WO2020163817A1 - Antibodies recognizing tau - Google Patents

Antibodies recognizing tau Download PDF

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Publication number
WO2020163817A1
WO2020163817A1 PCT/US2020/017357 US2020017357W WO2020163817A1 WO 2020163817 A1 WO2020163817 A1 WO 2020163817A1 US 2020017357 W US2020017357 W US 2020017357W WO 2020163817 A1 WO2020163817 A1 WO 2020163817A1
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WIPO (PCT)
Prior art keywords
seq
amino acid
occupied
chain variable
variable region
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
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PCT/US2020/017357
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English (en)
French (fr)
Inventor
Philip James Dolan Iii
Tarlochan S. Nijjar
Svetlana Alexander
Robin Barbour
Stephen Jed TAM
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Prothena Biosciences Ltd
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Prothena Biosciences Ltd
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Priority to EA202192113A priority Critical patent/EA202192113A1/ru
Priority to CN202510128272.8A priority patent/CN119954947A/zh
Priority to CA3128392A priority patent/CA3128392A1/en
Priority to JP2021569259A priority patent/JP7681316B2/ja
Priority to AU2020219374A priority patent/AU2020219374A1/en
Priority to SG11202106717PA priority patent/SG11202106717PA/en
Priority to US17/429,288 priority patent/US20220275067A1/en
Priority to KR1020217028112A priority patent/KR20210125037A/ko
Priority to EP20753068.4A priority patent/EP3921343A4/en
Priority to MX2021009440A priority patent/MX2021009440A/es
Priority to CN202080018281.7A priority patent/CN113597431B/zh
Priority to BR112021015501-5A priority patent/BR112021015501A2/pt
Application filed by Prothena Biosciences Ltd filed Critical Prothena Biosciences Ltd
Priority to PE2021001286A priority patent/PE20211709A1/es
Publication of WO2020163817A1 publication Critical patent/WO2020163817A1/en
Priority to IL285444A priority patent/IL285444A/en
Anticipated expiration legal-status Critical
Priority to CONC2021/0011140A priority patent/CO2021011140A2/es
Priority to JP2024209068A priority patent/JP7843068B2/ja
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4711—Alzheimer's disease; Amyloid plaque core protein
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • 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
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/567—Framework region [FR]
    • 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
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • 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
    • C07K2317/77—Internalization into the cell
    • 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
    • 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
    • C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/70—Mechanisms involved in disease identification
    • G01N2800/7047—Fibrils-Filaments-Plaque formation

Definitions

  • Tau is a well-known human protein that can exist in phosphorylated forms (see, e.g., Goedert, Proc. Natl. Acad. Sci. U.S.A. 85:4051-4055(1988); Goedert, EMBO J. 8:393- 399(1989); Lee, Neuron 2: 1615-1624(1989); Goedert, Neuron 3:519-526(1989); Andreadis, Biochemistry 31 : 10626-10633(1992). Tau has been reported to have a role in stabilizing microtubules, particularly in the central nervous system.
  • Total tau t-tau, i.e., phosphorylated and unphosphorylated forms
  • phospho-tau i.e., phosphorylated tau
  • Tau is the principal constituent of neurofibrillary tangles, which together with plaques are a hallmark characteristic of Alzheimer’s disease.
  • the tangles constitute abnormal fibrils measuring 10 nm in diameter occurring in pairs wound in a helical fashion with a regular periodicity of 80 nm.
  • the tau within neurofibrillary tangles is abnormally phosphorylated (hyperphosphorylated) with phosphate groups attached to specific sites on the molecule.
  • Severe involvement of neurofibrillary tangles is seen in the layer II neurons of the entorhinal cortex, the CA1 and subicular regions of the hippocampus, the amygdala, and the deeper layers (layers III, V, and superficial VI) of the neocortex in Alzheimer’s disease. Hyperphosphorylated tau has also been reported to interfere with microtubule assembly, which may promote neuronal network breakdown.
  • Tau inclusions are part of the defining neurophathology of several neurodegenerative diseases including Alzheimer’s disease, frontotemporal lobar degeneration, progressive supranuclear palsy and Pick’s disease.
  • the invention provide an isolated monoclonal antibody that competes for binding to human tau with antibody 9F5.
  • the heavy chain CDR-H3 has an amino acid sequence comprising SEQ ID NO: 10.
  • the heavy chain CDR-H1 has an amino acid sequence comprising SEQ ID NO:8.
  • the light chain CDRs CDR-L1, CDR-L2 and CDR-L3 have amino acid sequences comprising SEQ ID NO: 12, 13 and 14, respectively) in some such antibodies
  • the heavy chain CDR-H1 has an amino acid sequence comprising SEQ ID NO: 8.
  • Some such antibodies comprise three light chain CDRs and three heavy chain CDRs of monoclonal antibody 9F5, wherein 9F5 is a mouse antibody characterized by a heavy chain variable region having an amino acid sequence comprising SEQ ID NO:7 and a light chain variable region having an amino acid sequence comprising SEQ ID NO: 11.
  • the three heavy chain CDRs CDR-H1, CDR-H2, and CDR- H3 are as defined by Kabat/Chothia Composite (SEQ ID NOs:8, 9, and 10, respectively), except that position H28 can be occupied by N or T, position H51 can be occupied by I or V, position H54 can be occupied by N or D, and position H56 can be occupied by D or E, and the three light chain CDRs CDR-L1, CDR-L2, and CDR-L3 are as defined by Kabat/Chothia Composite (SEQ ID NOs: 12, 13, and 14, respectively), except that position L27b is occupied by L, D, T, or Q, position L27c is occupied by L, D, G, S, E, T, N, A, P, or I, position L30 can be occupied by I,
  • position L31 can be occupied by T, N, or G
  • position L33 is occupied by L N
  • position L51 can be occupied by M
  • position L54 can be occupied by L, R, G, or T
  • position L89 is occupied by A or G
  • position L92 is occupied by L, D, E, G, Q, T, or I
  • position L93 is occupied by E or G.
  • CDR-H1 has an amino acid sequence comprising SEQ ID NO:50.
  • CDR-H2 has an amino acid sequence comprising SEQ ID NO:51.
  • CDR-H2 has an amino acid sequence comprising SEQ ID NO:52.
  • CDR-L1 has an amino acid sequence comprising any of SEQ ID NO:53, SEQ ID NO:54, and SEQ ID NOs: 172-193.
  • CDR-L2 has an amino acid sequence comprising any of SEQ ID NO:55 and SEQ ID NOs: 194-205.
  • CDR-L3 has an amino acid sequence comprising any of SEQ ID NOs:206-213.
  • CDR-H1 has an amino acid sequence comprising SEQ ID NO:50 and CDR-H2 has an amino acid sequence comprising SEQ ID NO:51.
  • CDR-L1 has an amino acid sequence comprising SEQ ID NO: 53 and CDR-L2 has an amino acid sequence comprising SEQ ID NO:55.
  • CDR-L1 has an amino acid sequence comprising SEQ ID NO:54 and CDR-L2 has an amino acid sequence comprising SEQ ID NO:55.
  • variable heavy chain has > 85% identity to human sequence.
  • variable light chain has > 85% identity to human sequence.
  • each of the variable heavy chain and variable light chain has > 85% identity to human germline sequence.
  • Some antibodies are a humanized or chimeric 9F5 antibody that specifically binds to human tau, wherein 9F5 is a mouse antibody characterized by a mature heavy chain variable region of SEQ ID NO: 7 and a mature light chain variable region of SEQ ID NO: 11.
  • Some antibodies comprise a humanized mature heavy chain variable region comprising the three heavy chain CDRs of 9F5 and a humanized mature light chain variable region comprising the three light chain CDRs of 9F5.
  • the CDRs are of a definition selected from the group of Rabat, Chothia, Kabat/Chothia Composite, AbM and Contact.
  • the humanized mature heavy chain variable region comprises the three Kabat/Chothia Composite heavy chain CDRs of 9F5 (SEQ ID NOs:8-10) and the humanized mature light chain variable region comprises the three Kabat/Chothia Composite light chain CDRs of 9F5 (SEQ ID NOs: 12-14).
  • the humanized mature heavy chain variable region comprises the three Rabat heavy chain CDRs of 9F5 (SEQ ID NO:40, SEQ ID NO:9, and SEQ ID NO: 10) and the humanized mature light chain variable region comprises the three Rabat light chain CDRs of 9F5 (SEQ ID NOs: 12-14).
  • the humanized mature heavy chain variable region comprises the three Chothia heavy chain CDRs of 9F5 (SEQ ID NO:41, SEQ ID NO:42, and SEQ ID NO: 10) and the humanized mature light chain variable region comprises the three Chothia light chain CDRs of 9F5 (SEQ ID NOs: 12- 14).
  • the humanized mature heavy chain variable region comprises the three AbM heavy chain CDRs of 9F5 (SEQ ID NO:8, SEQ ID NO:43, and SEQ ID NO: 10) and the humanized mature light chain variable region comprises the three AbM light chain CDRs of 9F5 (SEQ ID NOs: 12-14).
  • the humanized mature heavy chain variable region comprises the three Contact heavy chain CDRs of 9F5 (SEQ ID NO:44-46) and the humanized mature light chain variable region comprises the three Contact light chain CDRs of 9F5 (SEQ ID NO:47-49).
  • the antibody can be a humanized antibody, veneered antibody, or chimeric antibody.
  • Some such antibodies comprise a humanized mature heavy chain variable region having an amino acid sequence at least 90% identical to any one of SEQ ID NOs: 15-22 and SEQ ID NOs: 109-129, and a humanized mature light chain variable region having an amino acid sequence at least 90% identical to any one of SEQ ID NOs:23-29, SEQ ID NOs:61-108, and SEQ ID NOs: 130-171.
  • At least one of the following positions in the VH region is occupied by the amino acid as specified: HI is occupied by E, HI 7 is occupied by T, H20 is occupied by I, H69 is occupied by M, H75 is occupied by T, H93 is occupied by T, H94 is occupied by T, and H109 is occupied by V.
  • positions HI, H17, H20, H69, H75, H94, and H109 are occupied by E, T, I, M, T, T, T, and V, respectively.
  • at least one of the following positions in the VH region is occupied by the amino acid as specified: H66 is occupied by R and H81 is occupied by E. In some antibodies, positions H66 and H81 are occupied by R and E, respectively.
  • H23 is occupied by I and H83 is occupied by R.
  • positions H23 and H83 are occupied by K and R, respectively.
  • At least one of the following positions in the VH region is occupied by the amino acid as specified: H43 is occupied by K, H51 is occupied by V, H76 is occupied by D, M80 is occupied by M, and H108 is occupied by L. In some antibodies, positions H43, H51, H76, H80, and HI 08 are occupied by K, V, D, M, and L, respectively.
  • position H28 in the VH region is occupied by T.
  • H54 is occupied by D and H56 is occupied by E.
  • positions H54 and H56 are occupied by D and E, respectively.
  • position H40 in the VH region is occupied by A.
  • At least one of the following positions in the VH region is occupied by the amino acid as specified: H5 is occupied by V, HI 1 is occupied by V, H12 is occupied by K, H38 is occupied by R, and H42 is occupied by G. In some antibodies, positions H5, HI 1, H12, H38, and H42 are occupied by V, V, K, R, and G, respectively.
  • HI is occupied by Q or E
  • H5 is occupied by Q or V
  • HI 1 is occupied by L or V
  • H12 is occupied by V or K
  • H17 is occupied by S or T
  • H20 is occupied by L or I
  • H23 is occupied by T or K
  • H28 is occupied by N or T
  • H38 is occupied by K
  • H40 is occupied by R or A
  • H42 is occupied by E or G
  • H43 is occupied by Q or K
  • H48 is occupied by I or M
  • H51 is occupied by I or V
  • H54 is occupied by N or D
  • H56 is occupied by D or E
  • H66 is occupied by K or R
  • H69 is occupied by I or M
  • H75 is occupied by S or T
  • H76 is occupied by N or D
  • H79 is occupied by Y
  • H80 is
  • positions HI, H17, H20, H69, H75, H93, H94, and H109 in the VH region are occupied by E, T, I, M, T, T, T, and V, respectively.
  • positions HI, H17, H20, H66, H69, H75, H81, H93, H94, and H109 in the VH region are occupied by E, T, I, R, M, T, E, T, T, and V, respectively.
  • positions HI, H17, H20, H23, H28, H66, H69, H75, H81, H83, H93, H94, and H109 in the VH region are occupied by E, T, I, K, T, R, M, T, E, R, T, T, and V, respectively.
  • HI 09 in the VH region are occupied by E, T, I, K, T, K, V, D, E, R, M, T, D, M, E, R, T, T, L, and V, respectively.
  • positions HI, H17, H20, H23, H28, H40, H43, H48, H51, H54, H56, H66, H69, H75, H76, H80, H81, H83, H93, H94, H108, and H109 in the VH region are occupied by E, T, I, K, T, A, K, M, V, D, E, R, M, T, D, M, E, R, T, T, L, and V, respectively.
  • VH region are occupied by E, V, V, K, T, I, K, R, A, G, K, V, D, E, R, M, T, D, M, E, R, T, T, L, and V, respectively.
  • HI, H5, HI 1, H12, H17, H20, H23, H38, H40, H42, H43, H51, H66, H69, H75, H76, H80, H81, H83, H93, H94, H108, and H109 in the VH region are occupied by E, V, V, K, T, I, K, R, A, G, K, V, R, M, T, D, M, E, R, T, T, L, and V, respectively.
  • positions HI, H5, HI 1, H12, H17, H20, H23, H38, H42, H43, H66, H69, H75, H80, H81, H83, H93, H94, H108, and H109 in the VH region are occupied by E, V, V, K, T, I, K, Q, G, K, R, M, T, M, E, R, T, T, L, and V, respectively.
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 127.
  • positions HI, H5, HI 1, H12, H17, H20, H23, H38, H42, H43, H66, H69, H75, H80, H81, H83, H93, H94, H108, and H109 in the VH region are occupied by E, V, V, K, T, I, K, K, E, K, R, M, T, M, E, R, T, T, L, and V, respectively.
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 128.
  • positions HI, H5, HI 1, H12, H17, H20, H23, H38, H42, H43, H66, H69, H75, H80, H81, H82c, H83, H93, H94, H108, and H109 in the VH region are occupied by E, V, V, K, T, I, K, K, E, K, R, M, T, M, E, G, R, T, T, L, and V, respectively.
  • position H80 in the VH region is occupied by P. In some antibodies, position H80 in the VH region is occupied by D. In some antibodies, position H82c in the VH region is occupied by G. In some antibodies, position H82c in the VH region is occupied by D. In some antibodies, position H82 in the VH region is occupied by P. In some antibodies, position H80 in the VH region is occupied by G. In some antibodies, position H82 in the VH region is occupied by K. In some antibodies, position H82 in the VH region is occupied by R.
  • position H82 in the VH region is occupied by E. In some antibodies, position H82 in the VH region is occupied by N.
  • position H79 in the VH region is occupied by D. In some antibodies, position H79 in the VH region is occupied by N. In some antibodies, position H79 in the VH region is occupied by G. In some antibodies, position H80 in the VH region is occupied by E.
  • position H80 in the VH region is occupied by G.
  • position H82c in the VH region is occupied by S.
  • position H79 in the VH region is occupied by Q.
  • position H82a in the VH region is occupied by G.
  • At least one of the following positions in the VL region is occupied by the amino acid as specified: L7 is occupied by S, L8 is occupied by P, LI 5 is occupied by P, and L100 is occupied by Q. In some antibodies, positions L7, L8, L15, and L100 are occupied by S, P, P, and Q, respectively.
  • position L66 in the VL region is occupied by G. In some antibodies, position L64 in the VL region is occupied by S.
  • position L17 in VL region is occupied by E.
  • at least one of the following positions in the VL region is occupied by the amino acid as specified: Ll l is occupied by L, L51 is occupied by G, and L54 is occupied by R.
  • positions Ll l, L51, and L54 are occupied by L, G, and R, respectively.
  • position L30 in the VL region is occupied by Y.
  • at least one of the following positions in the VL region is occupied by the amino acid as specified: L3 is V or Q, L7 is A or S, L8 is A or P, L9 is F or L, LI 1 is N or L, L15 is L or P, L17 is T or E, L18 is S or P, L27b is L, D.
  • L27c is L, D, G, S, E, T, N, A, P, or I, L30 is I,Y, E, K, G, L31 is T, N, or G, L33 is L, N, T, S, R, or G, L37 is L, Q, G, or I, L39 is R or K, L51 is M, G, E, D, K, or I, L54 is R, G, or T, L60 is N or D, L64 is G or S, L66 is E or G, L73 is L, P, or G, L74 is R or K, L75 is I, D, P, Q, or G, L76 is S, P, or G, L77 is R or D, L78 is V, R, D, E, P, K, G, or Q, L85 is V or G, L86 is Y or T, L89 is A or G, L92 is L, D, E, G, Q, T, or I, L93 is E or G , L100 is G, L100 is
  • positions L64 and L66 in the VL region are occupied by S and G, respectively.
  • positions L7, L8, LI 5, L64, L66, and LI 00 in the VL region are occupied by S, P, P, S, G, and Q, respectively.
  • positions L7, L8, LI 5, L17, L66, and L100 in the VL region are occupied by S, P, P, E, G, and Q, respectively.
  • positions L7, L8, LI 1, L15, L17, L51, L54, L66, and L100 in the VL region are occupied by S, P, L, P, E, G, R, G, and Q, respectively.
  • the light chain variable region comprises the amino acid sequence of any of SEQ ID NOs: 133, 135-137, 142-144, 149, 158, 159 and 168. In some antibodies, the light chain variable region comprises the amino acid sequence of SEQ ID NO: 133. In some antibodies, the light chain variable region comprises the amino acid sequence of SEQ ID NO: 169.
  • the light chain variable region comprises the amino acid sequence of SEQ ID NO: 149. In some antibodies, the light chain variable region comprises the amino acid sequence of SEQ ID NO : 159.
  • positions L7, L8, LI 1, L15, L17, L30, L51, L54, L66, and L100 in the VL region are occupied by S, P, L, P, E, Y, G, R, G, and Q, respectively.
  • positions L7, L8, Ll l, L15, L17, L30, L51, L54, and L100 in the VL region are occupied by S,
  • LI 7, LI 8, L31, L39, L51, L54, L60, L66, L74, and LI 00 in the VL region are occupied by S, P, L, L, P, E, P, N, K, G, R, D, G, K, and Q, respectively.
  • positions L7, L8, Ll l, L15, L17, L39, L60, L64, L66, L74, and L100 in the VL region are occupied by S, P, L, P, E, K, N, S, G, K and Q, respectively.
  • position L3 in the VL region is occupied by Q.
  • position L27c in the VL region is occupied by D, G, I, L or S
  • position L37 in the VL region is occupied by G, I, L, or Q
  • position L51 in the VL region is occupied by E, G, I, K or M
  • position L54 in the VL region is occupied by G, L, R or T
  • position L92 in the VL region is occupied by G, I or L.
  • position L27c in the VL region is occupied by D or S
  • position L37 in the VL region is occupied by G
  • L or Q position L51 in the VL region is occupied by G or K
  • position L54 in the VL region is occupied by R
  • position L92 in the VL region is occupied by I.
  • position L27c in the VL region is occupied by D
  • position L37 in the VL region is occupied by G
  • position L51 in the VL region is occupied by G.
  • the heavy chain variable region has an amino acid sequence comprising SEQ ID NO: 127 and the light chain variable region has an amino acid sequence comprising SEQ ID NO: 149.
  • position L27c in the VL region is occupied by D
  • position L37 in the VL region is occupied by Q
  • position L51 in the VL region is occupied by G.
  • the heavy chain variable region has an amino acid sequence comprising SEQ ID NO: 127 and the light chain variable region has an amino acid sequence comprising SEQ ID NO: 137.
  • position L27c in the VL region is occupied by S
  • position L37 in the VL region is occupied by L
  • position L51 in the VL region is occupied by G.
  • the heavy chain variable region has an amino acid sequence comprising SEQ ID NO: 127 and the light chain variable region has an amino acid sequence comprising SEQ ID NO: 159.
  • position L27c in the VL region is occupied by D
  • position L37 in the VL region is occupied by Q
  • position L51 in the VL region is occupied by K
  • the heavy chain variable region has an amino acid sequence comprising SEQ ID NO: 127 and the light chain variable region has an amino acid sequence comprising SEQ ID NO: 138.
  • position L27c in the VL region is occupied by S
  • position L37 in the VL region is occupied by Q
  • position L51 in the VL region is occupied by G
  • the heavy chain variable region has an amino acid sequence comprising SEQ ID NO: 127 and the light chain variable region has an amino acid sequence comprising SEQ ID NO: 133.
  • positions L7, L8, LI 1, L15, L17, L39, L60, L64, L66, L74, and L100 in the VL region are occupied by, respectively S, P, L, P, E, K, D, S, G, K, and Q.
  • position L3 in the VL region is occupied by Q.
  • position L27c in the VL region is occupied by G or S
  • position L37 in the VL region is occupied by G, I or Q
  • position L51 in the VL region is occupied by G, I or K
  • position L54 in the VL region is occupied by G or R
  • position L92 in the VL region is occupied by G, I, or L.
  • position L27c in the VL region is occupied by G
  • position L37 in the VL region is occupied by G
  • position L51 in the VL region is occupied by G
  • position L54 in the VL region is occupied by R.
  • position L92 in the VL region is occupied by I.
  • the heavy chain variable region has an amino acid sequence comprising SEQ ID NO: 129 and the light chain variable region has an amino acid sequence comprising SEQ ID NO: 168.
  • position L51 in the VL region is occupied by E. In some antibodies, position L51 in the VL region is occupied by D. In some antibodies, position L27c in the VL region is occupied by D. In some antibodies, position L27c in the VL region is occupied by G.
  • position L27c in the VL region is occupied by S. In some antibodies, position L27c in the VL region is occupied by E. In some antibodies, position L30 in the VL region is occupied by E. In some antibodies, position L30 in the VL region is occupied by K. In some antibodies, position L27c in the VL region is occupied by T.
  • position L27c in the VL region is occupied by N.
  • position L27b in the VL region is occupied by D.
  • position L30 in the VL region is occupied by G.
  • provided position L33 in the VL region is occupied by N.
  • position L27c in the VL region is occupied by A.
  • position L33 in the VL region is occupied by T.
  • position L33 in the VL region is occupied by S.
  • position L33 in the VL region is occupied by R.
  • position L30 in the VL region is occupied by Q.
  • position L27b in the VL region is occupied by T.
  • position L31 in the VL region is occupied by G.
  • position L27b in the VL region is occupied by Q
  • position L33 in the VL region is occupied by G.
  • position L27c in the VL region is occupied by P.
  • position L78 in the VL region is occupied by R. In some antibodies, position L75 in the VL region is occupied by D. In some antibodies, position L78 in the VL region is occupied by D. In some antibodies, position L78 in the VL region is occupied by E. In some antibodies, position L78 in the VL region is occupied by P. In some antibodies, position L78 in the VL region is occupied by K.
  • position L77 in the VL region is occupied by D.
  • position L78 in the VL region is occupied by G.
  • position L76 in the VL region is occupied by P.
  • position L75 in the VL region is occupied by P.
  • provided position L75 in the VL region is occupied by Q.
  • position L75 in the VL region is occupied by G.
  • position L73 in the VL region is occupied by P.
  • position L73 in the VL region is occupied by G.
  • position L78 in the VL region is occupied by Q.
  • position L76 in the VL region is occupied by G.
  • position L92 in the VL region is occupied by D. In some antibodies, position L86 in the VL region is occupied by T. In some antibodies, position L92 in the VL region is occupied by E. In some antibodies, position L92 in the VL region is occupied by G. In some antibodies, position L92 in the VL region is occupied by Q. In some antibodies, position L93 in the VL region is occupied by G. In some antibodies, provided position L85 in the VL region is occupied by G. In some antibodies, position L92 in the VL region is occupied by T. In some antibodies, position L89 in the VL region is occupied by G.
  • positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, S, Q, G, G, and I, respectively.
  • positions L3Q, L27c, L37, L51 L54, and L92 in the VL region are occupied by Q, S, Q, G, R, and I.
  • positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, S, Q, G, T, and I, respectively.
  • positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, S, Q, G, R, and G, respectively.
  • positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, G, Q, G, R, and I, respectively.
  • positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, D, Q, G, R, and I, respectively.
  • positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, D, Q, G, R, and I, respectively.
  • L51, L54, and L92 in the VL region are occupied by Q, D, Q, K, R, and I, respectively.
  • positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, G,
  • positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q. G, Q, K, G, and I, respectively.
  • positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, S, Q, K, G, and I, respectively.
  • positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, G, G, G, R, and I, respectively.
  • positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, G, G, G, R, and I, respectively.
  • L51, L54, and L92 in the VL region are occupied by Q, G, G, G, R, and G, respectively.
  • positions L3, L27c, L37, L51, and L54 in the VL region are occupied by Q, G, G, G, and R, respectively.
  • positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, G, G, G, T, and I.
  • positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, G, G, G, T, and G, respectively.
  • positions L3, L27c, L37, L51, and L54 in the VL region are occupied by Q, G, G, G, and T, respectively.
  • positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, S, G, G, T, and I, respectively.
  • positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, D, G, G, R, and I, respectively.
  • positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, S, I, I, R, and I, respectively.
  • positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, S, Q, I, G, and I, respectively.
  • positions L3, L27c, L37, L51, and L54 in the VL region are occupied by Q, S, Q, I, and G, respectively.
  • positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, S, Q, E, R, and I, respectively.
  • positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, G, Q, E, G, and I, respectively.
  • positions L3, L27c, L37, L51, L54, and L92L in the VL region are occupied by Q, G, I, E, R, and I, respectively.
  • positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, G, I, E, R. and G, respectively.
  • positions L3, L27c, L37, L51, and L54 in the VL region are occupied by Q, I, I, E, and R, respectively.
  • positions L3, L37, L51, L54, and L92 in the VL region are occupied by Q, Q, G, R, and I, respectively.
  • positions L3, L27c, L51, L54, and L92 in the VL region are occupied by Q, S, G, R, and I, respectively.
  • positions L3, L27c, L37, L54, and L92 in the VL region are occupied by Q, S, Q, R, and I, respectively.
  • positions L3, L27c, L37, L51, and L92 in the VL region are occupied by Q, S, Q, G, and I, respectively.
  • positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, S, Q, G, G, and I.
  • positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, S, Q, G, R, and I, respectively.
  • positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, S, Q, G, R, and G, respectively.
  • positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, G, Q, G, R, and I, respectively.
  • positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, G, Q, K, R, and I , respectively.
  • positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, S, Q, K, G, and I, respectively.
  • positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, S, Q, K, G, and I, respectively.
  • L51, L54, and L92 in the VL region are occupied by Q, G, G, G, R, and I, respectively.
  • positions L3, L27c, L37, L51, and L54 in the VL region are occupied by Q, G, G, G, and R, respectively.
  • positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, S, I, I, R, and I.
  • positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, S, Q, I, G, and I, respectively.
  • Some antibodies comprise a mature heavy chain variable region having an amino acid sequence at least 95% identical to any one of SEQ ID NOs: 15-22 and SEQ ID NOs: 109-129, and a mature light chain variable region having an amino acid sequence at least 95% identical to any one of SEQ ID NOs:23-29, SEQ ID NOs:61-108, and SEQ ID NOs: 130-171.
  • Some antibodies comprise a mature heavy chain variable region having an amino acid sequence at least 98% identical to any one of SEQ ID NOs: 15-22 and SEQ ID NOs: 109-129, and a mature light chain variable region having an amino acid sequence at least 98% identical to any one of SEQ ID NOs:23-29, SEQ ID NOs:61-108, and SEQ ID NOs: 130-171.
  • the mature heavy chain variable region has an amino acid sequence of any one of SEQ ID NOs: 15-22 and SEQ ID NOs: 109-129
  • the mature light chain variable region has an amino acid sequence of any one of SEQ ID NO:23-29, SEQ ID NOs:61-108, and SEQ ID NOs: 130-171.
  • the mature heavy chain variable region has an amino acid sequence of SEQ ID NO: 15 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:23. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO: 15 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:24. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO: 15 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:25. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO: 15 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:26.
  • the mature heavy chain variable region has an amino acid sequence of SEQ ID NO: 15 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:27. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO: 15 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:28. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO: 15 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:29. [0061] In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO: 16 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:23.
  • the mature heavy chain variable region has an amino acid sequence of SEQ ID NO: 16 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:24. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO: 16 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:25. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO: 16 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:26. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO: 16 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:27.
  • the mature heavy chain variable region has an amino acid sequence of SEQ ID NO: 16 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:28. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO: 16 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:29.
  • the mature heavy chain variable region has an amino acid sequence of SEQ ID NO: 17 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:23. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO: 17 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:24. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO: 17 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:25. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO: 17 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:26.
  • the mature heavy chain variable region has an amino acid sequence of SEQ ID NO: 17 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:27. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO: 17 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:28. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO: 17 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:29. [0063] In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO: 18 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:23.
  • the mature heavy chain variable region has an amino acid sequence of SEQ ID NO: 18 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:24. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO: 18 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:25. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO: 18 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:26. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO: 18 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:27.
  • the mature heavy chain variable region has an amino acid sequence of SEQ ID NO: 18 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:28. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO: 18 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:29.
  • the mature heavy chain variable region has an amino acid sequence of SEQ ID NO: 19 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:23. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO: 19 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:24. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO: 19 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:25. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO: 19 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:26.
  • the mature heavy chain variable region has an amino acid sequence of SEQ ID NO: 19 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:27. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO: 19 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:28. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO: 19 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:29. [0065] In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO:20 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:23.
  • the mature heavy chain variable region has an amino acid sequence of SEQ ID NO:20 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:24. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO:20 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:25. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO:20 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:26. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO:20 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:27.
  • the mature heavy chain variable region has an amino acid sequence of SEQ ID NO:20 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:28. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO:20 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:29.
  • the mature heavy chain variable region has an amino acid sequence of SEQ ID NO:21 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:23. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO:21 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:24. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO:21 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:25. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO:21 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:26.
  • the mature heavy chain variable region has an amino acid sequence of SEQ ID NO:21 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:27. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO:21 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:28. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO:21 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:29. [0067] In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO:22 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:23.
  • the mature heavy chain variable region has an amino acid sequence of SEQ ID NO:22 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:24. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO:22 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:25. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO:22 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:26. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO:22 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:27.
  • the mature heavy chain variable region has an amino acid sequence of SEQ ID NO:22 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:28. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO:22 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:29.
  • the mature heavy chain variable region has an amino acid sequence of SEQ ID NO: 127 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:. 149. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO: 127 and the mature light chain variable region has an amino acid sequence of SEQ ID NO: 142. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO: 127 and the mature light chain variable region has an amino acid sequence of SEQ ID NO: 159. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO: 127 and the mature light chain variable region has an amino acid sequence of SEQ ID NO: 148.
  • the mature heavy chain variable region has an amino acid sequence of SEQ ID NO: 127 and the mature light chain variable region has an amino acid sequence of SEQ ID NO: 137. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO: 127 and the mature light chain variable region has an amino acid sequence of SEQ ID NO: 145. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO: 127 and the mature light chain variable region has an amino acid sequence of SEQ ID NO: 136. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO: 127 and the mature light chain variable region has an amino acid sequence of SEQ ID NO: 138.
  • the mature heavy chain variable region has an amino acid sequence of SEQ ID NO: 127 and the mature light chain variable region has an amino acid sequence of SEQ ID NO: 158. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO: 127 and the mature light chain variable region has an amino acid sequence of SEQ ID NO: 143. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO: 127 and the mature light chain variable region has an amino acid sequence of SEQ ID NO: 144. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO: 127 and the mature light chain variable region has an amino acid sequence of SEQ ID NO: 133.
  • the mature heavy chain variable region has an amino acid sequence of SEQ ID NO: 127 and the mature light chain variable region has an amino acid sequence of SEQ ID NO: 160. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO: 127 and the mature light chain variable region has an amino acid sequence of SEQ ID NO: 161. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO: 127 and the mature light chain variable region has an amino acid sequence of SEQ ID NO: 139. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO: 128 and the mature light chain variable region has an amino acid sequence of SEQ ID NO: 168.
  • Some such antibodies comprise three light chain CDRs and three heavy chain CDRs of monoclonal antibody 10C12, wherein 1002 is a mouse antibody characterized by a heavy chain variable region having an amino acid sequence comprising SEQ ID NO:7 and a light chain variable region having an amino acid sequence comprising SEQ ID NO: 11.
  • the three heavy chain CDRs CDR-H1, CDR-H2, and CDR-H3 are as defined by Kabat/Chothia Composite (SEQ ID NOs:8, 9, and 10, respectively), and the three light chain CDRs CDR-L1, CDR-L2, and CDR-L3 are as defined by Kabat/Chothia Composite (SEQ ID NOs: 12, 13, and 14, respectively.
  • variable heavy chain has > 85% identity to human sequence.
  • variable light chain has > 85% identity to human sequence.
  • each of the variable heavy chain and variable light chain has > 85% identity to human germline sequence.
  • Some antibodies are a humanized or chimeric 1002 antibody that specifically binds to human tau, wherein 10C12 is a mouse antibody characterized by a mature heavy chain variable region of SEQ ID NO: 7 and a mature light chain variable region of SEQ ID NO: 11.
  • Some antibodies comprise a humanized mature heavy chain variable region comprising the three heavy chain CDRs of 10C12 and a humanized mature light chain variable region comprising the three light chain CDRs of 1002.
  • the CDRs are of a definition selected from the group of Rabat, Chothia, Kabat/Chothia Composite, AbM and Contact.
  • the humanized mature heavy chain variable region comprises the three Kabat/Chothia Composite heavy chain CDRs of 1002 (SEQ ID NOs:8-10) and the humanized mature light chain variable region comprises the three Kabat/Chothia Composite light chain CDRs of 1002 (SEQ ID NOs: 12-14).
  • the humanized mature heavy chain variable region comprises the three Rabat heavy chain CDRs of 1002 (SEQ ID NO:40,
  • the humanized mature light chain variable region comprises the three Rabat light chain CDRs of 1002 (SEQ ID NOs: 12-14).
  • the humanized mature heavy chain variable region comprises the three Chothia heavy chain
  • CDRs of 1002 (SEQ ID N0:41, SEQ ID NO:42, and SEQ ID NO: 10) and the humanized mature light chain variable region comprises the three Chothia light chain CDRs of 1002 (SEQ ID N0:41, SEQ ID NO:42, and SEQ ID NO: 10) and the humanized mature light chain variable region comprises the three Chothia light chain CDRs of 1002 (SEQ ID N0:41, SEQ ID NO:42, and SEQ ID NO: 10) and the humanized mature light chain variable region comprises the three Chothia light chain CDRs of 1002 (SEQ ID N0:41, SEQ ID NO:42, and SEQ ID NO: 10) and the humanized mature light chain variable region comprises the three Chothia light chain CDRs of 1002 (SEQ ID N0:41, SEQ ID NO:42, and SEQ ID NO: 10) and the humanized mature light chain variable region comprises the three Chothia light chain CDRs of 1002 (SEQ ID N0:41, SEQ ID NO
  • the humanized mature heavy chain variable region comprises the three AbM heavy chain CDRs of 1002 (SEQ ID N0:8, SEQ ID NO:43, and SEQ
  • the humanized mature light chain variable region comprises the three AbM light chain CDRs of 1002 (SEQ ID NOs: 12-14).
  • the humanized mature heavy chain variable region comprises the three Contact heavy chain CDRs of 1002 (SEQ ID NO:44- 46) and the humanized mature light chain variable region comprises the three Contact light chain CDRs of 1002 (SEQ ID NO:47-49).
  • the antibody can a humanized antibody, veneered antibody, or chimeric antibody.
  • Some such antibodies comprise a humanized mature heavy chain variable region having an amino acid sequence at least 90% identical to any one of SEQ ID NOs:214-215 and a humanized mature light chain variable region having an amino acid sequence at least 90% identical to any one of SEQ ID NOs:216-217.
  • At least one of the following positions in the VH region is occupied by the amino acid as specified: H24 is occupied by A, H48 is occupied by I, H67 is occupied by A, H69 is occupied by M, H93 is occupied by T, and H94 is occupied by T. In some antibodies, positions H24, H48, H67, H69, H93, and H94 are occupied by A, I, A, M, T, and T, respectively.
  • At least one of the following positions in the VH region is occupied by the amino acid as specified: HI is occupied by Q or E, H24 is occupied by A, H48 is occupied by I, H67 is occupied by A, H69 is occupied by M, H93 is occupied by T, H94 is occupied by T.
  • positions H24, H48, H67, H69, H93, and H94 are occupied by A, I, A, M, T, and T, respectively.
  • positions HI, H24, H48, H67, H69, H93, and H94 are occupied by E, A, I, A, M, T, and T, respectively.
  • position L64 in the VL region is occupied by S.
  • L64 is S
  • L104 is V or L.
  • position L64 is occupied by S.
  • positions L64 and LI 04 in the VL region are occupied by S and L, respectively.
  • Some antibodies comprise a mature heavy chain variable region having an amino acid sequence at least 95% identical to any one of SEQ ID NOs:214-215 and a mature light chain variable region having an amino acid sequence at least 95% identical to any one of SEQ ID NOs:216-217.
  • Some antibodies comprise a a mature heavy chain variable region having an amino acid sequence at least 98% identical to any one of SEQ ID NOs:214-215 and a mature light chain variable region having an amino acid sequence at least 98% identical to any one of SEQ ID NOs:216-217.
  • the mature heavy chain variable region has an amino acid sequence of any one of SEQ ID NOs:214-215 and the mature light chain variable region has an amino acid sequence of any one of SEQ ID NO:216-217.
  • the mature heavy chain variable region has an amino acid sequence of SEQ ID NO:214 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:216. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO:214 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:217. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO:215 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:216. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO:215 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:217.
  • Some such antibodies comprise three light chain CDRs and three heavy chain CDRs of monoclonal antibody 12C4, wherein 12C4 is a mouse antibody characterized by a heavy chain variable region having an amino acid sequence comprising SEQ ID NO:219 and a light chain variable region having an amino acid sequence comprising SEQ ID NO: 11.
  • the three heavy chain CDRs CDR-H1, CDR-H2, and CDR-H3 are as defined by Kabat/Chothia Composite (SEQ ID NOs:8, 220, and 10, respectively), and the three light chain CDRs CDR-L1, CDR-L2, and CDR-L3 are as defined by Kabat/Chothia Composite (SEQ ID NOs: 12, 13, and 14, respectively).
  • variable heavy chain has > 85% identity to human sequence.
  • variable light chain has > 85% identity to human sequence.
  • each of the variable heavy chain and variable light chain has > 85% identity to human germline sequence.
  • Some antibodies are a humanized or chimeric 12C4 antibody that specifically binds to human tau, wherein 12C4 is a mouse antibody characterized by a mature heavy chain variable region of SEQ ID NO:219 and a mature light chain variable region of SEQ ID NO: 11.
  • Some antibodies comprise a humanized mature heavy chain variable region comprising the three heavy chain CDRs of 12C4 and a humanized mature light chain variable region comprising the three light chain CDRs of 12C4.
  • the CDRs are of a definition selected from the group of Rabat, Chothia, Kabat/Chothia Composite, AbM and Contact.
  • the humanized mature heavy chain variable region comprises the three Kabat/Chothia Composite heavy chain CDRs of 12C4 (SEQ ID NOs:8, 220, and 10) and the humanized mature light chain variable region comprises the three Kabat/Chothia Composite light chain CDRs of 12C4 (SEQ ID NOs: 12-14).
  • the humanized mature heavy chain variable region comprises the three Rabat heavy chain CDRs of 12C4 (SEQ ID NO:40, SEQ ID NO:220, and SEQ ID NO: 10) and the humanized mature light chain variable region comprises the three Rabat light chain CDRs of 12C4 (SEQ ID NOs: 12-14).
  • the humanized mature heavy chain variable region comprises the three Chothia heavy chain CDRs of 12C4 (SEQ ID NO:41, SEQ ID NO:42, and SEQ ID NO: 10) and the humanized mature light chain variable region comprises the three Chothia light chain CDRs of 12C4 (SEQ ID NOs: 12-14).
  • the humanized mature heavy chain variable region comprises the three AbM heavy chain CDRs of 12C4 (SEQ ID NO:8, SEQ ID NO:257, and SEQ ID NO: 10) and the humanized mature light chain variable region comprises the three AbM light chain CDRs of 12C4 (SEQ ID NOs: 12-14).
  • the humanized mature heavy chain variable region comprises the three Contact heavy chain CDRs of 12C4 (SEQ ID NO:44, 258, and 46) and the humanized mature light chain variable region comprises the three Contact light chain CDRs of 12C4 (SEQ ID NO:47-49).
  • the antibody can be a humanized antibody, veneered antibody, or chimeric antibody.
  • Some such antibodies comprise a humanized mature heavy chain variable region having an amino acid sequence at least 90% identical to any one of SEQ ID NOs:221-222 and a humanized mature light chain variable region having an amino acid sequence at least 90% identical to any one of SEQ ID NOs:223-224.
  • At least one of the following positions in the VH region is occupied by the amino acid as specified: HI is occupied by Q or E, H48 is occupied by M or I, H93 is occupied by A or T, H94 is occupied by R or T. In some antibodies, positions HI, H48, H93, and H94 in the VH region are occupied by E, I, T, and T, respectively.
  • positions in the VL region is occupied by the amino acid as specified: L64 is G or S, L104 is V or L. In some antibodies, positions L64 and L104 in the VL region are occupied by S and L, respectively.
  • Some antibodies comprise a mature heavy chain variable region having an amino acid sequence at least 95% identical to any one of SEQ ID NOs:221-222 and a mature light chain variable region having an amino acid sequence at least 95% identical to any one of SEQ ID NOs:223-224. Some antibodies comprise a mature heavy chain variable region having an amino acid sequence at least 98% identical to any one of SEQ ID NOs:221-222 and a mature light chain variable region having an amino acid sequence at least 98% identical to any one of SEQ ID NOs:223-224. In some antibodies, the mature heavy chain variable region has an amino acid sequence of any one of SEQ ID NOs:221-222 and the mature light chain variable region has an amino acid sequence of any one of SEQ ID NO:223-224.
  • the mature heavy chain variable region has an amino acid sequence of SEQ ID NO:221 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:223. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO:221 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:224. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO:222 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:223. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO:222 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:224
  • Some such antibodies comprise three light chain CDRs and three heavy chain CDRs of monoclonal antibody 17C12, wherein 1702 is a mouse antibody characterized by a heavy chain variable region having an amino acid sequence comprising SEQ ID NO:225 and a light chain variable region having an amino acid sequence comprising SEQ ID NO:228.
  • the three heavy chain CDRs CDR-H1, CDR-H2, and CDR-H3 are as defined by Kabat/Chothia Composite (SEQ ID NOs:226, 227, and 10, respectively), and the three light chain CDRs CDR-L1, CDR-L2, and CDR-L3 are as defined by Kabat/Chothia Composite (SEQ ID NOs:229, 230, and 231, respectively).
  • variable heavy chain has > 85% identity to human sequence.
  • variable light chain has > 85% identity to human sequence.
  • each of the variable heavy chain and variable light chain has > 85% identity to human germline sequence.
  • Some antibodies are a humanized or chimeric 1702 antibody that specifically binds to human tau, wherein 1702 is a mouse antibody characterized by a mature heavy chain variable region of SEQ ID NO:225 and a mature light chain variable region of SEQ ID NO:228. Some antibodies comprise a humanized mature heavy chain variable region comprising the three heavy chain CDRs of 1702 and a humanized mature light chain variable region comprising the three light chain CDRs of 1702. In some antibodies, the CDRs are of a definition selected from the group of Rabat, Chothia, Kabat/Chothia Composite, AbM and Contact.
  • the humanized mature heavy chain variable region comprises the three Kabat/Chothia Composite heavy chain CDRs of 1702 (SEQ ID NOs:226, 227, and 10) and the humanized mature light chain variable region comprises the three Kabat/Chothia Composite light chain CDRs of 1702 (SEQ ID NOs:229-231).
  • the humanized mature heavy chain variable region comprises the three Rabat heavy chain CDRs of 17C12 (SEQ ID NO:40, SEQ ID NO:227, and SEQ ID NO: 10) and the humanized mature light chain variable region comprises the three Kabat light chain CDRs of 1702 (SEQ ID NOs:229- 231).
  • the humanized mature heavy chain variable region comprises the three Chothia heavy chain CDRs of 1702 (SEQ ID NO:259, SEQ ID NO:42, and SEQ ID NO: 10) and the humanized mature light chain variable region comprises the three Chothia light chain CDRs of 1702 (SEQ ID NOs:229-231).
  • the humanized mature heavy chain variable region comprises the three AbM heavy chain CDRs of 1702 (SEQ ID NO:226, SEQ ID NO:260, and SEQ ID NO: 10) and the humanized mature light chain variable region comprises the three AbM light chain CDRs of 1702 (SEQ ID NOs:229-231).
  • the humanized mature heavy chain variable region comprises the three Contact heavy chain CDRs of 1702 (SEQ ID NO:44, SEQ ID NO:261, and SEQ ID NO:46) and the humanized mature light chain variable region comprises the three Contact light chain CDRs of 1702 (SEQ ID NO:262-264).
  • the antibody can be is a humanized antibody, veneered antibody, or chimeric antibody.
  • Some such antibodies comprise a humanized mature heavy chain variable region having an amino acid sequence at least 90% identical to any one of SEQ ID NOs:232-233 and a humanized mature light chain variable region having an amino acid sequence at least 90% identical to any one of SEQ ID NOs:234-235.
  • At least one of the following positions in the VH region is occupied by the amino acid as specified: H2 is occupied by I, H24 is occupied by A, H48 is occupied by I, H67 is occupied by A, H69 is occupied by M, H93 is occupied by T, and H94 is occupied by T.
  • positions H2, H24, H48, H67, H69, H93, and H94 are occupied by E, A, I,
  • At least one of the following positions in the VH region is occupied by the amino acid as specified: HI is occupied by Q or E, H2 is occupied by I, H24 is occupied by A, H48 is occupied by I, H67 is occupied by A, H69 is occupied by M, H93 is occupied by T, H94 is occupied by T, H108 is occupied by T or L, HI 13 is occupied by R or S.
  • positions H2, H24, H48, H67, H69, H93, and H94 in the VH region are occupied by E, A, I, A, M, T, and T , respectively.
  • positions HI, H2, H24, H48, H67, H69, H93, H94, H108, and HI 13 in the VH region are occupied by E, I, A, I, A, M, T. T. L, and S, respectively.
  • At least one of the following positions in the VL region is occupied by the amino acid as specified: L2 is occupied by V, and L36 is occupied by L. In some antibodies, positions L2 and L36 are occupied by V and L, respectively.
  • positions in the VL region are occupied by the amino acid as specified: L2 is V, L36 is L, L43 is P or S.
  • positions L2 and L36 in the VL region are occupied by V and L, respectively.
  • positions L2, L36, and L43 in the VL region are occupied by V, L, and S, respectively.
  • Some antibodies comprise a mature heavy chain variable region having an amino acid sequence at least 95% identical to any one of SEQ ID NOs:232-233 and a mature light chain variable region having an amino acid sequence at least 95% identical to any one of SEQ ID NOs:234-235. Some antibodies comprise a mature heavy chain variable region having an amino acid sequence at least 98% identical to any one of SEQ ID NOs:232-233 and a mature light chain variable region having an amino acid sequence at least 98% identical to any one of SEQ ID NOs:234-235. In some antibodies, the mature heavy chain variable region has an amino acid sequence of any one of SEQ ID NOs:232-233and the mature light chain variable region has an amino acid sequence of any one of SEQ ID NO:234-235.
  • the mature heavy chain variable region has an amino acid sequence of SEQ ID NO:232 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:234. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO:232 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:235. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO:233 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:234. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO:233 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:235.
  • Some such antibodies comprise three light chain CDRs and three heavy chain CDRs of monoclonal antibody 14H3, wherein 14H3 is a mouse antibody characterized by a heavy chain variable region having an amino acid sequence comprising SEQ ID NO:240 and a light chain variable region having an amino acid sequence comprising SEQ ID NO:244.
  • the three heavy chain CDRs CDR-H1, CDR-H2, and CDR-H3 are as defined by Kabat/Chothia Composite (SEQ ID NOs:241, 242, and 243, respectively), except that position H35B can be occupied by G or S, and the three light chain CDRs CDR-L1, CDR-L2, and CDR-L3 are as defined by Kabat/Chothia Composite (SEQ ID NOs:245, 246, and 247, respectively).
  • CDR-H1 has an amino acid sequence comprising SEQ ID NO:277.
  • variable heavy chain has > 85% identity to human sequence.
  • variable light chain has > 85% identity to human sequence.
  • each of the variable heavy chain and variable light chain has > 85% identity to human germline sequence.
  • Some antibodies are a humanized or chimeric 14H3 antibody that specifically binds to human tau, wherein 14H3 is a mouse antibody characterized by a mature heavy chain variable region of SEQ ID NO:240 and a mature light chain variable region of SEQ ID NO:244. Some antibodies comprise a humanized mature heavy chain variable region comprising the three heavy chain CDRs of 14H3 and a humanized mature light chain variable region comprising the three light chain CDRs of 14H3.
  • the CDRs are of a definition selected from the group of Rabat, Chothia, Kabat/Chothia Composite, AbM and Contact.
  • the humanized mature heavy chain variable region comprises the three Kabat/Chothia Composite heavy chain CDRs of 14H3 (SEQ ID NOs:241- 243) and the humanized mature light chain variable region comprises the three Kabat/Chothia Composite light chain CDRs of 14H3 (SEQ ID NOs:245-247).
  • the humanized mature heavy chain variable region comprises the three Kabat heavy chain CDRs of 14H3 (SEQ ID NO:265, SEQ ID NO:242, and SEQ ID NO:243) and the humanized mature light chain variable region comprises the three Kabat light chain CDRs of 14H3 (SEQ ID NOs:245- 247).
  • the humanized mature heavy chain variable region comprises the three Chothia heavy chain CDRs of 14H3 (SEQ ID NO:266, SEQ ID NO:267, and SEQ ID NO:243) and the humanized mature light chain variable region comprises the three Chothia light chain CDRs of 14H3 (SEQ ID NOs:245-247).
  • the humanized mature heavy chain variable region comprises the three AbM heavy chain CDRs of 14H3 (SEQ ID NO:241, SEQ ID NO:268, and SEQ ID NO:243) and the humanized mature light chain variable region comprises the three AbM light chain CDRs of 14H3 (SEQ ID NOs:245-247).
  • the humanized mature heavy chain variable region comprises the three Contact heavy chain CDRs of 14H3 (SEQ ID NO:269-271) and the humanized mature light chain variable region comprises the three Contact light chain CDRs of 14H3 (SEQ ID NO:272-274).
  • the antibody can be a humanized antibody, veneered antibody, or chimeric antibody.
  • Some such antibodies comprise a humanized mature heavy chain variable region having an amino acid sequence at least 90% identical to any one of SEQ ID NOs:248-249 and a humanized mature light chain variable region having an amino acid sequence at least 90% identical to any one of SEQ ID NOs:250-251.
  • position H35B in the VH region is occupied by S.
  • At least one of the following positions in the VH region is occupied by the amino acid as specified: H35B is occupied by S, HI 08 is occupied by M or L, HI 13 is occupied by L or S. In some antibodies, position H35B in the VH region is occupied by S. In some antibodies, positions H35B, HI 08, and HI 13 in the VH region are occupied by S, L, and S, respectively. [0115] In some antibodies, at least one of the following positions in the VL region is occupied by the amino acid as specified: L2 is occupied by V and L87 is occupied by F. In some antibodies, positions L2 and L87 are occupied by V and F, respectively.
  • At least one of the following positions in the VL region is occupied by the amino acid as specified: L2 is V, L7 is T or S, L37 is L or Q, L87 is F, L100 is G or Q, L104 is V or L.
  • positions L2 and L87 in the VL region are occupied by V and F, respectively.
  • positions L2, L7, L37, L87, L100, and L104 in the VL region are occupied by V, S, Q, F, Q, and L, respectively.
  • Some antibodies comprise a mature heavy chain variable region having an amino acid sequence at least 95% identical to any one of SEQ ID NOs:248-249 and a mature light chain variable region having an amino acid sequence at least 95% identical to any one of SEQ ID NOs:250-251.
  • Some antibodies comprise a mature heavy chain variable region having an amino acid sequence at least 98% identical to any one of SEQ ID NOs:248-249 and a mature light chain variable region having an amino acid sequence at least 98% identical to any one of SEQ ID NOs:250-251.
  • the mature heavy chain variable region has an amino acid sequence of any one of SEQ ID NOs:248-249 and the mature light chain variable region has an amino acid sequence of any one of SEQ ID NO:250-251
  • the mature heavy chain variable region has an amino acid sequence of SEQ ID NO:248 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:250. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO:248 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:251. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO:249 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:250. In some antibodies, the mature heavy chain variable region has an amino acid sequence of SEQ ID NO:249 and the mature light chain variable region has an amino acid sequence of SEQ ID NO:251. [0119] For example, the antibody can be a chimeric antibody. For example, the antibody can be a veneered antibody.
  • the antibody can be an intact antibody.
  • the antibody can be a binding fragment.
  • the binding fragment is a single-chain antibody, Fab, or Fab’2 fragment.
  • the antibody can be a Fab fragment, or single chain Fv.
  • Some of the antibodies have a human IgGl isotype, while others may have a human IgG2 or IgG4 isotype.
  • Some antibodies have the mature light chain variable region fused to a light chain constant region and the mature heavy chain variable region fused to a heavy chain constant region.
  • the heavy chain constant region of some antibodies is a mutant form of a natural human heavy chain constant region which has reduced binding to a Fey receptor relative to the natural human heavy chain constant region.
  • the heavy chain constant region is of IgGl isotype.
  • Some antibodies may have at least one mutation in the constant region, such as a mutation that reduces complement fixation or activation by the constant region, for example a mutation at one or more of positions 241, 264, 265, 270, 296, 297, 318, 320, 322, 329 and 331 by EU numbering. Some antibodies have an alanine at positions 318, 320 and 322. Some antibodies can be at least 95% w/w pure.
  • the antibody can be conjugated to a therapeutic, cytotoxic, cytostatic, neurotrophic, or neuroprotective agent.
  • the invention provides a pharmaceutical composition comprising any of the antibodies disclosed herein and a pharmaceutically-acceptable carrier.
  • the invention provides a nucleic acid encoding the heavy chain and/or light chain of any of the antibodies disclosed herein, a recombinant expression vector comprising the nucleic acid and a host cell transformed with the recombinant expression vector.
  • Some nucleic acids have a sequence comprising any one of SEQ ID NOs:38-39.
  • the invention provides a vector comprising a nucleic acid encoding a mature heavy chain variable region and a mature light chain variable region operably linked to one or more regulatory sequences to effect expression in a mammalian cell of any of the antibodies disclosed herein, a recombinant expression vector comprising the nucleic acid, a host cell transformed with the recombinant expression vector, and a host cell transformed with the nucleic acid.
  • Some nucleic acids further encode a heavy chain constant region fused to the mature heavy chain variable region and a light chain constant region fused to the mature light chain variable region.
  • the antibody is a scFv.
  • the antibody is a Fab fragment.
  • the one or more regulatory sequences include one or more of a promoter, enhancer, ribosome binding site, and transcription termination signal.
  • the nucleic acid further encodes signal peptides fused to the mature heavy and light chain variable regions.
  • the nucleic acid is codon-optimized for expression in a host cell.
  • the one or more regulatory sequences include a eukaryotic promoter.
  • the nucleic acid further encodes a selectable gene.
  • the invention provides methods of expressing an antibody in a mammalian cell comprising incorporating the nucleic acids disclosed herein into the genome of a transgenic animal, whereby the antibody is expressed.
  • the invention provides first and second vectors respectively comprising nucleic acids encoding a mature heavy chain variable region and a mature light chain variable region, each operably linked to one or more regulatory sequences to effect expression in a mammalian cell of any of the antibodies disclosed herein, and a host cell comprising the nucleic acids.
  • the nucleic acids respectively further encode a heavy chain constant region fused to the mature heavy chain variable region and a light chain constant region fused to the mature light chain variable region.
  • the invention provides methods of expressing an antibody in a mammalian cell comprising incorporating any of the nucleic acids disclosed herein into the genome of a transgenic animal, whereby the antibody is expressed.
  • the invention provides methods of humanizing any non-human antibody described herein, for example, mouse antibody 9F5, wherein 9F5 is characterized by a mature heavy chain variable region of SEQ ID NO: 7 and a mature light chain variable region of SEQ ID NO: 11, for example, mouse antibody 10C12, wherein 1002 is characterized by a mature heavy chain variable region of SEQ ID NO: 7 and a mature light chain variable region of SEQ ID NO: 11; for example, mouse antibody is 2D11, wherein 2D11 is characterized by a mature heavy chain variable region of SEQ ID NO: 7 and a mature light chain variable region of SEQ ID NO: 11; for example mouse antibody 12C4, wherein 12C4 is characterized by a mature heavy chain variable region of SEQ ID NO:219 and a mature light chain variable region of SEQ ID NO: 11; for example mouse antibody 17C12, wherein 1702 is characterized by a mature heavy chain variable region of SEQ ID NO:225 and a mature light chain variable region of SEQ
  • Such methods can involve selecting one or more acceptor antibodies, identifying the amino acid residues of the mouse antibody to be retained; synthesizing a nucleic acid encoding a humanized heavy chain comprising CDRs of the mouse antibody heavy chain and a nucleic acid encoding a humanized light chain comprising CDRs of the mouse antibody light chain, and expressing the nucleic acids in a host cell to produce a humanized antibody.
  • Methods of producing antibodies such as a humanized, chimeric or veneered antibody, for example humanized, chimeric or veneered forms of 9F5, 10C12, 2D11, 12C4, 1702, or 14H3, are also provided.
  • cells transformed with nucleic acids encoding the heavy and light chains of the antibody are cultured so that the cells secrete the antibody.
  • the antibody can then be purified from the cell culture media.
  • Cell lines producing any of the antibodies disclosed herein can be produced by introducing a vector encoding heavy and light chains of the antibody and a selectable marker into cells, propagating the cells under conditions to select for cells having increased copy number of the vector, isolating single cells from the selected cells; and banking cells cloned from a single cell selected based on yield of antibody.
  • Some cells can be propagated under selective conditions and screened for cell lines naturally expressing and secreting at least 100 mg/L/10 6 cells/24 h. Single cells can be isolated from the selected cells. Cells cloned from a single cell can then be banked. Single cells can be selected based on desirable properties, such as the yield of the antibody. Exemplary cell lines are cell lines expressing 9F5, 1002, 2D11, 12C4, 1702, or 14H3.
  • the invention also provides methods of inhibiting or reducing aggregation of tau in a subject having or at risk of developing a tau-mediated amyloidosis, comprising administering to the subject an effective regime of an antibody disclosed herein, thereby inhibiting or reducing aggregation of tau in the subject.
  • exemplary antibodies include humanized versions of 9F5, 10C12, 2D11, 12C4, 17C12, or 14H3.
  • a tau-related disease comprising administering an effective regime of an antibody disclosed herein and thereby treating or effecting prophylaxis of the disease.
  • Alzheimer’s disease Down’s syndrome, mild cognitive impairment, primary age-related tauopathy, postencephalitic parkinsonism, posttraumatic dementia or dementia pugilistica, Pick’s disease, type C Niemann-Pick disease, supranuclear palsy, frontotemporal dementia,
  • CBD dementia with Lewy bodies
  • LBV D Lewy body variant of Alzheimer disease
  • CTE chronic traumatic encephalopathy
  • GTT globular glial tauopathy
  • Parkinson’s disease or progressive supranuclear palsy (PSP).
  • the tau-related disease is Alzheimer’s disease.
  • the patient is an ApoE4 carrier.
  • Also provided are methods of reducing aberrant transmission of tau comprising administering an effective regime of an antibody an antibody disclosed herein and thereby reducing transmission of tau.
  • Also provided are methods of inducing phagocytosis of tau comprising administering an effective regime of an antibody disclosed herein and thereby inducing phagocytosis of tau.
  • Also provided are methods of inhibiting tau aggregation or deposition comprising administering an effective regime of an antibody disclosed herein thereby inhibiting tau aggregation or deposition.
  • Also provided are methods of inhibiting formation of tau tangles comprising administering an effective regime of an antibody disclosed herein.
  • the invention also provides a method of detecting tau protein deposits in a subject having or at risk of a disease associated with tau aggregation or deposition, comprising administering to a subject an antibody disclosed herein, and detecting the antibody bound to tau in the subject.
  • Alzheimer’s disease Down’s syndrome, mild cognitive impairment, primary age-related tauopathy, postencephalitic parkinsonism, posttraumatic dementia or dementia pugilistica, Pick’s disease, type C Niemann-Pick disease, supranuclear palsy, frontotemporal dementia, frontotemporal lobar degeneration, argyrophilic grain disease, globular glial tauopathy, amyotrophic lateral sclerosis/parkinsonism dementia complex of Guam, corticobasal degeneration (CBD), dementia with Lewy bodies, Lewy body variant of Alzheimer disease (LBVAD), chronic traumatic encephalopathy (CTE), globular glial tauopathy (GGT), Parkinson’s disease, or progressive supranuclear palsy (PSP).
  • CBD corticobasal degeneration
  • LVAD dementia with Lewy bodies
  • LVAD chronic traumatic encephalopathy
  • GTT globular glial tauopathy
  • Parkinson’s disease or progressive supranuclear palsy (
  • the antibody is administered by intravenous injection into the body of the subject. In some embodiments, the antibody is administered directly to the brain of the subject by intracranial injection or by drilling a hole through the skull of the subject. In some embodiments, the antibody is labeled. In some embodiments, the antibody is labeled with a fluorescent label, a paramagnetic label, or a radioactive label. In some embodiments, the radioactive label is detected using positron emission tomography (PET) or single-photon emission computed tomography (SPECT).
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • the invention also provides a method of measuring efficacy of treatment in a subject being treated for a disease associated with tau aggregation or deposition, comprising measuring a first level of tau protein deposits in the subject prior to treatment by administering to a subject an antibody disclosed herein, and detecting a first amount of the antibody bound to tau in the subject, administering the treatment to the subject, measuring a second level of tau protein deposits in the subject after treatment by administering to a subject the antibody, and detecting the antibody bound to tau in the subject, wherein a decrease in the level of tau protein deposits indicates a positive response to treatment.
  • the invention also provides a method of measuring efficacy of treatment in a subject being treated for a disease associated with tau aggregation or deposition, comprising measuring a first level of tau protein deposits in the subject prior to treatment by administering to a subject an antibody disclosed herein,, and detecting a first amount of antibody bound to tau in the subject, administering the treatment to the subject, measuring a second level of tau protein deposits in the subject after treatment by administering to a subject the antibody, and detecting a second amount of antibody bound to tau in the subject, wherein no change in the level of tau protein deposits or a small increase in tau protein deposits indicates a positive response to treatment.
  • the invention also provides an isolated monoclonal antibody that specifically binds to a peptide consisting of residues (Q/E)IVYK(S/P) (SEQ ID NO:56).
  • the invention also provides an isolated monoclonal antibody that specifically binds to a peptide consisting of residues QIVYKP (SEQ ID NO:57).
  • the invention also provides an isolated monoclonal antibody that specifically binds to a peptide consisting of residues EIVYKSP (SEQ ID NO:58).
  • the invention also provides an isolated monoclonal antibody that specifically binds to a peptide consisting of residues EIVYKS (SEQ ID NO:277).
  • the invention also provides an isolated monoclonal antibody that specifically binds to the polypeptide of SEQ ID NO: 1 at an epitope including at least one residue within 307-312 of SEQ ID NO: 1. Some such antibodies bind to an epitope within residues 307-312 of SEQ ID NO: 1.
  • the invention also provides an isolated monoclonal antibody that specifically binds to the polypeptide of SEQ ID NO: 1 at an epitope including at least one residue within residues 391-397 of SEQ ID NO: 1. Some such antibodies bind to an epitope within residues 391-397 of SEQ ID NO: 1.
  • the invention also provides an isolated monoclonal antibody that specifically binds to the polypeptide of SEQ ID NO: 1 at an epitope including at least one residue within residues 391-396 of SEQ ID NO: 1. Some such antibodies bind to an epitope within residues 391-396 of SEQ ID NO: 1.
  • the invention also provides an isolated monoclonal antibody that specifically binds to the polypeptide of SEQ ID NO: 1 at an epitope including at least one residue from within residues 307-312 of SEQ ID NO: 1 and at least one residue from within residues 391-397 of SEQ ID NO: 1.
  • the invention also provides an isolated monoclonal antibody that specifically binds to the polypeptide of SEQ ID NO: 1 at an epitope including at least one residue from within residues 307-312 of SEQ ID NO: 1 and at least one residue from within residues 391-396 of SEQ ID NO: l.
  • the invention also provides a method of treating or effecting prophylaxis of a tau- related disease in a subject comprising administering an immunogen comprising a tau peptide of up to 20 contiguous amino acids of SEQ ID NO: 1 to which antibody 9F5, 10C12, 2D11, 12C4, 17C12, or 14H3 specifically binds, wherein the peptide induces formation of antibodies specifically binding to tau in the subject.
  • the tau peptide consists of 4-7 contiguous amino acids from residues 307-312 of SEQ ID NO: l or from residues 391-397 of SEQ ID NO: l or from residues 391-396 of SEQ ID NO: l.
  • the tau peptide consists of residues (Q/E)IVYK(S/P) (SEQ ID NO:56). In some such methods, the tau peptide consists of residues QIVYKP (SEQ ID NO:57). In some such methods, the tau peptide consists of residues EIVYKSP (SEQ ID NO:58). In some such methods, the tau peptide consists of residues EIVYKS (SEQ ID NO:277). In some such methods, the tau peptide is attached to a heterologous conjugate molecule.
  • the invention also provides a method of producing an antibody that specifically binds to an epitope comprising (Q/E)IVYK(S/P) (SEQ ID NO:56), comprising immunizing an animal with tau or a fragment thereof, and screening for antibodies that specifically bind to the epitope.
  • the animal is immunized with 383 amino acid human tau (4R0N).
  • the human tau contains a P301S mutation.
  • the human tau is recombinant N-terminally His-tagged.
  • the screening is performed against 15 amino acid peptides comprising QIVYKP (SEQ ID NO:57), EIVYKSP (SEQ ID NO:58) EIVYKS (SEQ ID NO:277) or any other consensus motif represented by (Q/E)IVYK(S/P) (SEQ ID NO: 56).
  • the peptides comprise QIVYKP (SEQ ID NO:57) or EIVYKSP (SEQ ID NO:58) or EIVYKS (SEQ ID NO:277).
  • the animal is immunized with a tau fragment comprising a peptide represented by (Q/E)IVYK(S/P) (SEQ ID NO:56), linked to a carrier.
  • the peptide is QIVYKP (SEQ ID NO:57) or EIVYKSP (SEQ ID NO:58) or EIVYKS (SEQ ID NO:277).
  • Figures 1A and IB depict an alignment of heavy chain variable regions of the mouse 9F5 antibody (SEQ ID NO:7) and humanized versions of the 9F5 antibody (hu9F5VHvl, hu9F5VHv2, hu9F5VHv3, hu9F5VHv4, hu9F5VHv5, hu9F5VHv6, hu9F5VHv7, and hu9F5VHv8) with human germline heavy chain variable region sequence IGHVl-69-2*01 (SEQ ID NO:33) with human acceptor heavy chain variable region sequence AAN16432-VH_huFrwk (AAN16432 H; SEQ ID NO:31), and with human acceptor heavy chain variable region sequence 2RCS-VH_huFrwk (2RCS H; SEQ ID NO:32).
  • hu9F5VHvl is SEQ ID NO: 15
  • hu9F5VHv2 is SEQ ID NO: 16
  • hu9F5VHv3 is SEQ ID NO: 17
  • hu9F5VHv4 is SEQ ID NO: 18
  • hu9F5VHv5 is SEQ ID NO: 19
  • hu9F5VHv6 is SEQ ID NO:20
  • hu9F5VHv7 is SEQ ID NO:21
  • hu9F5VHv8 is SEQ ID NO:22.
  • the CDRs of mouse 9F5 VH as defined by
  • Figures 2A and 2B depict an alignment of light chain variable regions of the mouse 9F5 antibody (SEQ ID NO: 11) and humanized versions of the 9F5 antibody (hu9F5VLvl, hu9F5VLv2, hu9F5VLv3, hu9F5VLv4, hu9F5VLv5, hu9F5VLv6, and hu9F5VLv7) with human germline light chain variable region sequence IGKV2-28*01 &_IGKJ2*01 (IGKV2- 28*01_IGKJ2*01; SEQ ID NO:37) with human acceptor CAB51297-VL_huFrwk
  • hu9F5VLvl is SEQ ID NO:23
  • hu9F5VLv2 is SEQ ID NO:24
  • hu9F5VLv3 is SEQ ID NO:25
  • hu9F5VLv4 is SEQ ID NO:26
  • hu9F5VLv5 is SEQ ID NO:27
  • hu9F5VLv6 is SEQ ID NO:28
  • hu9F5VLv7 is SEQ ID NO:29.
  • the CDRs of mouse 9F5 VL, as defined by Rabat, are in boldface.
  • Figure 3 depicts results of an assay showing that mouse 9F5 antibody blocks neuronal internalization of tau.
  • Figures 4A and 4B depict an alignment of heavy chain variable regions of the mouse 9F5 antibody (SEQ ID NO:7) and humanized versions of the 9F5 antibody (hu9F5VHvl, hu9F5VHv2, hu9F5VHv3, hu9F5VHv4, hu9F5VHv5, hu9F5VHv6, hu9F5VHv7, hu9F5VHv8, hu9F5VHv9, and hu9F5VHvlO) with human germline heavy chain variable region sequence IGHVl-69-2*01 (SEQ ID NO:33) with human acceptor heavy chain variable region sequence AAN16432-VH_huFrwk (AAN16432_H; SEQ ID NO:31), and with human acceptor heavy chain variable region sequence 2RCS-VH_huFrwk (2RCS H; SEQ ID NO:32).
  • hu9F5VHvl is SEQ ID NO: 15
  • hu9F5VHv2 is SEQ ID NO: 16
  • hu9F5VHv3 is SEQ ID NO: 17
  • hu9F5VHv4 is SEQ ID NO: 18
  • hu9F5VHv5 is SEQ ID NO: 19
  • hu9F5VHv6 is SEQ ID NO:20, and
  • hu9F5VHv7 is SEQ ID NO:21
  • hu9F5VHv8 is SEQ ID NO:22
  • hu9F5VHv9 is SEQ ID NO: 127
  • hu9F5VHvlO is SEQ ID NO: 128.
  • the CDRs of mouse 9F5 VH, as defined by Kabat/Chothia Composite, are in boldface. Residues identical to those of mouse 9F5 VH are indicated by“”
  • Figures 5 A and 5B depict an alignment of light chain variable regions of the mouse 9F5 antibody (SEQ ID NO: 11) and humanized versions of the 9F5 antibody (hu9F5VLvl, hu9F5VLv2, hu9F5VLv3, hu9F5VLv4, hu9F5VLv5, hu9F5VLv6, hu9F5VLv7, hu9F5VLv8, and hu9F5VLv9) with human germline light chain variable region sequence IGKV2-28*01 &_IGKJ2*01 (IGKV2-28*01_IGKJ2*01; SEQ ID NO:37) with human acceptor CAB51297- VL huFrwk (CAB51297 L; SEQ ID NO:35), and with human acceptor 1911357B-VL_huFRwk (1911357B L; SEQ ID NO:36).
  • hu9F5VLvl is SEQ ID NO:23
  • hu9F5VLv2 is SEQ ID NO:24
  • hu9F5VLv3 is SEQ ID NO:25
  • hu9F5VLv4 is SEQ ID NO:26
  • hu9F5VLv5 is SEQ ID NO:27
  • hu9F5VLv6 is SEQ ID NO:28
  • hu9F5VLv7 is SEQ ID NO:2
  • hu9F5VLv8 is SEQ ID NO: 130
  • hu9F5VLv9 is SEQ ID NO: 131.
  • the CDRs of mouse 9F5 VL, as defined by Rabat are in boldface. Residues identical to those of mouse 9F5 VL are indicated by
  • Figures 6A, 6B, and 6C depict an alignment of the light chain variable region of hu9F5VLv8 with light chain variable regions of humanized versions of the 9F5 antibody:
  • hu9F5VLv8_DIMl (SEQ ID NO: 132), hu9F5VLv8_DIM2 (SEQ ID NO: 133),
  • hu9F5VLv8_DIM3 (SEQ ID NO: 134), hu9F5VLv8_DIM4 (SEQ ID NO: 135),
  • hu9F5VLv8_DIM5 (SEQ ID NO: 136), hu9F5VLv8_DIM6 (SEQ ID NO: 137),
  • hu9F5VLv8_DIM7 (SEQ ID NO: 138), hu9F5VLv8_DIM8 (SEQ ID NO: 139),
  • hu9F5VLv8_DIM9 (SEQ ID NO: 140), hu9F5VLv8_DIM10 (SEQ ID NO: 141),
  • hu9F5VLv8_DIMl 1 (SEQ ID NO: 142 ), hu9F5VLv8_DIM12 (SEQ ID NO: 143),
  • hu9F5VLv8_DIM13 (SEQ ID NO: 144), hu9F5VLv8_DIM14 (SEQ ID NO: 145),
  • hu9F5VLv8_DIM15 (SEQ ID NO: 146), hu9F5VLv8_DIM16 (SEQ ID NO: 147),
  • hu9F5VLv8_DIM17 (SEQ ID NO: 148), hu9F5VLv8_DIM18 (SEQ ID NO: 149),
  • hu9F5VLv8_DIM19 (SEQ ID NO: 150), hu9F5VLv8_DIM20 (SEQ ID NO: 151),
  • hu9F5VLv8_DIM21 (SEQ ID NO: 152), hu9F5VLv8_DIM22 (SEQ ID NO: 153),
  • hu9F5VLv8_DIM23 (SEQ ID NO: 154), hu9F5VLv8_DIM24 (SEQ ID NO: 155),
  • hu9F5VLv8_DIM25 (SEQ ID NO: 156), hu9F5VLv8_DIM26 (SEQ ID NO: 157),
  • hu9F5 VLv9_DIM 1 (SEQ ID NO: 162)
  • hu9F5VLv9_DIM2 (SEQ ID NO: 163)
  • hu9F 5 VLv9_DIM4 (SEQ ID NO: 164), hu9F5VLv9_DIM5 (SEQ ID NO: 165), hu9F5VLv9_DIM8 (SEQ ID NO: 166), hu9F5VLv9_DIM 10 (SEQ ID NO: 167), hu9F5VLv9_DIMl 1 (SEQ ID NO: 168), hu9F5VLv9_DIM13 (SEQ ID NO: 169),
  • hu9F5 VLv9_DIM 19 (SEQ ID NO: 170), hu9F5VLv9_DIM20 (SEQ ID NO: 171),
  • hu9F5VLv8_DIM27 (SEQ ID NO: 158), hu9F5VLv8_DIM28 (SEQ ID NO: 159),
  • hu9F5VLv8_DIM29 (SEQ ID NO: 160), hu9F5VLv8_DIM30 (SEQ ID NO: 161).
  • the CDRs of hu9F5VLv8, as defined by Kabat, are in boldface.
  • Figure 7 depicts an alignment of heavy chain variable regions of the mouse 1002 antibody (SEQ ID NO: 7, labeled m IOC 12 VH in Figure 7) and humanized versions of the IOC 12 antibody (hulOC12VHvland hulOC12VHv2) with human germline heavy chain variable region sequence IGHVl-69-2*01 (SEQ ID NO:33) and with human acceptor heavy chain variable region sequence CAC20421 VH (SEQ ID NO:218).
  • hulOC12VHvl is SEQ ID NO:214
  • hulOC12VHv2 is SEQ ID NO:215.
  • the CDRs of mouse 1002 VH as defined by
  • Figure 8 depicts an alignment of light chain variable regions of the mouse 1002 (SEQ ID NO: 11) and humanized versions of the 1002 antibody (hulOC12VLvl and hulOC12VLv2) with human germline light chain variable region sequence IGKV2-28*01 &_IGKJ2*01 (SEQ ID NO:37) and with human acceptor CAB51297-VL_huFrwk (SEQ ID NO:35).
  • hulOC12VLvl is SEQ ID NO:216
  • hulOC12VLv2 is SEQ ID NO:217.
  • the CDRs of mouse 1002 VL as defined by Kabat, are in boldface.
  • Figure 9 depicts an alignment of heavy chain variable regions of the mouse 12C4 antibody (SEQ ID NO:219) and humanized versions of the 12C4 antibody (hul2C4VHvland hul2C4VHv2) with human germline heavy chain variable region sequence IGHVl-69-2*01 (SEQ ID NO:33) and with human acceptor heavy chain variable region sequence CAC20421 VH (SEQ ID NO:218).
  • hul2C4VHvl is SEQ ID NO:221
  • hul2C4VHv2 is SEQ ID NO:222.
  • mice 12C4 VH as defined by Kabat/Chothia Composite, are in boldface.
  • Figure 10 depicts an alignment of light chain variable regions of the mouse 12C4 antibody (SEQ ID NO: 11) and humanized versions of the 12C4 antibody (hul2C4VLvl and huvVLv2) with human germline light chain variable region sequence IGKV2-28*01
  • hul2C4VLvl is SEQ ID NO:223 and hul2C4VLv2 is SEQ ID NO:224.
  • the CDRs of mouse 12C4 VL, as defined by Kabat, are in boldface.
  • Figure 11 depicts an alignment of heavy chain variable regions of the mouse 1702 antibody (SEQ ID NO:225) and humanized versions of the 1702 antibody (hul7C12VHvland hul7C12VHv2) with human germline heavy chain variable region sequence IGHVl-69-2*01 (SEQ ID NO:33) and with human acceptor heavy chain variable region sequence CAC20421 VH (SEQ ID NO:218).
  • hul7C12VHvl is SEQ ID NO:232
  • hul7C12VHv2 is SEQ ID NO:233.
  • the CDRs of mouse 1702 VH as defined by Kabat/Chothia Composite, are in boldface.
  • Figure 12 depicts an alignment of light chain variable regions of the mouse 1702 antibody (SEQ ID NO:228) and humanized versions of the 1702 antibody (hul7C12VLvl and hul7C12VLv2) with human germline light chain variable region sequence IGKV2-29*02 & IGKJ4*01 (SEQ ID NO:239) and with human acceptor QD016713 VL (SEQ ID NO:238).
  • hul7C12VLvl is SEQ ID NO:234 and hul7C12VLv2 is SEQ ID NO:235.
  • the CDRs of mouse 1702 VL, as defined by Kabat, are in boldface.
  • Figure 13 depicts an alignment of heavy chain variable regions of the mouse 14H3 antibody (SEQ ID NO:240) and humanized versions of the 14H3 antibody (hul4H3VHvland hul4H3VHv2) with human germline heavy chain variable region sequence IGHV2-70*04 & IGHJ4*01 (SEQ ID NO:254) and with human acceptor heavy chain variable region sequence QDJ57937VH hFrwk (SEQ ID NO:253).
  • hul4H3VHvl is SEQ ID NO:248
  • hul4H3VHv2 is SEQ ID NO:249.
  • the CDRs of mouse 14H3 VH as defined by Kabat/Chothia Composite, are in boldface.
  • Figure 14 depicts an alignment of light chain variable regions of the mouse 14H3 antibody (SEQ ID NO:244) and humanized versions of the 14H3 antibody (hul4H3VLvl and hul4H3VLv2) with human germline light chain variable region sequence IGKV2-28*01
  • FIG. 15 depicts results of an assay showing that mouse 1002, mouse 12C4, mouse 2D11, mouse 1702, mouse 14H3, and mouse 9F5 antibodies block neuronal internalization of tau.
  • Figure 16 depicts results of an assay showing that mouse 1002, mouse 12C4, mouse 2D11, and mouse 9F5 antibodies prevent tau toxicity in primary neurons (neuronal viability).
  • Figure 17 depicts results of an assay showing that mouse 1002, mouse 12C4, mouse 2D11, and mouse 9F5 antibodies prevent tau toxicity in primary neurons (LDH release).
  • Figure 18 depicts results of a Western blot assay showing that mouse 1002, mouse 12C4, mouse 2D11, mouse 1702, mouse 14H3, and mouse 9F5 antibodies detect tau in samples from brains of Alzheimer’s disease patients.
  • Figure 19 depicts results of a immunoprecipitation assay with mouse 1002, mouse 12C4, mouse 2D11, mouse 1702, mouse 14H3, and mouse 9F5 antibodies and a sample from a brain of Alzheimer’s disease patient.
  • Figure 20 depicts results of an assay to measure ability of 9F5 humanized variants to withstand aggregation induced by agitation stress.
  • Figure 21 depicts results of an assay to measure ability of 9F5 humanized variants to withstand low pH exposure.
  • Figure 22 depicts results of an assay to measure ability of 9F5 humanized variants to aggregate under simulated high-concentration conditions.
  • FIGs 23 A-F depict results of immunohistochemistry assays using control, mouse 2D11, mouse 9F5, mouse 12C4, mouse 14H3, and mouse 17C12.
  • Figure 24 depicts an alignment of heavy chain variable regions of the mouse 9F5 antibody (SEQ ID NO: 7), mouse 10C12antibody (SEQ ID NO: 7), mouse 2D11 antibody (SEQ ID N0:7), mouse 12C4 antibody (SEQ ID NO:219), mouse 14H3 antibody (SEQ ID NO:240), and mouse 17C12 antibody (SEQ ID NO:225).
  • the CDRs of mouse 9F5 VH as defined by Kabat/Chothia Composite, are in boldface.
  • Figure 25 depicts an alignment of light chain variable regions of the mouse 9F5 antibody (SEQ ID NO: 11), mouse 10C12antibody (SEQ ID NO: 11), mouse 2D11 antibody (SEQ ID NO: 11), mouse 12C4 antibody (SEQ ID NO: 11), mouse 14H3 antibody (SEQ ID NO:244), and mouse 17C12 antibody (SEQ ID NO:228).
  • the CDRs of mouse 9F5 VL, as defined by Kabat, are in boldface.
  • SEQ ID NO: 1 sets forth the amino acid sequence of an isoform of human tau (Swiss- Prot P10636-8).
  • SEQ ID NO:2 sets forth the amino acid sequence of an isoform of human tau (Swiss- Prot PI 0636-7).
  • SEQ ID NO:3 sets forth the amino acid sequence of an isoform of human tau (Swiss- Prot PI 0636-6), (4R0N human tau).
  • SEQ ID NO:4 sets forth the amino acid sequence of an isoform of human tau (Swiss- Prot PI 0636-5)
  • SEQ ID NO:5 sets forth the amino acid sequence of an isoform of human tau (Swiss- Prot PI 0636-4).
  • SEQ ID NO:6 sets forth the amino acid sequence of an isoform of human tau (Swiss- Prot PI 0636-2).
  • SEQ ID NO:7 sets forth the amino acid sequence of the heavy chain variable region of the mouse 9F5 antibody.
  • SEQ ID NO:8 sets forth the amino acid sequence of Kabat/Chothia composite CDR-H1 of the mouse 9F5 antibody.
  • SEQ ID NO:9 sets forth the amino acid sequence of Kabat CDR-H2 of the mouse 9F5 antibody.
  • SEQ ID NO: 10 sets forth the amino acid sequence of Kabat CDR-H3 of the mouse 9F5 antibody.
  • SEQ ID NO: 11 sets forth the amino acid sequence of the light chain variable region of the mouse 9F5 antibody.
  • SEQ ID NO: 12 sets forth the amino acid sequence of Kabat CDR-L1 of the mouse 9F5 antibody.
  • SEQ ID NO: 13 sets forth the amino acid sequence of Kabat CDR-L2 of the mouse 9F5 antibody.
  • SEQ ID NO: 14 sets forth the amino acid sequence of Kabat CDR-L3 of the mouse 9F5 antibody.
  • SEQ ID NO: 15 sets forth the amino acid sequence of humanized heavy chain variable regi on hu9F 5 VHv 1.
  • SEQ ID NO: 16 sets forth the amino acid sequence of humanized heavy chain variable region hu9F5VHv2.
  • SEQ ID NO: 17 sets forth the amino acid sequence of humanized heavy chain variable region hu9F5VHv3.
  • SEQ ID NO: 18 sets forth the amino acid sequence of humanized heavy chain variable region hu9F5VHv4.
  • SEQ ID NO: 19 sets forth the amino acid sequence of humanized heavy chain variable region hu9F5VHv5:
  • SEQ ID NO:20 sets forth the amino acid sequence of humanized heavy chain variable region hu9F5VHv6.
  • SEQ ID NO:21 sets forth the amino acid sequence of humanized heavy chain variable region hu9F5VHv7.
  • SEQ ID NO:22 sets forth the amino acid sequence of humanized heavy chain variable region hu9F5VHv8.
  • SEQ ID NO:23 sets forth the amino acid sequence of the humanized light chain variable region hu9F5VLvl.
  • SEQ ID NO:24 sets forth the amino acid sequence of humanized light chain variable region hu9F5VLv2.
  • SEQ ID NO:25 sets forth the amino acid sequence of humanized light chain variable region hu9F5VLv3.
  • SEQ ID NO:26 sets forth the amino acid sequence of humanized light chain variable region hu9F5VLv4.
  • SEQ ID NO:27 sets forth the amino acid sequence of humanized light chain variable region of the humanized 9F5 antibody hu9F5VLv5.
  • SEQ ID NO:28 sets forth the amino acid sequence of humanized light chain variable region hu9F5VLv6.
  • SEQ ID NO:29 sets forth the amino acid sequence of humanized light chain variable region hu9F5VLv7.
  • SEQ ID NO:30 sets forth the amino acid sequence of the heavy chain variable region structural model PDB # 50BF-VH_mSt.
  • SEQ ID NO: 31 sets forth the amino acid sequence of the heavy chain variable region acceptor GenBank Acc.# AAN16432-VH_huFrwk.
  • SEQ ID NO:32 sets forth the amino acid sequence of the heavy chain variable region acceptor PDB # 2RCS-VH_huFrwk.
  • SEQ ID NO:33 sets forth the amino acid sequence of the heavy chain variable region germline sequence IMGT# IGHV1 -69-2*01.
  • SEQ ID NO:34 sets forth the amino acid sequence of the light chain variable region structural model PDB # 50BF-VL_mSt.
  • SEQ ID NO:35 sets forth the amino acid sequence of the light chain variable region acceptor GenBank Acc. # CAB51297-VL_huFrwk.
  • SEQ ID NO:36 sets forth the amino acid sequence of the light chain variable region acceptor GenBank Acc. # 1911357B-VL_huFrwk.
  • SEQ ID NO:37 sets forth the amino acid sequence of the light chain variable region germline sequence IMGT# IGKV2-28*01 & IGKJ2*01.
  • SEQ ID NO:38 sets forth a nucleic acid sequence encoding the heavy chain variable region of the mouse 9F5 antibody.
  • SEQ ID NO:39 sets forth a nucleic acid sequence encoding the light chain variable region of the mouse 9F5 antibody.
  • SEQ ID NO:40 sets forth the amino acid sequence of Kabat CDR-H1 of the mouse 9F5 antibody.
  • SEQ ID NO:41 sets forth the amino acid sequence of Chothia CDR-H1 of the mouse 9F5 antibody.
  • SEQ ID NO:42 sets forth the amino acid sequence of Chothia CDR-H2 of the mouse 9F5 antibody.
  • SEQ ID NO:43 sets forth the amino acid sequence of AbM CDR-H2 of the mouse 9F5 antibody.
  • SEQ ID NO:44 sets forth the amino acid sequence of Contact CDR-H1 of the mouse 9F5 antibody.
  • SEQ ID NO:45 sets forth the amino acid sequence of Contact CDR-H2 of the mouse 9F5 antibody.
  • SEQ ID NO:46 sets forth the amino acid sequence of Contact CDR-H3 of the mouse 9F5 antibody.
  • SEQ ID NO:47 sets forth the amino acid sequence of Contact CDR-L1 of the mouse 9F5 antibody.
  • SEQ ID NO:48 sets forth the amino acid sequence of Contact CDR-L2 of the mouse 9F5 antibody.
  • SEQ ID NO:49 sets forth the amino acid sequence of Contact CDR-L3 of the mouse 9F5 antibody.
  • SEQ ID NO:50 sets forth the amino acid sequence of an alternate Kabat-Chothia Composite CDR-H1 of a humanized 9F5 antibody (present in hu9F5VHv4, hu9F5VHv5, and hu9F5VHv6).
  • SEQ ID NO:51 sets forth the amino acid sequence of an alternate Kabat CDR-H2 of a humanized 9F5 antibody (present in hu9F5VHv5, hu9F5VHv6, and hu9F5VHv7).
  • SEQ ID NO: 52 sets forth the amino acid sequence of an alternate Kabat CDR-H2 of a humanized 9F5 antibody (present in hu9F5VHv8).
  • SEQ ID NO:53 sets forth the amino acid sequence of an alternate Kabat CDR-L1 of a humanized 9F5 antibody (present in hu9F5VLv5 and hu9F5VLv6).
  • SEQ ID NO: 54 sets forth the amino acid sequence of an alternate Kabat CDR-L1 of a humanized 9F5 antibody (present in hu9F5VLv7).
  • SEQ ID NO: 55 sets forth the amino acid sequence of an alternate Kabat CDR-L2 of a humanized 9F5 antibody (present in hu9F5VLv4, hu9F5VLv5, hu9F5VLv6, hu9F5VLv7, hu9F5VLv8_DIM2, hu9F5VLv8_DIM4, hu9F5VLv8_DIM5, hu9F5VLv8_DIM6,
  • hu9F5VLv8_DIMl 1 hu9F5VLv8_DIM12, hu9F5VLv8_DIM13, hu9F5VLv8_DIM18, hu9F5VLv8_DIM27, hu9F5VLv8_DIM28, hu9F5VLv9_DIM2, hu9F5VLv9_DIM4, hu9F5VLv9_DIM5, hu9F5VLv9_DIMl 1, and hu9F5VLv9_DIM13).
  • SEQ ID NO:56 sets forth the amino acid sequence of an epitope of antibody 9F5.
  • SEQ ID NO:57 sets forth the amino acid sequence of a consensus motif of a peptide bound by antibody 9F5.
  • SEQ ID NO: 58 sets forth the amino acid sequence of a consensus motif of a peptide bound by antibody 9F5.
  • SEQ ID NO:59 sets forth the amino acid sequence of a linker.
  • SEQ ID NO:60 sets forth the amino acid sequence of an HA control peptide.
  • SEQ ID NO:61 sets forth the amino acid sequence of a variant of hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_M5!E).
  • SEQ ID NO:62 sets forth the amino acid sequence of a variant of hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_M51D).
  • SEQ ID NO:63 sets forth the amino acid sequence of a variant of hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L27cD).
  • SEQ ID NO:64 sets forth the amino acid sequence of a variant of hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L27cG).
  • SEQ ID NO:65 sets forth the amino acid sequence of a variant of hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L27cS).
  • SEQ ID NO:66 sets forth the amino acid sequence of a variant of hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L27cE).
  • SEQ ID NO:67 sets forth the amino acid sequence of a variant of hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_I30E).
  • SEQ ID NO:68 sets forth the amino acid sequence of a variant of hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_I30K).
  • SEQ ID NO:69 sets forth the amino acid sequence of a variant of hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L27cT).
  • SEQ ID NO:70 sets forth the amino acid sequence of a variant of hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L27cN).
  • SEQ ID NO:71 sets forth the amino acid sequence of a variant of hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L27bD).
  • SEQ ID NO:72 sets forth the amino acid sequence of a variant of hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_I30G).
  • SEQ ID NO:73 sets forth the amino acid sequence of a variant of hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L33N).
  • SEQ ID NO:74 sets forth the amino acid sequence of a variant of hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L27cA).
  • SEQ ID NO:75 sets forth the amino acid sequence of a variant of hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L33T).
  • SEQ ID NO:76 sets forth the amino acid sequence of a variant of hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L33S).
  • SEQ ID NO:77 sets forth the amino acid sequence of a variant of hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L33R).
  • SEQ ID NO:78 sets forth the amino acid sequence of a variant of hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_I30Q).
  • SEQ ID NO:79 sets forth the amino acid sequence of a variant of hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L27bT).
  • SEQ ID NO:80 sets forth the amino acid sequence of a variant of hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_T31G).
  • SEQ ID NO:81 sets forth the amino acid sequence of a variant of hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L27bQ).
  • SEQ ID NO:82 sets forth the amino acid sequence of a variant of hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L33G).
  • SEQ ID NO:83 sets forth the amino acid sequence of a variant of hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L27cP).
  • SEQ ID NO:84 sets forth the amino acid sequence of a variant of hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_V78R).
  • SEQ ID NO:85 sets forth the amino acid sequence of a variant of hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_I75D).
  • SEQ ID NO:86 sets forth the amino acid sequence of a variant of hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_V78D).
  • SEQ ID NO:87 sets forth the amino acid sequence of a variant of hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_V78E).
  • SEQ ID NO:88 sets forth the amino acid sequence of a variant of hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_V78P).
  • SEQ ID NO:89 sets forth the amino acid sequence of a variant of hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_V78K).
  • SEQ ID NO:90 sets forth the amino acid sequence of a variant of hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_R77D).
  • SEQ ID NO:91 sets forth the amino acid sequence of a variant of hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_V78G).
  • SEQ ID NO:92 sets forth the amino acid sequence of a variant of hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_S76P).
  • SEQ ID NO:93 sets forth the amino acid sequence of a variant of hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_I75P).
  • SEQ ID NO:94 sets forth the amino acid sequence of a variant of hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_I75Q).
  • SEQ ID NO:95 sets forth the amino acid sequence of a variant of hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_I75G).
  • SEQ ID NO:96 sets forth the amino acid sequence of a variant of hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L73P).
  • SEQ ID NO:97 sets forth the amino acid sequence of a variant of hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L73G).
  • SEQ ID NO:98 sets forth the amino acid sequence of a variant of hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_V78Q).
  • SEQ ID NO:99 sets forth the amino acid sequence of a variant of hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_S76G).
  • SEQ ID NO: 100 sets forth the amino acid sequence of a variant of hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L92D).
  • SEQ ID NO: 101 sets forth the amino acid sequence of a variant of hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_Y86T).
  • SEQ ID NO: 102 sets forth the amino acid sequence of a variant of hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L92E).
  • SEQ ID NO: 103 sets forth the amino acid sequence of a variant of hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L92G).
  • SEQ ID NO: 104 sets forth the amino acid sequence of a variant of hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L92Q).
  • SEQ ID NO: 105 sets forth the amino acid sequence of a variant of hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L93G).
  • SEQ ID NO: 106 sets forth the amino acid sequence of a variant of hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_V85G).
  • SEQ ID NO: 107 sets forth the amino acid sequence of a variant of hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_L92T).
  • SEQ ID NO: 108 sets forth the amino acid sequence of a variant of hu9F5VLv2 light chain variable region (also known as hu9F5VLv2_A89G).
  • SEQ ID NO: 109 sets forth the amino acid sequence of a variant of hu9F5VHv4 heavy chain variable region (also known as hu9F5VHv4_L80P).
  • SEQ ID NO: 110 sets forth the amino acid sequence of a variant of hu9F5VHv4 heavy chain variable region (also known as hu9F5VHv4_L80D).
  • SEQ ID NO: 111 sets forth the amino acid sequence of a variant of hu9F5VHv4 heavy chain variable region (also known as hu9F5VHv4_L82cG).
  • SEQ ID NO: 112 sets forth the amino acid sequence of a variant of hu9F5VHv4 heavy chain variable region (also known as hu9F5VHv4_L82cD).
  • SEQ ID NO: 113 sets forth the amino acid sequence of a variant of hu9F5VHv4 heavy chain variable region (also known as hu9F5VHv4_L82P).
  • SEQ ID NO: 114 sets forth the amino acid sequence of a variant of hu9F5VHv4 heavy chain variable region (also known as hu9F5VHv4_L80G).
  • SEQ ID NO: 115 sets forth the amino acid sequence of a variant of hu9F5VHv4 heavy chain variable region (also known as hu9F5VHv4_L82K).
  • SEQ ID NO: 116 sets forth the amino acid sequence of a variant of hu9F5VHv4 heavy chain variable region (also known as hu9F5VHv4_L82R).
  • SEQ ID NO: 117 sets forth the amino acid sequence of a variant of hu9F5VHv4 heavy chain variable region (also known as hu9F5VHv4_L82E).
  • SEQ ID NO: 118 sets forth the amino acid sequence of a variant of hu9F5VHv4 heavy chain variable region (also known as hu9F5VHv4_L82N).
  • SEQ ID NO: 119 sets forth the amino acid sequence of a variant of hu9F5VHv4 heavy chain variable region (also known as hu9F5VHv4_Y79D).
  • SEQ ID NO: 120 sets forth the amino acid sequence of a variant of hu9F5VHv4 heavy chain variable region (also known as hu9F5VHv4_Y79N).
  • SEQ ID NO: 121 sets forth the amino acid sequence of a variant of hu9F5VHv4 heavy chain variable region (also known as hu9F5VHv4_Y79G).
  • SEQ ID NO: 122 sets forth the amino acid sequence of a variant of hu9F5VHv5 heavy chain variable region (also known as hu9F5VHv5_M80E).
  • SEQ ID NO: 123 sets forth the amino acid sequence of a variant of hu9F5VHv5 heavy chain variable region (also known as hu9F5VHv5_M80G).
  • SEQ ID NO: 124 sets forth the amino acid sequence of a variant of hu9F5VHv4 heavy chain variable region (also known as hu9F5VHv4_L82cS).
  • SEQ ID NO: 125 sets forth the amino acid sequence of a variant of hu9F5VHv4 heavy chain variable region (also known as hu9F5VHv4_Y79Q).
  • SEQ ID NO: 126 sets forth the amino acid sequence of a variant of hu9F5VHv4 heavy chain variable region (also known as hu9F5VHv4_S82aG).
  • SEQ ID NO: 127 sets forth the amino acid sequence of a Heavy chain variable region hu9F5VHv9.
  • SEQ ID NO: 128 sets forth the amino acid sequence of a Heavy chain variable region hu9F5VHvlO (also known as hu9F5VHv9_ Q38K G42E).
  • SEQ ID NO: 129 sets forth the amino acid sequence of a Heavy chain variable region hu9F5VHvlO_L82cG
  • SEQ ID NO: 130 sets forth the amino acid sequence of a Light chain variable region hu9F5VLv8.
  • SEQ ID NO: 131 sets forth the amino acid sequence of a Light chain variable region hu9F5VLv9 (also known as hu9F5VLv8 N60D)
  • SEQ ID NO: 132 sets forth the amino acid sequence of a variant of hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L27cS, L37Q, M51G, L54G, L92I, also known as hu9F 5 VL v8 ___ DIM 1 ) .
  • SEQ ID NO: 133 sets forth the amino acid sequence of a variant of hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L27cS, L37Q, M51G, L54R, L92I, also known as hu9F 5 VL v8_D IM 2) .
  • SEQ ID NO: 134 sets forth the amino acid sequence of a variant of hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L27cS, L37Q, M51G, L54T, L92I, also known as hu9F5VLv8_DIM3).
  • SEQ ID NO: 135 sets forth the amino acid sequence of a variant of hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L27cS, L37Q, M51G, L54R, L92G, also known as hu9F5VLv8_DIM4).
  • SEQ ID NO: 136 sets forth the amino acid sequence of a variant of hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L27cG, L37Q, M51G, L54R, L92I, also known as hu9F5VLv8__DIM5).
  • SEQ ID NO: 137 sets forth the amino acid sequence of a variant of hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L27cD, L37Q, M51G, L54R, L92I, also known as h u9 F 5 VL v8_DIM6) .
  • SEQ ID NO: 138 sets forth the amino acid sequence of a variant of hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L27cD, L37Q, M51K, L54R, L92I, also known as hu9F 5 VL v8_D ⁇ M 7) .
  • SEQ ID NO: 139 sets forth the amino acid sequence of a variant of hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L27cG, L37Q, M51K, L54R, L92I, also known as hu9F5VLv8_DIM8).
  • SEQ ID NO: 140 sets forth the amino acid sequence of a Variant of hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L27cG, L37Q, M51K, L54G, L92I, also known as hu9F5VLv8_DIM9).
  • SEQ ID NO: 141 sets forth the amino acid sequence of a Variant of hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L27cS, L37Q, M51K, L54G, L92I, also known as hu9F5VLv8_DIM 10).
  • SEQ ID NO: 142 sets forth the amino acid sequence of a variant of hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L27cG, L37G, M51G, L54R, L92I, also known as hu9F5VLv8 DIM! 1).
  • SEQ ID NO: 143 sets forth the amino acid sequence of a variant of hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L27cG, L37G, M51G, L54R, L92G, also known as hu9F 5 VL v8 __ DIM 12).
  • SEQ ID NO: 144 sets forth the amino acid sequence of a variant of hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L27cG, L37G, M51G, L54R, also known as hu9F5 VLv8_DIM 13).
  • SEQ ID NO: 145 sets forth the amino acid sequence of a variant of hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L27cG, L37G, M51G, L54T, L92I, also known as hu9F5 VLv8_DIMl 4).
  • SEQ ID NO: 146 sets forth the amino acid sequence of a variant of hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L27cG, L37G, M51G, L54T, L92G, also known as hu9F5VLv8_DIM15).
  • SEQ ID NO: 147 sets forth the amino acid sequence of a variant of hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L27cG, L37G, M51G, L54T, also known as hu9F5VLv8_DIMl 6)
  • SEQ ID NO: 148 sets forth the amino acid sequence of a variant of hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L27cS, L37G, M51G, L54T, L92I, also known as hu9F5VLv8_DIM17).
  • SEQ ID NO: 149 sets forth the amino acid sequence of a variant of hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L27cD, L37G, M51G, L54R, L92I, also known as hu9F5 VLv8_DIM 18).
  • SEQ ID NO: 150 sets forth the amino acid sequence of a variant of hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L27cS, L37I, M51I, L54R, L92I, also known as hu9F5VLv8_DIMl 9)
  • SEQ ID NO: 151 sets forth the amino acid sequence of a variant of hu9F5 VLv8 light chain variable region (hu9F5VLv8_V3Q, L27cS, L37Q, M51I, L54G, L92I, also known as hu9F5VLv8_DIM20).
  • SEQ ID NO: 152 sets forth the amino acid sequence of a variant of hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L27cS, L37Q, M51I, L54G, also known as hu9F5 VLv8__DIM21 ) .
  • SEQ ID NO: 153 sets forth the amino acid sequence of a variant of hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L27cS, L37Q, M51E, L54R, L92I, also known as h u9 F 5 VL v8_DIM22) .
  • SEQ ID NO: 155 sets forth the amino acid sequence of a variant of hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L27cG, L37I, M51E, L54R, L92I, also known as hu9F5 VLv8__DIM24) .
  • SEQ ID NO: 156 sets forth the amino acid sequence of a variant of hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L27cG, L37I, M51E, L54R, L92G, also known as h u9 F 5 VL v8_DIM25 ) .
  • SEQ ID NO: 157 sets forth the amino acid sequence of a variant of hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L27cl, L37I, M51E, L54R, also known as hu9F5VLv8_DIM26).
  • SEQ ID NO: 158 sets forth the amino acid sequence of a variant of hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L37Q, M51G, L54R, L92I, also known as hu9F 5 VL v8_D IM 27).
  • SEQ ID NO: 159 sets forth the amino acid sequence of a variant of hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L27cS, M51G, L54R, L92I, also known as h u9F 5 VL v 8_DIM28) .
  • SEQ ID NO: 160 sets forth the amino acid sequence of a variant of hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L27cS, L37Q, L54R, L92I, also known as hu9F5VLv8_DIM29).
  • SEQ ID NO: 161 sets forth the amino acid sequence of a variant of hu9F5VLv8 light chain variable region (hu9F5VLv8_V3Q, L27cS, L37Q, M51G, L92I, also known as hu9F5 VLv8__DIM30) .
  • SEQ ID NO: 162 sets forth the amino acid sequence of a variant of hu9F5VLv9 light chain variable region (hu9F5VLv9_V3Q, L27cS, L37Q, M51G, L54G, L92I, also known as hu9F5VLv9_DIMl ).
  • SEQ ID NO: 163 sets forth the amino acid sequence of a variant of hu9F5VLv9 light chain variable region (hu9F5VLv9_V3Q, L27cS, L37Q, M51G, L54R, L92I, also known as hu9F 5 VL v9_D ⁇ M 2) .
  • SEQ ID NO: 164 sets forth the amino acid sequence of a variant of hu9F5VLv9 light chain variable region (hu9F5VLv9_V3Q, L27cS, L37Q, M51G, L54R, L92G, also known as h u9F 5 VL v9_DIM4) .
  • SEQ ID NO: 165 sets forth the amino acid sequence of a variant of hu9F5VLv9 light chain variable region (hu9F5VLv9_V3Q, L27cG, L37Q, M51G, L54R, L92I, also known as hu9F 5 VLv9 DEVI 5 ) .
  • SEQ ID NO: 166 sets forth the amino acid sequence of a variant of hu9F5VLv9 light chain variable region (hu9F5VLv9_V3Q, L27cG, L37Q, M51K, L54R, L92I, also known as hu9F 5 VL v9_D IMS).
  • SEQ ID NO: 167 sets forth the amino acid sequence of a variant of hu9F5VLv9 light chain variable region (hu9F5VLv9_V3Q, L27cS, L37Q, M51K, L54G, L92I, also known as hu9F5VLv9_DIMl 0)
  • SEQ ID NO: 168 sets forth the amino acid sequence of a variant of hu9F5VLv9 light chain variable region (hu9F5VLv9_V3Q, L27cG, L37G, M51G, L54R, L92I, also known as hu9F 5 VLv9 DEVI 11).
  • SEQ ID NO: 169 sets forth the amino acid sequence of a variant of hu9F5VLv9 light chain variable region (hu9F5VLv9_V3Q, L27cG, L37G, M51G, L54R, also known as hu9F 5 VLv9__DIM 13).
  • SEQ ID NO: 170 sets forth the amino acid sequence of a variant of hu9F5VLv9 light chain variable region (hu9F5VLv9_V3Q, L27cS, L37I, M51I, L54R, L92I, also known as hu9F5VLv9_DIMl 9).
  • SEQ ID NO: 171 sets forth the amino acid sequence of a variant of hu9F5VLv9 light chain variable region (hu9F5VLv9_V3Q, L27cS, L37Q, M51I, L54G, L92I, also known as hu9F5VLv9_DIM20).
  • SEQ ID NO: 172 sets forth the amino acid sequence of an alternate Rabat CDR-L1 of a humanized 9F5 antibody (present in hu9F5VLv2_L27bD).
  • SEQ ID NO: 173 sets forth the amino acid sequence of an alternate Rabat CDR-L1 of a humanized 9F5 antibody (present in hu9F5VLv2_L27bT).
  • SEQ ID NO: 174 sets forth the amino acid sequence of an alternate Rabat CDR-L1 of a humanized 9F5 antibody (present in hu9F5VLv2_L27bQ).
  • SEQ ID NO: 175 sets forth the amino acid sequence of an alternate Kabat CDR-L1 of a humanized 9F5 antibody (present in hu9F5VLv2_L27cD, hu9F5VLv8 DIM6,
  • SEQ ID NO: 176 sets forth the amino acid sequence of an alternate Kabat CDR-L1 of a humanized 9F5 antibody (present in hu9F5VLv2_L27cG, hu9F5VLv8_DIM5,
  • hu9F5VLv8_DIM8_DIM8_DIM9 in hu9F5VLv8 DIMl l, hu9F5VLv8_DIM12, hu9F 5 VL v8_DIM 13, hu9F5VLv8_DIM14, hu9F5VLv8_DIM15, hu9F5VLv8_DIM16, hu9F5VLv8_DIM23, hu9F5VLv8_DIM24, hu9F5VLv8_DIM25, hu9F5VLv9_DIM5, hu9F5 VLv9_DIM 8, hu9F5VLv9_DIMl l, and hu9F5VLv9_DIM 13).
  • SEQ ID NO: 177 sets forth the amino acid sequence of an alternate Kabat CDR-L1 of a humanized 9F5 antibody (present in hu9F5VLv2_L27cS, hu9F5VLv8_DIMl,
  • hu9F5VLv8_DIM2 hu9F5VLv8_DIMl 9, hu9F5VLv8_DIM20, hu9F5 VLv8_DIM21, hu9F 5 VLv8_DIM22, hu9F5VLv8_DIM28, hu9F5VLv8JDIM29, hu9F5VLv8___DIM30, hu9F5 VLv9_DIM I , hu9F5VLv9_DIM2, hu9F5VLv9_DIM4, hu9F5VLv9_DIM10, in hu9F5 VLv9_DIM 19, and hu9F5VLv9_DlM20).
  • SEQ ID NO: 178 sets forth the amino acid sequence of an alternate Kabat CDR-L1 of a humanized 9F5 antibody (present in hu9F5VLv2_L27cE).
  • SEQ ID NO: 179 sets forth the amino acid sequence of an alternate Kabat CDR-L1 of a humanized 9F5 antibody (present in hu9F5VLv2_L27cT).
  • SEQ ID NO: 180 sets forth the amino acid sequence of an alternate Kabat CDR-L1 of a humanized 9F5 antibody (present in hu9F5VLv2_L27cN).
  • SEQ ID NO: 181 sets forth the amino acid sequence of an alternate Kabat CDR-L1 of a humanized 9F5 antibody (present in hu9F5VLv2_L27cA).
  • SEQ ID NO: 182 sets forth the amino acid sequence of an alternate Kabat CDR-L1 of a humanized 9F5 antibody (present in hu9F5VLv2_L27cP).
  • SEQ ID NO: 183 sets forth the amino acid sequence of an alternate Kabat CDR-L1 of a humanized 9F5 antibody (present in hu9F5VLv8 DIM 26).
  • SEQ ID NO: 184 sets forth the amino acid sequence of an alternate Kabat CDR-L1 of a humanized 9F5 antibody (present in hu9F5VLv2_I30E).
  • SEQ ID NO: 185 sets forth the amino acid sequence of an alternate Kabat CDR-L1 of a humanized 9F5 antibody (present in hu9F5VLv2_I30K).
  • SEQ ID NO: 186 sets forth the amino acid sequence of an alternate Kabat CDR-L1 of a humanized 9F5 antibody (present in hu9F5VLv2_I30G).
  • SEQ ID NO: 187 sets forth the amino acid sequence of an alternate Kabat CDR-L1 of a humanized 9F5 antibody (present in hu9F5VLv2_I30Q).
  • SEQ ID NO: 188 sets forth the amino acid sequence of an alternate Kabat CDR-L1 of a humanized 9F5 antibody (present in hu9F5VLv2_T31G).
  • SEQ ID NO: 189 sets forth the amino acid sequence of an alternate Kabat CDR-L1 of a humanized 9F5 antibody (present in hu9F5VLv2_L33N).
  • SEQ ID NO: 190 sets forth the amino acid sequence of an alternate Kabat CDR-L1 of a humanized 9F5 antibody (present in hu9F5VLv2_L33T).
  • SEQ ID NO: 191 sets forth the amino acid sequence of an alternate Kabat CDR-L1 of a humanized 9F5 antibody (present in hu9F5VLv2_L33S).
  • SEQ ID NO: 192 sets forth the amino acid sequence of an alternate Kabat CDR-L1 of a humanized 9F5 antibody (present in hu9F5VLv2_L33R).
  • SEQ ID NO: 193 sets forth the amino acid sequence of an alternate Kabat CDR-L1 of a humanized 9F5 antibody (present in hu9F5VLv2_L33G).
  • SEQ ID NO: 194 sets forth the amino acid sequence of an alternate Kabat CDR-L2 of a humanized 9F5 antibody (present in hu9F5VLv2_M51E).
  • SEQ ID NO: 195 sets forth the amino acid sequence of an alternate Kabat CDR-L2 of a humanized 9F5 antibody (present in hu9F5VLv2_M51D).
  • SEQ ID NO: 196 sets forth the amino acid sequence of an alternate Kabat CDR-L2 of a humanized 9F5 antibody (present in hu9F5VLv8 DIM30).
  • SEQ ID NO: 197 sets forth the amino acid sequence of an alternate Kabat CDR-L2 of a humanized 9F5 antibody (present in hu9F5VLv8 DIM29).
  • SEQ ID NO: 198 sets forth the amino acid sequence of an alternate Kabat CDR-L2 of a humanized 9F5 antibody (present in hu9F5VLv8 DIM I, and hu9F5VLv9 DIM!).
  • SEQ ID NO: 199 sets forth the amino acid sequence of an alternate Kabat CDR-L2 of a humanized 9F5 antibody (present in hu9F5VLv8_DIM3, hu9F5VLv8_DIM14,
  • SEQ ID NO:200 sets forth the amino acid sequence of an alternate Kabat CDR-L2 of a humanized 9F5 antibody (present in hu9F5VLv8 DIM7, hu9F5VLv8 DIMS, and
  • SEQ ID NO:201 sets forth the amino acid sequence of an alternate Kabat CDR-L2 of a humanized 9F5 antibody (present in hu9F5VLv8 DEM9, hu9F5VLv8 DIM 10, and
  • SEQ ID NO:202 sets forth the amino acid sequence of an alternate Kabat CDR-L2 of a humanized 9F5 antibody (present in hu9F5VLv8_DIM19, and hu9F5VLv9_DIM19).
  • SEQ ID NO:203 sets forth the amino acid sequence of an alternate Kabat CDR-L2 of a humanized 9F5 antibody (present in hu9F5VLv8 DIM20, hu9F5VLv8 DIM21, and
  • SEQ ID NO:204 sets forth the amino acid sequence of an alternate Kabat CDR-L2 of a humanized 9F5 antibody (present in hu9F5VLv8 DBM22, hu9F5VLv8 DIM24,
  • SEQ ID NO:205 sets forth the amino acid sequence of an alternate Kabat CDR-L2 of a humanized 9F5 antibody (present in hu9F5VLv8 DIM23).
  • SEQ ID NO:206 sets forth the amino acid sequence of an alternate Kabat CDR-L3 of a humanized 9F5 antibody (present in hu9F5VLv2_A89G).
  • SEQ ID NO:207 sets forth the amino acid sequence of an alternate Kabat CDR-L3 of a humanized 9F5 antibody (present in hu9F5VLv2_L92D).
  • SEQ ID NO:208 sets forth the amino acid sequence of an alternate Kabat CDR-L3 of a humanized 9F5 antibody (present in hu9F5VLv2_L92E).
  • SEQ ID NO:209 sets forth the amino acid sequence of an alternate Kabat CDR-L3 of a humanized 9F5 antibody (present in hu9F5VLv8_DIM4, hu9F5VLv8_DIM12,
  • SEQ ID NO:210 sets forth the amino acid sequence of an alternate Kabat CDR-L3 of a humanized 9F5 antibody (present in hu9F5VLv2_L92Q).
  • SEQ ID NO:211 sets forth the amino acid sequence of an alternate Kabat CDR-L3 of a humanized 9F5 antibody (present in hu9F5VLv2_L92T).
  • SEQ ID NO:212 sets forth the amino acid sequence of an alternate Kabat CDR-L3 of a humanized 9F5 antibody (present in hu9F5VLv8 DIM! , hu9F5VLv8 DEV12,
  • hu9F5VLv9_DIM10 hu9F5VLv9_DIMl l
  • hu9F5VLv9_DIM19 hu9F5VLv9_DIM19
  • u9F5VLv9 DIM20 u9F5VLv9 DIM20
  • SEQ ID NO:213 sets forth the amino acid sequence of an alternate Kabat CDR-L3 of a humanized 9F5 antibody (present in hu9F5VLv2_L93G).
  • SEQ ID NO:214 sets forth the amino acid sequence of humanized heavy chain variable region hu 10C 12VHv 1.
  • SEQ ID NO:215 sets forth the amino acid sequence of humanized heavy chain variable region hulOC12VHv2.
  • SEQ ID NO:216 sets forth the amino acid sequence of humanized light chain variable region hu 10C 12VLv 1.
  • SEQ ID NO:217 sets forth the amino acid sequence of humanized light chain variable region hulOC12VLv2.
  • SEQ ID NO:218 sets forth the amino acid sequence of heavy chain variable region acceptor CAC20421-VH_huFrwk.
  • SEQ ID NO:219 sets forth the amino acid sequence of the heavy chain variable region of the mouse 12C4 antibody.
  • SEQ ID NO:220 sets forth the amino acid sequence of Kabat CDR-H2 of the mouse 12C4 antibody.
  • SEQ ID NO:221 sets forth the amino acid sequence of humanized heavy chain variable region hul2C4VHvl.
  • SEQ ID NO:222 sets forth the amino acid sequence of humanized heavy chain variable region hul2C4VHv2.
  • SEQ ID NO:223 sets forth the amino acid sequence of humanized light chain variable region hul2C4VLvl.
  • SEQ ID NO:224 sets forth the amino acid sequence of humanized light chain variable region hul2C4VLv2.
  • SEQ ID NO:225 sets forth the amino acid sequence of the heavy chain variable region of the mouse 17C12 antibody.
  • SEQ ID NO:226 sets forth the amino acid sequence of Kabat-Chothia composite CDR HI of the mouse 1702 antibody.
  • SEQ ID NO:227 sets forth the amino acid sequence of Kabat CDR H2 of the mouse 17C12 antibody.
  • SEQ ID NO:228 sets forth the amino acid sequence of the light chain variable region of the mouse 17C12 antibody.
  • SEQ ID NO:229 sets forth the amino acid sequence of Kabat CDR-L1 of the mouse 17C12 antibody.
  • SEQ ID NO:230 sets forth the amino acid sequence of Kabat CDR-L2 of the mouse 17C12 antibody.
  • SEQ ID NO:231 sets forth the amino acid sequence of Kabat CDR-L3 of the mouse 17C12 antibody.
  • SEQ ID NO:232 sets forth the amino acid sequence of humanized heavy chain variable region hul7C12VHvl.
  • SEQ ID NO:233 sets forth the amino acid sequence of humanized heavy chain variable region hul7C12VHv2.
  • SEQ ID NO:234 sets forth the amino acid sequence of humanized light chain variable region hul7C12VLvl.
  • SEQ ID NO:235 sets forth the amino acid sequence of humanized light chain variable region hul7C12VLv2.
  • SEQ ID NO:236 sets forth the amino acid sequence of the heavy chain variable region structural model 3PP3-VH_mSt.
  • SEQ ID NO:237 sets forth the amino acid sequence of the light chain variable region structural model 3PP3-VL_mSt.
  • SEQ ID NO:238 sets forth the amino acid sequence of the light chain variable region acceptor QDO 16713 -VL huFrwk.
  • SEQ ID NO:239 sets forth the amino acid sequence of the light chain variable region germline sequence IGKV2-29*02 & IGKJ4*01.
  • SEQ ID NO:240 sets forth the amino acid sequence of the heavy chain variable region of the mouse 14H3 antibody.
  • SEQ ID NO:241 sets forth the amino acid sequence of Kabat-Chothia composite CDR HI of the mouse 14H3 antibody.
  • SEQ ID NO:242 sets forth the amino acid sequence of Kabat CDR H2 of the mouse 14H3 antibody.
  • SEQ ID NO:243 sets forth the amino acid sequence of Kabat CDR H3 of the mouse 14H3 antibody.
  • SEQ ID NO:244 sets forth the amino acid sequence of the light chain variable region of the mouse 14H3 antibody.
  • SEQ ID NO:245 sets forth the amino acid sequence of Kabat CDR LI of the mouse 14H3 antibody
  • SEQ ID NO:246 sets forth the amino acid sequence of Kabat CDR L2 of the mouse 14H3 antibody.
  • SEQ ID NO:247 sets forth the amino acid sequence of Kabat CDR L3 of the mouse 14H3 antibody.
  • SEQ ID NO:248 sets forth the amino acid sequence of humanized heavy chain variable region hul4H3VHvl.
  • SEQ ID NO:249 sets forth the amino acid sequence of humanized heavy chain variable region hul4H3VHv2.
  • SEQ ID NO:250 sets forth the amino acid sequence of humanized light chain variable region hul4H3VLvl.
  • SEQ ID NO:251 sets forth the amino acid sequence of humanized light chain variable region hul4H3VLv2.
  • SEQ ID NO:252 sets forth the amino acid sequence of the heavy chain variable region structural model 2VQl-VH_mSt.
  • SEQ ID NO:253 sets forth the amino acid sequence of the heavy chain variable region acceptor QDJ57937-VH_huFrwk.
  • SEQ ID NO:254 sets forth the amino acid sequence of the heavy chain variable region germline sequence IGHVl-70*04 & IGHJ4*01.
  • SEQ ID NO:255 sets forth the amino acid sequence of the light chain variable region structural model 2VQl-VL_mSt.
  • SEQ ID NO:256 sets forth the amino acid sequence of the light chain variable region acceptor ABC66914-VL_huFrwk.
  • SEQ ID NO:257 sets forth the amino acid sequence of AbM CDR-H2 of the mouse 12C4 antibody.
  • SEQ ID NO:258 sets forth the amino acid sequence of Contact CDR-H2 of the mouse 12C4 antibody.
  • SEQ ID NO:259 sets forth the amino acid sequence of Chothia CDR-H1 of the mouse 17C12 antibody.
  • SEQ ID NO:260 sets forth the amino acid sequence of AbM CDR-H2 of the mouse 17C12 antibody
  • SEQ ID NO:261 sets forth the amino acid sequence of Contact CDR-H2 of the mouse 17C12 antibody.
  • SEQ ID NO:262 sets forth the amino acid sequence of Contact CDR-L1 of the mouse 17C12 antibody.
  • SEQ ID NO:263 sets forth the amino acid sequence of Contact CDR-L2 of the mouse 17C12 antibody.
  • SEQ ID NO:264 sets forth the amino acid sequence of Contact CDR-L3 of the mouse 17C12 antibody.
  • SEQ ID NO:265 sets forth the amino acid sequence of Rabat CDR-H1 of the mouse 14H3 antibody.
  • SEQ ID NO:266 sets forth the amino acid sequence of Chothia CDR-H1 of the mouse 14H3 antibody.
  • SEQ ID NO:267 sets forth the amino acid sequence of Chothia CDR-H2 of the mouse 14H3 antibody.
  • SEQ ID NO:268 sets forth the amino acid sequence of AbM CDR-H2 of the mouse 14H3 antibody.
  • SEQ ID NO:269 sets forth the amino acid sequence of Contact CDR-H1 of the mouse 14H3 antibody.
  • SEQ ID NO:270 sets forth the amino acid sequence of Contact CDR-H2 of the mouse 14H3 antibody.
  • SEQ ID NO:271 sets forth the amino acid sequence of Contact CDR-H3 of the mouse 14H3 antibody.
  • SEQ ID NO:272 sets forth the amino acid sequence of Contact CDR-L1 of the mouse 14H3 antibody.
  • SEQ ID NO:273 sets forth the amino acid sequence of Contact CDR-L2 of the mouse 14H3 antibody.
  • SEQ ID NO:274 sets forth the amino acid sequence of Contact CDR-L3 of the mouse 14H3 antibody.
  • SEQ ID NO:275 sets forth the amino acid sequence of an alternate Kabat-Chothia composite CDR H1 of a humanized 14H3 antibody (present in hul4H3VHvl and
  • SEQ ID NO:276 sets forth the amino acid sequence of a consensus motif of a peptide bound by antibody 9F5, 10C12, 2D11, 12C4, 17C12, and 14H3.
  • SEQ ID NO:277 sets forth the amino acid sequence of a consensus motif of a peptide bound by antibody 2D11.
  • Monoclonal antibodies or other biological entities are typically provided in isolated form. This means that an antibody or other biologically entity is typically at least 50% w/w pure of interfering proteins and other contaminants arising from its production or purification but does not exclude the possibility that the monoclonal antibody is combined with an excess of pharmaceutically acceptable carrier(s) or other vehicle intended to facilitate its use. Sometimes monoclonal antibodies are at least 60%, 70%, 80%, 90%, 95% or 99% w/w pure of interfering proteins and contaminants from production or purification. Often an isolated monoclonal antibody or other biological entity is the predominant macromolecular species remaining after its purification.
  • Specific binding of an antibody to its target antigen means an affinity and/or avidity of at least 10 6 , 10 7 , 10 8 , 10 9 , 10 10 , 10 11 , or 10 12 M 1 .
  • Specific binding is detectably higher in magnitude and distinguishable from non-specific binding occurring to at least one unrelated target.
  • Specific binding can be the result of formation of bonds between particular functional groups or particular spatial fit ( e.g ., lock and key type) whereas nonspecific binding is usually the result of van der Waals forces.
  • Specific binding does not however necessarily imply that an antibody binds one and only one target.
  • the basic antibody structural unit is a tetramer of subunits.
  • Each tetramer includes two identical pairs of polypeptide chains, each pair having one "light” (about 25 kDa) and one "heavy" chain (about 50-70 kDa).
  • the amino-terminal portion of each chain includes a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition. This variable region is initially expressed linked to a cleavable signal peptide.
  • the variable region without the signal peptide is sometimes referred to as a mature variable region.
  • a light chain mature variable region means a light chain variable region without the light chain signal peptide.
  • the carboxy -terminal portion of each chain defines a constant region primarily responsible for effector function.
  • Light chains are classified as either kappa or lambda.
  • Heavy chains are classified as gamma, mu, alpha, delta, or epsilon, and define the antibody's isotype as IgG, IgM, IgA, IgD and IgE, respectively.
  • the variable and constant regions are joined by a "J" region of about 12 or more amino acids, with the heavy chain also including a "D” region of about 10 or more amino acids. See generally , Fundamental Immunology , Paul, W., ed., 2nd ed. Raven Press, N.Y., 1989, Ch. 7 (incorporated by reference in its entirety for all purposes).
  • An immunoglobulin light or heavy chain variable region (also referred to herein as a “light chain variable domain” (“VL domain”) or“heavy chain variable domain” (“VH domain”), respectively) consists of a“framework” region interrupted by three“complementarity
  • both VL and VH domains comprise the following framework (FR) and CDR regions: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.
  • FR1 framework
  • CDR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4 framework
  • CDRs 1, 2, and 3 of a VL domain are also referred to herein, respectively, as CDR-L1, CDR-L2, and CDR-L3
  • CDRs 1, 2, and 3 of a VH domain are also referred to herein, respectively, as CDR-H1, CDR-H2, and CDR-H3.
  • the application discloses a VL sequence with R as the C-terminal residue
  • the R can alternatively be considered as being the N-terminal residue of the light chain constant region.
  • the application should also be understood as disclosing the VL sequence without the C-terminal R.
  • an antibody comprising CDRs defined by Kabat includes among other possibilities, an antibody in which the CDRs contain Kabat CDR residues and no other CDR residues, and an antibody in which CDR HI is a composite Chothia-Kabat CDR HI and other CDRs contain Kabat CDR residues and no additional CDR residues based on other definitions.
  • *CDR-H1 by Chothia can end at H32, H33, or H34 (depending on the length of the loop).
  • H35A is present, it ends at H33. If both H35A and H35B are present, it ends at H34.
  • antibody includes intact antibodies and binding fragments thereof.
  • fragments compete with the intact antibody from which they were derived for specific binding to the target including separate heavy chains, light chains Fab, Fab', F(ab')2, F(ab)c, Dabs, nanobodies, and Fv. Fragments can be produced by recombinant DNA techniques, or by enzymatic or chemical separation of intact immunoglobulins.
  • the term“antibody” also includes a bispecific antibody and/or a humanized antibody.
  • a bispecific or bifunctional antibody is an artificial hybrid antibody having two different heavy /light chain pairs and two different binding sites (see, e.g., Songsivilai and Lachmann, Clin. Exp.
  • the two different heavy/light chain pairs include a humanized 9F5, 1002, 2D11, 12C4, 1702, or 14H3 heavy chain/light chain pair and a heavy chain/light chain pair specific for a different epitope on tau than that bound by 9F5, 1002, 2D11, 12C4, 1702, or 14H3.
  • one heavy chain/light chain pair is a humanized 9F5 antibody, humanized 1002 antibody, humanized 2D11 antibody, humanized 12C4 antibody, humanized 1702 antibody, or humanized 14H3 antibody as further disclosed below and the other heavy chain/light chain pair is from an antibody that binds to a receptor expressed on the blood brain barrier, such as an insulin receptor, an insulin-like growth factor (IGF) receptor, a leptin receptor, or a lipoprotein receptor, or a transferrin receptor (Friden et al., Proc. Natl. Acad. Sci. USA 88:4771-4775, 1991; Friden et al., Science 259:313-311 , 1993).
  • a bispecific antibody can be transferred cross the blood brain barrier by receptor-mediated transcytosis.
  • Brain uptake of the bispecific antibody can be further enhanced by engineering the bi-specific antibody to reduce its affinity to the blood brain barrier receptor. Reduced affinity for the receptor resulted in a broader distribution in the brain (see, e.g, Atwal et al., Sci. Trans. Med. 3, 84ra43, 2011; Yu et al., Sci. Trans. Med. 3, 84ra44, 2011).
  • Exemplary bispecific antibodies can also be: (1) a dual -variable-domain antibody (DVD-Ig), where each light chain and heavy chain contains two variable domains in tandem through a short peptide linkage (Wu et al., Generation and Characterization of a Dual Variable Domain Immunoglobulin (DVD-IgTM) Molecule, In: Antibody Engineering, Springer Berlin Heidelberg (2010)); (2) a Tandab, which is a fusion of two single chain diabodies resulting in a tetravalent bispecific antibody that has two binding sites for each of the target antigens; (3) a flexibody, which is a combination of scFvs with a diabody resulting in a multivalent molecule; (4) a so-called “dock and lock” molecule, based on the "dimerization and docking domain" in Protein Kinase A, which, when applied to Fabs, can yield a trivalent bispecific binding protein consisting of two identical Fab fragments linked
  • bispecific antibodies examples include BiTE (Micromet), DART (MacroGenics), Fcab and Mab2 (F-star), Fc-engineered IgGl (Xencor) or DuoBody (based on Fab arm exchange, Genmab).
  • the term“epitope” refers to a site on an antigen to which an antibody binds.
  • An epitope can be formed from contiguous amino acids or noncontiguous amino acids juxtaposed by tertiary folding of one or more proteins.
  • Epitopes formed from contiguous amino acids are typically retained on exposure to denaturing solvents whereas epitopes formed by tertiary folding (also known as conformational epitopes) are typically lost on treatment with denaturing solvents.
  • An epitope typically includes at least 3, and more usually, at least 5 or 8-10 amino acids in a unique spatial conformation. Methods of determining spatial conformation of epitopes include, for example, x-ray crystallography and 2-dimensional nuclear magnetic resonance. See, e.g ., Epitope Mapping Protocols, in Methods in Molecular Biology, Vol. 66, Glenn E. Morris, Ed. (1996).
  • Antibodies that recognize the same or overlapping epitopes can be identified in a simple immunoassay showing the ability of one antibody to compete with the binding of another antibody to a target antigen.
  • the epitope of an antibody can also be defined X-ray
  • two antibodies have the same epitope if all amino acid mutations in the antigen that reduce or eliminate binding of one antibody reduce or eliminate binding of the other.
  • Two antibodies have overlapping epitopes if some amino acid mutations that reduce or eliminate binding of one antibody reduce or eliminate binding of the other.
  • Competition between antibodies is determined by an assay in which an antibody under test inhibits specific binding of a reference antibody to a common antigen (see, e.g. , Junghans et al., Cancer Res. 50: 1495, 1990).
  • a test antibody competes with a reference antibody if an excess of a test antibody (e.g, at least 2x, 5x, lOx, 20x or lOOx) inhibits binding of the reference antibody by at least 50% as measured in a competitive binding assay.
  • Some test antibodies inhibit binding of the references antibody by at least 75%, 90% or 99%.
  • Antibodies identified by competition assay include antibodies binding to the same epitope as the reference antibody and antibodies binding to an adjacent epitope sufficiently proximal to the epitope bound by the reference antibody for steric hindrance to occur.
  • the term“pharmaceutically acceptable” means that the carrier, diluent, excipient, or auxiliary is compatible with the other ingredients of the formulation and not substantially deleterious to the recipient thereof.
  • patient includes human and other mammalian subjects that receive either prophylactic or therapeutic treatment.
  • An individual is at increased risk of a disease if the subject has at least one known risk- factor (e.g ., genetic, biochemical, family history, and situational exposure) placing individuals with that risk factor at a statistically significant greater risk of developing the disease than individuals without the risk factor.
  • risk- factor e.g ., genetic, biochemical, family history, and situational exposure
  • biological sample refers to a sample of biological material within or obtainable from a biological source, for example a human or mammalian subject.
  • samples can be organs, organelles, tissues, sections of tissues, bodily fluids, peripheral blood, blood plasma, blood serum, cells, molecules such as proteins and peptides, and any parts or
  • biological sample can also encompass any material derived by processing the sample. Derived material can include cells or their progeny.
  • Processing of the biological sample may involve one or more of filtration, distillation, extraction, concentration, fixation, inactivation of interfering components, and the like.
  • control sample refers to a biological sample not known or suspected to include tau-related disease-affected regions, or at least not known or suspect to include diseased regions of a given type.
  • Control samples can be obtained from individuals not afflicted with the tau-related disease.
  • control samples can be obtained from patients afflicted with the tau-related disease.
  • Such samples can be obtained at the same time as a biological sample thought to comprise the tau-related disease or on a different occasion.
  • a biological sample and a control sample can both be obtained from the same tissue.
  • control samples consist essentially or entirely of normal, healthy regions and can be used in comparison to a biological sample thought to comprise tau-related disease-affected regions.
  • the tissue in the control sample is the same type as the tissue in the biological sample.
  • the tau-related disease-affected cells thought to be in the biological sample arise from the same cell type (e.g., neurons or glia ) as the type of cells in the control sample.
  • the term“disease” refers to any abnormal condition that impairs physiological function. The term is used broadly to encompass any disorder, illness, abnormality, pathology, sickness, condition, or syndrome in which physiological function is impaired, irrespective of the nature of the etiology.
  • symptom refers to a subjective evidence of a disease, such as altered gait, as perceived by the subject.
  • a "sign” refers to objective evidence of a disease as observed by a physician.
  • positive response to treatment refers to a more favorable response in an individual patient or average response in a population of patients relative to an average response in a control population not receiving treatment.
  • amino acids are grouped as follows: Group I (hydrophobic side chains): met, ala, val, leu, ile; Group II (neutral hydrophilic side chains): cys, ser, thr; Group III (acidic side chains): asp, glu; Group IV (basic side chains): asn, gin, his, lys, arg; Group V (residues influencing chain orientation): gly, pro; and Group VI (aromatic side chains): trp, tyr, phe.
  • Conservative substitutions involve substitutions between amino acids in the same class. Non conservative substitutions constitute exchanging a member of one of these classes for a member of another.
  • Percentage sequence identities are determined with antibody sequences maximally aligned by the Kabat numbering convention. After alignment, if a subject antibody region (e.g ., the entire mature variable region of a heavy or light chain) is being compared with the same region of a reference antibody, the percentage sequence identity between the subject and reference antibody regions is the number of positions occupied by the same amino acid in both the subject and reference antibody region divided by the total number of aligned positions of the two regions, with gaps not counted, multiplied by 100 to convert to percentage.
  • a subject antibody region e.g ., the entire mature variable region of a heavy or light chain
  • compositions or methods“comprising” or“including” one or more recited elements may include other elements not specifically recited.
  • a composition that “comprises” or“includes” an antibody may contain the antibody alone or in combination with other ingredients.
  • Designation of a range of values includes all integers within or defining the range, and all subranges defined by integers within the range.
  • the invention provides antibodies that bind to tau. Some antibodies specifically bind to an epitope within (Q/E)IVYK(S/P) (SEQ ID NO:56). Some antibodies specifically bind to a peptide comprising amino acid sequence QIVYKP (SEQ ID NO:57, corresponding to residues 307-312 of the tau isoform of SEQ ID NO:l). Some antibodies specifically bind to a peptide comprising amino acid sequence EIVYKSP (SEQ ID NO:58, corresponding to residues 391-397 of the tau isoform of SEQ ID NO: 1).
  • the antibodies differ from 3D6 and other antibodies characterized in binding to the microtubule binding region (MTBR) of human tau in having an additional epitope near the C-terminus of tau.
  • the epitope s additional C-terminal specificity provides a basis for an antibody to bind an increased number of conformational forms of tau associated with pathology.
  • Some antibodies specifically bind to a peptide comprising amino acid sequence EIVYKS (SEQ ID NO:277, corresponding to residues 391-396 of the tau isoform of SEQ ID NO: l).
  • Exemplary antibodies of the invention are 9F5, 1002, 2D11, 12C4, 1702, and 14H3.
  • Some antibodies of the invention serve to inhibit or delay tau-associated pathologies and associated symptomatic deterioration.
  • a reduction in toxicity may occur as a result of the antibody inducing phagocytosis of tau, inhibiting tau from inter or intramolecular aggregation, or from binding to other molecules, by stabilizing a non-toxic conformation, by inhibiting intercellular or intracellular transmission of pathogenic tau forms, by blockade of tau
  • Some antibodies of the invention are useful in increasing aggregation of tau, by increasing the molecular weight of certain aggregated tau species to decrease toxicity/cell uptake and/or increase clearance. Large aggregates of tau molecules may exhibit reduced uptake into neuronal cells. Some antibodies of the invention, by bivalent binding to tau, bring separate tau molecules into closer proximity, encouraging aggregation into a tau aggregate too large for uptake into neuronal cells.
  • Fc-mediated phagocytosis requires several tau-binding antibodies to be in close proximity. A large aggregate of tau molecules may have many anti -tau antibodies bound to it and provide the cluster needed for Fc-mediated
  • the antibodies of the invention or agents that induce such antibodies can be used in methods of treating or effecting prophylaxis of Alzheimer’s and other diseases associated with tau.
  • tau means a natural human form of tau including all isoforms irrespective of whether posttranslational modification (e.g ., phosphorylation, gly cation, or acetylation) is present.
  • posttranslational modification e.g ., phosphorylation, gly cation, or acetylation
  • reference to a phosphorylation at position 404 means position 404 of the 441 isoform, or corresponding position of any other isoform when maximally aligned with the 441 isoform.
  • the amino acid sequences of the isoforms and Swiss-Prot numbers are indicated below.
  • P10636-6 4R0N human tau (SEQ ID NO : 3 )
  • PKTPPSSGEP PKSGDRSGYS SPGSPGTPGS RSRTPSLPTP PTREPKKVAV VRTPPKSPSS
  • PKTPPSSGEP PKSGDRSGYS SPGSPGTPGS RSRTPSLPTP PTREPKKVAV VRTPPKSPSS
  • Reference to tau includes known natural variations about 30 of which are listed in the Swiss-Prot database and permutations thereof, as well as mutations associated with tau pathologies, such as dementia, Pick’s disease, supranuclear palsy, etc. (see, e.g ., Swiss-Prot database and Poorkaj, et al. Ann Neurol.43:815-825 (1998)).
  • tau mutations numbered by the 441 isoform are a lysine to threonine mutation at amino acid residue 257 (K257T), an isoleucine to valine mutation at amino acid position 260 (I260V); a glycine to valine mutation at amino acid position 272 (G272V); an asparagine to lysine mutation at amino acid position 279 (N279K); an asparagine to histidine mutation at amino acid position 296 (N296H); a proline to serine mutation at amino acid position 301 (P301S); a proline to leucine mutation at amino acid 301 (P301L); a glycine to valine mutation at amino acid position 303 (G303V); a serine to asparagine mutation at position 305 (S305N); a glycine to serine mutation at amino acid position 335 (G335S); a valine to methionine mutation at position 337 (V337M); a glutamic acid
  • Tau can be phosphorylated at one or more amino acid residues including tyrosine at amino acid positions 18, 29, 97, 310, and 394 serine at amino acid positions 184, 185, 198, 199, 202, 208, 214, 235, 237, 238, 262, 293, 324, 356, 396, 400, 404, 409, 412, 413, and 422; and threonine at amino acids positions 175, 181, 205, 212, 217, 231, and 403.
  • reference to tau includes the natural human amino acid sequences including isoforms, mutants, and allelic variants thereof.
  • the invention provides antibodies that specifically bind to tau.
  • Some antibodies specifically bind to tau at an epitope formed by amino acids from either or both of two regions of tau having a common core motif of IVYK (SEQ ID NO:276). These regions are defined by residues 307-312 and 391-397 or 391-396 of SEQ ID NO: l respectively.
  • an antibody with one binding site for tau such as an scFv can specifically bind to tau at an epitope formed from amino acids within either of these regions individually or to a hybrid epitope formed by amino acids from both these regions.
  • An antibody with two binding sites for tau can also bind epitopes within 307-312 and 391-397 or within 391-396 simultaneously from its two binding sites.
  • the epitope can be on the same or different molecules of tau.
  • Some antibodies of the invention specifically bind to a peptide consisting of residues 307-312 of tau, namely residues QIVYKP (SEQ ID NO:57).
  • Some antibodies of the invention specifically bind to a peptide consisting of residues 391-397 of tau, namely EIVYKSP (SEQ ID NO:58).
  • Some antibodies of the invention specifically bind to a peptide consisting of residues 391-396 of tau, namely EIVYKS (SEQ ID NO:277).
  • Some antibodies of the invention specifically bind to a peptide consisting of the consensus motif (Q/E)IVYK(S/P) (SEQ ID NO:56).
  • antibodies can be obtained by immunizing with a tau polypeptide purified from a natural source or recombinantly expressed.
  • Antibodies can be screened for binding tau in unphosphorylated form as well as a form in which one or more residues susceptible to phosphorylation are phosphorylated.
  • the invention also provides antibodies binding to the same epitope as any of the foregoing antibodies, such as, for example, the epitope of 9F5, 1002, 2D11, 12C4, 1702, or 14H3.
  • antibodies competing for binding to tau with any of the foregoing antibodies such as, for example, competing with 9F5, 1002, 2D11, 12C4, 1702, or 14H3.
  • antibodies binding to the same epitope as a reference antibody such as 9F5 or competing with the reference antibody share one or more of its functional properties, such as capacity to inhibit tau
  • such property is possessed to the same extent within experimental error, or greater than that of the reference antibody.
  • the invention provides an antibody that competes with 9F5 for binding to tau and reduces tau-induced toxicity in neurons.
  • the invention provides an antibody that competes with 9F5 for binding to tau and has increased resistance to agitation stress.
  • Exemplary 9F5 humanized antibodies that compete with 9F5 for binding to tau and have increased resistance to agitation stress are L27cS/L37Q/M51G/L54R (DIM2), also known as
  • hu9F5VHv9/hu9F5VLv8_DIM2 SEQ ID NO: 127/ SEQ ID NO: 133, L27cG/L37G/M51G/L54T (DIM 14), also known as hu9F5VHv9/hu9F5VLv8_DIM14 SEQ ID NO: 127/ SEQ ID NO: 145, and L27cG/L37G/M51G/L54R (DIM13), also known as hu9F5VHv9/hu9F5VLv8_DIM13 SEQ ID NO: 127/ SEQ ID NO: 144.
  • the invention provides an antibody that competes with 9F5 for binding to tau and has increased resistance to low pH stress.
  • exemplary 9F5 humanized antibodies that compete with 9F5 for binding to tau and have increased resistance to low pH stress are L27cS/L37Q/M51G/L54R (DIM2), also known as hu9F5VHv9/hu9F5VLv8_DIM2 SEQ ID NO: 127/ SEQ ID NO: 133, L27cD/L37Q/M51G/L54R (DIM6), also known as hu9F5VHv9/hu9F5VLv8_DIM6 , SEQ ID NO: 127/ SEQ ID NO: 137, and L27cG/L37G/M51G/L54R (DIM13), also known as hu9F5VHv9/hu9F5VLv8_DIM13 SEQ ID
  • Exemplary 9F5 humanized antibodies that compete with 9F5 for binding to tau and have increased resistance to agitation stress and have increased resistance to low pH stress are DIM 2 [hu9F5VHv9/hu9F5VLv8_DIM2 SEQ ID NO: 127/ SEQ ID NO: 133],
  • DIM6 [hu9F5VHv9/hu9F5VLv8_DIM6 SEQ ID NO: 127/ SEQ ID NO: 137], DIM7
  • the invention provides an antibody that competes with 9F5 for binding to tau and has reduced propensity to aggregate under high concentration conditions.
  • An exemplary antibody that competes with 9F5 for binding to tau and has reduced propensity to aggregate under high concentration conditions is L37Q/M51G/L54R combined with the original leucine at position L27c(DIM27), also known as hu9F5VHv9/hu9F5VLv8_DIM27 SEQ ID NO: 127/ SEQ ID NO: 158.
  • the above-mentioned antibodies can be generated de novo by immunizing with a tau peptide comprising or consisting of amino acid sequence QIVYKP (SEQ ID NO:57), comprising amino acid sequence EIVYKSP (SEQ ID NO:58), comprising amino acid sequence EIVYKS (SEQ ID NO:277) or comprising or consisting of amino acid sequence (Q/E)IVYK(S/P) (SEQ ID NO:56) or by immunizing with a full length tau polypeptide or fragment thereof comprising such residues and screening for specific binding to a peptide including such residues.
  • tau peptides are preferably attached to a heterologous conjugate molecule that helps elicit an antibody response to the peptide.
  • Attachment can be direct or via a spacer peptide or amino acid.
  • Cysteine is used as a spacer amino acid because its free SH group facilitates attachment of a carrier molecule.
  • a polyglycine linker e.g ., 2-6 glycines
  • the carrier molecule serves to provide a T-cell epitope that helps elicit an antibody response against the peptide.
  • Several carriers are commonly used particularly keyhole limpet hemocyanin (KLH), ovalbumin and bovine serum albumin (BSA).
  • KLH keyhole limpet hemocyanin
  • BSA bovine serum albumin
  • Carriers are typically added by chemical cross-linking.
  • chemical crosslinkers that can be used include cross-N-maleimido-6-aminocaproyl ester or m- maleimidobenzoyl-N-hydroxysuccinimide ester (MBS) (see for example, Harlow, E. et ah, Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. 1988; Sinigaglia et ak, Nature, 336:778-780 (1988); Chicz et ak, J. Exp. Med., 178:27-47 (1993); Hammer et ak, Cell 74: 197-203 (1993); Falk K.
  • the carrier and spacer if present can be attached to either end of the immunogen.
  • a peptide with optional spacer and carrier can be used to immunize laboratory animals or B-cells as described in more detail below.
  • Hybridoma supernatants can be tested for ability to bind a tau peptide comprising or consisting of amino acid sequence QIVYKP (SEQ ID NO:57), a peptide comprising or consisting of amino acid sequence EIVYKSP (SEQ ID NO:58), a peptide comprising or consisting of amino acid sequence EIVYKS (SEQ ID NO:277),or a peptide comprising or consisting of the amino acid sequence (Q/E)IVYK(S/P) (SEQ ID NO:56) and/or phosphorylated and non-phosphorylated forms of tau, such as, for example, a full-length isoform of tau with position 404 in phosphorylated form.
  • the peptide can be attached to a carrier or other tag to facilitate the screening assay.
  • the carrier or tag is preferentially different than the combination of spacer and carrier molecule used for immunization to eliminate antibodies specific for the spacer or carrier rather than the tau peptide. Any of the tau isoforms can be used.
  • An antibody designated 9F5 is an exemplary antibody specifically binding to tau. Unless otherwise apparent from context, reference to 9F5 should be understood as referring to any of the mouse, chimeric, veneered, and humanized forms of this antibody.
  • the antibody has been deposited as [DEPOSIT NUMBER] This antibody specifically binds a peptide comprising or consisting of amino acid sequence QIVYKP (SEQ ID NO:57), a peptide comprising or consisting of amino acid sequence EIVYKSP (SEQ ID NO:58), or a peptide comprising or consisiting of amino acid sequence (Q/E)IVYK(S/P) (SEQ ID NO:56). Kabat/Chothia
  • Composite CDRs of the heavy chain of 9F5 are designated SEQ ID NOs:8, 9, and 10, respectively, and Kabat CDRs of the light chain of 9F5 are designated SEQ ID NOs: 12, 13, and 14, respectively.
  • IOC 12 has mature variable heavy and light regions (after cleavage of signal peptide) characterized by SEQ ID NO: 7 and SEQ ID NO: 11 respectively.
  • reference to 1002 should be understood as referring to any of the mouse, chimeric, veneered, and humanized forms of this antibody.
  • 1002 has been deposited as [DEPOSIT NUMBER] 1002 is further characterized by its ability to bind both non-pathological and pathological forms and conformations of tau, and misfolded/aggregated forms of tau. 1002 binds structural features such as tau tangles and dystrophic neurites in tissue from Alzheimer’s disease, and precipitates both monomeric and aggregated tau from Alzheimer’s disease extracts.
  • 2D11 has mature variable heavy and light regions (after cleavage of signal peptide) characterized by SEQ ID N0:7 and SEQ ID NO: 11 respectively. Unless otherwise apparent from the context, reference to 2D 11 should be understood as referring to any of the mouse, chimeric, veneered, and humanized forms of this antibody. 2D11 has been deposited as
  • 2D11 is further characterized by its ability to bind both non- pathological and pathological forms and conformations of tau, and misfolded/aggregated forms of tau. 2D11 binds structural features such as tau tangles and dystrophic neurites in tissue from Alzheimer’s disease, and precipitates both monomeric and aggregated tau from Alzheimer’s disease extracts.
  • 12C4 has mature variable heavy and light regions (after cleavage of signal peptide) characterized by SEQ ID NO:219 and SEQ ID NO: 11 respectively. Unless otherwise apparent from the context, reference to 12C4 should be understood as referring to any of the mouse, chimeric, veneered, and humanized forms of this antibody. 12C4 has been deposited as
  • 12C4 is further characterized by its ability to bind both non- pathological and pathological forms and conformations of tau, and misfolded/aggregated forms of tau. 12C4 binds structural features such as tau tangles and dystrophic neurites in tissue from Alzheimer’s disease, and precipitates both monomeric and aggregated tau from Alzheimer’s disease extracts.
  • 17C12 has mature variable heavy and light regions (after cleavage of signal peptide) characterized by SEQ ID NO:225 and SEQ ID NO:228 respectively. Unless otherwise apparent from the context, reference to 17C12 should be understood as referring to any of the mouse, chimeric, veneered, and humanized forms of this antibody. 17C12 has been deposited as
  • [DEPOSIT NUMBER] 17C12 is further characterized by its ability to bind both non- pathological and pathological forms and conformations of tau, and misfolded/aggregated forms of tau.
  • 14H3 has mature variable heavy and light regions (after cleavage of signal peptide) characterized by SEQ ID NO:240 and SEQ ID NO:244 respectively. Unless otherwise apparent from the context, reference to 14H3 should be understood as referring to any of the mouse, chimeric, veneered, and humanized forms of this antibody. 14H3 has been deposited as
  • 14H3 is further characterized by its ability to bind both non- pathological and pathological forms and conformations of tau, and misfolded/aggregated forms of tau. 14H3 binds structural features such as tau tangles and dystrophic neurites in tissue from Alzheimer’s disease.
  • Alignments of the mature heavy chain variable regions of mouse 9F5, 1002, 2D11, 12C4, 14H3, and 1702 antibodies are depicted in Figure 24, and alignments of the mature light chain variable regions of mouse 9F5, 1002, 2D11, 12C4, 14H3, and 1702 antibodies are depicted in Figure 25.
  • the amino acid sequence of the mature heavy chain variable region of mouse 1002 antibody has 100% sequence identity to that of mouse 9F5 antibody, and the mature light chain variable region of mouse 1002 antibody has 100% sequence identity to that of mouse 9F5 antibody.
  • the amino acid sequence of the mature heavy chain variable region of mouse 2D11 antibody has 100% sequence identity to that of mouse 9F5 antibody, and the mature light chain variable region of mouse 2D11 antibody has 100% sequence identity to that of mouse 9F5 antibody.
  • the amino acid sequence of the mature heavy chain variable region of mouse 12C4 antibody has 96.6% sequence identity to that of mouse 9F5 antibody, and the mature light chain variable region of mouse 12C4 antibody has 100% sequence identity to that of mouse 9F5 antibody.
  • the amino acid sequence of the mature heavy chain variable region of mouse 17C12 antibody has 95.9% sequence identity to that of mouse 9F5 antibody, and the mature light chain variable region of mouse 17C12 antibody has 70.5% sequence identity to that of mouse 9F5 antibody.
  • the amino acid sequence of the mature heavy chain variable region of mouse 14H3 antibody has 35.0% sequence identity to that of mouse 9F5 antibody, and the mature light chain variable region of mouse 14H3 antibody has 73.2% sequence identity to that of mouse 9F5 antibody.
  • the antibodies of the invention do not include a 10C12 antibody.
  • the antibodies of the invention do not include a 2D11 antibody.
  • the antibodies of the invention do not include an 12C4 antibody.
  • the antibodies of the invention do not include a 17C12 antibody.
  • the antibodies of the invention do not include a 14H3 antibody.
  • Some antibodies of the invention bind to the same or overlapping epitope as an antibody designated 9F5, 10C12, 2D11, 12C4, 17C12, or 14H3.
  • the sequences of the heavy and light chain mature variable regions of this 9F5 are designated SEQ ID NOs:7 and 11,
  • the sequences of the heavy and light chain mature variable regions of 1002 are designated SEQ ID NOs:7 and 11, respectively.
  • the sequences of the heavy and light chain mature variable regions of 2D11 are designated SEQ ID NOs:7 and 11, respectively.
  • the sequences of the heavy and light chain mature variable regions of 12C4 are designated SEQ ID NOs:219 and 11, respectively.
  • the sequences of the heavy and light chain mature variable regions of 1702 are designated SEQ ID NOs:225 and 228, respectively.
  • the sequences of the heavy and light chain mature variable regions of 14H3 are designated SEQ ID NOs:240 and 244, respectively.
  • Other antibodies having such a binding specificity can be produced by immunizing mice with tau or a portion thereof including the desired epitope (e.g.
  • a tau peptide comprising or consisting of the amino acid sequence QIVYKP (SEQ ID NO:57), a tau peptide comprising or consisting of the amino acid sequence EIVYKSP (SEQ ID NO:58), a tau peptide comprising or consisting of the amino acid sequence EIVYKS (SEQ ID NO:277),or a tau peptide comprising or consisting of the amino acid sequence (Q/E)IVYK(S/P) (SEQ ID NO:56)) and screening resulting antibodies for binding to tau optionally in competition with an antibody having the variable regions of mouse 9F5 (IgGl/ kappa), 10C12 (IgG2a/kappa), 2D11 (IgG2a/kappa), 12C4 (IgG2a/kappa), 17C12 (IgG2a/kappa), or 14H3 (IgG2a/kappa).
  • Fragments of tau including the desired epitope can be linked to a carrier that helps elicit an antibody response to the fragment and/or be combined with an adjuvant the helps elicit such a response.
  • Such antibodies can be screened for differential binding to tau or a fragment thereof compared with mutants of specified residues. Screening against such mutants more precisely defines the binding specificity to allow identification of antibodies whose binding is inhibited by mutagenesis of particular residues and which are likely to share the functional properties of other exemplified antibodies.
  • the mutations can be systematic replacement substitution with alanine (or serine if an alanine is present already) one residue at a time, or more broadly spaced intervals, throughout the target or throughout a section thereof in which an epitope is known to reside. If the same set of mutations significantly reduces the binding of two antibodies, the two antibodies bind the same epitope.
  • Antibodies having the binding specificity of a selected murine antibody can also be produced using a variant of the phage display method. See Winter, WO 92/20791. This method is particularly suitable for producing human antibodies.
  • either the heavy or light chain variable region of the selected murine antibody is used as a starting material. If, for example, a light chain variable region is selected as the starting material, a phage library is constructed in which members display the same light chain variable region (i.e., the murine starting material) and a different heavy chain variable region.
  • the heavy chain variable regions can for example be obtained from a library of rearranged human heavy chain variable regions.
  • a phage showing strong specific binding for tau or a fragment thereof (e.g., at least 10 8 and preferably at least 10 9 M 1 ) is selected.
  • the heavy chain variable region from this phage then serves as a starting material for constructing a further phage library.
  • each phage displays the same heavy chain variable region (i.e., the region identified from the first display library) and a different light chain variable region.
  • the light chain variable regions can be obtained for example from a library of rearranged human variable light chain regions.
  • phage showing strong specific binding for tau or a fragment thereof are selected.
  • the resulting antibodies usually have the same or similar epitope specificity as the murine starting material.
  • Kabat/Chothia Composite CDRs of the heavy chain of 9F5 are designated SEQ ID NOs:8-10, respectively, and Kabat CDRs of the light chain of 9F5 are designated SEQ ID NOs: 12-14, respectively.
  • Table 2 indicates the 9F5, 1002, and 2D11 CDRs as defined by Kabat, Chothia, Composite of Chothia and Kabat (also referred to herein as“Kabat/Chothia Composite”), AbM, and Contact.
  • Table 3 indicates the 12C4 CDRs as defined by Kabat, Chothia, Composite of Chothia and Kabat (also referred to herein as“Kabat/Chothia Composite”), AbM, and Contact.
  • Table 4 indicates the 1702 CDRs as defined by Kabat, Chothia, Composite of Chothia and Kabat (also referred to herein as“Kabat/Chothia Composite”), AbM, and Contact.
  • Table 4 1702 CDRs as defined by Kabat, Chothia, Composite of Chothia and Kabat,
  • Table 5 indicates the 14H3 CDRs as defined by Kabat, Chothia, Composite of Chothia and Kabat (also referred to herein as“Kabat/Chothia Composite”), AbM, and Contact.
  • antibodies can be obtained by mutagenesis of cDNA encoding the heavy and light chains of an exemplary antibody, such as 9F5, 1002, 2D11, 12C4, 1702, or 14H3.
  • Monoclonal antibodies that are at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% identical to 9F5, 1002, 2D11, 12C4, 1702, or 14H3 in amino acid sequence of the mature heavy and/or light chain variable regions and maintain its functional properties, and/or which differ from the respective antibody by a small number of functionally inconsequential amino acid substitutions (e.g ., conservative substitutions), deletions, or insertions are also included in the invention.
  • the invention also provides antibodies having some or all (e.g., 3, 4, 5, and 6) CDRs entirely or substantially from 9F5, 1002, 2D11, 12C4, 17C12, or 14H3.
  • Such antibodies can include a heavy chain variable region that has at least two, and usually all three, CDRs entirely or substantially from the heavy chain variable region of 9F5, 10C12, 2D11, 12C4, 1702, or 14H3 and/or a light chain variable region having at least two, and usually all three, CDRs entirely or substantially from the light chain variable region of 9F5, 10C12, 2D11, 12C4, 17C12, or 14H3.
  • the antibodies can include both heavy and light chains.
  • a CDR is substantially from a corresponding 9F5 CDR when it contains no more than 4, 3, 2, or 1 substitutions, insertions, or deletions, except that CDR-H2 (when defined by Rabat) can have no more than 6, 5, 4, 3, 2, or 1 substitutions, insertions, or deletions.
  • Such antibodies can have at least 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% identity to 9F5, 10C12, 2D11, 12C4, 17C12, or 14H3 in the amino acid sequence of the mature heavy and/or light chain variable regions and maintain their functional properties, and/or differ from 9F5, 1002, 2D11, 12C4, 17C12, or 14H3 by a small number of functionally inconsequential amino acid substitutions (e.g ., conservative substitutions), deletions, or insertions.
  • Some antibodies identified by such assays can bind to monomeric, misfolded, aggregated, phosphorylated, or unphosphorylated forms of tau or otherwise. Likewise, some antibodies are immunoreactive on non-pathological and pathological forms and conformations of tau.
  • the invention further provides a means for specifically binding to a peptide consisting of residues (Q/E)IVYK(S/P) (SEQ ID NO:56), residues QIVYKP (SEQ ID NO:57) residues EIVYKSP (SEQ ID NO:58), or residues EIVYKS (SEQ ID NO:277).
  • An exemplary means is an antibody comprising the heavy chain CDRs of SEQ ID NOs:8-10 and light chain CDRs of SEQ ID NOs.: 12-14.
  • An exemplary means is an antibody comprising the heavy chain CDRs of SEQ ID NOs:8, 220, and 10 and light chain CDRs of SEQ ID NOs: 12-14.
  • An exemplary means is an antibody comprising the heavy chain CDRs of SEQ ID NOs:226, 227, and 10 and light chain CDRs of SEQ ID NOs: 229-231.
  • An exemplary means is an antibody comprising the heavy chain CDRs of SEQ ID NOs:241-243 and light chain CDRs of SEQ ID NOs:245-247.
  • non-human antibodies e.g., murine, guinea pig, primate, rabbit or rat, against tau or a fragment thereof (e.g., a peptide comprising an amino acid sequence of QIVYKP (SEQ ID NO:57), EIVYKSP (SEQ ID NO:58), EIVYKS (SEQ ID NO:277). or (Q/E)IVYK(S/P) (SEQ ID NO:56)
  • QIVYKP SEQ ID NO:57
  • EIVYKSP SEQ ID NO:58
  • EIVYKS SEQ ID NO:277
  • Q/E)IVYK(S/P) SEQ ID NO:56
  • immunizing the animal with tau or a fragment thereof See Harlow & Lane, Antibodies, A Laboratory Manual (CSHP NY, 1988) (incorporated by reference for all purposes).
  • the immunogen can be a 383 amino acid human tau (4R0N).
  • the immunogen can be a human tau containing a P301 S mutation.
  • the immunogen can be a human tau, wherein the human tau is recombinant N-terminally His-tagged.
  • the animal is immunized with a tau fragment comprising a peptide represented by (Q/E)IVYK(S/P) (SEQ ID NO:56), linked to a carrier.
  • the peptide is QIVYKP (SEQ ID NO:57), EIVYKSP (SEQ ID NO:58), or EIVYKS (SEQ ID NO:277).
  • Such an immunogen can be obtained from a natural source, by peptide synthesis, or by recombinant expression.
  • the immunogen can be obtained from a natural source, by peptide synthesis, or by recombinant expression.
  • the immunogen can be
  • the immunogen can be administered fused or otherwise complexed with a carrier protein.
  • the immunogen can be administered with an adjuvant.
  • adjuvant Several types of adjuvant can be used as described below. Complete Freund’s adjuvant followed by incomplete adjuvant can be used for immunization of laboratory animals. Rabbits or guinea pigs are typically used for making polyclonal antibodies. Mice are typically used for making monoclonal antibodies.
  • Antibodies are screened for specific binding to tau or an epitope within tau (e.g., QIVYKP (SEQ ID NO:57), EIVYKSP (SEQ ID NO:58), EIVYKS (SEQ ID NO:277). or (Q/E)IVYK(S/P) (SEQ ID NO:56)).
  • the screening can be performed against 15 amino acid peptides comprising QIVYKP (SEQ ID NO:57), EIVYKSP (SEQ ID NO:58), EIVYKS (SEQ ID NO:277). or any other consensus motif represented by (Q/E)IVYK(S/P) (SEQ ID NO:56).
  • the peptides comprise QIVYKP (SEQ ID NO:57) EIVYKSP (SEQ ID NO:58), EIVYKS (SEQ ID NO:277).
  • Such screening can be accomplished by determining binding of an antibody to a collection of tau variants, such as tau variants comprising or consisting of amino acid residues 307-312 or 391- 397 or 391-396 of SEQ ID NO: 1) or mutations within these residues, and determining which tau variants bind to the antibody. Binding can be assessed, for example, by Western blot, FACS or ELISA.
  • a humanized antibody is a genetically engineered antibody in which CDRs from a non human“donor” antibody are grafted into human“acceptor” antibody sequences (see, e.g.,
  • the acceptor antibody sequences can be, for example, a mature human antibody sequence, a composite of such sequences, a consensus sequence of human antibody sequences, or a germline region sequence.
  • a humanized antibody is an antibody having at least three, four, five or all CDRs entirely or substantially from a donor antibody and variable region framework sequences and constant regions, if present, entirely or substantially from human antibody sequences.
  • a humanized heavy chain has at least one, two and usually all three CDRs entirely or substantially from a donor antibody heavy chain, and a heavy chain variable region framework sequence and heavy chain constant region, if present, substantially from human heavy chain variable region framework and constant region sequences.
  • a humanized light chain has at least one, two and usually all three CDRs entirely or substantially from a donor antibody light chain, and a light chain variable region framework sequence and light chain constant region, if present, substantially from human light chain variable region framework and constant region sequences.
  • a humanized antibody comprises a humanized heavy chain and a humanized light chain.
  • a CDR in a humanized antibody is substantially from a corresponding CDR in a non-human antibody when at least 85%, 90%, 95% or 100% of corresponding residues (as defined by any conventional definition but preferably defined by Rabat) are identical between the respective CDRs.
  • the variable region framework sequences of an antibody chain or the constant region of an antibody chain are substantially from a human variable region framework sequence or human constant region respectively when at least 85%, 90%, 95% or 100% of corresponding residues defined by Rabat are identical.
  • WHO World Health Organization
  • INN International non-proprietary names
  • humanized as used herein is not intended to be limited to the 2014 WHO INN definition of humanized antibodies.
  • Some of the humanized antibodies provided herein have at least 85% sequence identity to human germline sequences and some of the humanized antibodies provided herein have less than 85% sequence identity to human germline sequences.
  • Some of the heavy chains of the humanized antibodies provided herein have from about 60% to 100% sequence identity to human germ line sequences, such as, for example, in the range of about 60% to 69%, 70% to 79%, 80% to 84%, or 85% to 89%.
  • Some heavy chains fall below the 2014 WHO INN definition and have, for example, about 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, or 82%, 83%, or 84% sequence identity to human germ line sequences, while other heavy chains meet the 2014 WHO INN definition and have about 85%, 86%, 87%, 88%, 89% or greater sequence identity to human germ line sequences.
  • Some of the light chains of the humanized antibodies provided herein have from about 60% to 100% sequence identity to human germ line sequences, such as, for example, in the range of about 80% to 84% or 85% to 89%.
  • Some humanized antibodies provided herein that are "chimeric" under the 2014 WHO INN definition have heavy chains with less than 85% identity to human germ line sequences paired with light chains having less than 85% identity to human germ line sequences.
  • Some humanized antibodies provided herein are "mixed" under the 2014 WHO INN definition, for example, having a heavy chain with at least 85% sequence identity to human germ line sequences paired with a light chain having less than 85% sequence identity to human germ line sequences, or vice versa.
  • Some humanized antibodies provided herein meet the 2014 WHO INN definition of "humanized” and have a heavy chain with at least 85% sequence identity to human germ line sequences paired with a light chain having at least 85% sequence identity to human germ line sequences.
  • Exemplary 12C4 antibodies that meet the 2014 WHO INN definition of "humanized” include antibodies having a mature heavy chain with the amino acid sequence of SEQ ID NO:221 or SEQ ID NO:222 paired with a mature light chain sequence having an amino acid sequence of SEQ ID NO:223 or SEQ ID NO:224.
  • Exemplary 14H3 antibodies that meet the 2014 WHO INN definition of "humanized” include antibodies having a mature heavy chain with the amino acid sequence of SEQ ID NO:248 or SEQ ID NO:249 paired with a mature light chain sequence having an amino acid sequence of SEQ ID NO:251 or SEQ ID NO:252.
  • Exemplary 9F5 antibodies that meet the 2014 WHO INN definition of "mixed” include antibodies having a mature heavy chain with the amino acid sequence of any of SEQ ID NOs: 15- 22 and SEQ ID NOs: 127-128 paired with a mature light chain sequence having an amino acid sequence of any of SEQ ID NO:26-29 and SEQ ID NOs: 130-131.
  • Exemplary IOC 12 antibodies that meet the 2014 WHO INN definition of "mixed” include antibodies having a mature heavy chain with the amino acid sequence of SEQ ID NO:214 or SEQ ID NO:215 paired with a mature light chain sequence having an amino acid sequence of SEQ ID NO:216 or SEQ ID NO:217.
  • Exemplary 1702 antibodies that meet the 2014 WHO INN definition of "mixed” include antibodies having a mature heavy chain with the amino acid sequence of SEQ ID NO:232 or SEQ ID NO:233 paired with a mature light chain sequence having an amino acid sequence of SEQ ID NO:235.
  • Additional humanized 9F5 antibodies of the invention include antibodies having a mature heavy chain having an amino acid sequence of any of SEQ ID NOs: 15-22 and SEQ ID NOs: 127-128 paired with a mature light chain having an amino acid sequence of any of SEQ ID NOs:23-25.
  • Additional humanized 17C12 antibodies of the invention include antibodies having a mature heavy chain having an amino acid sequence of of SEQ ID NO:232 or SEQ ID NO:233 paired with a mature light chain having an amino acid sequence of SEQ ID NO:234.
  • humanized antibodies often incorporate all six CDRs (defined by any conventional definition but preferably as defined by Kabat) from a mouse antibody, they can also be made with less than all CDRs (e.g ., at least 3, 4, or 5 CDRs) from a mouse antibody (e.g, Pascalis et a/., J. Immunol. 169:3076, 2002; Vajdos et al., J. of Mol. Biol., 320: 415-428, 2002; Iwahashi et al., Mol. Immunol. 36: 1079-1091, 1999; Tamura et al, J. Immunol., 164: 1432-1441, 2000).
  • CDRs defined by any conventional definition but preferably as defined by Kabat
  • CDR residues not contacting antigen and not in the SDRs can be identified based on previous studies (for example residues H60-H65 in CDR H2 are often not required), from regions of Rabat CDRs lying outside Chothia hypervariable loops (Chothia, J Mol. Biol. 196:901, 1987), by molecular modeling and/or empirically, or as described in Gonzales et a , Mol. Immunol. 41 : 863, 2004.
  • the amino acid occupying the position can be an amino acid occupying the corresponding position (by Rabat numbering) in the acceptor antibody sequence.
  • the number of such substitutions of acceptor for donor amino acids in the CDRs to include reflects a balance of competing considerations.
  • Such substitutions are potentially advantageous in decreasing the number of mouse amino acids in a humanized antibody and consequently decreasing potential immunogenicity and/or for meeting the WHO INN definition of“humanized”.
  • substitutions can also cause changes of affinity, and significant reductions in affinity are preferably avoided.
  • Positions for substitution within CDRs and amino acids to substitute can also be selected empirically.
  • the human acceptor antibody sequences can optionally be selected from among the many known human antibody sequences to provide a high degree of sequence identity (e.g ., 65- 85% identity) between a human acceptor sequence variable region frameworks and
  • variable region frameworks of a donor antibody chain are corresponding variable region frameworks of a donor antibody chain.
  • Some humanized and chimeric antibodies have the same (within experimental error) or improved functional properties, e.g., binding affinity for human tau, inhibition of tau internalization into neurons as described in the examples as a murine antibody from which they were derived.
  • some humanized and chimeric antibodies have a binding affinity within a factor of 3, 2 or 1 of the murine antibody from which they were derived or an affinity indistinguishable within experimental error.
  • Some humanized and chimeric antibodies inhibit tau internalization into neurons as described in the examples within a factor of 3, 2 or 1 of the murine antibody from thwich they were derived or inhibit the same within experimental error as the mouse antibody from which they were derived.
  • An example of an acceptor sequence for the 9F5 heavy chain is the human mature heavy chain variable region of humanized 48G7 Fab with PDB accession code 2RCS- VH huFrwk (SEQ ID NO:32).
  • An example of an acceptor sequence for the 9F5 heavy chain is the human mature heavy chain GenBank AAN16432-VH_huFrwk (SEQ ID NO:31).
  • the variable domains of 9F5, and 48G7 Fab also share identical lengths for the CDR-H1, H2 loops.
  • An example of an acceptor sequence for the 9F5 heavy chain is the human mature heavy chain variable region IMGT# IGH V I -69-2*01 (SEQ ID NO:33).
  • IMGT# IGHVl-69-2*01 (SEQ ID NO:33) is canonical class 1, and the Chothia CDR-H2 is canonical class 2.
  • IMGT# IGHVl-69-2*01 (SEQ ID NO:33) belongs to human heavy chain subgroup 1.
  • An example of an acceptor sequence for the 9F5 light chain is the human mature light chain variable region 1911357B-VL_huFrwk (SEQ ID NO:36).
  • An example of an acceptor sequence for the 9F5 light chain is the human mature light chain variable region CAB51297-VL_huFrwk (SEQ ID NO:35).
  • variable light domain of 9F5 and CAB51297 & 1911357B antibodies also share identical lengths for the CDR-L1, L2 and L3 loops.
  • An example of an acceptor sequence for the 9F5 light chain is the human mature light chain variable region with IGKV2-28*01 & IGKJ2*01 (SEQ ID NO:37). Chothia CDR-L1 of IGKV2-28*01 & IGKJ2*01 (SEQ ID NO:37) is canonical class 4. Chothia CDR-L2 of IGKV2-28*01 & IGKJ2*01 (SEQ ID NO:37) is canonical class 1.
  • IGKV2-28*01 & IGKJ2*01 (SEQ ID NO:37) Chothia CDR-L3 of IGKV2-28*01 & IGKJ2*01 (SEQ ID NO:37) is canonical class 1.
  • IGKV2-28*01 & IGKJ2*01 (SEQ ID NO:37) belongs to human kappa subgroup 2.
  • An example of an acceptor sequence for the 1002 heavy chain is the human mature CAC20421 (SEQ ID NO:218).
  • the variable domains of 1002 and CAC20421 VH also share identical lengths for the CDR-H1, H2 loops.
  • An example of an acceptor sequence for the 1002 heavy chain is the human mature heavy chain variable region IMGT# IGHV1 -69-2*01 (SEQ ID NO:33).
  • the Chothia CDR-H1 of IMGT# IGHVl-69-2*01 (SEQ ID NO:33) is canonical class 1
  • the Chothia CDR-H2 is canonical class 2.
  • IMGT# IGHVl-69-2*01 (SEQ ID NO:33) belongs to human heavy chain subgroup 1.
  • An example of an acceptor sequence for the 1002 light chain is the human mature light chain variable region CAB51297-VL_huFrwk (SEQ ID NO:35).
  • the variable light domain of 1002 and CAB51297 VL also share identical lengths for the CDR-L1, L2 and L3 loops.
  • An example of an acceptor sequence for the 1002 light chain is the human mature light chain variable region with IGKV2-28*01 & IGKJ2*01 (SEQ ID NO:37). Chothia CDR-L1 of IGKV2-28*01 & IGKJ2*01 (SEQ ID NO:37) is canonical class 4.
  • Chothia CDR-L2 of IGKV2-28*01 & IGKJ2*01 is canonical class 1.
  • Chothia CDR-L3 of IGKV2-28*01 & IGKJ2*01 is canonical class 1.
  • IGKJ2*01 belongs to human kappa subgroup 2.
  • An example of an acceptor sequence for the 12C4 heavy chain is the human mature heavy chain variable region of CAC20421-VH_huFrwk (SEQ ID NO:218).
  • the variable domains of 12C4 and CAC20421 VH also share identical lengths for the CDR-H1, H2 loops.
  • An example of an acceptor sequence for the 12C4 heavy chain is the human mature heavy chain variable region IMGT# IGH V I -69-2*01 (SEQ ID NO:33).
  • the Chothia CDR-H1 of IMGT# IGHVl-69-2*01 (SEQ ID NO:33) is canonical class 1
  • the Chothia CDR-H2 is canonical class 2.
  • IMGT# IGHVl-69-2*01 belongs to human heavy chain subgroup 1.
  • An example of an acceptor sequence for the 12C4 light chain is the human mature light chain variable region CAB51297-VL_huFrwk (SEQ ID NO:35).
  • the variable light domain of 12C4 and CAB51297 VL also share identical lengths for the CDR-L1, L2 and L3 loops.
  • An example of an acceptor sequence for the 12C4 light chain is the human mature light chain variable region with IGKV2-28*01 & IGKJ2*01 (SEQ ID NO:37).
  • Chothia CDR-L1 of IGKV2-28*01 & IGKJ2*01 (SEQ ID NO:37) is canonical class 4.
  • IGKJ2*01 (SEQ ID NO:37) is canonical class 1. Chothia CDR-L3 of IGKV2-28*01 &
  • IGKJ2*01 (SEQ ID NO:37) is canonical class 1.
  • IGKV2-28*01 & IGKJ2*01 (SEQ ID NO:37) belongs to human kappa subgroup 2.
  • An example of an acceptor sequence for the 1702 heavy chain is the human mature heavy chain variable region of CAC20421-VH_huFrwk (SEQ ID NO:218).
  • the variable heavy domains of 17C12 and CAC20421 also share identical lengths for the CDR-H1, H2 loops.
  • An example of an acceptor sequence for the 1702 heavy chain is the human mature heavy chain variable region IMGT# IGH V I -69-2*01 (SEQ ID NO:33).
  • the Chothia CDR-H1 of IMGT# IGHVl-69-2*01 (SEQ ID NO:33) is canonical class 1
  • the Chothia CDR-H2 is canonical class 2.
  • IMGT# IGHVl-69-2*01 belongs to human heavy chain subgroup 1.
  • An example of an acceptor sequence for the 1702 light chain is the human mature light chain variable region QD016713-VL_huFrwk (SEQ ID NO:238).
  • the variable light domain of 1702 and QD016713 antibody also share identical lengths for the CDR-L1, L2 and L3 loops.
  • An example of an acceptor sequence for the 1702 light chain is the human mature light chain variable region with IGKV2-29*02 & IGKJ4*01 (SEQ ID NO:239).
  • An example of an acceptor sequence for the 14H3 heavy chain is the human mature heavy chain variable region of QDJ57937-VH_huFrwk (SEQ ID NO:253).
  • the variable domains of 14H3 and QDJ57937 VH also share identical lengths for the CDR-H1, H2 loops.
  • An example of an acceptor sequence for the 14H3 heavy chain is the human mature heavy chain variable region IGHVl-70*04 & IGHJ4*01 (SEQ ID NO:254).
  • An example of an acceptor sequence for the 14H3 light chain is the human mature light chain variable region ABC66914- VL huFrwk (SEQ ID NO:256).
  • variable light domain of 14H3 and ABC66914 VL also share identical lengths for the CDR-L1, L2 and L3 loops.
  • An example of an acceptor sequence for the 14H3 light chain is the human mature light chain variable region with IGKV2-28*01 & IGKJ2*01 (SEQ ID NO:37). Chothia CDR-L1 of IGKV2-28*01 & IGKJ2*01 (SEQ ID NO:37) is canonical class 4. Chothia CDR-L2 of IGKV2-28*01 & IGKJ2*01 (SEQ ID NO:37) is canonical class 1.
  • IGKV2-28*01 & IGKJ2*01 (SEQ ID NO:37) Chothia CDR-L3 of IGKV2-28*01 & IGKJ2*01 (SEQ ID NO:37) is canonical class 1.
  • IGKV2-28*01 & IGKJ2*01 (SEQ ID NO:37) belongs to human kappa subgroup 2.
  • human acceptor antibody sequence a composite or hybrid of those acceptors can be used, and the amino acids used at different positions in the humanized light chain and heavy chain variable regions can be taken from any of the human acceptor antibody sequences used.
  • human mature heavy chain variable regions of AAN16432-VH_huFrwk (SEQ ID NO:31) and humanized 48G7 Fab with PDB accession code 2RCS-VH_huFrwk (SEQ ID NO:32) were used as hybrid acceptor sequences for the
  • positions in which these two acceptors differ are position HI (E or Q), H5 (V or Q), HI 1 (V or L), H12 (K or V), H20 (V or L), H23 (K or T), H28 (T or N), H38(R or K), H40 (A or R), H42 (G or E), H43 (K or Q), H48 (M or I), H54 (D or N), H66 (R or K), H69 (M or I), H75 (T or S), H76 (D or N), H80 (M or L), H81 (E or Q), H83 (R or T), HI 08 (L or T), or HI 09 (V or L).
  • Humanized versions of the 9F5 heavy chain variable region can include either amino acid at any of these positions.
  • Human germline sequence IMGT# IGHVl-69-2*01 (SEQ ID NO:25) was also used as acceptor sequence for humanization of the 9F5 mature heavy chain variable region.
  • the human mature light chain variable regions of CAB51297-VL_huFrwk (SEQ ID NO:35) and 1911357B-VL_huFrwk (SEQ ID NO:36) were used as hybrid acceptor sequences for the humanization of the 9F5 mature light chain variable region.
  • positions in which these two acceptors differ are positions L7 (S or A), L8 (P or A), L9 (L or F), LI 1 (L or N), LI 5 (P or L), LI 7 (E or T), LI 8 (P or S), L30 (Y or I), L31 (N or T), L54 (R or L), L60 (D or N), L66 (G or E), or L74 (K or R)).
  • Humanized versions of the9F5 light chain variable region can include either amino acid at any of these positions.
  • Human germline sequence IGKV2-28*01 & IGKJ2*01 was also used as an acceptor sequence for humanization of the 9F5 mature light chain variable region.
  • Certain amino acids from the human variable region framework residues can be selected for substitution based on their possible influence on CDR conformation and/or binding to antigen. Investigation of such possible influences is by modeling, examination of the characteristics of the amino acids at particular locations, or empirical observation of the effects of substitution or mutagenesis of particular amino acids.
  • the human framework amino acid when an amino acid differs between a murine variable region framework residue and a selected human variable region framework residue, the human framework amino acid can be substituted by the equivalent framework amino acid from the mouse antibody when it is reasonably expected that the amino acid:
  • CDR region e.g ., is within about 6 A of a CDR region
  • a CDR region e.g., identified by modeling the light or heavy chain on the solved structure of a homologous known immunoglobulin chain
  • humanized sequences are generated using a two-stage PCR protocol that allows introduction of multiple mutations, deletions, and insertions using QuikChange site- directed mutagenesis [Wang, W. and Malcolm, B.A. (1999) BioTechniques 26:680-682)].
  • Framework residues from classes (1) through (3) as defined by Queen, US 5,530,101, are sometimes alternately referred to as canonical and vernier residues. Framework residues that help define the conformation of a CDR loop are sometimes referred to as canonical residues
  • framework residues that are candidates for substitution are residues creating a potential glycosylation site. Still other candidates for substitution are acceptor human framework amino acids that are unusual for a human immunoglobulin at that position. These amino acids can be substituted with amino acids from the equivalent position of the mouse donor antibody or from the equivalent positions of more typical human immunoglobulins.
  • N-terminal glutamine residues (Q) that may be replaced with glutamic acid (E) to minimize potential for pyroglutamate conversion
  • E glutamic acid
  • Glutamic acid (E) conversion to pyroglutamate (pE) occurs more slowly than from glutamine (Q). Because of the loss of a primary amine in the glutamine to pE conversion, antibodies become more acidic. Incomplete conversion produces heterogeneity in the antibody that can be observed as multiple peaks using charge-based analytical methods. Heterogeneity differences may indicate a lack of process control.
  • Exemplary 9F5 humanized heavy chain variable regions with N-terminal glutamine to glutamate substitutions are SEQ ID NO: 16 (hu9F5VHv2), SEQ ID NO: 17
  • Exemplary humanized antibodies include humanized forms of the mouse 9F5, designated Hu9F5.
  • the mouse antibody 9F5 comprises mature heavy and light chain variable regions having amino acid sequences comprising SEQ ID NO:7 and SEQ ID NO: 11, respectively.
  • the invention provides 29 exemplified humanized mature heavy chain variable regions: hu9F5VHvl (SEQ ID NO: 15), hu9F5VHv2 (SEQ ID NO: 16), hu9F5VHv3 (SEQ ID NO: 17), hu9F5VHv4 (SEQ ID NO: 18), hu9F5VHv5 (SEQ ID NO: 19), hu9F5VHv6 (SEQ ID NO:20 hu9F5VHv7 (SEQ ID NO:21), hu9F5VHv8 (SEQ ID NO:22), hu9F5VHv4_L80P (SEQ ID NO: 109), hu9F 5 VHv4_L 8 OD (SEQ ID NO: 110), hu9F5VHvl
  • hu9F5VHv4_L82cD (SEQ ID NO: 112)
  • hu9F5VHv4_L82P (SEQ ID NO: 113)
  • hu9F5VHv5_M80E (SEQ ID NO: 122), hu9F5VHv5_M80G (SEQ ID NO: 123),
  • hu9F5VHv4_L82cS (SEQ ID NO: 124), hu9F5VHv4_Y79Q (SEQ ID NO: 125),
  • hu9F5VHv4_S82aG (SEQ ID NO: 126), hu9F5VHv9 (SEQ ID NO: 127), hu9F5VHvlO (SEQ ID NO: 128), and hu9F5VHvlO_L82cG (SEQ ID NO: 129).
  • the invention further provides 95 exemplified mature light chain variable regions hu9F5VLvl (SEQ ID NO:23), hu9F5VLv2 (SEQ ID NO:24), hu9F5VLv3 (SEQ ID NO:25), hu9F5VLv4 (SEQ ID NO:26), hu9F5VLv5 (SEQ ID NO:27), hu9F5VLv6 (SEQ ID NO 28: ), hu9F5VLv7 (SEQ ID NO:29), hu9F5VLv8 (SEQ ID NO: 130), hu9F5VLv9 (SEQ ID NO: 131), hu9F5VLv2_M51E (SEQ ID NO:61), hu9F5 VLV2_M51 D (SEQ ID NO:62), hu9F5VLv2_L27cD (SEQ ID NO:63),
  • hu9F5VLv2_L27cE (SEQ ID NO:66), hu9F5VLv2_I30E (SEQ ID NO 67:), hu9F5VLv2_I30K (SEQ ID NO:68), hu9F5VLv2_L27cT (SEQ ID NO:69), hu9F5VLv2_L27cN (SEQ ID NO:70, hu9F5 VLv2_L27bD (SEQ ID NO:71), hu9F5VLv2_I30G (SEQ ID NO:72), hu9F5VLv2_L33N (SEQ ID NO:73), hu9F5VLv2_L27cA (SEQ ID NO:74), hu9F5VLv2_L33T (SEQ ID NO:75), hu9F5 VLv2_L33 S (SEQ ID NO:76), hu9F5
  • hu9F5VLv2_L27cP (SEQ ID NO:83), hu9F5VLv2_V78R (SEQ ID NO:84), hu9F5VLv2_I75D (SEQ ID NO:85), hu9F5VLv2_V78D (SEQ ID NO:86), hu9F5VLv2_V78E (SEQ ID NO:87), hu9F5VLv2_V78P (SEQ ID NO:88), hu9F5VLv2_V78K (SEQ ID NO:89), hu9F5VLv2_R77D (SEQ ID NO:90), hu9F5VLv2_V78G (SEQ ID N0:91), hu9F5VLv2_S76P (SEQ ID NO:92), hu9F5 VLv2_I75P (SEQ ID NO:93), hu9F5VLv2
  • hu9F5VLv8_DIMl (SEQ ID NO: 132), hu9F5VLv8_DIM2 (SEQ ID NO: 133),
  • hu9F5VLv8_DIM3 (SEQ ID NO: 134), hu9F5VLv8_DIM4 (SEQ ID NO: 135),
  • hu9F5VLv8_DIM5 (SEQ ID NO: 136), hu9F5VLv8 DIM6 (SEQ ID NO: 137),
  • hu9F5VLv8_DIMl 1 (SEQ ID NO: 142), hu9F5VLv8_DIM12 (SEQ ID NO: 143),
  • hu9F5VLv8_DIMl 5 (SEQ ID NO: 146), hu9F5VLv8_DIM16 (SEQ ID NO: 147),
  • hu9F5VLv8_DIM17 (SEQ ID NO: 148), hu9F5VLv8_DIM18 (SEQ ID NO: 149),
  • hu9F5 VLv8_DIM 19 (SEQ ID NO: 150), hu9F5VLv8_DIM20 (SEQ ID NO: 151),
  • hu9F5VLv8_DIM23 (SEQ ID NO: 154), hu9F5VLv8 DIM24 (SEQ ID NO: 155),
  • hu9F5VLv8 DIM27 (SEQ ID NO: 158), hu9F5VLv8 DIM28 (SEQ ID NO: 159), hu9F5VLv8_DIM29 (SEQ ID NO: 160), hu9F5VLv8_DIM30 (SEQ ID NO: 161), hu9F 5 VLv9__ DIM 1 (SEQ ID NO: 162), hu9F 5 VLv9 _ DIM2 (SEQ ID NO: 163),
  • hu9F 5 VL v9_D IM 4 (SEQ ID NO: 164), hu9F5VI,v9 DIMS (SEQ ID NO: 165),
  • hu9F5 VLv9__DIM8 (SEQ ID NO: 166), hu9F5VLv9_DIM10 (SEQ ID NO: 167),
  • hu9F5VLv9_DIMl 1 (SEQ ID NO: 168), (hu9F5VLv9 DIM13 (SEQ ID NO: 169),
  • FIG. 1 A-1B and 4A-4B show alignments of the heavy chain variable region of murine 9F5 and various humanized antibodies.
  • Figures 2A-2B and 5A-5B show alignments of the light chain variable region of murine 9F5 and various humanized antibodies.
  • Figure 6A-6C show alignments of the light chain variable region of humanized variant hu9F5VLv8 and various humanized antibodies,
  • variable region framework positions were considered as candidates for substitutions in the 95 exemplified human mature light chain variable regions and the 29 exemplified human mature heavy chain variable regions, as further specified in the examples: L3 (V3Q), L7 (A7S), L8 (A8P), L9 (F9L), Ll l (N11L), L15 (L15P), L17 (T17E), L18 (S18P), L37 (L37Q, L37G, L37I), L39 (R39K), L60 (N60D), L64 (G64S), L66 (E66G), L73 (L73P, L73G), L74 (R74 (R74
  • variable region CDR positions were considered as candidates for substitutions in the 95 exemplified human mature light chain variable regions and 29 exemplified human mature heavy chain variable regions, as further specified in the examples: L27b (L27bD, L27bT, L27bQ), L27c (L27cD, L27cG, L27cS,
  • Kabat-Chothia Composite CDR-H1 has an amino acid sequence comprising SEQ ID NO:50. In some humanized 9F5 antibodies, Kabat-Chothia Composite CDR-H1 has an amino acid sequence comprising SEQ ID NO:50, and Rabat CDR-H2 has an amino acid sequence comprising SEQ ID NO:51. In some humanized 9F5 antibodies, Rabat CDR-H2 has an amino acid sequence comprising SEQ ID NO:51. In some humanized 9F5 antibodies, Rabat CDR-H2 has an amino acid sequence comprising SEQ ID NO:52. In some humanized 9F5 antibodies, Rabat CDR-L2 has an amino acid sequence comprising SEQ ID NO:55.
  • Rabat CDR-L1 has an amino acid sequence comprising SEQ ID NO:53 and Rabat CDR-L2 has an amino acid sequence comprising SEQ ID NO:55.
  • Rabat CDR-L1 has an amino acid sequence comprising SEQ ID NO:54, and Rabat CDR-L2 has an amino acid sequence comprising SEQ ID NO:55.
  • Rabat CDR-L1 has an amino acid sequence comprising a sequence selected from the group consisting of SEQ ID NOs: 172-193.
  • Rabat CDR- L2 has an amino acid sequence comprising sequence selected from the group consisting of SEQ ID NOs: 194-205.
  • Rabat CDR-L3 has an amino acid sequence comprising a sequence selected from the group consisting of SEQ ID NOs:206-213.
  • the first-mentioned residue is the residue of a humanized antibody formed by grafting Rabat CDRs or a composite Chothia-Kabat CDR in the case of CDR-H1 into a human acceptor framework, and the second-mentioned residue is a residue being considered for replacing such residue.
  • the first mentioned residue is human
  • the first mentioned residue is mouse.
  • Exemplified antibodies include any permutations or combinations of the exemplified mature heavy and light chain variable regions hu9F5VHvl/ hu9F5VLvl, hu9F5VHvl/ hu9F5VLv2, hu9F5VHvl/ hu9F5VLv3, hu9F5VHvl/ hu9F5VLv4, hu9F5VLvl/ hu9F5VLv5, hu9F5VHvl/ hu9F5VLv6, hu9F5VHvl/ hu9F5VLv7, hu9F5VHv2/ hu9F5VLvl, hu9F5VHv2/ hu9F5VLvl, hu9F5VHv2/ hu9F5VLv2, hu9F5VHv2/ hu9F5
  • Exemplified antibodies include any permutations or combinations of the exemplified mature heavy chain variable regions hu9F5VHvl (SEQ ID NO: 15), hu9F5VHv2 (SEQ ID NO: 16), hu9F5VHv3 (SEQ ID NO: 17), hu9F5VHv4 (SEQ ID NO: 18), hu9F5VHv5 (SEQ ID NO: 19), hu9F5VHv6 (SEQ ID NO:20), hu9F5VHv7 (SEQ ID NO:21), hu9F5VHv8 (SEQ ID NO:22), hu9F5VHv9 (SEQ ID NO: 127), hu9F5VHvlO (SEQ ID NO: 128), hu9F5VHvlO_L82cG (SEQ ID NO: 129), hu9F5VHv4_L80P (SEQ ID NO: 15
  • hu9F5VHv4_L82K (SEQ ID NO: 115), hu9F5VHv4_L82R (SEQ ID NO: 116),
  • hu9F5VHv4_Y79D (SEQ ID NO: 119), hu9F5VHv4_Y79N (SEQ ID NO: 120),
  • hu9F5VHv5_M80G (SEQ ID NO: 123), hu9F5VHv4_L82Cs (SEQ ID NO: 124),
  • hu9F5VHv4_Y79Q (SEQ ID NO: 125), and hu9F5VHv4_S82aG (SEQ ID NO: 126), with any of the exemplified mature light chain variable regions hu9F5VLvl (SEQ ID NO:23), hu9F5VLv2 (SEQ ID NO:24), hu9F5VLv3 (SEQ ID NO:25), hu9F5VLv4 (SEQ ID NO:26), hu9F5VLv5 (SEQ ID NO:27, hu9F5VLv6 (SEQ ID NO:28), hu9F5VLv7 (SEQ ID NO:29), hu9F5VLv8 (SEQ ID NO: 130), hu9F5VLv9 (SEQ ID NO: 131), hu9F5VLv2_M51E (SEQ ID NO:61), hu9F5 V
  • hu9F5VLv2_L27cE (SEQ ID NO: 66), hu9F5VLv2_I30E (SEQ ID NO: 67), hu9F5VLv2_I30K (SEQ ID NO:68), hu9F5VLv2_L27cT (SEQ ID NO:69), hu9F5VLv2_L27cN (SEQ ID NO:70), hu9F5 VLv2_L27bD (SEQ ID NO:71), hu9F5VLv2_I30G, (SEQ ID NO: 72), hu9F5VLv2_L33N (SEQ ID NO:73), hu9F5VLv2_L27cA (SEQ ID NO:74), hu9F5VLv2_L33T (SEQ ID NO:75), hu9F5 VLv2_L33 S (SEQ ID NO:76), hu9
  • hu9F5VLv2_L27cP (SEQ ID NO:83), hu9F5VLv2_V78R (SEQ ID NO:84), hu9F5VLv2_I75D (SEQ ID NO:85), hu9F5VLv2_V78D (SEQ ID NO:86), hu9F5VLv2_V78E (SEQ ID NO:87), hu9F5VLv2_V78P (SEQ ID NO:88), hu9F5VLv2_V78K (SEQ ID NO:89), hu9F5VLv2_R77D (SEQ ID NO:90), hu9F5VLv2_V78G (SEQ ID NO:91), hu9F5VLv2_S76P (SEQ ID NO:92), hu9F5 VLv2_I75P (SEQ ID NO:93), hu9F5VLv2_
  • hu9F5VLv8_DIM5 (SEQ ID NO: 136), hu9F5VLv8_DIM6 (SEQ ID NO: 137),
  • hu9F5 VLv8_DIM 7 (SEQ ID NO: 138), hu9F5VLv8_DIM8 (SEQ ID NO: 139),
  • hu9F5 VLv8_DIM 13 (SEQ ID NO: 144), hu9F5VLv8_DIM14 (SEQ ID NO: 145),
  • hu9F5VLv8 .. DIM ES (SEQ ID NO: 146), hu9F5VLv8 DIM16 (SEQ ID NO: 147), hu9F5VLv8_DIMl 7 (SEQ ID NO: 148), hu9F5VLv8_DIM18 (SEQ ID NO: 149), hu9F5VLv8_DIM19 (SEQ ID NO: 150), hu9F5VLv8_DIM20 (SEQ ID NO: 151),
  • hu9F5 VLv8__DIM23 (SEQ ID NO: 154), hu9F5VLv8_DIM24 (SEQ ID NO: 155),
  • hu9F5VLv8_DIM25 (SEQ ID NO: 156), hu9F5VLv8 DIM26 (SEQ ID NO: 157),
  • hu9F5VLv8_DIM29 (SEQ ID NO: 160), hu9F5VLv8_DIM30 (SEQ ID NO: 161),
  • hu9F5 VLv9_DIM 1 (SEQ ID NO: 162)
  • hu9F5VLv9_DIM2 (SEQ ID NO: 163)
  • hu9F5VLv9_DIM4 (SEQ ID NO: 164), hu9F5VLv9_DIM5 (SEQ ID NO: 165),
  • hu9F5 VLv9_DIMl 1 (SEQ ID NO: 168), hu9F5VLv9_DIM13 (SEQ ID NO: 169),
  • hu9F5VLv9 .. DIM 19 (SEQ ID NO: 170), and hu9F5VLv9 DIM20 (SEQ ID NO: 171)
  • the invention provides an antibody in which humanized heavy chain variable region hu9F5VHv9 (SEQ ID NO: 127) is combined with humanized light chain variable region hu9F5VLv8_DIM18 (also known as hu9F5VLv8_V3Q, L27cD, L37G, M51G, L54R, L92I, SEQ ID NO: 149).
  • the invention provides an antibody in which humanized heavy chain variable region hu9F5VHv9 (SEQ ID NO: 127) is combined with humanized light chain variable region hu9F5VLv8_DIMl 1 (also known as hu9F5VLv8_V3Q, L27cG, L37G, M51G, L54R, L92I, SEQ ID NO: 142).
  • the invention provides an antibody in which humanized heavy chain variable region hu9F5VHv9 (SEQ ID NO: 127) is combined with humanized light chain variable region hu9F5VLv8_DIM28 (also known as hu9F5VLv8_V3Q, L27cS, M51G, L54R, L92I, SEQ ID NO: 159).
  • the invention provides an antibody in which humanized heavy chain variable region hu9F5VHv9 (SEQ ID NO: 127) is combined with humanized light chain variable region hu9F5VLv8_DIM17 (also known as hu9F5VLv8_V3Q, L27cS, L37G, M51G, L54T, L92I, SEQ ID NO: 148).
  • the invention provides an antibody in which humanized heavy chain variable region hu9F5VHv9 (SEQ ID NO: 127) is combined with humanized light chain variable region
  • /hu9F 5 VLv8_DIM6 also known as hu9F5VLv8_V3Q, L27cD, L37Q, M51G, L54R, L92I, SEQ ID NO: 137.
  • the invention provides an antibody in which humanized heavy chain variable region hu9F5VHv9 (SEQ ID NO: 127) is combined with humanized light chain variable region hu9F5VLv8_DIM14 (also known as hu9F5VLv8_V3Q, L27cG, L37G, M51G, L54T, L92I, SEQ ID NO: 145).
  • the invention provides an antibody in which humanized heavy chain variable region hu9F5VHv9 (SEQ ID NO: 127) is combined with humanized light chain variable region hu9F5VLv8_DIM5 (also known as hu9F5VLv8_V3Q, L27cG, L37Q, M51G, L54R, L92I, SEQ ID NO: 136).
  • the invention provides an antibody in which humanized heavy chain variable region hu9F5VHv9 (SEQ ID NO: 127) is combined with humanized light chain variable region hu9F5VLv8_DIM7 (also known as hu9F5VLv8_V3Q, L27cD, L37Q, M51K, L54R, L92I, SEQ ID NO: 138).
  • the invention provides an antibody in which humanized heavy chain variable region hu9F5VHv9 (SEQ ID NO: 127) is combined with humanized light chain variable region hu9F5VLv8_DIM27 (also known as hu9F5VLv8_V3Q, L37Q, M51G, L54R, L92I, SEQ ID NO: 158).
  • the invention provides an antibody in which humanized heavy chain variable region hu9F5VHv9 (SEQ ID NO: 127) is combined with humanized light chain variable region hu9F5VLv8_DIM12 (also known as hu9F5VLv8_V3Q, L27cG, L37G, M51G, L54R, L92G, SEQ ID NO: 143).
  • the invention provides an antibody in which humanized heavy chain variable region hu9F5VHv9 (SEQ ID NO: 127) is combined with humanized light chain variable region hu9F5VLv8_DIM13 (also known as hu9F5VLv8_V3Q, L27cG, L37G, M51G, L54R, SEQ ID NO: 144).
  • the invention provides an antibody in which humanized heavy chain variable region hu9F5VHv9 (SEQ ID NO: 127) is combined with humanized light chain variable region hu9F5VLv8_DIM2 (also known as hu9F5VLv8_V3Q, L27cS, L37Q, M51G, L54R, L92I, SEQ ID NO: 133).
  • the invention provides an antibody in which humanized heavy chain variable region hu9F5VHv9 (SEQ ID NO: 127) is combined with humanized light chain variable region hu9F5VLv8_DIM29 (also known as hu9F5VLv8_V3Q, L27cS, L37Q, L54R, L92I, SEQ ID NO: 160).
  • the invention provides an antibody in which humanized heavy chain variable region hu9F5VHv9 (SEQ ID NO: 127) is combined with humanized light chain variable region
  • /hu9F5VLv8_DIM30 also known as hu9F5VLv8_V3Q, L27cS, L37Q, M51G, L92I, SEQ ID NO: 161).
  • the invention provides an antibody in which humanized heavy chain variable region hu9F5VHv9 (SEQ ID NO: 127) is combined with humanized light chain variable region hu9F5VLv8_DIM8 (also known as hu9F5VLv8_V3Q, L27cG, L37Q, M51K, L54R, L92I, SEQ ID NO: 139).
  • the invention provides an antibody in which humanized heavy chain variable region hu9F5VHvlO (SEQ ID NO: 128) is combined with humanized light chain variable region hu9F5VLv9_DIMl 1 (also known as hu9F5VLv9_V3Q, L27cG, L37G, M51G, L54R, L92I, SEQ ID NO: 168).
  • the invention provides variants of the 9F5 humanized antibody in which the humanized mature heavy chain variable region shows at least 90%, 95%, 96%, 97%, 98%, or 99% identity to hu9F5VHvl (SEQ ID NO: 15), hu9F5VHv2 (SEQ ID NO: 16), hu9F5VHv3 (SEQ ID NO: 17), hu9F5VHv4 (SEQ ID NO: 18), hu9F5VHv5 (SEQ ID NO: 19), hu9F5VHv6 (SEQ ID NO:20), hu9F5VHv7 (SEQ ID NO:21), hu9F5VHv8 (SEQ ID NO:22), hu9F5VHv9 (SEQ ID NO: 127), hu9F5VHvlO (SEQ ID NO: 128), hu9F5VHvlO_L82cG (SEQ ID NO: 15), h
  • hu9F5VHv4_L82cG (SEQ ID NO: 111), hu9F5VHv4_L82cD (SEQ ID NO: 112),
  • hu9F5VHv4_L82P (SEQ ID NO: 113), hu9F5VHv4_L80G (SEQ ID NO: 114),
  • hu9F5VHv4_L82K (SEQ ID NO: 115), hu9F5VHv4_L82R (SEQ ID NO: 116),
  • hu9F5VHv4_Y79D (SEQ ID NO: 119), hu9F5VHv4_Y79N (SEQ ID NO: 120),
  • hu9F5VHv5_M80G (SEQ ID NO: 123), hu9F5VHv4_L82Cs (SEQ ID NO: 124),
  • hu9F5VHv4_Y79Q (SEQ ID NO: 125), or hu9F5VHv4_S82aG (SEQ ID NO: 126)
  • the humanized mature light chain variable region shows at least 90%, 95%, 96%, 97%, 98%, or 99% identity to hu9F5VLvl (SEQ ID NO:23), hu9F5VLv2 (SEQ ID NO:24), hu9F5VLv3 (SEQ ID NO:25), hu9F5VLv4 (SEQ ID NO:26), hu9F5VLv5 (SEQ ID NO:27, hu9F5VLv6 (SEQ ID NO:28), hu9F5VLv7 (SEQ ID NO:29) , hu9F5VLv8 (SEQ ID NO: 130, hu9F5VLv9 (SEQ ID NO: 131), hu9F5VLv
  • hu9F5VLv2_L27cS (SEQ ID NO: 65), hu9F5VLv2_L27cE (SEQ ID NO: 66), hu9F5VLv2_I30E (SEQ ID NO:67), hu9F5VLv2_I30K (SEQ ID NO:68), hu9F5VLv2_L27cT (SEQ ID NO:69), hu9F5VLv2_L27cN (SEQ ID NO:70), hu9F5VLv2_L27bD (SEQ ID NO:71), hu9F5VLv2_I30G, (SEQ ID NO:72), hu9F5VLv2_L33N (SEQ ID NO:73), hu9F5VLv2_L27cA (SEQ ID NO:74), hu9F5VLv2_L33T (SEQ ID NO:75), hu9
  • hu9F5VLv2_L92Q (SEQ ID NO: 104), hu9F5VLv2_L93G (SEQ ID NO: 105),
  • hu9F5VLv8_DIM2 (SEQ ID NO: 133), hu9F5VLv8_DIM3 (SEQ ID NO: 134),
  • hu9F5VLv8_DIM4 (SEQ ID NO: 135)
  • hu9F5VLv8_DIM5 (SEQ ID NO: 136)
  • hu9F5VLv8_DIM6 (SEQ ID NO: 137), hu9F5VLv8 DIM7 (SEQ ID NO: 138),
  • hu9F5VLv8_DIM8 (SEQ ID NO: 139), hu9F5VLv8_DIM9 (SEQ ID NO: 140),
  • hu9F5 VLv8__DIM 12 (SEQ ID NO: 143), hu9F5VLv8_DIM13 (SEQ ID NO: 144),
  • hu9F5VLv8_DIMl 6 (SEQ ID NO: 147), hu9F5VLv8_DIM17 (SEQ ID NO: 148),
  • hu9F5VLv8_DIM18 (SEQ ID NO: 149), hu9F5VLv8_DIM19 (SEQ ID NO: 150),
  • hu9F5VLv8_DIM20 (SEQ ID NO: 151), hu9F5VLv8_DIM21 (SEQ ID NO: 152),
  • hu9F5 VLv8__DIM22 (SEQ ID NO: 153), hu9F5VLv8_DIM23 (SEQ ID NO: 154),
  • hu9F5VLv8_DIM24 (SEQ ID NO: 155), hu9F5VLv8 DIM25 (SEQ ID NO: 156),
  • hu9F5VLv8_DIM26 (SEQ ID NO: 157), hu9F5VLv8_DIM27 (SEQ ID NO: 158),
  • hu9F5VLv8 DIM28 (SEQ ID NO: 159), hu9F5VLv8 DIM29 (SEQ ID NO: 160), hu9F5 VLv8_DIM30 (SEQ ID NO: 161 ), hu9F5VLv9_DIMl (SEQ ID NO: 162),
  • hu9F5VLv9_DIM2 (SEQ ID NO: 163)
  • hu9F5VLv9_DIM4 (SEQ ID NO: 164)
  • hu9F5VLv9 DIMS (SEQ ID NO: 165), hu9F5VLv9_DIM8 (SEQ ID NO: 166),
  • hu9F5 VLv9_DIM 10 (SEQ ID NO: 167), hu9F5VLv9_DIMl 1 (SEQ ID NO: 168),
  • hu9F5VLv9_DIMl 3 (SEQ ID NO: 169), hu9F5VLv9 DIM 19 (SEQ ID NO: 170), or
  • hu9F 5 VL v9_DIM20 (SEQ ID NO: 171). In some such antibodies at least 1, 2, 3, 4, 5, 6, 7, 8, 9,
  • HI is occupied by E
  • HI 7 is occupied by T
  • H20 is occupied by I
  • H69 is occupied by M
  • H75 is occupied by T
  • H93 is occupied by T
  • H94 is occupied by T
  • HI 09 is occupied by V.
  • positions HI, H17, H20, H69, H75, H94, and H109 are occupied by E, T, I, M, T, T, T, and V, respectively.
  • H66 is occupied by R and H81 is occupied by E.
  • positions H66 and H81 are occupied by R and E, respectively.
  • H23 is occupied by I and H83 is occupied by R.
  • positions H23 and H83 are occupied by K and R, respectively.
  • H43 is occupied by K
  • H51 is occupied by V
  • H76 is occupied by D
  • M80 is occupied by M
  • HI 08 is occupied by L.
  • positions H43, H51, H76, H80, and H108 are occupied by K, V, D, M, and L, respectively.
  • position H28 in the VH region is occupied by T.
  • H54 is occupied by D and H56 is occupied by E.
  • positions H54 and H56 are occupied by D and E, respectively.
  • position H40 in the VH region is occupied by A.
  • H5 is occupied by V
  • HI 1 is occupied by V
  • H12 is occupied by K
  • H38 is occupied by R
  • H42 is occupied by G.
  • positions H5, HI 1, H12, H38, and H42 are occupied by V, V, K, R, and G, respectively.
  • HI is occupied by Q or E
  • H5 is occupied by Q or V
  • HI 1 is occupied by L or V
  • H12 is occupied by V or K
  • H17 is occupied by S or T
  • H20 is occupied by L or I
  • H23 is occupied by T or K
  • H28 is occupied by N or T
  • H38 is occupied by K
  • R or Q H40 is occupied by R or A
  • H42 is occupied by E or G
  • H43 is occupied by Q or K
  • H48 is occupied by I or M
  • H51 is occupied by I or V
  • H54 is occupied by N or D
  • H56 is occupied by D or E
  • H66 is occupied by K or R
  • H69 is occupied by I or M
  • H75 is occupied by S or T
  • H76 is occupied by N or D
  • H79 is occupied by Y
  • positions HI, H17, H20, H69, H75, H93, H94, and HI 09 in the VH region are occupied by E, T, I, M, T, T, T, and V , respectively, as in
  • positions HI, H17, H20, H66, H69, H75, H81, H93, H94, and H109 in the VH region are occupied by E, T, I, R, M, T, E, T, T, and V, respectively, as in hu9F5VHv3.
  • positions HI, HI 7, H20, H23, H28, H66, H69, H75, H81, H83, H93, H94, and H109 in the VH region are occupied by E, T, I, K, T, R, M, T, E, R, T, T, and V, respectively, as in hu9F5VHv4.
  • positions HI, H17, H20, H23, H28, H43, H51, H54, H56, H66, H69, H75, H76, H80, H81, H83, H93, H94, H108, and H109 in the VH region are occupied by E, T, I, K, T, K, V, D, E, R, M, T, D, M, E, R, T, T, L, and V, respectively, as in hu9F5VHv5.
  • positions HI, H17, H20, H23, H28, H40, H43, H48, H51, H54, H56, H66, H69, H75, H76, H80, H81, H83, H93, H94, H108, and H109 in the VH region are occupied by E, T, I, K, T, A, K, M, V, D, E, R, M, T, D, M, E, R, T, T, L, and V, respectively, as in hu9F5VHv6.
  • positions HI, H5, HI 1, H12, H17, H20, H23, H38, H40, H42, H43, H51, H54, H56, H66, H69, H75, H76, H80, H81, H83, H93, H94, H108, and H109 in the VH region are occupied by E, V, V, K, T, I, K, R, A, G, K, V, D, E, R, M, T, D, M, E, R, T, T, L, and V, respectively, as in hu9F5VHv7.
  • positions HI, H5 positions HI, H5,
  • HI 1, H12, H17, H20, H23, H38, H40, H42, H43, H51, H66, H69, H75, H76, H80, H81, H83, H93, H94, H108, and H109 in the VH region are occupied by E, V, V, K, T, I, K, R, A, G, K, V, R, M, T, D, M, E, R, T, T, L, and V, respectively, as in hu9F5VHv8.
  • positions HI, H5, HI 1, H12, H17, H20, H23, H38, H42, H43, H66, H69, H75, H80, H81, H83, H93, H94, H108, and H109 in the VH region are occupied by E, V, V, K, T, I, K, Q, G, K, R, M, T, M, E, R, T, T, L, and V, respectively, as in hu9F5VHv9.
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 127.
  • positions HI, H5, HI 1, H12, H17, H20, H23, H38, H42, H43, H66, H69, H75, H80, H81, H83, H93, H94, H108, and H109 in the VH region are occupied by E, V, V, K, T, I, K, K, E, K, R, M, T, M, E, R, T, T, L, and V, respectively, as in hu9F5VHvlO.
  • the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 128.
  • positions HI, H5, HI 1, H12, H17, H20, H23, H38, H42, H43, H66, H69, H75, H80, H81, H82c, H83, H93, H94, H108, and H109 in the VH region are occupied by E, V, V, K, T, I, K, K, E, K, R, M, T, M, E, G, R, T, T, L, and V, respectively, as in hu9F5VHvlO L82cG.
  • positions in the VL region are occupied by the amino acid as specified: L7 is occupied by S, L8 is occupied by P, LI 5 is occupied by P, and L100 is occupied by Q.
  • positions L7, L8, LI 5, and LI 00 are occupied by S, P, P, and Q, respectively.
  • position L66 in the VL region is occupied by G.
  • position L64 in the VL region is occupied by S.
  • position L17 in VL region is occupied by E.
  • At least one of the following positions in the VL region is occupied by the amino acid as specified: LI 1 is occupied by L, L51 is occupied by G, and L54 is occupied by R. In some humanized 9F5 antibodies, positions LI 1, L51, and L54 are occupied by L, G, and R, respectively.
  • position L30 in the VL region is occupied by Y.
  • L3 is V or Q
  • L7 is A or S
  • L8 is A or P
  • L9 is F or L
  • LI 1 is N or L
  • L15 is L or P
  • L17 is T or E
  • L18 is S or P
  • L27b is L
  • D is D.
  • L27c is L, D, G, S, E, T, N, A, P, or I, L30 is I, Y, E, K, G, or Q, L31 is T,N, or G, L33 is L, N, T, S, R, or G, L37 is L, Q, G, or I, L39 is R or K, L51 is M, G, E, D, K, or I, L54 is L, R, G, or T, L60 is N or D, L64 is G or S, L66 is E or G, L73 is L, P, or G, L74 is R or K, L75 is I, D, P, Q, or G, L76 is S, P, or G, L77 is SEQ ID NO: 146 or D, L78 is V, R, D, E, P, K, G, or Q, L85 is V or G, L86 is Y or T, L89 is A or G, L92 is L, D, E, G, Q, T, or I,
  • positions L64 and L66 in the VL region are occupied by S and G, respectively, as in hu9F5VLvl .
  • positions L7, L8, L15, L64, L66, and L100 in the VL region are occupied by S, P, P, S, G, and Q, respectively, as in hu9F5VLv2.
  • positions L7, L8, L15, L17, L66, and LI 00 in the VL region are occupied by S, P, P, E, G, and Q, respectively, as in hu9F5VLv3.
  • positions L7, L8, Ll l, L15, L17, L51, L54, L66, and LI 00 in the VL region are occupied by S, P, L, P, E, G, R, G, and Q, respectively, as in hu9F5VLv4.
  • the light chain variable region comprises the amino acid sequence of any of SEQ ID NOs: 133, 135-137, 142-144, 149, 158, 159 and 168.
  • the light chain variable region comprises the amino acid sequence of SEQ ID NO: 133.
  • the light chain variable region comprises the amino acid sequence of SEQ ID NO: 137. In some humanized 9F5 antibodies, the light chain variable region comprises the amino acid sequence of SEQ ID NO: 149. In some humanized 9F5 antibodies, the light chain variable region comprises the amino acid sequence of SEQ ID NO: 159.
  • positions L7, L8, Ll l, L15, L17, L30, L51, L54, L66, and LI 00 in the VL region are occupied by S, P, L, P, E, Y, G, R, G, and Q, respectively, as in hu9F5VLv5.
  • positions L7, L8, Ll l, L15, L17, L30, L51, L54, and LI 00 in the VL region are occupied by S, P, L, P, E, Y, G, R, and Q, respectively, as in hu9F5VLv6.
  • L31, L39, L51, L54, L60, L66, L74, and LI 00 in the VL region are occupied by S, P, L, L, P, E,
  • L74, and LI 00 in the VL region are occupied by S, P, L, P, E, K, S, G, K and Q, respectively, as in hu9F5VLv8.
  • position L3 in the VL region is occupied by
  • position L27c in the VL region is occupied by D, G, I, L or S
  • position L37 in the VL region is occupied by G, I, L, or Q
  • position L51 in the VL region is occupied by E, G, I, K or M
  • position L54 in the VL region is occupied by G, L, R or T
  • position L92 in the VL region is occupied by G, I or L.
  • position L27c in the VL region is occupied by D or S
  • position L37 in the VL region is occupied by G
  • L or Q position L51 in the VL region is occupied by G or K
  • position L54 in the VL region is occupied by R
  • position L92 in the VL region is occupied by I.
  • position L27c in the VL region is occupied by D
  • position L37 in the VL region is occupied by G
  • position L51 in the VL region is occupied by G
  • the heavy chain variable region has an amino acid sequence comprising SEQ ID NO: 127
  • the light chain variable region has an amino acid sequence comprising SEQ ID NO: 149.
  • position L27c in the VL region is occupied by D
  • position L37 in the VL region is occupied by Q
  • position L51 in the VL region is occupied by G
  • the heavy chain variable region has an amino acid sequence comprising SEQ ID NO: 127 and the light chain variable region has an amino acid sequence comprising SEQ ID NO: 137.
  • position L27c in the VL region is occupied by S
  • position L37 in the VL region is occupied by L
  • position L51 in the VL region is occupied by G.
  • the heavy chain variable region has an amino acid sequence comprising SEQ ID NO: 127 and the light chain variable region has an amino acid sequence comprising SEQ ID NO: 159.
  • position L27c in the VL region is occupied by D
  • position L37 in the VL region is occupied by Q
  • position L51 in the VL region is occupied by K.
  • the heavy chain variable region has an amino acid sequence comprising SEQ ID NO: 127 and the light chain variable region has an amino acid sequence comprising SEQ ID NO: 138.
  • position L27c in the VL region is occupied by S
  • position L37 in the VL region is occupied by Q
  • position L51 in the VL region is occupied by G.
  • the heavy chain variable region has an amino acid sequence comprising SEQ ID NO: 127 and the light chain variable region has an amino acid sequence comprising SEQ ID NO: 133.
  • L66, L74, and LI 00 in the VL region are occupied by, respectively S, P, L, P, E, K, D, S, G, K, and Q, as in hu9F5VLv9.
  • position L3 in the VL region is occupied by Q.
  • position L27c in the VL region is occupied by G or S
  • position L37 in the VL region is occupied by G, I or Q
  • position L51 in the VL region is occupied by G, I or K
  • position L54 in the VL region is occupied by G or R
  • position L92 in the VL region is occupied by G, I or L.
  • position L27c in the VL region is occupied by G
  • position L37 in the VL region is occupied by G
  • position L51 in the VL region is occupied by G
  • position L54 in the VL region is occupied by R
  • position L92 in the VL region is occupied by I.
  • the heavy chain variable region has an amino acid sequence comprising SEQ ID NO: 129 and the light chain variable region has an amino acid sequence comprising SEQ ID NO: 168.
  • the light chain variable region of any of the above referenced antibodies can be modified to further reduce immunogenicity.
  • position L27b in the VL region is occupied by D, T or Q
  • position L27c in the VL region is occupied by D, G, S, E, T, N, A, I, or P
  • position L30 in the VL region is occupied by E, K, G or Q
  • position L31 in the VL region is occupied by G
  • position L33 in the VL region is occupied by N, T, S, R or G
  • position L37 in the VL region is occupied by Q, G, or I
  • position L51 in the VL region is occupied by E, D, G, K, or I
  • position L54 in the VL region is occupied by G, R, or T
  • position L60 in the VL region is occupied by D
  • position L73 in the VL region is occupied by P or G
  • position L75 in the VL region is occupied by D, P, Q or G
  • position L51 in the VL region is occupied by E, as in hu9F5VLv2_M5!E.
  • position L51 in the VL region is occupied by D, as in hu9F5VLv2_M51D.
  • position L27c in the VL region is occupied by D, as in hu9F5VLv2_L27cD.
  • position L27c in the VL region is occupied by G, as in hu9F5VLv2_L27cG.
  • position L27c in the VL region is occupied by S, as in hu9F5VLv2_L27cS.
  • position L27c in the VL region is occupied by E, as in hu9F5VLv2_L27cE.
  • position L30 in the VL region is occupied by E, as in hu9F5VLv2_I30E.
  • position L30 in the VL region is occupied by K, as in hu9F5VLv2_I30K.
  • position L27c in the VL region is occupied by T, as in hu9F5VLv2_L27cT. In some humanized 9F5 antibodies, position L27c in the VL region is occupied by N, as in hu9F5VLv2_L27cN)
  • position L27b in the VL region is occupied by D, as in hu9F5VLv2_L27bD.
  • position L30 in the VL region is occupied by G, as in hu9F5VLv2_I30G.
  • position L33 in the VL region is occupied by N, as in hu9F5VLv2_L33N.
  • position L27c in the VL region is occupied by A, as in hu9F5VLv2_L27cA.
  • position L33 in the VL region is occupied by T, as in hu9F5VLv2_L33T.
  • position L33 in the VL region is occupied by S, as in hu9F5VLv2_L33S.
  • position L33 in the VL region is occupied by R, as in hu9F5VLv2_L33R.
  • position L30 in the VL region is occupied by Q, as in hu9F5VLv2_I30Q.
  • position L27b in the VL region is occupied by T, as in hu9F5VLv2_L27bT.
  • position L31 in the VL region is occupied by G, as in hu9F5VLv2_T31G.
  • position L27b in the VL region is occupied by Q, as in hu9F5VLv2_L27bQ)
  • position L33 in the VL region is occupied by G, as in hu9F5VLv2_L33G.
  • position L27c in the VL region is occupied by P, as in hu9F5VLv2_L27cP.
  • position L78 in the VL region is occupied by R, as in hu9F5VLv2_V78R.
  • position L75 in the VL region is occupied by D, as in hu9F5VLv2_I75D.
  • position L78 in the VL region is occupied by D, as in hu9F5VLv2_V78D.
  • position L78 in the VL region is occupied by E, as in hu9F5VLv2_V78E.
  • position L78 in the VL region is occupied by P, as in hu9F5VLv2_V78P.
  • position L78 in the VL region is occupied by K, as in hu9F5VLv2_V78K.
  • position L77 in the VL region is occupied by D, as in hu9F5VLv2_R77D.
  • position L78 in the VL region is occupied by G, as in hu9F5VLv2_V78G.
  • position L76 in the VL region is occupied by P, as in hu9F5VLv2_S76P.
  • position L75 in the VL region is occupied by P, as in hu9F5VLv2_I75P.
  • position L75 in the VL region is occupied by Q, as in hu9F5VLv2_I75Q.
  • position L75 in the VL region is occupied by G, as in hu9F5VLv2_I75G.
  • position L73 in the VL region is occupied by P, as in hu9F5VLv2_L73P.
  • position L73 in the VL region is occupied by G, as in hu9F5VLv2_L73G.
  • position L78 in the VL region is occupied by Q, as in hu9F5VLv2_V78Q.
  • position L76 in the VL region is occupied by G, as in hu9F5VLv2_S76G.
  • position L92 in the VL region is occupied by D, as in hu9F5VLv2_L92D.
  • position L86 in the VL region is occupied by T, as in hu9F5VLv2_Y86T.
  • position L92 in the VL region is occupied by E, as in hu9F5VLv2_L92E.
  • position L92 in the VL region is occupied by G, as in hu9F5VLv2_L92G.
  • position L92 in the VL region is occupied by Q, as in hu9F5VLv2_L92Q.
  • position L93 in the VL region is occupied by G, as in hu9F5VLv2_L93G).
  • position L85 in the VL region is occupied by G, as in hu9F5VLv2_V85G.
  • position L92 in the VL region is occupied by T, as in hu9F5VLv2_L92T.
  • position L89 in the VL region is occupied by G, as in hu9F5VLv2_A89G.
  • positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, S, Q, G, G, and I, respectively, as in hu9F5VLv8_V3Q, L27cS, L37Q, M51G, L54G, L92I, also known as hu9F5VLv8 DIME
  • positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, S,
  • hu9F5VLv8 DIM2 positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, S, Q, G, T, and I, respectively, as in hu9F5VLv8_V3Q, L27cS, L37Q, M51G, L54T, L92I, also known as hu9F5VLv8_DIM3.
  • positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, S, Q, G, R, and G, respectively, as in hu9F5VLv8_V3Q, L27cS, L37Q, M51G, L54R, L92G, also known as hu9F5VLv8_DIM4.
  • positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, G, Q, G, R, and I, respectively, as in hu9F5VLv8_V3Q, L27cG, L37Q, M51G, L54R, L92I, also known as hu9F5VLv8JDIM5.
  • positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, D, Q, G, R, and I, respectively, as in hu9F5VLv8_V3Q, L27cD, L37Q, M51G, L54R, L92I, also known as hu9F5VLv8_DIM6.
  • positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, D, Q, K, R, and I, respectively, as in hu9F5VLv8_V3Q, L27cD, L37Q, M51K, L54R, L92I, also known as hu9F5VLv8_DIM7.
  • positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, G, Q, K, R, and I, respectively, as in hu9F5VLv8_V3Q, L27cG, L37Q, M51K, L54R, L92I, also known as hu9F5VLv8_DIM8.
  • positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q.
  • positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, S, Q, K, G, and I, respectively, as in hu9F5VLv8_V3Q, L27cS, L37Q, M51K, L54G, L92I, also known as hu9F5VLv8_DIMl 0.
  • positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, G, G, G, R, and I, respectively, as in hu9F5VLv8_V3Q, L27cG, L37G, M51G, L54R, L92I, also known as hu9F5VLv8 DIM I 1.
  • positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, G, G, G, R, and G, respectively, as in hu9F5VLv8_V3Q, L27cG, L37G, M51G, L54R, L92G, also known as hu9F5VLv8_DIM 12.
  • positions L3, L27c, L37, L51, and L54 in the VL region are occupied by Q, G, G, G, and R, respectively, as in hu9F5VLv8_V3Q, L27cG, L37G, M51G, L54R, also known as hu9F5VLv8 DIM13.
  • positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, G, G, G, T, and I, respectively, as in hu9F5VLv8_V3Q, L27cG, L37G, M51G, L54T, L92I, also known as hu9F5VLv8 DIMM.
  • positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, G, G, G, T, and G, respectively, as in hu9F5VLv8_V3Q, L27cG, L37G, M51G, L54T, L92G, also known as h u9F 5 VL v 8_DIM 15.
  • positions L3, L27c, L37, L51, and L54 in the VL region are occupied by Q, G, G, G, and T, respectively, as in hu9F5VLv8_V3Q, L27cG, L37G, M51G, L54T, also known as hu9F5VLv8 DIM16.
  • positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, S, G, G, T, and I, respectively, as in hu9F5VLv8_V3Q, L27cS, L37G, M51G, L54T, L92I, also known as hu9F5VLv8 DIM! 7.
  • positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, D, G, G, R, and I, respectively, as in
  • positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, S, I, I, R, and I, respectively, as in hu9F5VLv8_V3Q, L27cS, L37I, M51I, L54R, L92I, also known as bu9F5VLv8_DlM19.
  • positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, S, Q, I, G, and I, respectively, as in hu9F5VLv8_V3Q, L27cS, L37Q, M51I, L54G, L92I, also known as hu9F5 VLv8__DIM20.
  • positions L3, L27c, L37, L51, and L54 in the VL region are occupied by Q, S, Q, I, and G, respectively, as in hu9F5VLv8_V3Q, L27cS, L37Q, M51I, L54G, also known as hu9F5VLv8_DIM21.
  • positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, S, Q, E, R, and I, respectively, as in hu9F5VLv8_V3Q, L27cS, L37Q, M51E, L54R, L92I, also known as hu9F5VLv8 DIM22.
  • positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, G, Q, E, G, and I, respectively, as in
  • hu9F5VLv8_V3Q, L27cG, L37Q, M51E, L54G, L92I, also known as hu9F5VLv8_DIM23 positions L3, L27c, L37, L51, L54, and L92L in the VL region are occupied by Q, G, I, E, R, and I, respectively, as in hu9F5VLv8_V3Q, L27cG, L37I, M51E, L54R, L92I, also known as hu9F5VLv8_DIM24.
  • positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, G, I, E, R. and G, respectively, as in hu9F5VLv8_V3Q, L27cG, L37I, M51E, L54R, L92G, also known as hu9F5 VLv8__DIM25.
  • positions L3, L27c, L37, L51, and L54 in the VL region are occupied by Q, I, I, E, and R, respectively, as in hu9F5VLv8_V3Q, L27cl, L37I, M51E, L54R, also known as hu9F5VLv8_DJM26.
  • positions L3, L37, L51, L54, and L92 in the VL region are occupied by Q, Q, G, R, and I, respectively, as in hu9F5VLv8_V3Q, L37Q, M51G, L54R, L92I, also known as hu9F5VLv8_DIM27.
  • positions L3, L27c, L51, L54, and L92 in the VL region are occupied by Q, S, G, R, and I, respectively, as in hu9F5VLv8_V3Q, L27cS, M51G, L54R, L92I, also known as hu9F5VLv8_DIM28.
  • positions L3, L27c, L37, L54, and L92 in the VL region are occupied by Q, S, Q, R, and I, respectively, as in
  • hu9F5VLv8_V3Q, L27cS, L37Q, L54R, L92I also known as hu9F5VLv8_DIM29.
  • positions L3, L27c, L37, L51, and L92 in the VL region are occupied by Q, S, Q, G, and I, respectively, as in hu9F5VLv8_V3Q, L27cS, L37Q, M51G, L92I, also known as hu9F5VLv8 DIM30.
  • positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, S, Q, G, G, and I, respectively, as in hu9F5VLv9_V3Q, L27cS, L37Q, M51G, L54G, L92I, also known as hu9F5VLv9_DIMl .
  • positions L3, L27c, L37, L51, L54, and L92in the VL region are occupied by Q, S, Q, G, R, and I, respectively, as in hu9F5VLv9_V3Q, L27cS, L37Q, M51G, L54R, L92I, also known as hu9F5VLv9 DIM2.
  • positions L3, L27c, L37, L51, L54, and L92in the VL region are occupied by Q, S, Q, G, R, and I, respectively, as in hu9F5VLv9_V3Q, L27cS, L37Q, M51G, L54R, L92I, also known as hu9F5VLv9 DIM2.
  • L51, L54, and L92 in the VL region are occupied by Q, S, Q, G, R, and G, respectively, as in hu9F5VLv9_V3Q, L27cS, L37Q, M51G, L54R, L92G, also known as hu9F5VLv9_DIM4).
  • positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, G, Q, G, R, and I, respectively, as in hu9F5VLv9_V3Q, L27cG, L37Q, M51G, L54R, L92I, also known as hu9F5VLv9 DIMS.
  • positions L3, L27c, L37, L51, L54, and L92 in the VL region are occupied by Q, G, Q, K, R, and I , respectively, as in hu9F5VLv9_V3Q, L27cG, L37Q, M51K, L54R, L92I, also known as hu9F5VLv9 DIMS.

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MX2021009440A MX2021009440A (es) 2019-02-08 2020-02-07 Anticuerpos que reconocen tau.
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BR112021015501-5A BR112021015501A2 (pt) 2019-02-08 2020-02-07 Anticorpos que reconhecem tau
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