ ID NOs:32, 33, and 35, respectively.
  • sequence identity e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity
  • a bispecific antibody comprises (i) a first antigen-binding portion comprising anti-Tau antibody clone 1H B 12 or one or more CDR, heavy chain, and/or light chain sequences corresponding to anti-Tau antibody clone 1H B12, and (ii) a second antigen-binding portion comprising an anti-BACEl antibody clone selected from the group consisting of Clone 1A11, Clone hulAl l .vl, Clone hulAl l .v2, Clone hulAl l .v3, Clone hulAl l .v4, Clone hulAl l .v5, Clone hulAl l .v6, Clone hulAl l .v7, Clone hulAl l .v8, Clone hulAl l .v9, Clone hulAl l .vlO, Clone hul
  • the first antigen-binding portion comprises one or more CDR, heavy chain, and/or light chain sequences corresponding to anti-Tau antibody clone 17G2.A1. In some embodiments, the first antigen-binding portion comprises an antibody or antigen-binding portion thereof that competes for binding with anti-Tau antibody clone 17G2.A1.
  • the first antigen-binding portion comprises a CDR-H1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:42 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO:42, a CDR-H2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:43 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO:43, a CDR-H3 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:44 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 44, a CDR-L1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:46 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO:46, a CDR-L2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:47 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO
  • the first antigen-binding portion comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:42, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:43, a CDR-H3 comprising the amino acid sequence of SEQ ID NO:44, a CDR-L1 comprising the amino acid sequence of SEQ ID NO:46, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:47, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:48.
  • the first antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:41.
  • the first antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:41.
  • the first antigen-binding portion comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:45.
  • the first antigen-binding portion comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:45.
  • the first antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:41 and comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:45.
  • sequence identity e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity
  • the first antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:41 and comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:45. [0209] In some embodiments, the first antigen-binding portion comprises:
  • a heavy chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:41 and (ii) a CDR-H1, CDR-H2, and CDR-H3 that is identical to SEQ ID NOs:42, 43, and 44, respectively; and/or
  • a light chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:45 and (ii) a CDR-L1, CDR-L2, and CDR-L3 that is identical to SEQ ID NOs:46, 47, and 48, respectively.
  • sequence identity e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity
  • a bispecific antibody comprises (i) a first antigen-binding portion comprising anti-Tau antibody clone 17G2.A1 or one or more CDR, heavy chain, and/or light chain sequences corresponding to anti-Tau antibody clone 17G2.A1, and (ii) a second antigen-binding portion comprising an anti-BACEl antibody clone selected from the group consisting of Clone 1A11, Clone hulAl l .vl, Clone hulAl l .v2, Clone hulAl l .v3, Clone hulAl l .v4, Clone hulAl l .v5, Clone hulAl l .v6, Clone hulAl l .v7, Clone hulAl l .v8, Clone hulAl l .v9, Clone hulAl l .vlO, Clone h
  • the first antigen-binding portion comprises one or more CDR, heavy chain, and/or light chain sequences that are humanized and/or affinity matured.
  • the first antigen-binding portion comprises a humanized and/or affinity matured form of an antibody clone described herein (e.g., clone 1A1, 1A5, 1D10, 1G7, 1C7, 1H G11, 1H B 12, or 17G2.A1).
  • the first antigen-binding portion comprises a humanized and/or affinity matured form of clone 1C7
  • the first antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to any one of SEQ ID NOs:36, 37, 38, or 39.
  • the first antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of any one of SEQ ID NOs:36, 37, 38, or 39.
  • the first antigen-binding portion comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:40.
  • the first antigen-binding portion comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:40.
  • the first antigen-binding portion comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to any one of SEQ ID NOs:538 or 539.
  • the first antigen-binding portion comprises a light chain variable region comprising the amino acid sequence of any one of SEQ ID NOs:538 or 539.
  • the first antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to any one of SEQ ID NOs:36, 37, 38, or 39 and comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:40.
  • sequence identity e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity
  • the first antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of any one of SEQ ID NOs:36, 37, 38, or 39 and comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:40.
  • the first antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:37 and comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 538 or 539.
  • sequence identity e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity
  • the first antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:37 and comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:538 or 539.
  • the first antigen-binding portion comprises one or more CDR, heavy chain, and/or light chain sequences that are affinity matured. Methods for making affinity matured antibodies are known in the art. For example, in some embodiments, phage libraries containing changes in hypervariable regions may be generated to improve the affinity of an antibody (e.g., an anti-Tau antibody). Phage selections may be performed to enrich for clones with high binding affinity.
  • the first antigen-binding portion comprises one or more affinity matured anti-Tau sequences derived from an anti-Tau sequence disclosed herein (e.g., one or more sequences for clone 1A1, 1A5, 1D10, 1G7, 1C7, 1H_G11, 1H_B 12, or 17G2.A1).
  • an affinity-matured anti-Tau antibody or antigen-binding portion thereof comprises one or more CDRs selected from the group consisting of: (a) a heavy chain CDR1 comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%o, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to any one of SEQ ID NOs: l l, 49, 50, 51, 52, 53, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 555, or 556;
  • a heavy chain CDR2 comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to any one of SEQ ID NOs: 12, 513, 514, 515, 516, 517, 518, and 572;
  • a heavy chain CDR3 comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%), at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to any one of SEQ ID NOs: 13 and 54;
  • a light chain CDR1 comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to any one of SEQ ID NOs: 14, 55, 56, 57, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, and 534;
  • a light chain CDR2 comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 15; and
  • a light chain CDR3 comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to any one of SEQ ID NOs: 16, 58, 59, 60, 61, 535, 536, and 537.
  • an affinity matured anti-Tau antibody comprises two, three, four, five, or all six of (a)-(f).
  • an anti-Tau antibody comprises the heavy chain CDRl of (a), the heavy chain CDR2 of (b), and the heavy chain CDR3 of (c).
  • an anti-Tau antibody comprises the light chain CDRl of (d), the light chain CDR2 of (e), and the light chain CDR3 of (f).
  • a bispecific antibody comprises a first antigen-binding portion comprising a heavy chain CDRl sequence comprising the amino acid sequence of any one of SEQ ID NOs:50, 52, 501, 502, 503, 504, 505, 507, 508, 509, 510, 51 1, 512, 555, or 556, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO:572, and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 13.
  • a bispecific antibody comprises a first antigen-binding portion comprising a heavy chain variable region that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to any one of SEQ ID NOs:557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, or 571.
  • sequence identity e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity
  • a bispecific antibody comprises a first antigen-binding portion comprising a light chain CDRl sequence comprising the amino acid sequence of any one of SEQ ID NOs:57, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, or 533, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 15, and a heavy chain CDR3 comprising the amino acid sequence of any one of SEQ ID NOs: 16 or 536.
  • a bispecific antibody comprises a first antigen-binding portion comprising a heavy chain variable region that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to any one of SEQ ID NOs:573, 574, 575, 576, 577, 578, 579, 580, 581, 582, 583, 584, 585, or 586.
  • sequence identity e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity
  • a bispecific antibody comprises a first antigen-binding portion comprising a heavy chain variable region that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 570 and a light chain variable region that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:573.
  • a first antigen-binding portion comprising a heavy chain variable region that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:
  • a bispecific antibody comprises a first antigen-binding portion comprising a heavy chain variable region that comprises SEQ ID NO:570 and a light chain variable region that comprises SEQ ID NO:573.
  • a bispecific antibody comprises a first antigen-binding portion comprising a heavy chain variable region that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 570 and a light chain variable region that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:585.
  • a bispecific antibody comprises a first antigen-binding portion comprising a heavy chain
  • a bispecific antibody comprises a first antigen-binding portion comprising a heavy chain variable region that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 570 and a light chain variable region that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:586.
  • a bispecific antibody comprises a first antigen-binding portion comprising a heavy chain variable region that comprises SEQ ID NO:570 and a light chain variable region that comprises SEQ ID NO:586.
  • a bispecific antibody comprises a first antigen-binding portion comprising a heavy chain variable region that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 571 and a light chain variable region that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:573.
  • a first antigen-binding portion comprising a heavy chain variable region that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:
  • a bispecific antibody comprises a first antigen-binding portion comprising a heavy chain variable region that comprises SEQ ID NO:571 and a light chain variable region that comprises SEQ ID NO:573.
  • a bispecific antibody comprises a first antigen-binding portion comprising a heavy chain variable region that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 571 and a light chain variable region that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:585.
  • a bispecific antibody comprises a first antigen-binding portion comprising a heavy chain variable region that comprises SEQ ID NO:571 and a light chain variable region that comprises SEQ ID NO:585.
  • a bispecific antibody comprises a first antigen-binding portion comprising a heavy chain variable region that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 571 and a light chain variable region that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:586.
  • a bispecific antibody comprises a first antigen-binding portion comprising a
  • a bispecific antibody comprises a first antigen-binding portion comprising a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1 1, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 12, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 13, a CDR-Ll comprising the amino acid sequence of SEQ ID NO:525, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 15, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 536.
  • a bispecific antibody comprises a first antigen-binding portion comprising a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1 1, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 12, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 13, a CDR-Ll comprising the amino acid sequence of SEQ ID NO:534, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 15, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:536.
  • a bispecific antibody comprises (i) a first antigen-binding portion comprising an anti-Tau antibody clone Clone hulC7.vl, Clone hulC7.v2, Clone hulC7.v2-l, Clone hulC7.v2-2, Clone hulC7.v3, or Clone hulC7.v4, or one or more CDR, heavy chain, and/or light chain sequences corresponding to a humanized or affinity matured 1C7 antibody clone, and (ii) a second antigen-binding portion comprising an anti-BACEl antibody clone selected from the group consisting of Clone 1A1 1, Clone hulAl l .vl, Clone hulAl l .v2, Clone hulAl l .v3, Clone hulAl l .v4, Clone hulAl l .v5, Clone hulAl l
  • a bispecific antibody comprises one or more sequences that are variants of one or more anti-Tau consensus sequences or are encompassed by one or more anti-Tau consensus sequences.
  • consensus sequences can be identified by aligning heavy chain or light chain sequences (e.g., CDRs) for antibodies that are from the same (or similar) germlines.
  • consensus sequences may be generated from antibodies that contain sequences that are of the same (or similar) length and/or have at least one highly similar CDR (e.g., highly similar CDR3).
  • sequences in these antibodies may be aligned and compared to identify conserved amino acids or motifs (i.e., where alteration in sequences may alter protein function) and/or regions where variation occurs the sequences (i.e., where variation of sequence is not likely to significantly affect protein function).
  • consensus sequences can be identified by aligning heavy chain or light chain sequences (e.g., CDRs) for antibodies that bind to the same or similar (e.g., overlapping) epitopes to determine conserved amino acids or motifs (i.e., where alteration in sequences may alter protein function) and regions where variation occurs in alignment of sequences (i.e., where variation of sequence is not likely to significantly affect protein function).
  • one or more consensus sequences can be identified for antibodies that recognize the same or similar epitope as 1C7.
  • Exemplary lC7-like consensus sequences include SEQ ID NOs: l 194-1204.
  • the capitalized letter represents an amino acid residue that is absolutely conserved among the aligned sequences (e.g., aligned CDR sequences), while "x" represents an amino acid residue that is not absolutely conserved among the aligned sequences. It will be appreciated that when selecting an amino acid to insert at a position marked by an "x" that in some embodiments, the amino acid is selected from those amino acids found at the corresponding position in the aligned sequences.
  • the bispecific antibody comprises a heavy chain CDRl sequence having the consensus sequence X1X2X3X4X5X6X7GX8S (SEQ ID NO: 1 194), wherein Xi is G or V; X2 is F or I; X 3 is T, K, R, Q, or M; X 4 is F or W; X 5 is S or R; X 6 is S, R, G, I, Q, M, L, or K; X7 is Y, V, or P; and Xs is M, V, or T.
  • the heavy chain CDRl sequence comprises the consensus sequence GFX1FSX2X3GX4S (SEQ ID NO: 1195), wherein Xi is T, K, R, Q, or M; X 2 is S, R, Q, M, L, K, G, or, S; X3 is Y, V, or P;
  • the heavy chain CDR2 sequence comprises the consensus sequence SISGX1X2GSYIX3YAX4X5VK (SEQ ID NO: 1 197), wherein Xi is D, E, T, or S; X2 is G or A; X3 is H or R; X4 is D or S; and X5 is S or A.
  • the bispecific antibody comprises a heavy chain CDR2 sequence having the consensus sequence SISGX1X2GSYIHYAX3X4VK (SEQ ID NO: 1196), wherein Xi is D, E, T, or S; X2 is G or A; and X3 is D or S; X4 is S or A.
  • the bispecific antibody comprises a heavy chain CDR3 sequence having the consensus sequence X1X2LX3X4 (SEQ ID NO: 1 198), wherein Xi is A, T,or N; X2 is R, K, or T; X3 is P or R; and X 4 is Y or F.
  • the heavy chain CDR3 sequence comprises the consensus sequence AX1LPX2 (SEQ ID NO: 1 199), wherein Xi is R or K; and X2 is Y or F.
  • the bispecific antibody comprises a light chain CDRl sequence having the consensus sequence KSSX1SLX2X3X4X5X6X7X8X9YLX10 (SEQ ID NO: 1200), wherein Xi is Q or H; X 2 is L, Y, H, or V; X3 is N, S, R, Y, Q, M, K, or L; X 4 is S or A; X 5 is G or R; X 6 is N, R, K, or T; X 7 is Q, H, or R; Xs is K or Q; X 9 is N, H, or D; and X10 is T, A, or V.
  • SEQ ID NO: 1200 the consensus sequence KSSX1SLX2X3X4X5X6X7X8X9YLX10
  • the light chain CDRl sequence comprises the consensus sequence KSSQSLX1X2X3GX4QKX5YLX6 (SEQ ID NO: 1201), wherein Xi is L, H, or V; X2 is N, Y, S, Q, R, M, K, or L; X 3 is S or A; X 4 is T or N; X 5 is N or D; X 6 is T, V, or A.
  • the bispecific antibody comprises a light chain CDR2 sequence having the consensus sequence X1X2SX3X4X5X6 (SEQ ID NO: 1202), wherein Xi is S, W, R, or L; X 2 is A, M, or V; X 3 is Y, T, F, N, or K; X 4 is R, L, or K; X 5 is Y, H, A, or E;
  • the bispecific antibody comprises a light chain CDR3 sequence having the consensus sequence QX1YX2X3YPX4T (SEQ ID NO: 1203), wherein Xi is Q, K, or H; X2 is N, D, R, Y, or S; X3 is S, T, or A; and X4 is L or M.
  • the light chain CDR3 sequence comprises the consensus sequence QQYX1X2YPLT (SEQ ID NO: 1204), wherein Xi is N, Y, or S; X2 is S or A.
  • the bispecific antibodies disclosed herein further comprise a second antigen- binding portion comprising a second variable region that specifically binds to a BACE1 protein (e.g., a human BACE1 protein).
  • the second antigen-binding portion comprises a second variable region that specifically binds to one or more splice isoforms of human BACE1 protein (i.e., one or more of the splice isoforms Isoform A, Isoform B, Isoform C, Isoform D, Isoform 5, and Isoform 6).
  • the second antigen-binding portion comprises a second variable region that specifically binds to two or more splice isoforms of human Tau protein, e.g., to two, three, four, five, or all six of Isoform A, Isoform B, Isoform C, Isoform D, Isoform 5, and Isoform 6.
  • a bispecific antibody comprises a second antigen-binding portion comprising a second variable region that binds to BACE1 protein (e.g., human BACE1 protein) with high affinity.
  • the second antigen-binding portion comprises a second variable region that has a binding affinity (KD) for BACE1 protein of less than about 75 nM, e.g., less than about 70 nM, less than about 65 nM, less than about 60 nM, less than about 55 nM, less than about 50 nM, less than about 45 nM, less than about 40 nM, less than about 35 nM, less than about 30 nM, less than about 25 nM, less than about 20 nM, less than about 15 nM, less than about 10 nM, less than about 5 nM, less than about 1 nM, less than about 500 pM, less than about 250 pM, less than about 150 pM, less than about 100 p
  • KD binding affinity
  • the antibody has a KD for BACE1 protein in the range of about 50 pM to about 75 nM, e.g., about 50 pM to about 70 nM, about 50 pM to about 60 nM, about 50 pM to about 50 nM, about 50 pM to about 40 nM, about 50 pM to about 30 nM, about 50 pM to about 20 nM, about 50 pM to about 10 nM, about 50 pM to about 5 nM, about 50 pM to about 1 nM, about 50 pM to about 500 pM, about 5 pM to about 250 pM, or about 10 pM to about 100 pM.
  • a bispecific antibody comprises a second antigen-binding portion comprising a second variable region that specifically binds to a human BACEl protein and that exhibits cross-reactivity with one or more other BACEl proteins of other species.
  • the second antigen-binding portion comprising a second variable region that specifically binds to a human BACEl protein exhibits cross-reactivity with a cyno BACEl protein.
  • the second antigen-binding portion comprising a second variable region that specifically binds to a human BACEl protein exhibits cross-reactivity with a mouse BACEl protein.
  • the second antigen-binding portion comprises a second variable region that specifically binds to a human BACEl protein and exhibits cross-reactivity with both a cyno BACEl protein and a mouse BACEl protein.
  • the second antigen-binding portion comprises a second variable region that recognizes an epitope within residues 314-460 of a full-length human BACEl protein (i.e., SEQ ID NO: 64).
  • the second antigen-binding portion comprises a second variable region that recognizes an epitope comprising 4-15, 4-12, 4-10, 4-8, 5-15, 5-12, 5-10, 5-8, 6-15, 6-12, 6-10, 6-8, 8-15, 8-12, 8-10, 10-15, 10-12, or 12- 15 amino acids within residues 314-460 of SEQ ID NO:64.
  • the epitope is a conformational epitope.
  • the second antigen-binding portion comprises a second variable region that recognizes an epitope comprising residues 332-334 and/or 376-379 of SEQ ID NO:64. In some embodiments, the second antigen- binding portion comprises a second variable region that recognizes a conformational epitope comprising residues 332-334 and residues 376-379 of SEQ ID NO:64. [0242] In some embodiments, the second antigen-binding portion is chimeric. In some embodiments, the second antigen-binding portion is humanized. In some embodiments, the second antigen-binding portion is fully human.
  • a bispecific antibody comprises a second antigen-binding portion that comprises a heavy chain sequence, or a portion thereof, and/or a light chain sequence, or a portion thereof, derived from any of the following anti-BACEl antibodies described herein: Clone 1A1 1, Clone hulAl l .vl, Clone hulAl l .v2, Clone hulAl l .v3, Clone hulAll.v4, Clone hulAll.v5, Clone hulAll.v6, Clone hulAll.v7, Clone hulAll.v8, Clone hulAll.v9, Clone hulAll.vlO, Clone hulAll.vll, Clone hulAll.vl2, Clone hulAll.vl3, Clone hul All.
  • the amino acid sequences of the VL and VH sequences of these anti-BACEl antibodies are as follows: Clone hulAll.vl (e.g., SEQ ID NOs:77 and 85), Clone hulAll.v2 (e.g., SEQ ID NOs:78 and 85), Clone hulAll.v3 (e.g., SEQ ID NOs:79 and 85), Clone hulAll.v4 (e.g., SEQ ID NOs:80 and 85), Clone hulAll.v5 (e.g., SEQID Os:81 and 85), Clone hul All.
  • Clone hulAll.vl e.g., SEQ ID NOs:77 and 85
  • Clone hulAll.v2 e.g., SEQ ID NOs:78 and 85
  • Clone hulAll.v3 e.g., SEQ ID NOs:79 and 85
  • Clone hulAll.v4 e.g., SEQ
  • v6 (e.g., SEQ ID NOs:82 and 85), Clone hulAll.v7 (e.g., SEQ ID NOs:83 and 85), Clone hulAll.v8 (e.g., SEQ ID NOs:84 and 85), Clone hulAll.v9 (e.g., SEQ ID NOs:77 and 86), Clone hulAll.vlO (e.g., SEQ ID NOs:78 and 86), Clone hulAll.vll (e.g., SEQ ID NOs:79 and 86), Clone hulAll.vl2 (e.g., SEQ ID NOs:80 and 86), Clone hulAll.vl3 (e.g., SEQ ID NOs:81 and 86), Clone hulAll.vH (e.g., SEQ ID NOs:82 and 86), Clone hulAll.vl5 (e.g., SEQ ID NOs:83 and 86
  • a CDR-H1 having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs:70, 1 10, 111, 112, 113, 1 14, 1 15, 116, 117, 118, 1 19, 120, 121, 122, 123, 124, 125, 126, 127, 128, 243, 244, 245, 719, 720, 721, 722, 723, 1140, 1141, 1142, 1 143, 1144, 1 145, 1146, or 1 147, or having up to two amino acid substitutions relative to the amino acid sequence of any one of SEQ ID NOs:70, 110, 111, 112, 1 13, 1 14, 115, 116, 1 17, 1 18, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 243, 244, 245, 719, 720, 721, 722, 723, 1140, 1141, 1142, 1 143, 1144, 1145, 1146, or 1147;
  • a CDR-H2 having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs:71, 72, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 246, 247, 248, 249, 250, 540, 541, 724, 725, 726, 843, 1148, 1 149, 1 150, 1151, 1 152, 1153, 1154, 1 155, 1156, or 1157, or having up to two amino acid substitutions relative to the amino acid sequence of any one of SEQ ID NOs:71, 72, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 246, 247, 72
  • a CDR-H3 having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs:73, 151, 152, 153, 154, 155, 156, 157, 158, 159, 170, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 251, 542, 543, 544, 545, 546, 547, 548, 549, 915, 1158, 1 159, 1 160, 1161, 1 162, 1 163, or 1164, or having up to two amino acid substitutions relative to the amino acid sequence of any one of SEQ ID NOs:73, 151, 152, 153, 154, 155, 156, 157, 158, 159, 170, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 251, 542, 543, 544, 545, 546, 547, 548,
  • a CDR-L1 having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs:32, 74, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 258, 1 119, 1120, 1 121, or 1122, or having up to two amino acid substitutions relative to the amino acid sequence of any one of SEQ ID NOs:32, 74, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 258, 1119, 1120, 1121, or 1122;
  • a CDR-L2 having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs:75, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 259, 1015, 1 123, 1124, 1125, 1 126, 1127, 1 128, 1129, 1130, 1 131, or 1132, or having up to two amino acid substitutions relative to the amino acid sequence of any one of SEQ ID NOs:75, 209, 210, 21 1, 212, 213, 214, 215, 216, 217, 218, 219, 220, 259, 1015, 1123, 1124, 1125, 1 126, 1127, 1128, 1129, 1 130, 1131, or 1132; and
  • a bispecific antibody comprises a second antigen-binding portion that comprises one or more CDRs selected from the group consisting of:
  • a CDR-H1 comprising the amino acid sequence of any one of SEQ ID NOs:70, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126,
  • a CDR-H2 comprising the amino acid sequence of any one of SEQ ID NOs:71, 72, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 246, 247, 248, 249, 250, 540, 541, 724, 725, 726, 843, 1148, 1149, 1150, 1151, 1 152, 1153, 1154, 1155, 1 156, or 1 157;
  • a CDR-H3 comprising the amino acid sequence of any one of SEQ ID NOs:73, 151, 152, 153, 154, 155, 156, 157, 158, 159, 170, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 251, 542, 543, 544, 545, 546, 547, 548, 549, 915, 1 158, 1159, 1160, 1161, 1162, 1163, or 1164;
  • a CDR-L1 comprising the amino acid sequence of any one of SEQ ID NOs:32, 74, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 258, 11 19, 1120, 1121, or 1122;
  • a CDR-L2 comprising the amino acid sequence of any one of SEQ ID NOs:75, 209, 210, 21 1, 212, 213, 214, 215, 216, 217, 218, 219, 220, 259, 1015, 1123, 1124,
  • a CDR-L3 comprising the amino acid sequence of any one of SEQ ID NOs: 16, 35, 76, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 260, 550, 551, 552, 553, 554, 727, 728, 729, 730, 731, 732, 1112, 1 133, 1134, 1135, 1136, 1137, 1 138, or 1 139.
  • the second antigen-binding portion comprises two, three, four, five, or all six of (a)-(f).
  • the second antigen-binding portion comprises the heavy chain CDR1 of (a), the heavy chain CDR2 of (b), and the heavy chain CDR3 of (c).
  • the second antigen-binding portion comprises the light chain CDR1 of (d), the light chain CDR2 of (e), and the light chain CDR3 of (f).
  • a CDR having up to two amino acid substitutions has one amino acid substitution relative to the reference sequence.
  • a CDR having up to two amino acid substitutions has two amino acid substitutions relative to the reference sequence.
  • the up to two amino acid substitutions are conservative substitutions.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to any one of SEQ ID NOs:66, 77, 78, 79, 80, 81, 82, 83, 84, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 238, 239, 240, 241, 242, 261, 262, 263, 264, 265, 266, 733, 734, 735, 736, 1176, 1 177, 1178, 1 179, 1180, 1 181, 1182, 1183, 1
  • sequence identity e.g.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of any one of SEQ ID NOs:66, 77, 78, 79, 80, 81, 82, 83, 84, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 238, 239, 240, 241, 242, 261, 262, 263, 264, 265, 266, 733, 734, 735, 736, 1 176, 1177, 1 178, 1179, 1180, 1181, 1182, 1183, 1184, 1185, 1186, 1187, 1188, 1189, 1190, 1192, or 1193.
  • a heavy chain variable region sequence having at least 90% sequence identity to a reference sequence contains one, two, three, four, five, six, seven, eight, nine, ten or more substitutions (e.g., conservative substitutions), insertions
  • the heavy chain variable region contains one, two, or three substitutions (e.g., conservative substitutions) in any one of SEQ ID NOs:66, 77, 78, 79, 80, 81, 82, 83, 84, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 238, 239, 240, 241, 242, 261, 262, 263, 264, 265, 266, 733, 734, 735, 736, 1 176, 1177, 1178, 1 179, 1180, 1181, 1 182, 1183, 1184, 1 185, 1186, 1187, 1188, 1189, 1 190, 1192, or 1193.
  • substitutions e.g., conservative substitutions
  • the second antigen-binding portion comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to any one of SEQ ID NOs:7, 85, 86, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 252, 253, 254, 255, 256, 257, 267, 268, 269, 270, 271, 737, 738, 739, 1165, 1 166, 1 167, 1168, 1169, 1 170, 1 171, 1172, 1173, 1 174, 1 175, or 1 191.
  • sequence identity e.g., at least 91%, at least 92%
  • the second antigen-binding portion comprises a light chain variable region comprising the amino acid sequence of any one of SEQ ID NOs:7, 85, 86, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 252, 253, 254, 255, 256, 257, 267, 268, 269, 270, 271, 737, 738, 739, 1 165, 1166, 1167, 1168, 1 169, 1170, 1 171, 1172, 1 173, 1174, 1175, or 1 191.
  • a light chain variable region sequence having at least 90% sequence identity to a reference sequence contains one, two, three, four, five, six, seven, eight, nine, ten or more substitutions (e.g., conservative substitutions), insertions, or deletions relative to the reference sequence but retains the ability to specifically bind to a human BACE1 protein.
  • the light chain variable region contains one, two, or three substitutions (e.g., conservative substitutions) in any one of SEQ ID NOs:7, 85, 86, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 252, 253, 254, 255, 256, 257, 267, 268, 269, 270, 271, 737, 738, 739, 1 165, 1 166, 1167, 1168, 1 169, 1170, 1171, 1172, 1173, 1174, 1 175, or 1 191.
  • substitutions e.g., conservative substitutions
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to any one of SEQ ID NOs:66, 77, 78, 79, 80, 81, 82, 83, 84, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 238, 239, 240, 241, 242, 261, 262, 263, 264, 265, 266, 733, 734, 735, 736, 1176, 1177, 1178, 1179, 1180, 1181, 1182, 1183, 1184, 11
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of any one of SEQ ID NOs:66, 77, 78, 79, 80, 81, 82, 83, 84, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 238, 239, 240, 241, 242, 261, 262, 263, 264, 265, 266, 733, 734, 735, 736, 1176, 1177, 1178, 1179, 1180, 1181, 1182, 1183, 1184, 1185, 1186, 1187, 1188, 1189, 1190, 1192, or 1193 and further comprises a light chain variable region comprising the amino acid sequence of any one of SEQ IDNOs:7, 85, 86, 173, 174, 175, 176,
  • the second antigen-binding portion comprises:
  • a heavy chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to the heavy chain variable sequence of any one of Clone 1A11, Clone hulAll.vl, Clone hulAll.v2, Clone hulAll.v3, Clone hulAll.v4, Clone hulAll.v5, Clone hulAll.v6, Clone hulAll.v7, Clone hulAll.v8, Clone hulAll.v9, Clone hulAll.vlO, Clone hulAll.vll, Clone hulAll.vl2, Clone hulAll.vl3, Clone hulAll.vH, Clone hulAll.vl5, Clone hulAll.v
  • a light chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to the light chain variable sequence of any one of Clone 1A1 1, Clone hulAl l .vl, Clone hulAl l .v2, Clone hulAl l .v3, Clone hulAl l .v4, Clone hulAl l .v5, Clone hulAl l .v6, Clone hulAl l .v7, Clone hulAl l .v8, Clone hulAl l .v9, Clone hulAl l .vlO, Clone hulAl l .vl l,
  • the second antigen-binding portion comprises one or more CDR, heavy chain, and/or light chain sequences corresponding to anti-BACEl antibody clone 1A1 1.
  • the second antigen-binding portion comprises an antibody or antigen-binding portion thereof that competes for binding with anti-BACEl antibody clone 1A1 1.
  • the 1A11 antibody is a chimeric antibody.
  • the 1A11 antibody is a humanized and/or affinity matured antibody, e.g., as disclosed in Section IV below.
  • the second antigen-binding portion comprises a CDR-H1 having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs:70, 719, 720, 721, 722, or 723 or having up to two amino acid substitutions relative to the amino acid sequence of any one of SEQ ID NOs:70, 719, 720, 721, 722, or 723, a CDR- H2 having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs:71, 72, 540, 541, 724, 725, or 726 or having up to two amino acid substitutions relative to the amino acid sequence of any one of SEQ ID NOs:71, 72, 540, 541, 724, 725, or 726, a CDR-H3 having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs:73, 542, 543, 544, 545, 546, 547, 548, or 549 or having up to two amino acid substitutions relative to
  • the second antigen- binding portion comprises a CDR-H1 comprising the amino acid sequence of any one of SEQ
  • a CDR-H2 comprising the amino acid sequence of any one of SEQ ID NOs:71, 540, 541, 724, 725, or 726
  • a CDR-H3 comprising the amino acid sequence of any one of SEQ ID NOs:73, 542, 543, 544, 545, 546, 547, 548, or 549
  • a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 74
  • a CDR-L2 comprising the amino acid sequence of SEQ ID NO:75
  • a CDR-L3 comprising the amino acid sequence of any one of SEQ ID NOs:76, 550, 551, 552, 553, 554, 727, 728, 729, 730, 731, or 732.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to any one of SEQ ID NOs: 66, 77, 78, 79, 80, 81, 82, 83, or 84.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of any one of SEQ ID NOs:66, 77, 78, 79, 80, 81, 82, 83, or 84.
  • the second antigen-binding portion comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to any one of SEQ ID NOs:67, 85, or 86.
  • the second antigen-binding portion comprises a light chain variable region comprising the amino acid sequence of any one of SEQ ID NOs: 67, 85, or 86.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to any one of SEQ ID NOs:66, 77, 78, 79, 80, 81, 82, 83, or 84 and comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to any one of SEQ ID NOs:67, 85, or 86.
  • sequence identity e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of any one of SEQ ID NOs:66, 77, 78, 79, 80, 81, 82, 83, or 84 and comprises a light chain variable region comprising the amino acid sequence of any one of SEQ ID NOs:67, 85, or 86.
  • the second antigen-binding portion comprises a heavy chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:66 and (ii) a CDR-H1, CDR-H2, and CDR-H3 that is identical to SEQ ID NOs:70, 71, and 73, respectively.
  • sequence identity e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity
  • the second antigen-binding portion comprises a light chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:67 and (ii) a CDR-H1, CDR-H2, and CDR-H3 that is identical to SEQ ID NOs:74, 75, and 76, respectively.
  • sequence identity e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity
  • the second antigen-binding portion comprises (a) a heavy chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:66 and (ii) a CDR-H1, CDR-H2, and CDR-H3 that is identical to SEQ ID NOs:70, 71, and 73, respectively; and (b) a light chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:67 and (ii)
  • the second antigen-binding portion comprises: (a) a heavy chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to any one of SEQ ID NOs:77, 78, 79, 80, 81, 82, 83, or 84 and (ii) a CDR-H1, CDR-H2, and CDR-H3 that is identical to SEQ ID NOs:70, 72, and 73, respectively; and/or
  • a light chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to any one of SEQ ID NOs:85 or 86 and (ii) a CDR-L1, CDR-L2, and CDR-L3 that is identical to SEQ ID NOs:74, 75, and 76, respectively.
  • sequence identity e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity
  • the second antigen-binding portion comprises the amino acid sequence of one or more CDRs (e.g., one, two, three, four, five, or all six) of a CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 for a humanized 1A11 clone or a humanized 1A1 1 variant sequence as disclosed in Section IV below.
  • the second antigen-binding portion comprises the amino acid sequence of a heavy chain variable region sequence and/or a light chain variable region sequence for a humanized 1A1 1 clone or a humanized 1 Al 1 variant sequence as disclosed in Section IV below.
  • the second antigen-binding portion comprises the CDR-H1 of SEQ ID NO:719, the CDR-H2 of SEQ ID NO:540, the CDR-H3 of SEQ ID NO:547, the CDR-L1 of SEQ ID NO:74, the CDR-L2 of SEQ ID NO:75, and the CDR-L3 of SEQ ID NO:552.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:733 and/or a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:737.
  • sequence identity e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity
  • the second antigen-binding portion comprises the CDR-H1 of SEQ ID NO:719, the CDR-H2 of SEQ ID NO:540, the CDR-H3 of SEQ ID NO:548, the CDR-L1 of SEQ ID NO:74, the CDR-L2 of SEQ ID NO:75, and the CDR-L3 of SEQ ID NO:553.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:734 and/or a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:738.
  • sequence identity e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity
  • the second antigen-binding portion comprises the CDR-H1 of SEQ ID NO:719, the CDR-H2 of SEQ ID NO:540, the CDR-H3 of SEQ ID NO:543, the CDR-L1 of SEQ ID NO:74, the CDR-L2 of SEQ ID NO:75, and the CDR-L3 of SEQ ID NO:550.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:736 and/or a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 86.
  • the second antigen-binding portion comprises the CDR-H1 of SEQ ID NO:721, the CDR-H2 of SEQ ID NO:843, the CDR-H3 of SEQ ID NO:915, the CDR-L1 of SEQ ID NO: 74, the CDR-L2 of SEQ ID NO: 1015, and the CDR-L3 of SEQ ID NO: 11 12.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:735 and/or a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:739.
  • a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO
  • a bispecific antibody comprises (i) a first antigen-binding portion comprising an anti-Tau antibody clone selected from the group consisting of Clone 1A1, Clone 1A5, Clone 1D10, Clone 1G7, Clone 1C7, Clone 1H G11, Clone 1H B12, Clone 17G2.A1, Clone hulC7.vl, Clone hulC7.v2, Clone hulC7.v2-l, Clone hulC7.v2-2, Clone hulC7.v3, and Clone hulC7.v4, and (ii) a second antigen-binding portion comprising anti- BACE1 antibody clone 1A11 or one or more CDR, heavy chain, and/or light chain sequences corresponding to anti-BACEl antibody clone 1A11.
  • a first antigen-binding portion comprising an anti-Tau antibody clone selected from the group consisting of Clone 1A1, Clone 1A5, Clone
  • a bispecific antibody comprises (i) a first antigen-binding portion comprising an anti-Tau antibody clone selected from the group consisting of Clone 1A1, Clone 1A5, Clone 1D10, Clone 1G7, Clone 1C7, Clone 1H_G11, Clone 1H_B12, Clone 17G2.A1, Clone hulC7.vl, Clone hulC7.v2, Clone hulC7.v2-l, Clone hulC7.v2-2, Clone hulC7.v3, and Clone hulC7.v4, and (ii) a second antigen-binding portion comprising anti-BACEl antibody clone hulAll.vl, hulAll.v2, hulAll.v3, hulAll.v4, hulAll.v5, hulAll.v6, hulAll.v7, hulAll.v8, hulAll.v9, hulAll.v
  • the second antigen-binding portion comprises one or more CDR, heavy chain, and/or light chain sequences corresponding to anti-BACEl antibody clone 3G10. In some embodiments, the second antigen-binding portion comprises an antibody or antigen-binding portion thereof that competes for binding with anti-BACEl antibody clone 3G10.
  • the second antigen-binding portion comprises a CDR-H1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 110 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 110, a CDR-H2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 129 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 129, a CDR-H3 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 151 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 151, a CDR-Ll having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 195 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 195, a CDR-L2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:209 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO:
  • the second antigen-binding portion comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 110, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 129, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 151, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 195, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:209, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:221.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:87.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:87.
  • the second antigen-binding portion comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 173.
  • the second antigen-binding portion comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 173.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:87 and comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 173.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 87 and comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 173.
  • the second antigen-binding portion comprises:
  • a heavy chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:87 and (ii) a CDR-H1, CDR-H2, and CDR-H3 that is identical to SEQ ID NOs: l 10, 129, and 151, respectively; and/or (b) a light chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 173 and (ii) a CDR-Ll, CDR-
  • a bispecific antibody comprises (i) a first antigen-binding portion comprising an anti-Tau antibody clone selected from the group consisting of Clone 1A1, Clone 1A5, Clone 1D10, Clone 1G7, Clone 1C7, Clone 1H G11, Clone 1H B12, Clone 17G2.A1, Clone hulC7.vl, Clone hulC7.v2, Clone hulC7.v2-l, Clone hulC7.v2-2, Clone hulC7.v3, and Clone hulC7.v4, and (ii) a second antigen-binding portion comprising anti- BACE1 antibody clone 3G10 or one or more CDR, heavy chain, and/or light chain sequences corresponding to anti-BACEl antibody clone 3G10.
  • the second antigen-binding portion comprises one or more CDR, heavy chain, and/or light chain sequences corresponding to anti-BACEl antibody clone 2E1. In some embodiments, the second antigen-binding portion comprises an antibody or antigen-binding portion thereof that competes for binding with anti-BACEl antibody clone 2E1.
  • the second antigen-binding portion comprises a CDR-H1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: l l l or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 11 1, a CDR-H2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 130 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 130, a CDR-H3 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 152 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 152, a CDR-Ll having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 196 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 196, a CDR-L2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:210 or having up to two amino acid substitutions relative to
  • the second antigen-binding portion comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1 1 1, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 130, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 152, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 196, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:210, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:222.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 88.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:88.
  • the second antigen-binding portion comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 174.
  • the second antigen-binding portion comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 174.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:88 and comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 174.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 88 and comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 174.
  • the second antigen-binding portion comprises: (a) a heavy chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:88 and (ii) a CDR-H1, CDR-H2, and CDR-H3 that is identical to SEQ ID NOs: l 1, 130, and 152, respectively; and/or
  • a light chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 174 and (ii) a CDR-Ll, CDR-L2, and CDR-L3 that is identical to SEQ ID NOs: 196, 210, and 222, respectively.
  • sequence identity e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity
  • a bispecific antibody comprises (i) a first antigen-binding portion comprising an anti-Tau antibody clone selected from the group consisting of Clone 1A1, Clone 1A5, Clone 1D10, Clone 1G7, Clone 1C7, Clone 1H_G11, Clone 1H B12, Clone 17G2.A1, Clone hulC7.vl, Clone hulC7.v2, Clone hulC7.v2-l, Clone hulC7.v2-2, Clone hulC7.v3, and Clone hulC7.v4, and (ii) a second antigen-binding portion comprising anti- BACE1 antibody clone 2E1 or one or more CDR, heavy chain, and/or light chain sequences corresponding to anti-BACEl antibody clone 2E1.
  • a first antigen-binding portion comprising an anti-Tau antibody clone selected from the group consisting of Clone 1A1, Clone 1A5, Cl
  • the second antigen-binding portion comprises one or more CDR, heavy chain, and/or light chain sequences corresponding to anti-BACEl antibody clone 1B4. In some embodiments, the second antigen-binding portion comprises an antibody or antigen-binding portion thereof that competes for binding with anti-BACEl antibody clone 1B4.
  • the second antigen-binding portion comprises a CDR-H1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 112 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 112, a CDR-H2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 131 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 131, a CDR-H3 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 153 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 153, a CDR-Ll having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 197 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 197, a CDR-L2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:21 1 or having up to two amino acid substitutions relative to the
  • the second antigen-binding portion comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1 12, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 131, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 153, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 197, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:21 1, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:223.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:89.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:89.
  • the second antigen-binding portion comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 175.
  • the second antigen-binding portion comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 175.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:89 and comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 175.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 89 and comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 175.
  • the second antigen-binding portion comprises: (a) a heavy chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:89 and (ii) a CDR-H1, CDR-H2, and CDR-H3 that is identical to SEQ ID NOs: l 12, 131, and 153, respectively; and/or
  • a light chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 175 and (ii) a CDR-Ll, CDR-L2, and CDR-L3 that is identical to SEQ ID NOs: 197, 211, and 223, respectively.
  • sequence identity e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity
  • a bispecific antibody comprises (i) a first antigen-binding portion comprising an anti-Tau antibody clone selected from the group consisting of Clone 1A1, Clone 1A5, Clone 1D10, Clone 1G7, Clone 1C7, Clone 1H G11, Clone 1H B12, Clone 17G2.A1, Clone hulC7.vl, Clone hulC7.v2, Clone hulC7.v2-l, Clone hulC7.v2-2, Clone hulC7.v3, and Clone hulC7.v4, and (ii) a second antigen-binding portion comprising anti- BACE1 antibody clone 1B4 or one or more CDR, heavy chain, and/or light chain sequences corresponding to anti-BACEl antibody clone 1B4.
  • a first antigen-binding portion comprising an anti-Tau antibody clone selected from the group consisting of Clone 1A1, Clone 1A5, Clone
  • the second antigen-binding portion comprises one or more CDR, heavy chain, and/or light chain sequences corresponding to anti-BACEl antibody clone 1A12. In some embodiments, the second antigen-binding portion comprises an antibody or antigen-binding portion thereof that competes for binding with anti-BACEl antibody clone 1A12.
  • the second antigen-binding portion comprises a CDR-H1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 113 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 113, a CDR-H2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 132 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 132, a CDR-H3 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 154 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 154, a CDR-Ll having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 198 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 198, a CDR-L2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:212 or having up to two amino acid substitutions relative to the
  • the second antigen-binding portion comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1 13, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 132, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 154, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 198, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:212, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:224.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:90.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:90.
  • the second antigen-binding portion comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 176.
  • the second antigen-binding portion comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 176.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:90 and comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 176.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:90 and comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 176.
  • the second antigen-binding portion comprises:
  • a heavy chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least
  • a light chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least
  • a bispecific antibody comprises (i) a first antigen-binding portion comprising an anti-Tau antibody clone selected from the group consisting of Clone 1A1, Clone 1A5, Clone 1D10, Clone 1G7, Clone 1C7, Clone 1H G11, Clone 1H B12, Clone 17G2.A1, Clone hulC7.vl, Clone hulC7.v2, Clone hulC7.v2-l, Clone hulC7.v2-2, Clone hulC7.v3, and Clone hulC7.v4, and (ii) a second antigen-binding portion comprising anti- BACE1 antibody clone 1A12 or one or more CDR, heavy chain, and/or light chain sequences corresponding to anti -BACEl antibody clone 1A12.
  • the second antigen-binding portion comprises one or more CDR, heavy chain, and/or light chain sequences corresponding to anti -BACEl antibody clone 1D7. In some embodiments, the second antigen-binding portion comprises an antibody or antigen-binding portion thereof that competes for binding with anti-BACEl antibody clone 1D7.
  • the second antigen-binding portion comprises a CDR-H1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 114 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 114, a CDR-H2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 133 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 133, a CDR-H3 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 155 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 155, a CDR-L1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 199 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 199, a CDR-L2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:21 1 or having up to two amino acid substitutions relative to
  • the second antigen-binding portion comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1 14, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 133, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 155, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 199, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:21 1, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:225.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:91.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:91.
  • the second antigen-binding portion comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 177.
  • the second antigen-binding portion comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 177.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:91 and comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 177.
  • sequence identity e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:91 and comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 177. [0297] In some embodiments, the second antigen-binding portion comprises:
  • a heavy chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:91 and (ii) a CDR-H1, CDR-H2, and CDR-H3 that is identical to SEQ ID NOs: l 14, 133, and 155, respectively; and/or
  • a light chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 177 and (ii) a CDR-L1, CDR-L2, and CDR-L3 that is identical to SEQ ID NOs: 199, 211, and 225, respectively.
  • sequence identity e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity
  • a bispecific antibody comprises (i) a first antigen-binding portion comprising an anti-Tau antibody clone selected from the group consisting of Clone 1A1, Clone 1A5, Clone 1D10, Clone 1G7, Clone 1C7, Clone 1H G11, Clone 1H B12, Clone 17G2.A1, Clone hulC7.vl, Clone hulC7.v2, Clone hulC7.v2-l, Clone hulC7.v2-2, Clone hulC7.v3, and Clone hulC7.v4, and (ii) a second antigen-binding portion comprising anti- BACE1 antibody clone 1D7 or one or more CDR, heavy chain, and/or light chain sequences corresponding to anti-BACEl antibody clone 1D7.
  • the second antigen-binding portion comprises one or more CDR, heavy chain, and/or light chain sequences corresponding to anti-BACEl antibody clone 1A5. In some embodiments, the second antigen-binding portion comprises an antibody or antigen-binding portion thereof that competes for binding with anti-BACEl antibody clone 1A5.
  • the second antigen-binding portion comprises a CDR-H1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 115 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 115, a CDR-H2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 134 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 134, a CDR-H3 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 156 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 156, a CDR-L1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:200 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO:200, a CDR-L2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:213 or having up to two amino acid substitutions relative to the amino amino acid substitutions relative to the amino
  • the second antigen-binding portion comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1 15, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 134, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 156, a CDR-L1 comprising the amino acid sequence of SEQ ID NO:200, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:213, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:226.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:92.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:92.
  • the second antigen-binding portion comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 178.
  • the second antigen-binding portion comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 178.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:92 and comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 178.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:92 and comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 178.
  • the second antigen-binding portion comprises:
  • a heavy chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:92 and (ii) a CDR-H1, CDR-H2, and CDR-H3 that is identical to SEQ ID NOs: l 15, 134, and 156, respectively; and/or
  • a light chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 178 and (ii) a CDR-L1, CDR-L2, and CDR-L3 that is identical to SEQ ID NOs:200, 213, and 226, respectively.
  • sequence identity e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity
  • a bispecific antibody comprises (i) a first antigen-binding portion comprising an anti-Tau antibody clone selected from the group consisting of Clone 1A1, Clone 1A5, Clone 1D10, Clone 1G7, Clone 1C7, Clone 1H G11, Clone 1H B12, Clone 17G2.A1, Clone hulC7.vl, Clone hulC7.v2, Clone hulC7.v2-l, Clone hulC7.v2-2, Clone hulC7.v3, and Clone hulC7.v4, and (ii) a second antigen-binding portion comprising anti- BACE1 antibody clone 1A5 or one or more CDR, heavy chain, and/or light chain sequences corresponding to anti -BACEl antibody clone 1A5.
  • a first antigen-binding portion comprising an anti-Tau antibody clone selected from the group consisting of Clone 1A1, Clone 1A5, Cl
  • the second antigen-binding portion comprises one or more CDR, heavy chain, and/or light chain sequences corresponding to anti -BACEl antibody clone 1H6. In some embodiments, the second antigen-binding portion comprises an antibody or antigen-binding portion thereof that competes for binding with anti-BACEl antibody clone 1H6.
  • the second antigen-binding portion comprises a CDR-H1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 116 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 116, a CDR-H2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 135 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 135, a CDR-H3 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 157 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 157, a CDR-L1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:201 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO:201, a CDR-L2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:212 or having up to two amino acid substitutions relative to the amino acid sequence
  • the second antigen-binding portion comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1 16, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 135, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 157, a CDR-L1 comprising the amino acid sequence of SEQ ID NO:201, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:212, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:227.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:93.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:93.
  • the second antigen-binding portion comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 179.
  • the second antigen-binding portion comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 179.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:93 and comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 179.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:93 and comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 179.
  • the second antigen-binding portion comprises: (a) a heavy chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:93 and (ii) a CDR-H1, CDR-H2, and CDR-H3 that is identical to SEQ ID NOs: l 16, 135, and 157, respectively; and/or
  • a light chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 179 and (ii) a CDR-L1, CDR-L2, and CDR-L3 that is identical to SEQ ID NOs:201, 212, and 227, respectively.
  • sequence identity e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity
  • a bispecific antibody comprises (i) a first antigen-binding portion comprising an anti-Tau antibody clone selected from the group consisting of Clone 1A1, Clone 1A5, Clone 1D10, Clone 1G7, Clone 1C7, Clone 1H G11, Clone 1H B12, Clone 17G2.A1, Clone hulC7.vl, Clone hulC7.v2, Clone hulC7.v2-l, Clone hulC7.v2-2, Clone hulC7.v3, and Clone hulC7.v4, and (ii) a second antigen-binding portion comprising anti- BACEl antibody clone 1H6 or one or more CDR, heavy chain, and/or light chain sequences corresponding to anti-BACEl antibody clone 1H6.
  • the second antigen-binding portion comprises one or more CDR, heavy chain, and/or light chain sequences corresponding to anti-BACEl antibody clone 4H10. In some embodiments, the second antigen-binding portion comprises an antibody or antigen-binding portion thereof that competes for binding with anti-BACEl antibody clone 4H10.
  • the second antigen-binding portion comprises a CDR-H1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 117 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 117, a CDR-H2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 136 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 136, a CDR-H3 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 158 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 158, a CDR-L1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:202 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO:202, a CDR-L2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:214 or having up to two amino acid substitutions relative to the amino acid
  • the second antigen-binding portion comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1 17, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 136, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 158, a CDR-L1 comprising the amino acid sequence of SEQ ID NO:202, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:214, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:228.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:94.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:94.
  • the second antigen-binding portion comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 180.
  • the second antigen-binding portion comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 180.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:94 and comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 180.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:94 and comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 180.
  • the second antigen-binding portion comprises:
  • a heavy chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:94 and (ii) a CDR-H1, CDR-H2, and CDR-H3 that is identical to SEQ ID NOs: l 17, 136, 258, respectively; and/or
  • a light chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 180 and (ii) a CDR-L1, CDR-L2, and CDR-L3 that is identical to SEQ ID NOs:202, 214, and 228, respectively.
  • sequence identity e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity
  • a bispecific antibody comprises (i) a first antigen-binding portion comprising an anti-Tau antibody clone selected from the group consisting of Clone 1A1, Clone 1A5, Clone 1D10, Clone 1G7, Clone 1C7, Clone 1H G11, Clone 1H B12, Clone 17G2.A1, Clone hulC7.vl, Clone hulC7.v2, Clone hulC7.v2-l, Clone hulC7.v2-2, Clone hulC7.v3, and Clone hulC7.v4, and (ii) a second antigen-binding portion comprising anti- BACE1 antibody clone 4H10 or one or more CDR, heavy chain, and/or light chain sequences corresponding to anti-BACEl antibody clone 4H10.
  • the second antigen-binding portion comprises one or more CDR, heavy chain, and/or light chain sequences corresponding to anti-BACEl antibody clone 3C1 1.
  • the second antigen-binding portion comprises an antibody or antigen-binding portion thereof that competes for binding with anti-BACEl antibody clone 3C11.
  • the second antigen-binding portion comprises a CDR-H1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 118 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 118, a CDR-H2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 137 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 137 a CDR-H3 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 159 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 159, a CDR-L1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:203 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO:203, a CDR-L2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:215 or having up to two amino acid substitutions relative to the amino acid
  • the second antigen-binding portion comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1 18, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 137, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 159, a CDR-L1 comprising the amino acid sequence of SEQ ID NO:203, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:x215 and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:222.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 95.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:95.
  • the second antigen-binding portion comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 181.
  • the second antigen-binding portion comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 181.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:95 and comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 181.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:95 and comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 181.
  • the second antigen-binding portion comprises:
  • a heavy chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least
  • a light chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least
  • a bispecific antibody comprises (i) a first antigen-binding portion comprising an anti-Tau antibody clone selected from the group consisting of Clone 1A1, Clone 1A5, Clone 1D10, Clone 1G7, Clone 1C7, Clone 1H G11, Clone 1H B12, Clone 17G2.A1, Clone hulC7.vl, Clone hulC7.v2, Clone hulC7.v2-l, Clone hulC7.v2-2, Clone hulC7.v3, and Clone hulC7.v4, and (ii) a second antigen-binding portion comprising anti- BACE1 antibody clone 3C11 or one or more CDR, heavy chain, and/or light chain sequences corresponding to anti -BACEl antibody clone 3C 11. 4A4
  • the second antigen-binding portion comprises one or more CDR, heavy chain, and/or light chain sequences corresponding to anti-BACEl antibody clone 4A4. In some embodiments, the second antigen-binding portion comprises an antibody or antigen-binding portion thereof that competes for binding with anti-BACEl antibody clone 4A4.
  • the second antigen-binding portion comprises a CDR-H1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 119 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 119, a CDR-H2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 138 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 138, a CDR-H3 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 160 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 160, a CDR-L1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 199 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 199, a CDR-L2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:21 1 or having up to two amino acid substitutions relative to the amino acid substitutions relative to the amino acid
  • the second antigen-binding portion comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1 19, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 138, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 160, a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 199, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:21 1, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:229.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:96.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:96.
  • the second antigen-binding portion comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 182.
  • the second antigen-binding portion comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 182.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:96 and comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 182.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:96 and comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 182.
  • the second antigen-binding portion comprises:
  • a heavy chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:96 and (ii) a CDR-H1, CDR-H2, and CDR-H3 that is identical to SEQ ID NOs: l 19, 138, and 160, respectively; and/or
  • a light chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 182 and (ii) a CDR-L1, CDR-L2, and CDR-L3 that is identical to SEQ ID NOs: 199, 211, and 229, respectively.
  • sequence identity e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity
  • a bispecific antibody comprises (i) a first antigen-binding portion comprising an anti-Tau antibody clone selected from the group consisting of Clone 1A1, Clone 1A5, Clone 1D10, Clone 1G7, Clone 1C7, Clone 1H G11, Clone 1H B12, Clone 17G2.A1, Clone hulC7.vl, Clone hulC7.v2, Clone hulC7.v2-l, Clone hulC7.v2-2, Clone hulC7.v3, and Clone hulC7.v4, and (ii) a second antigen-binding portion comprising anti- BACEl antibody clone 4A4 or one or more CDR, heavy chain, and/or light chain sequences corresponding to anti -BACEl antibody clone 4A4.
  • the second antigen-binding portion comprises one or more CDR, heavy chain, and/or light chain sequences corresponding to anti -BACEl antibody clone 1D2. In some embodiments, the second antigen-binding portion comprises an antibody or antigen-binding portion thereof that competes for binding with anti-BACEl antibody clone 1D2.
  • the second antigen-binding portion comprises a CDR-H1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 117 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 117, a CDR-H2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 139 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 139, a CDR-H3 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 161 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 161, a CDR-L1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:32 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 32, a CDR-L2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:214 or having up to two amino acid substitutions relative to the amino acid sequence
  • the second antigen-binding portion comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1 17, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 139, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 161, a CDR-L1 comprising the amino acid sequence of SEQ ID NO:32, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:214, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:230.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity ⁇ e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:97.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:97.
  • the second antigen-binding portion comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 183.
  • the second antigen-binding portion comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 183.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:97 and comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 183.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:97 and comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 183.
  • the second antigen-binding portion comprises: (a) a heavy chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:97 and (ii) a CDR-H1, CDR-H2, and CDR-H3 that is identical to SEQ ID NOs: l 17, 139, and 161, respectively; and/or
  • a light chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 183 and (ii) a CDR-L1, CDR-L2, and CDR-L3 that is identical to SEQ ID NOs:32, 214, and 230, respectively.
  • sequence identity e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity
  • a bispecific antibody comprises (i) a first antigen-binding portion comprising an anti-Tau antibody clone selected from the group consisting of Clone 1A1, Clone 1A5, Clone 1D10, Clone 1G7, Clone 1C7, Clone 1H G11, Clone 1H B12, Clone 17G2.A1, Clone hulC7.vl, Clone hulC7.v2, Clone hulC7.v2-l, Clone hulC7.v2-2, Clone hulC7.v3, and Clone hulC7.v4, and (ii) a second antigen-binding portion comprising anti- BACEl antibody clone 1D21A11 or one or more CDR, heavy chain, and/or light chain sequences corresponding to anti-BACEl antibody clone 1D2.
  • a first antigen-binding portion comprising an anti-Tau antibody clone selected from the group consisting of Clone 1A1, Clone 1A5,
  • the second antigen-binding portion comprises one or more CDR, heavy chain, and/or light chain sequences corresponding to anti-BACEl antibody clone 2G7. In some embodiments, the second antigen-binding portion comprises an antibody or antigen-binding portion thereof that competes for binding with anti-BACEl antibody clone
  • the second antigen-binding portion comprises a CDR-H1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 120 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 120, a CDR-H2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 140 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 140, a CDR-H3 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 162 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 162, a CDR-L1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:32 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 32, a CDR-L2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:216 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID
  • the second antigen-binding portion comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 120, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 140, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 162, a CDR-L1 comprising the amino acid sequence of SEQ ID NO:32, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:216, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:35.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 98.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:98.
  • the second antigen-binding portion comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 184.
  • the second antigen-binding portion comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 184.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:98 and comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 184.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:98 and comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 184.
  • the second antigen-binding portion comprises:
  • a heavy chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:98 and (ii) a CDR-H1, CDR-H2, and CDR-H3 that is identical to SEQ ID NOs: 120, 140, and 162, respectively; and/or
  • a light chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 184 and (ii) a CDR-L1, CDR-L2, and CDR-L3 that is identical to SEQ ID NOs:22, 216, and 35, respectively.
  • sequence identity e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity
  • a bispecific antibody comprises (i) a first antigen-binding portion comprising an anti-Tau antibody clone selected from the group consisting of Clone 1A1, Clone 1A5, Clone 1D10, Clone 1G7, Clone 1C7, Clone 1H G11, Clone 1H B12, Clone 17G2.A1, Clone hulC7.vl, Clone hulC7.v2, Clone hulC7.v2-l, Clone hulC7.v2-2, Clone hulC7.v3, and Clone hulC7.v4, and (ii) a second antigen-binding portion comprising anti- BACE1 antibody clone 2G7 or one or more CDR, heavy chain, and/or light chain sequences corresponding to anti -BACEl antibody clone 2G7.
  • a first antigen-binding portion comprising an anti-Tau antibody clone selected from the group consisting of Clone 1A1, Clone 1A5,
  • the second antigen-binding portion comprises one or more CDR, heavy chain, and/or light chain sequences corresponding to anti -BACEl antibody clone 5A4. In some embodiments, the second antigen-binding portion comprises an antibody or antigen-binding portion thereof that competes for binding with anti-BACEl antibody clone 5A4.
  • the second antigen-binding portion comprises a CDR-H1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 121 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 121, a CDR-H2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 141 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 141, a CDR-H3 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 163 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 163, a CDR-L1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:32 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 32, a CDR-L2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:217 or having up to two amino acid substitutions relative to the amino acid
  • the second antigen-binding portion comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 121, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 141, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 163, a CDR-L1 comprising the amino acid sequence of SEQ ID NO:32, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:x217 and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:231.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:99.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:99.
  • the second antigen-binding portion comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 185.
  • the second antigen-binding portion comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 185.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:99 and comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 185.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:99 and comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 185.
  • the second antigen-binding portion comprises:
  • a heavy chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least
  • a light chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least
  • a bispecific antibody comprises (i) a first antigen-binding portion comprising an anti-Tau antibody clone selected from the group consisting of Clone 1A1, Clone 1A5, Clone 1D10, Clone 1G7, Clone 1C7, Clone 1H G11, Clone 1H B12, Clone 17G2.A1, Clone hulC7.vl, Clone hulC7.v2, Clone hulC7.v2-l, Clone hulC7.v2-2, Clone hulC7.v3, and Clone hulC7.v4, and (ii) a second antigen-binding portion comprising anti- BACE1 antibody clone 5A4 or one or more CDR, heavy chain, and/or light chain sequences corresponding to anti -BACEl antibody clone 5A4.
  • the second antigen-binding portion comprises one or more CDR, heavy chain, and/or light chain sequences corresponding to anti -BACEl antibody clone 1B 1. In some embodiments, the second antigen-binding portion comprises an antibody or antigen-binding portion thereof that competes for binding with anti-BACEl antibody clone 1B 1.
  • the second antigen-binding portion comprises a CDR-H1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 122 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 122, a CDR-H2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 142 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 142, a CDR-H3 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 164 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 164, a CDR-L1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:32 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 32, a CDR-L2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:216 or having up to two amino acid substitutions relative to the amino acid
  • the second antigen-binding portion comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 122, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 142, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 164, a CDR-L1 comprising the amino acid sequence of SEQ ID NO:32, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:216, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 16.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 100.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 100.
  • the second antigen-binding portion comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 186.
  • the second antigen-binding portion comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 186.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 100 and comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 186.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 100 and comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 186.
  • the second antigen-binding portion comprises:
  • a heavy chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 100 and (ii) a CDR-H1, CDR-H2, and CDR-H3 that is identical to SEQ ID NOs: 122, 142, and 164, respectively; and/or (b) a light chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 186 and (ii) a CDR-L1, CDR-L
  • a bispecific antibody comprises (i) a first antigen-binding portion comprising an anti-Tau antibody clone selected from the group consisting of Clone 1A1, Clone 1A5, Clone 1D10, Clone 1G7, Clone 1C7, Clone 1H G11, Clone 1H B12, Clone 17G2.A1, Clone hulC7.vl, Clone hulC7.v2, Clone hulC7.v2-l, Clone hulC7.v2-2, Clone hulC7.v3, and Clone hulC7.v4, and (ii) a second antigen-binding portion comprising anti- BACE1 antibody clone 1B1 or one or more CDR, heavy chain, and/or light chain sequences corresponding to anti-BACEl antibody clone 1B 1.
  • a first antigen-binding portion comprising an anti-Tau antibody clone selected from the group consisting of Clone 1A1, Clone 1A5, Clone
  • the second antigen-binding portion comprises one or more CDR, heavy chain, and/or light chain sequences corresponding to anti-BACEl antibody clone IF 1. In some embodiments, the second antigen-binding portion comprises an antibody or antigen-binding portion thereof that competes for binding with anti-BACEl antibody clone 1F1.
  • the second antigen-binding portion comprises a CDR-H1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 123 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 123, a CDR-H2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 143 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 143, a CDR-H3 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 165 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 165, a CDR-L1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:204 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO:204, a CDR-L2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:212 or having up to two amino acid substitutions relative to the amino acid
  • the second antigen-binding portion comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 123, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 143, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 165, a CDR-L1 comprising the amino acid sequence of SEQ ID NO:204, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:212, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:232.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 101.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 101.
  • the second antigen-binding portion comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 187.
  • the second antigen-binding portion comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 187.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 101 and comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 187.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 101 and comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 187.
  • the second antigen-binding portion comprises: (a) a heavy chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 101 and (ii) a CDR-H1, CDR-H2, and CDR-H3 that is identical to SEQ ID NOs: 123, 143, and 165, respectively; and/or
  • a light chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 187 and (ii) a CDR-Ll, CDR-L2, and CDR-L3 that is identical to SEQ ID NOs:204, 212, and 232, respectively.
  • sequence identity e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity
  • a bispecific antibody comprises (i) a first antigen-binding portion comprising an anti-Tau antibody clone selected from the group consisting of Clone 1A1, Clone 1A5, Clone 1D10, Clone 1G7, Clone 1C7, Clone 1H_G11, Clone 1H B12, Clone 17G2.A1, Clone hulC7.vl, Clone hulC7.v2, Clone hulC7.v2-l, Clone hulC7.v2-2, Clone hulC7.v3, and Clone hulC7.v4, and (ii) a second antigen-binding portion comprising anti- BACE1 antibody clone 1F 1 or one or more CDR, heavy chain, and/or light chain sequences corresponding to anti-BACEl antibody clone 1F1.
  • 1C6 a first antigen-binding portion comprising an anti-Tau antibody clone selected from the group consisting of Clone 1A1, Clone 1
  • the second antigen-binding portion comprises one or more CDR, heavy chain, and/or light chain sequences corresponding to anti-BACEl antibody clone 1C6. In some embodiments, the second antigen-binding portion comprises an antibody or antigen-binding portion thereof that competes for binding with anti-BACEl antibody clone 1C6.
  • the second antigen-binding portion comprises a CDR-H1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 115 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 115, a CDR-H2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 144 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 144, a CDR-H3 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 166 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 166, a CDR-Ll having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:200 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO:200, a CDR-L2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:213 or having up to two amino acid substitutions relative to the amino acid substitutions relative to the amino acid
  • the second antigen-binding portion comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1 15, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 144, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 166, a CDR-L1 comprising the amino acid sequence of SEQ ID NO:200, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:213, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:213.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 102.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 102.
  • the second first antigen-binding portion comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 188.
  • the second antigen-binding portion comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 188.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 102 and comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 188.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 102 and comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 188.
  • the second antigen-binding portion comprises: (a) a heavy chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 102 and (ii) a CDR-H1, CDR-H2, and CDR-H3 that is identical to SEQ ID NOs: l 15, 144, and 166, respectively; and/or
  • a light chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 188 and (ii) a CDR-L1, CDR-L2, and CDR-L3 that is identical to SEQ ID NOs:200, 213, and 233, respectively.
  • sequence identity e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity
  • a bispecific antibody comprises (i) a first antigen-binding portion comprising an anti-Tau antibody clone selected from the group consisting of Clone 1A1, Clone 1A5, Clone 1D10, Clone 1G7, Clone 1C7, Clone 1H G11, Clone 1H B12, Clone 17G2.A1, Clone hulC7.vl, Clone hulC7.v2, Clone hulC7.v2-l, Clone hulC7.v2-2, Clone hulC7.v3, and Clone hulC7.v4, and (ii) a second antigen-binding portion comprising anti- BACE1 antibody clone 1C6 or one or more CDR, heavy chain, and/or light chain sequences corresponding to anti-BACEl antibody clone 1C6.
  • the second antigen-binding portion comprises one or more CDR, heavy chain, and/or light chain sequences corresponding to anti-BACEl antibody clone 1F7. In some embodiments, the second antigen-binding portion comprises an antibody or antigen-binding portion thereof that competes for binding with anti-BACEl antibody clone 1F7.
  • the second antigen-binding portion comprises a CDR-H1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 124 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 124, a CDR-H2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 145 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 145, a CDR-H3 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 167 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 167, a CDR-L1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:205 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO:205, a CDR-L2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:218 or having up to two amino acid substitutions relative to the amino amino acid sequence of SEQ ID NO
  • the second antigen-binding portion comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 124, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 145, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 167, a CDR-L1 comprising the amino acid sequence of SEQ ID NO:205, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:218, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:234.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 103.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 103.
  • the second antigen-binding portion comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 189.
  • the second antigen-binding portion comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 189.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 103 and comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 189.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 103 and comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 189.
  • the second antigen-binding portion comprises:
  • a heavy chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least
  • a light chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least
  • a bispecific antibody comprises (i) a first antigen-binding portion comprising an anti-Tau antibody clone selected from the group consisting of Clone 1A1, Clone 1A5, Clone 1D10, Clone 1G7, Clone 1C7, Clone 1H G11, Clone 1H B12, Clone 17G2.A1, Clone hulC7.vl, Clone hulC7.v2, Clone hulC7.v2-l, Clone hulC7.v2-2, Clone hulC7.v3, and Clone hulC7.v4, and (ii) a second antigen-binding portion comprising anti- BACE1 antibody clone 1F7 or one or more CDR, heavy chain, and/or light chain sequences corresponding to anti-BACEl antibody clone 1F7.
  • the second antigen-binding portion comprises one or more CDR, heavy chain, and/or light chain sequences corresponding to anti-BACEl antibody clone ID 10. In some embodiments, the second antigen-binding portion comprises an antibody or antigen-binding portion thereof that competes for binding with anti-BACEl antibody clone ID 10.
  • the second antigen-binding portion comprises a CDR-H1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 125 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 125, a CDR-H2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 146 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 146, a CDR-H3 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 168 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 168, a CDR-L1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:206 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO:206, a CDR-L2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:219 or having up to two amino acid substitutions relative to the amino amino acid substitutions relative to the amino
  • the second antigen-binding portion comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 125, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 146, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 168, a CDR-L1 comprising the amino acid sequence of SEQ ID NO:206, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:219, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:235.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 104.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 104.
  • the second antigen-binding portion comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 190.
  • the second antigen-binding portion comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 190.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 104 and comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 190.
  • sequence identity e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 104 and comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 190. [0388] In some embodiments, the second antigen-binding portion comprises:
  • a heavy chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 104 and (ii) a CDR-H1, CDR-H2, and CDR-H3 that is identical to SEQ ID NOs: 125, 146, and 168, respectively; and/or
  • a light chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 190 and (ii) a CDR-L1, CDR-L2, and CDR-L3 that is identical to SEQ ID NOs:206, 219, and 235, respectively.
  • sequence identity e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity
  • a bispecific antibody comprises (i) a first antigen-binding portion comprising an anti-Tau antibody clone selected from the group consisting of Clone 1A1, Clone 1A5, Clone 1D10, Clone 1G7, Clone 1C7, Clone 1H G11, Clone 1H B12, Clone 17G2.A1, Clone hulC7.vl, Clone hulC7.v2, Clone hulC7.v2-l, Clone hulC7.v2-2, Clone hulC7.v3, and Clone hulC7.v4, and (ii) a second antigen-binding portion comprising anti- BACEl antibody clone ID 10 or one or more CDR, heavy chain, and/or light chain sequences corresponding to anti-BACEl antibody clone 1D 10.
  • a first antigen-binding portion comprising an anti-Tau antibody clone selected from the group consisting of Clone 1A1, Clone 1A5, Clone 1
  • the second antigen-binding portion comprises one or more CDR, heavy chain, and/or light chain sequences corresponding to anti-BACEl antibody clone 4B 1. In some embodiments, the second antigen-binding portion comprises an antibody or antigen-binding portion thereof that competes for binding with anti-BACEl antibody clone 4B 1.
  • the second antigen-binding portion comprises a CDR-H1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 126 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 126, a CDR-H2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 147 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 147, a CDR-H3 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 169 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 169, a CDR-L1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:207 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO:207, a CDR-L2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:220 or having up to two amino acid substitutions relative to the amino acid substitutions relative to the amino acid
  • the second antigen-binding portion comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 126, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 147, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 169, a CDR-L1 comprising the amino acid sequence of SEQ ID NO:207, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:220, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:236.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 105.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 105.
  • the second antigen-binding portion comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 191.
  • the second antigen-binding portion comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 191.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 105 and comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 191.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 105 and comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 191.
  • the second antigen-binding portion comprises:
  • a heavy chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 105 and (ii) a CDR-H1, CDR-H2, and CDR-H3 that is identical to SEQ ID NOs: 126, 147, and 169, respectively; and/or
  • a light chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 191 and (ii) a CDR-L1, CDR-L2, and CDR-L3 that is identical to SEQ ID NOs:207, 220, and 236, respectively.
  • sequence identity e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity
  • a bispecific antibody comprises (i) a first antigen-binding portion comprising an anti-Tau antibody clone selected from the group consisting of Clone 1A1, Clone 1A5, Clone 1D10, Clone 1G7, Clone 1C7, Clone 1H G11, Clone 1H B12, Clone 17G2.A1, Clone hulC7.vl, Clone hulC7.v2, Clone hulC7.v2-l, Clone hulC7.v2-2, Clone hulC7.v3, and Clone hulC7.v4, and (ii) a second antigen-binding portion comprising anti- BACE1 antibody clone 4B1 or one or more CDR, heavy chain, and/or light chain sequences corresponding to anti-BACEl antibody clone 4B 1.
  • a first antigen-binding portion comprising an anti-Tau antibody clone selected from the group consisting of Clone 1A1, Clone 1A5, Clone
  • the second antigen-binding portion comprises one or more CDR, heavy chain, and/or light chain sequences corresponding to anti-BACEl antibody clone 1F8. In some embodiments, the second antigen-binding portion comprises an antibody or antigen-binding portion thereof that competes for binding with anti-BACEl antibody clone 1F8.
  • the second antigen-binding portion comprises a CDR-H1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 126 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 126, a CDR-H2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 148 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 148, a CDR-H3 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 170 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 170, a CDR-L1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:32 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 32, a CDR-L2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:216 or having up to two amino acid substitutions relative to the amino acid
  • the second antigen-binding portion comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 126, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 148, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 170, a CDR-L1 comprising the amino acid sequence of SEQ ID NO:32, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:216, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:35.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 106.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 106.
  • the second antigen-binding portion comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 192.
  • the second antigen-binding portion comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 192.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 106 and comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 192.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 106 and comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 192.
  • the second antigen-binding portion comprises: (a) a heavy chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 106 and (ii) a CDR-H1, CDR-H2, and CDR-H3 that is identical to SEQ ID NOs: 126, 148, and 170, respectively; and/or
  • a light chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 192 and (ii) a CDR-L1, CDR-L2, and CDR-L3 that is identical to SEQ ID NOs:32, 216, and 35, respectively.
  • sequence identity e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity
  • a bispecific antibody comprises (i) a first antigen-binding portion comprising an anti-Tau antibody clone selected from the group consisting of Clone 1A1, Clone 1A5, Clone 1D10, Clone 1G7, Clone 1C7, Clone 1H G11, Clone 1H B12, Clone 17G2.A1, Clone hulC7.vl, Clone hulC7.v2, Clone hulC7.v2-l, Clone hulC7.v2-2, Clone hulC7.v3, and Clone hulC7.v4, and (ii) a second antigen-binding portion comprising anti- BACEl antibody clone 1F8 or one or more CDR, heavy chain, and/or light chain sequences corresponding to anti-BACEl antibody clone 1F8.
  • a first antigen-binding portion comprising an anti-Tau antibody clone selected from the group consisting of Clone 1A1, Clone 1A5, Cl
  • the second antigen-binding portion comprises one or more CDR, heavy chain, and/or light chain sequences corresponding to anti-BACEl antibody clone 2B8. In some embodiments, the second antigen-binding portion comprises an antibody or antigen-binding portion thereof that competes for binding with anti-BACEl antibody clone 2B8.
  • the second antigen-binding portion comprises a CDR-H1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 127 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 127, a CDR-H2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 149 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 149, a CDR-H3 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 171 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 171, a CDR-L1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:32 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 32, a CDR-L2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:216 or having up to two amino acid substitutions relative to the amino acid sequence
  • the second antigen-binding portion comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 127, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 149, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 171, a CDR-L1 comprising the amino acid sequence of SEQ ID NO:32, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:216, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:237.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 107.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 107.
  • the second antigen-binding portion comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 193.
  • the second antigen-binding portion comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 193.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 107 and comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 193.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 107 and comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 193.
  • the second antigen-binding portion comprises:
  • a heavy chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 107 and (ii) a CDR-H1, CDR-H2, and CDR-H3 that is identical to SEQ ID NOs: 127, 149, and 171, respectively; and/or
  • a light chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 193 and (ii) a CDR-L1, CDR-L2, and CDR-L3 that is identical to SEQ ID NOs:32, 216, and 237, respectively.
  • sequence identity e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity
  • a bispecific antibody comprises (i) a first antigen-binding portion comprising an anti-Tau antibody clone selected from the group consisting of Clone 1A1, Clone 1A5, Clone 1D10, Clone 1G7, Clone 1C7, Clone 1H G11, Clone 1H B12, Clone 17G2.A1, Clone hulC7.vl, Clone hulC7.v2, Clone hulC7.v2-l, Clone hulC7.v2-2, Clone hulC7.v3, and Clone hulC7.v4, and (ii) a second antigen-binding portion comprising anti- BACE1 antibody clone 2B8 or one or more CDR, heavy chain, and/or light chain sequences corresponding to anti-BACEl antibody clone 2B8.
  • a first antigen-binding portion comprising an anti-Tau antibody clone selected from the group consisting of Clone 1A1, Clone 1A5, Cl
  • the second antigen-binding portion comprises one or more CDR, heavy chain, and/or light chain sequences corresponding to anti-BACEl antibody clone 1E7. In some embodiments, the second antigen-binding portion comprises an antibody or antigen-binding portion thereof that competes for binding with anti-BACEl antibody clone 1E7.
  • the second antigen-binding portion comprises a CDR-H1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 126 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 126, a CDR-H2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 149 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 149, a CDR-H3 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 171 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 171, a CDR-L1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:32 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 32, a CDR-L2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:216 or having up to two amino acid substitutions relative to the amino acid sequence
  • the second antigen-binding portion comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 126, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 149, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 171, a CDR-L1 comprising the amino acid sequence of SEQ ID NO:32, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:216, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 16.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 108.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 108.
  • the second antigen-binding portion comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 186.
  • the second antigen-binding portion comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 186.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 108 and comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 186.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 108 and comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 186.
  • the second antigen-binding portion comprises:
  • a heavy chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least
  • a light chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least
  • a bispecific antibody comprises (i) a first antigen-binding portion comprising an anti-Tau antibody clone selected from the group consisting of Clone 1A1, Clone 1A5, Clone 1D10, Clone 1G7, Clone 1C7, Clone 1H G11, Clone 1H B12, Clone 17G2.A1, Clone hulC7.vl, Clone hulC7.v2, Clone hulC7.v2-l, Clone hulC7.v2-2, Clone hulC7.v3, and Clone hulC7.v4, and (ii) a second antigen-binding portion comprising anti- BACE1 antibody clone 1E7 or one or more CDR, heavy chain, and/or light chain sequences corresponding to anti-BACEl antibody clone 1E7. 2H8, Humanized 2H8, and 2H8 Variants
  • the second antigen-binding portion comprises one or more CDR, heavy chain, and/or light chain sequences corresponding to anti-BACEl antibody clone 2H8, a heavy chain and/or light chain sequence corresponding to humanized 2H8, or a CDR, heavy chain, and/or light chain sequence corresponding to a variant of 2H8.
  • the second antigen-binding portion comprises an antibody or antigen-binding portion thereof that competes for binding with anti-BACEl antibody clone 2H8.
  • the 2H8 antibody is a chimeric antibody.
  • the 2H8 antibody is a humanized and/or affinity matured antibody.
  • the second antigen-binding portion comprises a CDR-H1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 128 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 128, a CDR-H2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 150 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 150, a CDR-H3 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 172 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 172, a CDR-L1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:208 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO:208, a CDR-L2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:210 or having up to two amino acid substitutions relative to the amino acid sequence of S
  • the second antigen-binding portion comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 128, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 150, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 172, a CDR-L1 comprising the amino acid sequence of SEQ ID NO:208, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:210, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:222.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 109.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 109.
  • the second antigen-binding portion comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 194.
  • the second antigen-binding portion comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 194.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 109 and comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 194.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 109 and comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 194.
  • the second antigen-binding portion comprises: (a) a heavy chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 109 and (ii) a CDR-H1, CDR-H2, and CDR-H3 that is identical to SEQ ID NOs: 128, 150, and 172, respectively; and/or
  • a light chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 194 and (ii) a CDR-L1, CDR-L2, and CDR-L3 that is identical to SEQ ID NOs:208, 210, and 222, respectively.
  • sequence identity e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity
  • second antigen-binding portion comprises a CDR-H1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 128 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 128, a CDR- H2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 1149 or SEQ ID NO: 1 153 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 1149 or SEQ ID NO: 1 153, a CDR-H3 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 1 160 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO: 1160, a CDR-L1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:208 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO:208, a CDR- L2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO
  • the second antigen-binding portion comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 128, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 1149 or SEQ ID NO: 1 153, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 1160, a CDR-L1 comprising the amino acid sequence of SEQ ID NO:208, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 1123, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 1135.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 1192 or SEQ ID NO: 1193.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1192.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1 193.
  • the second antigen-binding portion comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 1191.
  • the second antigen-binding portion comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: l 191.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 1192 or SEQ ID NO: 1193 and comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%), at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 1191.
  • sequence identity e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1192 or SEQ ID NO: 1 193 and comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 1 191.
  • the second antigen-binding portion comprises:
  • a heavy chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 1 192 and (ii) a CDR-H1, CDR-H2, and CDR-H3 that is identical to SEQ ID NOs: 128, 1 149, and 1160, respectively; and/or
  • a light chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 1191 and (ii) a CDR-L1, CDR-L2, and CDR-L3 that is identical to SEQ ID NOs:208, 1 123, and 1135, respectively.
  • sequence identity e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity
  • the second antigen-binding portion comprises:
  • a heavy chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least
  • a light chain variable region comprising (i) at least 75% sequence identity (e.g., at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least
  • a bispecific antibody comprises (i) a first antigen-binding portion comprising an anti-Tau antibody clone selected from the group consisting of Clone 1A1, Clone 1A5, Clone 1D10, Clone 1G7, Clone 1C7, Clone 1H G11, Clone 1H B12, Clone 17G2.A1, Clone hulC7.vl, Clone hulC7.v2, Clone hulC7.v2-l, Clone hulC7.v2-2, Clone hulC7.v3, and Clone hulC7.v4, and (ii) a second antigen-binding portion comprising anti- BACE1 antibody clone 2H8 or one or more CDR, heavy chain, and/or light chain sequences corresponding to anti-BACEl antibody clone 2H8.
  • a first antigen-binding portion comprising an anti-Tau antibody clone selected from the group consisting of Clone 1A1, Clone 1A5, Cl
  • the second antigen-binding portion comprises one or more CDR, heavy chain, and/or light chain sequences that are variants of a 2H8 CDR, heavy chain, and/or light chain sequence.
  • the second antigen-binding portion comprises a CDR-Hl having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs:243, 244, or 245 or having up to two amino acid substitutions relative to the amino acid sequence of any one of SEQ ID NOs:243, 244, or 245, a CDR-H2 having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs:246, 247, 248, 249, or 250 or having up to two amino acid substitutions relative to the amino acid sequence of any one of SEQ ID NOs:246, 247, 248, 249, or 250, a CDR-H3 having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 172 or 251 or having up to two amino
  • the second antigen-binding portion comprises a CDR-Hl comprising the amino acid sequence of any one of SEQ ID NOs:243, 244, or 245, a CDR-H2 comprising the amino acid sequence of any one of SEQ ID NOs:246, 247, 248, 249, or 250, a CDR-H3 comprising the amino acid sequence of any one of SEQ ID NOs: 172 or 251, a CDR-Ll comprising the amino acid sequence of any one of SEQ ID NOs:32, 196, or 258, a CDR-L2 comprising the amino acid sequence of any one of SEQ ID NOs:210, 216, or 259, and a CDR-L3 comprising the amino acid sequence of any one of SEQ ID NOs:222 or 260.
  • the second antigen-binding portion comprises a CDR-H1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:245 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO:245, a CDR-H2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:250 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO:250, a CDR-H3 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:251 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO:251, a CDR-L1 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:258 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO:258, a CDR-L2 having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:210 or having up to two amino acid substitutions relative to the amino acid sequence of SEQ ID NO:245, a
  • the second antigen-binding portion comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:245, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:250, a CDR-H3 comprising the amino acid sequence of SEQ ID NO:251, a CDR-L1 comprising the amino acid sequence of SEQ ID NO:258, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:210, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:222.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to any one of SEQ ID NOs:238, 239, 240, 241, or 242.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of any one of SEQ ID NOs:238, 239, 240, 241, or 242.
  • the second antigen-binding portion comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to any one of SEQ ID NOs:252, 253, 254, 255, 256, or 257.
  • the second antigen-binding portion comprises a light chain variable region comprising the amino acid sequence of any one of SEQ ID NOs:252, 253, 254, 255, 256, or 257.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to any one of SEQ ID NOs:238, 239, 240, 241, or 242 and comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to any one of SEQ ID NOs:252, 253, 254, 255, 256, or 257.
  • sequence identity e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 9
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of any one of SEQ ID NOs:238, 239, 240, 241, or 242 and comprises a light chain variable region comprising the amino acid sequence of any one of SEQ ID NOs:252, 253, 254, 255, 256, or 257.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:242, and/or comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:257.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence SEQ ID NO:242 and/or comprises a light chain variable region comprising the amino acid sequence SEQ ID NO:257.
  • a bispecific antibody comprises (i) a first antigen-binding portion comprising an anti-Tau antibody clone selected from the group consisting of Clone 1A1, Clone 1A5, Clone 1D10, Clone 1G7, Clone 1C7, Clone 1H G11, Clone 1H B12, Clone 17G2.A1, Clone hulC7.vl, Clone hulC7.v2, Clone hulC7.v2-l, Clone hulC7.v2-2, Clone hulC7.v3, and Clone hulC7.v4, and (ii) a second antigen-binding portion comprising one or more CDR, heavy chain, and/or light chain sequences corresponding to an anti-BACEl antibody clone 2H8 variant sequence.
  • a first antigen-binding portion comprising an anti-Tau antibody clone selected from the group consisting of Clone 1A1, Clone 1A5, Clone 1D10, Clone 1G7,
  • the second antigen-binding portion comprises one or more heavy chain and/or light chain sequences corresponding to a humanized 2H8 antibody clone.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to any one of SEQ ID NOs:261, 262, 263, 264, 265, or 266.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of any one of SEQ ID NOs:261,
  • the second antigen-binding portion comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to any one of SEQ ID NOs:267, 268, 269, 270, or 271.
  • the second antigen-binding portion comprises a light chain variable region comprising the amino acid sequence of any one of SEQ ID NOs:267, 268, 269, 270, or 271.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to any one of SEQ ID NOs:261, 262,
  • 263, 264, 265, or 266 and comprises a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to any one of SEQ ID NOs:267, 268, 269, 270, or 271.
  • sequence identity e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of any one of SEQ ID NOs:261, 262, 263, 264, 265, or 266 and comprises a light chain variable region comprising the amino acid sequence of any one of SEQ ID NOs:267, 268, 269, 270, or 271.
  • a bispecific antibody comprises (i) a first antigen-binding portion comprising an anti-Tau antibody clone selected from the group consisting of Clone 1A1, Clone 1A5, Clone 1D10, Clone 1G7, Clone 1C7, Clone 1H Gi l, Clone 1H B12, Clone 17G2.A1, Clone hulC7.vl, Clone hulC7.v2, Clone hulC7.v2-l, Clone hulC7.v2-2, Clone hulC7.v3, and Clone hulC7.v4, and (ii) a second antigen-binding portion comprising one or more heavy chain, and/or light chain sequences corresponding to an anti-BACEl humanized 2H8 sequence.
  • a bispecific antibody comprises one or more sequences that are variants of one or more anti-BACEl consensus sequences or are encompassed by one or more anti-BACEl consensus sequences.
  • one or more consensus sequences can be identified for antibodies that recognize the same or similar epitope as 2H8.
  • Exemplary consensus sequences include SEQ ID NOs: 1 1 19-1122, 1129-1 132, 1 137-1139, 1144-1 147, 1154-1157, and 1163-1 164.
  • the capitalized letter represents an amino acid residue that is absolutely conserved among the aligned sequences ⁇ e.g., aligned CDR sequences), while "x" represents an amino acid residue that is not absolutely conserved among the aligned sequences. It will be appreciated that when selecting an amino acid to insert at a position marked by an "x" that in some embodiments, the amino acid is selected from those amino acids found at the corresponding position in the aligned sequences.
  • the bispecific antibody comprises a heavy chain CDR1 sequence having the consensus sequence GYTFxxxxxH (SEQ ID NO: 1144).
  • the heavy chain CDR1 consensus sequence comprises the sequence GYTF[T/N][N/S][F/Y][W/Y][I/M]H (SEQ ID NO: 1145).
  • the bispecific antibody comprises a heavy chain CDR1 sequence having the consensus sequence GYTFxxxxIH (SEQ ID NO: 1146).
  • the heavy chain CDR1 consensus sequence comprises the sequence GYTF[T/N][N/S][F/Y][W/Y]IH (SEQ ID NO: 1 147).
  • the bispecific antibody comprises a heavy chain CDR2 sequence having the consensus sequence xIDPxxxxxxxNQxxKx (SEQ ID NO: 1154).
  • the heavy chain CDR2 consensus sequence comprises the sequence [M/I]IDP[S/D] [D/S/E/G/A] [S/A/T/N/D] [Y D][T/I] [K/N] [Y/F/N]NQ[K/N] [F/L]K[A/G/D] (SEQ ID NO: 1 155).
  • the bispecific antibody comprises a heavy chain CDR2 sequence having the consensus sequence xIDPxxxYTKYNQKFKA (SEQ ID NO: 1 156).
  • the heavy chain CDR2 consensus sequence comprises the sequence [M/I]IDP[S/D][D/S/E/G][S/A]YTKYNQKFKA (SEQ ID NO: l 157).
  • the bispecific antibody comprises a heavy chain CDR3 sequence having the consensus sequence ARSGxxxPx (SEQ ID NO: 1 163).
  • the heavy chain CDR3 consensus sequence comprises the sequence ARSG[V/A/G][A/S][F/L]P[Y/S] (SEQ ID NO: 1164).
  • the bispecific antibody comprises a light chain CDR1 sequence having the consensus sequence KASQxVxxxVA (SEQ ID NO: 1 119).
  • the light chain CDR1 consensus sequence comprises the sequence KASQ[D/N]V[G/S][T/R/S][N/A]VA (SEQ ID NO: 1 120).
  • the bispecific antibody comprises a light chain CDR1 sequence having the consensus sequence KASQxVGxNVA (SEQ ID NO: 1121).
  • the light chain CDR1 consensus sequence comprises the sequence KASQ[D/N]VG[R/S/T]NVA (SEQ ID NO: 1 122).
  • the bispecific antibody comprises a light chain CDR2 sequence having the consensus sequence SASxxYS (SEQ ID NO: 1129).
  • the light chain CDR2 consensus sequence comprises the sequence SAS[H/Y][R/Y/N/M/Q/K/L/W]YS (SEQ ID NO: 1 130).
  • the bispecific antibody comprises a light chain CDR2 sequence having the consensus sequence SASHxYS (SEQ ID NO: 1131). In some embodiments, the light chain CDR2 consensus sequence comprises the sequence SASH[R/Y N/M/Q/K/L]YS (SEQ ID NO: 1132). [0451] In some embodiments, the bispecific antibody comprises a light chain CDR3 sequence having the consensus sequence QQYxxYxYT (SEQ ID NO: 1137). In some embodiments, the light chain CDR3 consensus sequence comprises the sequence QQY[N/S/Q/Y][S/A]Y[P/A/M]YT (SEQ ID NO: 1138).
  • the light chain CDR3 consensus sequence comprises the sequence QQY[N/S/Q/Y][S/A]Y[P/A]YT (SEQ ID NO: 1 139).
  • a bispecific antibody comprises:
  • a first antigen-binding portion comprising a first variable region that specifically binds to a Tau protein, wherein the first variable region comprises one or more CDR, heavy chain, and/or light chain sequences corresponding to anti-Tau antibody clone 1C7 (e.g., a chimeric 1C7, humanized 1C7, or affinity matured 1C7 sequence as disclosed herein); and
  • a second antigen-binding portion comprising a second variable region that specifically binds to a BACE1 protein, wherein the second variable region comprises one or more CDR, heavy chain, and/or light chain sequences corresponding to anti-BACEl antibody clone 1A1 1 (e.g., a chimeric 1A11 or a humanized 1A1 1 variant sequence as disclosed herein).
  • the first antigen-binding portion comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: l l, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 12, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 13, a CDR-Ll comprising the amino acid sequence of SEQ ID NO: 14, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 15, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 16.
  • the first antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:23, and/or a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:24.
  • sequence identity e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity
  • the first antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:23 and/or a light chain variable region comprising the amino acid sequence of SEQ ID NO:24.
  • the second antigen-binding portion comprises a CDR-H1 comprising the amino acid sequence of any one of SEQ ID NOs:70, 719, 720, 721, 722, or 723, a CDR-H2 comprising the amino acid sequence of any one of SEQ ID NOs:71, 72, 540, 541, 724, 725, or 726, a CDR-H3 comprising the amino acid sequence of any one of SEQ ID NOs:73, 542, 543, 544, 545, 546, 547, 548, and 549, a CDR-Ll comprising the amino acid sequence of SEQ ID NO:74, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:75, and a CDR-L3 comprising the amino acid sequence
  • the second antigen comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to any one of SEQ ID NOs:66, 77, 78, 79, 80, 81, 82, 83, 84, 733, 734, 735, or 736 and/or a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to any one of SEQ ID NOs:67, 85, 86, 737, 738, or 739.
  • sequence identity e.g., at least 91%, at least 92%, at least 93%, at
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of any one of SEQ ID NOs:66, 77, 78, 79, 80, 81, 82, 83, 84, 733, 734, 735, or 736 and/or a light chain variable region comprising the amino acid sequence of any one of SEQ ID NOs:67, 85, 86, 737, 738, or 739.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 80 and comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 86.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:733 and comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:737. In some embodiments, the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ED NO:734 and comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:738. In some embodiments, the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:735 and comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:739. In some embodiments, the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:736 and comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:86.
  • the first antigen-binding portion comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:555 or 556, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:572, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 13, a CDR-L1 comprising the amino acid sequence of SEQ ID NO:57 or 525, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 15, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 16 or 536.
  • the first antigen- binding portion comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:555, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:572, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 13, a CDR-Ll comprising the amino acid sequence of SEQ ID NO:57, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 15, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 16.
  • the first antigen-binding portion comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:555, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:572, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 13, a CDR-Ll comprising the amino acid sequence of SEQ ID NO:57, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 15, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:536.
  • the first antigen-binding portion comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:555, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 572, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 13, a CDR-Ll comprising the amino acid sequence of SEQ ID NO:525, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 15, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:536.
  • the first antigen-binding portion comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:556, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:572, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 13, a CDR-Ll comprising the amino acid sequence of SEQ ID NO:57, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 15, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 16.
  • the first antigen-binding portion comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:556, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:572, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 13, a CDR-Ll comprising the amino acid sequence of SEQ ID NO:57, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 15, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:536.
  • the first antigen-binding portion comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:556, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:572, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 13, a CDR-Ll comprising the amino acid sequence of SEQ ID NO:525, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 15, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:536.
  • the first antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:570 or 571, and/or a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to any one of SEQ ID NOs:573, 585, and 586.
  • sequence identity e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity
  • the first antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:570 or 571 and/or a light chain variable region comprising the amino acid sequence of any one of SEQ ID NOs:573, 585, and 586 (e.g., the heavy chain sequence of SEQ ID NO:570 and the light chain sequence of SEQ ID NO: 573; the heavy chain sequence of SEQ ID NO: 570 and the light chain sequence of SEQ ID NO: 585; the heavy chain sequence of SEQ ID NO: 570 and the light chain sequence of SEQ ID NO: 586; the heavy chain sequence of SEQ ID NO: 571 and the light chain sequence of SEQ ID NO: 573; the heavy chain sequence of SEQ ID NO:571 and the light chain sequence of SEQ ID NO:585; or the heavy chain sequence of SEQ ID NO:571 and the light chain sequence of SEQ ID NO:586).
  • the heavy chain sequence of SEQ ID NO:570 and the light chain sequence of SEQ ID NO: 573 the heavy
  • the second antigen-binding portion comprises a CDR-H1 comprising the amino acid sequence of any one of SEQ ID NOs:70, 719, 720, 721, 722, or 723, a CDR-H2 comprising the amino acid sequence of any one of SEQ ID NOs:71, 72, 540, 541, 724, 725, or 726, a CDR-H3 comprising the amino acid sequence of any one of SEQ ID NOs:73, 542, 543, 544, 545, 546, 547, 548, and 549, a CDR-L1 comprising the amino acid sequence of SEQ ID NO:74, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:75, and a CDR-L3 comprising the amino acid sequence of any one of SEQ ID NOs:76, 550, 551, 552, 553, 554, 727, 728, 729, 730, 731, or 732.
  • the second antigen comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%), at least 97%, at least 98%, or at least 99% sequence identity) to any one of SEQ ID NOs:66, 77, 78, 79, 80, 81, 82, 83, 84, 733, 734, 735, or 736 and/or a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to any one of SEQ ID NOs:67, 85, 86, 737, 738, or 739.
  • sequence identity e.g., at least 91%, at least 92%, at least 93%,
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of any one of SEQ ID NOs:66, 77, 78, 79, 80, 81, 82, 83, 84, 733, 734, 735, or 736 and/or a light chain variable region comprising the amino acid sequence of any one of SEQ ID NOs:67, 85, 86, 737, 738, or 739.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:80 and comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 86.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ED NO:733 and comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:737. In some embodiments, the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:734 and comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:738. In some embodiments, the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:735 and comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:739. In some embodiments, the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:736 and comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:86.
  • a bispecific antibody comprises:
  • a first antigen-binding portion comprising a first variable region that specifically binds to a Tau protein, wherein the first variable region comprises one or more CDR, heavy chain, and/or light chain sequences corresponding to anti-Tau antibody clone 1C7 (e.g., a chimeric 1C7, humanized 1C7, or affinity matured 1C7 sequence as disclosed herein); and
  • a second antigen-binding portion comprising a second variable region that specifically binds to a BACEl protein, wherein the second variable region comprises one or more CDR, heavy chain, and/or light chain sequences corresponding to anti-BACEl antibody clone 2H8 (e.g., a chimeric 2H8, a humanized 2H8, or 2H8 variant sequence as disclosed herein).
  • the first antigen-binding portion comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: l l, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 12, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 13, a CDR-Ll comprising the amino acid sequence of SEQ ID NO: 14, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 15, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 16.
  • the first antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:23, and/or a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:24.
  • sequence identity e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity
  • the first antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:23 and/or a light chain variable region comprising the amino acid sequence of SEQ ID NO:24.
  • the second antigen-binding portion comprises a CDR-H1 comprising the amino acid sequence of any one of SEQ ID NOs: 128, 243, 244, or 245, a CDR-H2 comprising the amino acid sequence of any one of SEQ ID NOs: 150, 246, 247, 248, 249, or 250, a CDR-H3 comprising the amino acid sequence of any one of SEQ ID NOs: 172 or 251, a CDR-L1 comprising the amino acid sequence of any one of SEQ ID NOs:32, 196, 208, or 258, a CDR-L2 comprising the amino acid sequence of any one of SEQ ID NOs:210, 216, or
  • the second antigen-binding portion comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 128, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 150, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 172, a CDR-L1 comprising the amino acid sequence of SEQ ID NO:208, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:210, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:222.
  • the second antigen comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to any one of SEQ ID NOs: 109, 238, 239, 240, 241, 242, 261, 262, 263, 264, 265, or 266 and/or a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to any one of SEQ ID NOs: 194, 252, 253, 254, 255, 256, 257, 267, 268, 269, 270, or 271.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of any one of SEQ ID NOs: 109, 238, 239, 240, 241, 242, 261, 262, 263, 264, 265, or 266 and/or a light chain variable region comprising the amino acid sequence of any one of SEQ ID NOs: 194, 252, 253, 254, 255, 256, 257, 267, 268, 269, 270, or 271.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 109 and comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 194.
  • the first antigen-binding portion comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:555 or 556, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:572, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 13, a CDR-L1 comprising the amino acid sequence of SEQ ID NO:57 or 525, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 15, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 16 or 536.
  • the first antigen- binding portion comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:555, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:572, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 13, a CDR-L1 comprising the amino acid sequence of SEQ ID NO:57, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 15, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 16.
  • the first antigen-binding portion comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:555, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:572, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 13, a CDR-L1 comprising the amino acid sequence of SEQ ID NO:57, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 15, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:536.
  • the first antigen-binding portion comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:555, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 572, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 13, a CDR-L1 comprising the amino acid sequence of SEQ ID NO:525, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 15, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:536.
  • the first antigen-binding portion comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:556, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:572, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 13, a CDR-L1 comprising the amino acid sequence of SEQ ID NO:57, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 15, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 16.
  • the first antigen-binding portion comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:556, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:572, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 13, a CDR-L1 comprising the amino acid sequence of SEQ ID NO:57, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 15, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:536.
  • the first antigen-binding portion comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:556, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:572, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 13, a CDR-L1 comprising the amino acid sequence of SEQ ID NO:525, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 15, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:536.
  • the first antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:570 or 571, and/or a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to any one of SEQ ID NOs:573, 585, and 586.
  • sequence identity e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity
  • the first antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:570 or 571 and/or a light chain variable region comprising the amino acid sequence of any one of SEQ ID NOs:573, 585, and 586 (e.g., the heavy chain sequence of SEQ ID NO:570 and the light chain sequence of SEQ ID NO: 573; the heavy chain sequence of SEQ ID NO: 570 and the light chain sequence of SEQ ID NO: 585; the heavy chain sequence of SEQ ID NO: 570 and the light chain sequence of SEQ ID NO: 586; the heavy chain sequence of SEQ ID NO: 571 and the light chain sequence of SEQ ID NO: 573; the heavy chain sequence of SEQ ID NO:571 and the light chain sequence of SEQ ID NO:585; or the heavy chain sequence of SEQ ID NO:571 and the light chain sequence of SEQ ID NO:586).
  • the heavy chain sequence of SEQ ID NO:570 and the light chain sequence of SEQ ID NO: 573 the heavy
  • the second antigen-binding portion comprises a CDR-H1 comprising the amino acid sequence of any one of SEQ ID NOs: 128, 243, 244, or 245, a CDR-H2 comprising the amino acid sequence of any one of SEQ ID NOs: 150, 246, 247, 248, 249, or 250, a CDR-H3 comprising the amino acid sequence of any one of SEQ ID NOs: 172 or 251, a CDR-L1 comprising the amino acid sequence of any one of SEQ ID NOs:32, 196, 208, or 258, a CDR- L2 comprising the amino acid sequence of any one of SEQ ID NOs:210, 216, or 259, and a CDR-L3 comprising the amino acid sequence of any one of SEQ ID NOs:222 or 260.
  • a CDR-H1 comprising the amino acid sequence of any one of SEQ ID NOs: 128, 243, 244, or 245, a CDR-H2 comprising the amino acid sequence of any one
  • the second antigen-binding portion comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 128, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 150, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 172, a CDR-L1 comprising the amino acid sequence of SEQ ID NO:208, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:210, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:222.
  • the second antigen comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to any one of SEQ ID NOs: 109, 238, 239, 240, 241, 242, 261, 262, 263, 264, 265, or 266 and/or a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to any one of SEQ ID NOs: 194, 252, 253, 254, 255, 256, 257, 267, 268, 269, 270, or 271.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of any one of SEQ ID NOs: 109, 238, 239, 240, 241, 242, 261, 262, 263, 264, 265, or 266 and/or a light chain variable region comprising the amino acid sequence of any one of SEQ ID NOs: 194, 252, 253, 254, 255, 256, 257, 267, 268, 269, 270, or 271.
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 109 and comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 194.
  • the first antigen-binding portion comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:555, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 572, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 13, a CDR-L1 comprising the amino acid sequence of SEQ ID NO:525, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 15, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:536.
  • the first antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:570 and a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO:586.
  • sequence identity e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity
  • the first antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:570 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:586.
  • the second antigen-binding portion comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 128, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 1149 or SEQ ID NO: 1153, a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 1 160, a CDR-L1 comprising the amino acid sequence of SEQ ID NO:208, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 1123, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 1135.
  • the second antigen-binding portion comprises a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 1 192 or SEQ ID NO: 1193 and a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity (e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to SEQ ID NO: 1191.
  • sequence identity e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity
  • the second antigen-binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1 192 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 1191. In some embodiments, the second antigen- binding portion comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1 193 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 1 191. IV. HUMANIZED ANTI-BACE1 ANTIBODIES
  • humanized antibodies and antigen-binding portions of antibodies comprising a variable region that specifically bind to a BACE1 protein are provided.
  • the antibody comprises a variable region that specifically binds to a human BACE1 protein.
  • the anti-BACEl antibody is selective for BACE1 over other beta-secretase proteins (e.g., BACE2).
  • a humanized anti-BACEl antibody comprises a variable region that binds to the ectodomain of BACE1.
  • a humanized anti- BACE1 antibody recognizes an epitope within residues 314-460 of human BACE1 protein (SEQ ID NO:64).
  • the epitope is a linear epitope.
  • the epitope is a discontinuous or conformational epitope.
  • a humanized anti-BACEl antibody recognizes an epitope that is the same or substantially the same as the epitope recognized by an antibody clone as described herein.
  • a humanized anti-BACEl antibody recognizes an epitope that is the same or substantially the same as the epitope recognized by an antibody produced by the hybridoma cell line MAB-Bl-lAl 1, deposited as Accession Number LMBP 6871CB as deposited under the provisions of the Budapest Treaty with the Belgian Coordinated Collections of Micro-organisms, Zwijnaarde, Belgium, on May 13, 2009.
  • the term "substantially the same,” as used with reference to an epitope recognized by a reference antibody, means that the anti-BACEl antibody recognizes an epitope that is identical, within, or nearly identical to (e.g., has at least 90% sequence identity to, or has one, two, or three amino acid substitutions, e.g., conservative substitutions, relative to), or has substantial overlap with (e.g., at least 50%, 60%, 70%, 80%, 90%, or 95% overlap with) the epitope recognized by the reference antibody (e.g., an antibody clone as described herein or an antibody produced by the hybridoma cell line MAB-Bl-lAl 1).
  • the reference antibody e.g., an antibody clone as described herein or an antibody produced by the hybridoma cell line MAB-Bl-lAl 1).
  • the humanized anti-BACEl antibody recognizes an epitope that is the same or substantially the same as the epitope recognized by an antibody clone selected from the group consisting of hulAll.vl, hulAll.v2, hulAll.v3, hulAll.v4, hulAll.v5, hulAll.v6, hulAll.v7, hulAll.v8, hulAll.v9, hulAll.vlO, hulAll.vll, hulAll.vl2, hulAll.vl3, hulAll.vH, hulAll.vl5, and hulAll.vl6.
  • the humanized anti-BACEl antibody recognizes an epitope that is identical to the epitope recognized by an antibody clone selected from the group consisting of hulAll.vl, hulAll.v2, hulAll.v3, hulAll.v4, hulAll.v5, hulAll.v6, hulAll.v7, hulAll.v8, hulAll.v9, hulAll.vlO, hulAll.vll, hulAll.vl2, hulAll.vl3, hulAll.vl4, hulAll.vl5, and hulAll.vl6.
  • the humanized anti-BACEl antibody recognizes an epitope that is within the epitope recognized by an antibody clone selected from the group consisting of hulAll.vl, hulAll.v2, hulAll.v3, hulAll.v4, hulAll.v5, hulAll.v6, hulAll.v7, hulAll.v8, hulAll.v9, hulAll.vlO, hulAll.vll, hulAll.vl2, hulAll.vl3, hulAll.vH, hulAll.vl5, and hulAll.vl6.
  • the humanized anti-BACEl antibody recognizes an epitope that has at least 90% identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) to the epitope recognized by an antibody clone selected from the group consisting of hulAll.vl, hulAll.v2, hulAll.v3, hulAll.v4, hulAll.v5, hulAll.v6, hulAll.v7, hulAll.v8, hulAll.v9, hulAll.vlO, hulAll.vll, hulAll.vl2, hulAll.vl3, hulAll.vl4, hulAll.vl5, and hulAll.vl6.
  • an antibody clone selected from the group consisting of hulAll.vl, hulAll.v2, hulAll.v3, hulAll.v4, hulAll.v5, h
  • the humanized anti-BACEl antibody recognizes an epitope that has one, two, or three amino acid substitutions (e.g., conservative substitutions) relative to the epitope recognized by an antibody clone selected from the group consisting of hulAll.vl, hulAll.v2, hulAll.v3, hulAll.v4, hulAll.v5, hulAll.v6, hulAll.v7, hulAll.v8, hulAll.v9, hulAll.vlO, hulAll.vll, hulAll.vl2, hulAll.vl3, hulAll.vl4, hulAll.vl5, and hulAl l.vl6.
  • an antibody clone selected from the group consisting of hulAll.vl, hulAll.v2, hulAll.v3, hulAll.v4, hulAll.v5, hulAll.vl6, hulAll.v7, h
  • the humanized anti-BACEl antibody recognizes an epitope that substantially overlaps (e.g., has at least 50%, 60%, 70%, 80%, 90%, or 95% overlap) with the epitope recognized by an antibody clone selected from the group consisting of hulAll.vl, hulAll.v2, hulAll.v3, hulAll.v4, hulAll.v5, hulAll.v6, hulAll.v7, hulAll.v8, hulAll.v9, hulAll.vlO, hulAll.vll, hulAll.vl2, hulAll.vl3, hulAll.vl4, hulAll.vl5, andhulAll.vl6.
  • a humanized antibody that specifically binds to human BACEl protein exhibits cross-reactivity with one or more other BACEl proteins of another species.
  • a humanized anti-BACEl antibody that specifically binds to human BACEl exhibits cross-reactivity with a cynomolgus monkey ("cyno") BACEl protein.
  • a humanized anti-BACEl antibody that specifically binds to human BACEl exhibits cross-reactivity with a mouse BACEl protein.
  • a humanized anti-BACEl antibody that specifically binds to human BACEl exhibits cross-reactivity with a rat BACEl protein.
  • an antibody that specifically binds to human BACEl protein exhibits cross-reactivity with one, two, or all three of mouse BACEl, cyno BACEl, and rat BACEl.
  • a humanized anti-BACEl antibody exhibits cross-reactivity with human BACEl, cyno BACEl, and mouse BACEl.
  • a humanized antibody or antigen-binding portion thereof that specifically binds to a human BACEl protein comprises a light chain sequence, or a portion thereof, and/or a heavy chain sequence, or a portion thereof, derived from any of the following anti-BACEl antibodies described herein: Clone hulAll.vl, Clone hulAll.v2, Clone hulAll.v3, Clone hulAll.v4, Clone hulAll.v5, Clone hulAll.v6, Clone hulAll.v7, Clone hulAll.v8, Clone hulAll.v9, Clone hulAll.vlO, Clone hulAll.vll, Clone hulAll.vl2, Clone hulAll.vl3, Clone hulAll.vl4, Clone hulAll.vl 5, or Clone hulAll.vl6.
  • the amino acid sequences of the light chain variable region (VL) and heavy chain variable region (VH) of these humanized anti-BACEl antibodies are as follows: Clone hulAll.vl (e.g., SEQ ID NOs:77 and 85), Clone hulAll.v2 (e.g., SEQ ID NOs:78 and 85), Clone hulAll.v3 (e.g., SEQ ID NOs:79 and 85), Clone hulAll.v4 (e.g., SEQ ID NOs:80 and 85), Clone hulAll.v5 (e.g., SEQ ID NOs:81 and 85), Clone hulAll.v6 (e.g., SEQ ID NOs:82 and 85), Clone hulAll.v7 (e.g., SEQ ID NOs:83 and 85), Clone hulAll.v8 (e.g., SEQ ID NOs:84 and 85), Clone hulAll.v9 (e.g., SEQ
  • the antibody comprises one or more CDR, heavy chain, and/or light chain sequences that are an affinity matured form of a CDR, heavy chain, and/or light chain sequence from Clone hulAll.vl, Clone hulAll.v2, Clone hulAll.v3, Clone hulAll.v4, Clone hulAll.v5, Clone hulAll.v6, Clone hulAll.v7, Clone hulAll.v8, Clone hulAll.v9, Clone hulAll.vlO, Clone hulAll.vll, Clone hulAll.vl2, Clone hulAll.vl3, Clone hul Al l.vl4, Clone hulAl 1.vl5, or Clone hulAl 1.vl6.
  • the humanized antibody or antigen-binding portion thereof is a bivalent antibody comprising one or more CDR, heavy chain, and/or light chain sequences derived from an anti-BACEl antibody as described herein (e.g., Clone hulAll.vl, Clone hulAll.v2, Clone hulAll.v3, Clone hulAll.v4, Clone hulAll.v5, Clone hulAll.v6, Clone hulAll.v7, Clone hulAll.v8, Clone hulAll.v9, Clone hulAll.vlO, Clone hulAll.vll, Clone hulAll.vl2, Clone hulAll.vl3, Clone hulAll.vM, Clone hulAll.vl 5, or Clone hulAll.vl6).
  • Clone hulAll.vl Clone hulAll.v2, Clone hulAll.v3, Clone hulAll.vM, Clone
  • a humanized anti-BACEl antibody comprises one or more CDRs selected from the group consisting of: (a) a CDR-H1 having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs:70, 719, 720, 721, 722, 723, or 746-834, or having up to two amino acid substitutions relative to the amino acid sequence of any one of SEQ ID NOs:70, 719, 720, 721, 722, 723, or 746-834;
  • a CDR-H2 having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs:72, 540, 541, 724, 725, 726, or 835-878, or having up to two amino acid substitutions relative to the amino acid sequence of any one of SEQ ID NOs:72, 540, 541, 724, 725, 726, or 835-878;
  • a CDR-H3 having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs:73, 542, 543, 544, 545, 546, 547, 548, 549, or 879-940, or having up to two amino acid substitutions relative to the amino acid sequence of any one of SEQ ID NOs:73, 542, 543, 544, 545, 546, 547, 548, 549, or 879-940;
  • a CDR-L2 having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs:75 or 968-1040, or having up to two amino acid substitutions relative to the amino acid sequence of any one of SEQ ID NOs:75 or 968-1040;
  • a CDR-L3 having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs:76, 550, 551, 552, 553, 554, 727, 728, 729, 730, 731, 732, or 1041-1118, or having up to two amino acid substitutions relative to the amino acid sequence of any one of SEQ ID NO:76, 550, 551, 552, 553, 554, 727, 728, 729, 730, 731, 732, or 1041-1 1 18.
  • the humanized anti-BACEl antibody comprises one or more CDRs selected from the group consisting of:
  • a CDR-H2 comprising the amino acid sequence of any one of SEQ ID NOs:72, 540, 541, 724, 725, 726, or 835-878;
  • a CDR-H3 comprising the amino acid sequence of any one of SEQ ID NOs:73, 542, 543, 544, 545, 546, 547, 548, 549, or 879-940;
  • a CDR-Ll comprising the amino acid sequence of any one of SEQ ID NOs:74 or 941-967;
  • a humanized anti-BACEl antibody comprises two, three, four, five, or all six of (a)-(f).
  • the anti-BACEl antibody comprises the heavy chain CDR1 of (a), the heavy chain CDR2 of (b), and the heavy chain CDR3 of (c).
  • the anti-BACEl antibody comprises the light chain CDR1 of (d), the light chain CDR2 of (e), and the light chain CDR3 of (f).
  • the humanized anti-BACEl antibody comprises a CDR-H1 comprising the amino acid sequence of any one of SEQ ID NO: 7, 719, 720, 721, 722, or 723, a CDR-H2 comprising the amino acid sequence of any one of SEQ ID NOs:72, 540, 541, 724, 725, 726, or 843, a CDR-H3 comprising the amino acid sequence of any one of SEQ ID NOs:73, 542, 543, 544, 545, 546, 547, 548, 549, or 915, a CDR-Ll comprising the amino acid sequence of SEQ ID NO:74, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:75 or 1015, and a CDR-L3 comprising the amino acid sequence of any one of SEQ ID NOs:76, 550, 551, 552, 553, 554, 727, 728, 729, 730, 731, 732, or 1 112.
  • an anti-BACEl antibody comprises one or more sequences that are variants of one or more consensus sequences.
  • consensus sequences can be identified by aligning heavy chain or light chain sequences (e.g., CDRs) for antibodies that are from the same (or similar) germlines.
  • consensus sequences may be generated from antibodies that contain sequences that are of the same (or similar) length and/or have at least one highly similar CDR (e.g., highly similar CDR3).
  • sequences in these antibodies may be aligned and compared to identify conserved amino acids or motifs (i.e., where alteration in sequences may alter protein function) and/or regions where variation occurs the sequences (i.e., where variation of sequence is not likely to significantly affect protein function).
  • consensus sequences can be identified by aligning heavy chain or light chain sequences (e.g., CDRs) for antibodies that bind to the same or similar (e.g., overlapping) epitopes to determine conserved amino acids or motifs (i.e., where alteration in sequences may alter protein function) and regions where variation occurs in alignment of sequences (i.e., where variation of sequence is not likely to significantly affect protein function).
  • one or more consensus sequences can be identified by aligning heavy chain or light chain sequences (e.g., CDRs) for sequences disclosed in Table 16, e.g., for sequences that are affinity matured variants of a humanized 1A11 antibody such as hulAl l .vl2.
  • one or more consensus sequences can be identified for antibodies that recognize the same or similar epitope as an anti-BACEl antibody as disclosed herein.
  • Exemplary consensus sequences include SEQ ID NOs:740-745.
  • the capitalized letter represents an amino acid residue that is absolutely conserved among the aligned sequences (e.g., aligned CDR sequences), while "X” represents an amino acid residue that is not absolutely conserved among the aligned sequences. It will be appreciated that when selecting an amino acid to insert at a position marked by an "X" that in some embodiments, the amino acid is selected from those amino acids found at the corresponding position in the aligned sequences.
  • the antibody comprises a heavy chain CDR1 (CDR-H1) consensus sequence comprising the formula G-Y-X1-X2-X3-X4-X5-G-X6-X7 (I) (SEQ ID NO:740), wherein: Xi is T, A, D, E, K, L, N, P, Q, R, S, or V; X 2 is F, I, L, or Y; X 3 is T, A,
  • X 4 is T, S, K, R, A, I, N, or L;
  • Xs is Y, H, or N;
  • Xe is M, I, L, or V; and
  • Xv is S, A, F, G, H, T, V, or Y.

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Abstract

Selon un aspect, l'invention concerne des anticorps bispécifiques qui se lient de manière spécifique à une protéine Tau et à une protéine bêta-secrétase 1 (BACE1). Dans certains modes de réalisation, l'anticorps bispécifique comprend une première partie de liaison à l'antigène comprenant une première région variable qui se lie spécifiquement à une protéine Tau et une seconde partie de liaison à l'antigène comprenant une seconde région variable qui se lie spécifiquement à une protéine BACE1.
PCT/US2018/059801 2017-11-08 2018-11-08 Anticorps bispécifiques bace-tau WO2019094576A1 (fr)

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