Anti-amyloid beta antibodies and methods of use

Abstract

Described are engineered antibodies that specifically bind amyloid beta (Aβ), nucleic acids encoding the anti-Aβ antibodies and methods of manufacturing the anti-Aβ antibodies. The anti-Aβ antibodies can be used to diagnose or treat neurodegenerative diseases or conditions associated with Aβ protein aggregation.

Description

Anti-Amyloid Beta Antibodies and Methods of Use RELATED APPLICATION

[0001] The application claims the benefit of priority to U.S. Provisional Application No. 63 / 693,937, filed on September 12, 2024, the entire contents of which are incorporated herein by reference. SEQUENCE LISTING

[0002] The Sequence Listing written in file DNL-044-02_SeqListing.xml is 89 kilobytes in size, was created September 2, 2025, and is hereby incorporated by reference. BACKGROUND

[0003] Several neurodegenerative diseases or conditions are associated with amyloid beta (Aβ) protein aggregation. Hallmarks of these neurodegenerative diseases or conditions include extracellular amyloid plaques, intraneuronal neurofibrillary tangles, neuronal dysfunction and ultimately brain atrophy. Soluble, aggregated, intermediate forms of Aβ, including protofibrils, may play a significant role in causing these neurodegenerative diseases and the symptoms observed in patients.

[0004] Aberrant Aβ proteins and aggregates can accumulate in different tissues and organs and are linked to several neurodegenerative diseases and conditions including Alzheimer’s, Parkinson’s, and prion diseases. In some cases, the accumulation of amyloid is closely linked to inflammation and activation of the immune system, which extends tissue damage even further.

[0005] Alzheimer's disease (AD) is a progressive neurodegenerative disorder clinically characterized by cognitive impairment, behavioral disturbances, psychiatric symptoms, and disability in activities of daily living. These clinical manifestations constitute AD dementia. In Alzheimer’s disease, amyloid-beta peptides accumulate in the brain and form plaques.

[0006] While the precise mechanism by which Aβ contributes to neurodegenerative disease is not yet known, drugs targeting Aβ have shown promise in treating Alzheimer’s disease. Lecanemab is an anti-Aβ antibody therapeutic that has been FDA approved for treating Alzheimer’s disease. However, lecanemab has certain side effects, including amyloid-related imaging abnormalities (ARIA) and the clinical benefit, while significant, is modest. In addition, lecanemab exhibits an undesirable high plasma clearance relative to a control IgG antibody. Thus, there is a need for improved drugs that target Aβ.1 LEGAL02 / 46562464v1SUMMARY

[0007] Described are antibodies, or antigen binding fragments thereof, having affinity for amyloid beta (Aβ). The described anti-Aβ antibodies, or antigen binding fragments thereof, comprise a light chain variable domain and a heavy chain variable domain, wherein: (a) the light chain variable domain comprises: a CDR-L1 having the sequence RSSQSIVHSNGNTYLE (SEQ ID NO: 1), a CDR-L2 having the sequence KVSNRFS (SEQ ID NO: 2), a CDR-L3 having the sequence FQGSXVPPT (SEQ ID NO: 3) wherein X is leucine or arginine, a valine at position 3, a threonine at position 7, a threonine at position 14, a proline or leucine at position 15, an aspartate or glutamine at position 17, a glutamine or proline at position 18, a glutamine at position 45, a lysine at position 74, a valine at position 83, a valine at position 85, a glutamine at position 100, and a valine at position 104, wherein the positions are according to Chothia / Martin numbering; and (b) a heavy chain variable domain comprising: a CDR-H1 having the sequence SFGMH (SEQ ID NO: 4), a CDR-H2 having the sequence YISSGSSTIYYGDTVKG (SEQ ID NO: 5), and a CDR-H3 having the sequence EGGYYYGRSYXTMDY (SEQ ID NO: 6), wherein X is tyrosine, asparagine, or glutamine. In some embodiments, the CDR-L3 comprises FQGSLVPPT (SEQ ID NO: 59). In some embodiments, the CDR-L3 comprises FQGSRVPPT (SEQ ID NO: 60).

[0008] The anti-Aβ antibody, or antigen binding fragment thereof, can be, but is not limited to, an immunoglobulin, a scFv, a Fab, or a scFab. The anti-Aβ antibody, or antigen binding fragment thereof, can be monovalent or multivalent. In some embodiments, the anti-Aβ antibody, or antigen binding fragment thereof, is monospecific. In some embodiments, the anti-2 LEGAL02 / 46562464v1Aβ antibody, or antigen binding fragment thereof, is part of a multi-specific antibody or antibody-like molecule.

[0009] In some embodiments, the described anti-Aβ antibody, or antigen binding fragment thereof, comprises at least one modification to increase serum stability, modulate effector function, influence glycosylation, reduce immunogenicity in humans, and / or facilitate heterodimerization.

[0010] In some embodiments, the described anti-Aβ antibodies, or antigen binding fragments thereof, have one or more of: increase affinity to Aβ, improved PK, improved affinity to one or more variant Aβ species, and reduced immunogenicity relative to lecanemab.

[0011] Also described are pharmaceutical compositions and therapeutic combinations comprising any of the described anti-Aβ antibodies, or antigen binding fragments thereof.

[0012] Also described are nucleic acid sequences encoding any of the described anti-Aβ antibodies, of antigen binding fragments thereof.

[0013] Also described are host cells comprising nucleic acid sequences encoding any of the described anti-Aβ antibodies, or antigen binding fragments thereof, and host cells expressing any of the described anti-Aβ antibodies, or antigen binding fragments thereof. Methods of manufacturing using the host cells are also described.

[0014] The described anti-Aβ antibodies, or antigen binding fragments thereof, can be used to treat a subject having a neurodegenerative disease or condition associated with Aβ protein aggregation. The methods comprise administering to the subject a described anti-Aβ antibody, or antigen binding fragment thereof or a pharmaceutical composition and therapeutic combination comprising the anti-Aβ antibodies, or antigen binding fragments thereof. The neurodegenerative disease or condition associated with Aβ protein aggregation can be, but is not limited to, Alzheimer's disease, a cognitive impairment associated with Aβ oligomers, a traumatic brain injury (TBI), Lewy body dementia (LBD), Downs syndrome (DS), amyotrophic lateral sclerosis (ALS), frontotemporal dementia, a tauopathy, a systemic amyloidosis, atherosclerosis, or Parkinson's disease dementia (PDD).

[0015] In some embodiments, administering a described anti-Aβ antibody, or antigen binding fragment thereof, reduces, delays, or prevents the neurodegenerative disease or condition associated with Aβ protein aggregation. In some embodiments, administering a described anti-Aβ antibody, or antigen binding fragment thereof, reduces, delays, or prevents one or more symptoms associated with the neurodegenerative disease or condition associated with Aβ protein aggregation.3 LEGAL02 / 46562464v1

[0016] In some embodiments, administering a described anti-Aβ antibody, or antigen binding fragment thereof, reduces or prevents Aβ accumulation, β-Amyloid plaque formation, Aβ amyloid fibril formation, Aβ-mediated synaptic toxicity, or Aβ protofibril formation.

[0017] The described anti-Aβ antibodies, or antigen binding fragments thereof, can also be used in methods of diagnosis of Alzheimer's disease or risk of developing Alzheimer's disease in a subject. In some embodiments, the anti-Aβ antibodies, or antigen binding fragments thereof, are used to determine a level of aggregated Aβ protein in a sample, wherein the level of aggregated Aβ protein indicates whether the subject has or is at risk of developing Alzheimer's disease.

[0018] The described anti-Aβ antibodies, or antigen binding fragments thereof, can also be used to measure the amount of Aβ protofibrils and / or aggregated Aβ protein in a subject. BRIEF DESCRIPTION OF THE FIGURES

[0019] FIG.1. Graph illustrating PK for engineered anti-Aβ antibodies.

[0020] FIG.2. Graph illustrating PK for engineered anti-Aβ antibodies.

[0021] FIG.3. Graph illustrating PK for various anti-Aβ antibodies.

[0022] FIG. 4. Image illustrating immunohistochemistry of human brain sections using control antibody or lecanamab and rabbit anti-human Amyloid Beta. DESCRIPTION I. Definitions

[0023] As used herein, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to “a polypeptide” may include two or more such polypeptides, and the like.

[0024] As used herein, the terms “about” and “approximately,” when used to modify an amount specified in a numeric value or range, indicates the numeric value as well as reasonable deviations from the value known to the skilled person in the art. In some embodiments, the term “about” means within the typical ranges of tolerances in the art. In some embodiments, the term “about” means within 1 or 2 standard deviations from the mean. In some embodiments, the term “about” means ±10%. In some embodiments, the term “about” means ±5%. When the term “about” is present before a series of numbers or a range, it is understood that “about” can modify each of the numbers in the series or range.

[0025] The term “antibody” refers to a protein with an immunoglobulin fold that specifically binds to an antigen via its variable regions (antibody antigen binding domains). The term4 LEGAL02 / 46562464v1encompasses intact polyclonal antibodies, intact monoclonal antibodies, single chain antibodies, multispecific antibodies such as bispecific antibodies, monospecific antibodies, monovalent antibodies, chimeric antibodies, humanized antibodies, and human antibodies. The term “antibody,” as used herein, includes both full-length antibodies (e.g., IgG1 antibody that has two heavy chains made up of variable heavy (VH or HV), CH1, CH2, and CH3 domains and two light chains made up of variable light (VLor VL) and CL domains). Antibodies can contain heavy chains that are classified as gamma, mu, alpha, delta, or epsilon, which in turn define the immunoglobulin classes, IgG, IgM, IgA, IgD and IgE, respectively. Antibodies can contain light chains that are classified as either kappa or lambda.

[0026] An “antigen binding fragment” of an antibody refers to a portion or region of an antibody that retains all or a significant part of the antigen binding of the corresponding full- length antibody. In some embodiments, an antigen binding fragment comprises the heavy chain variable region (VH) and the light chain variable region (VL) of an antibody. The VH region or domain typically contains three CDRs, i.e., CDR-H1, CDR-H2 and CDR-H3, flanked by VH framework regions, i.e., FR1, FR2, FR3 and FR4. The VL region or domain typically contains three CDRs, i.e., CDR-L1, CDR-L2 and CDR-L3, flanked by VL framework regions, i.e., FR1, FR2, FR3 and FR4. Antigen binding fragments include but are not limited to, Fab, Fab′, F(ab′)2, scFab, Fv, scFv, and combinations thereof (e.g., bivalent scFv).

[0027] The term “variable region” refers to a domain in an antibody heavy chain or light chain derived from a germline Variable (V) gene, Diversity (D) (heavy chain only) gene, and Joining (J) gene (and not derived from a Constant (Cμ and Cδ) gene segment), and that gives an antibody its specificity for binding to an antigen. Typically, an antibody variable region comprises four conserved “framework” regions interspersed with three hypervariable “complementarity determining regions” (CDRs).

[0028] A variant, with respect to a given sequence, is an alteration in a nucleic acid or amino acid sequence relative to a reference (e.g., wild-type or most common) sequence. A variant can be a naturally occurring sequence (e.g., an allelic variant) or a non-naturally occurring sequence. A non-naturally occurring variant domain refers to a variant or mutant domain that is not present in a cell in nature and that is produced by genetic modification (e.g., using genetic engineering technology or mutagenesis techniques) of a native domain. An alteration in a nucleic acid or amino acid sequence (e.g., a mutation) can include one or more substitutions, one or more insertions, one or more deletions, or combinations thereof.

[0029] “Binding affinity” refers to the strength of the non-covalent interaction between two molecules, e.g., between single binding region or site on a protein and a target. Binding affinity5 LEGAL02 / 46562464v1may be quantified by measuring an equilibrium dissociation constant (KD), which refers to the dissociation rate constant (kd, time−1) divided by the association rate constant (ka, time−1M−1). KD can be determined by measurement of the kinetics of complex formation and dissociation, e.g., using Surface Plasmon Resonance (SPR) methods, e.g., a Biacore™ system; kinetic exclusion assays such as KinExA®; and BioLayer interferometry (e.g., using the ForteBio®Octet®platform). The term “binding affinity” includes not only formal binding affinities, such as those reflecting 1:1 interactions between a polypeptide and its target, but also apparent affinities for which KD’s are calculated that may reflect avid binding (avidity).

[0030] The term “specifically binds” or “selectively binds” to a target (e.g., Aβ) when referring to a binding region (e.g., antigen binding domain) refers to a binding reaction whereby the binding region binds to the target with greater affinity, greater avidity, and / or greater duration than it binds to a structurally different target. A binding region may have at least 5- fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 25-fold, 50-fold, 100-fold, 1,000-fold, 10,000-fold, or greater affinity to a specific target compared to an unrelated target when assayed under the same affinity assay conditions. The term “specific binding,” “specifically binds to,” or “is specific for” a particular target can be exhibited, for example, by a molecule having an equilibrium dissociation constant KD for the target to which it binds of, e.g., 10−4M or smaller (e.g., 10−5M, 10−6M (1000 nM), 10−7M (100 nM), 10−8M (10 nM), 10−9M (1 nM), 10−10M, 10−11M, or 10−12M). In some embodiments, a binding region specifically binds to a target (e.g., protein) that is conserved among species, (e.g., structurally conserved among species).

[0031] The term “amino acid” refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, γ- carboxyglutamate and O-phosphoserine. “Amino acid analogs” refers to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., a carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid. “Amino acid mimetics” refers to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that function in a manner similar to a naturally occurring amino acid.6 LEGAL02 / 46562464v1

[0032] Naturally occurring α-amino acids include, without limitation, alanine (Ala, A), cysteine (Cys, C), aspartic acid (Asp, D), glutamic acid (Glu, E), phenylalanine (Phe, F), glycine (Gly, G), histidine (His, H), isoleucine (Ile, I), arginine (Arg, R), lysine (Lys, K), leucine (Leu, L), methionine (Met, M), asparagine (Asn, N), proline (Pro, P), glutamine (Gln, Q), serine (Ser, S), threonine (Thr, T), valine (Val, V), tryptophan (Trp, W), and tyrosine (Tyr, Y). Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission.

[0033] A “polypeptide” is a polymer of two or more amino acid residues in a single chain. The term applies to amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymers.

[0034] The term “protein” as used herein refers to either a polypeptide, a polypeptide dimer, or polypeptide multimer. A polypeptide dimer can be a homodimer or a heterodimer. A polypeptide multimer can be a homomultimer or a heteromultimer. A heteromultimer may comprise two or more copies of any given single chain polypeptide. For example, an immunoglobulin is a heteromultimer comprising two heavy chains and two light chains. The two heavy chains can be the same or different and the two light chains can be the same or different. The single polypeptide chains of a dimer or multimer may be joined by one or more covalent bonds (e.g., a disulfide bonds), by non-covalent interactions, or by a combination thereof.

[0035] The terms “identical” or percent “identity,” in the context of two or more nucleic acid or polypeptide sequences, refer to two or more sequences or subsequences that are the same or have a specified percentage of nucleic acid or amino acid residues (e.g., at least 60%, at least 65%, at least 70%), at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% or greater) that are identical over a specified region when compared and aligned for maximum correspondence over a comparison window or designated region, as measured using a sequence comparison algorithm or by manual alignment and visual inspection. For sequence comparison, typically one sequence acts as a reference sequence to which a candidate sequence is compared. Alignment can be performed using various methods available to one of skill in the art, e.g., visual alignment or using publicly available software using known algorithms to achieve maximal alignment. Such programs include the BLAST programs, ALIGN, ALIGN-2 (Genentech, South San Francisco, Calif.) or Megalign (DNASTAR). The parameters employed for an alignment to achieve maximal alignment can be determined by one of skill in the art.7 LEGAL02 / 46562464v1For sequence comparison of polypeptide sequences for purposes of this application, the BLASTP algorithm standard protein BLAST for aligning two proteins sequence with the default parameters is used.

[0036] The terms “corresponding to,” “positions are according to,” “numbered with reference to” and the like, when used in the context of the identification of a given nucleotide or amino acid residue in a nucleic acid or polypeptide sequence, refers to the position of the residue of a specified reference sequence when the given amino acid sequence is maximally aligned and compared to the reference sequence. The sequence that is aligned to the reference sequence need not be the same length as the reference sequence.

[0037] “Chothia / Martin numbering” is generally used in the art when referring to a residue (amino acid) in an antibody variable domain. Chothia / Martin numbering is shown below with respect to an anti-Aβ light chain variable domain, SEQ ID NO: 38 (bold / solid underline = CDR sequences; dotted underline = Framework sequences). Positions a, b, c, d, and e correspond to Chothia / Martin positions 30a, 30b, 30c, 30d, and 30e, respectively. DVVMTQTPLS LPVTXGXXAS ISCRSSQSIVHSNGN TYLEWYLQKP GQSPQLLIYK 123456789112345678921234567893abcde 12345678941234567895 0 0 0 0 0 VSNRFSGVPD RFSGSGSGTD FTLKISRVEA EDVGVYYCFQ GSLVPPTFGQ GTKVEIK 123456789612345678971234567898123456789912345678911234567 0 0 0 0 00 II. ANTI-Aβ ANTIBODIES and ANTIGEN BINDING FRAGMENTS THEREOF

[0038] Anti-Aβ antibodies, and antigen binding fragments thereof, compositions containing the anti-Aβ antibodies, or the antigen binding fragments thereof, nucleic acids encoding the anti-Aβ antibodies, or antigen binding fragments thereof, and methods of manufacturing anti- Aβ antibodies, or the antigen binding fragments thereof, are described. Method of using the anti-Aβ antibodies, or the antigen binding fragments thereof, to treat or diagnose neurological disorders or conditions, such as Alzheimer's disease, are also described.

[0039] The described anti-Aβ antibodies, and antigen binding fragments thereof, that bind to Amyloid beta (Abeta or Aβ). In some embodiments, the described anti-Aβ antibodies, and the antigen binding fragments thereof, bind to Aβ protein aggregates or Aβ protofibrils. In some embodiments, the described anti-Aβ antibodies, or the antigen binding fragments thereof, specifically bind human Aβ.8 LEGAL02 / 46562464v1

[0040] Described are anti-Aβ antibodies, or antigen binding fragments thereof, having affinity for amyloid beta (Aβ), comprising a light chain variable domain and a heavy chain variable domain, wherein: (a) the light chain variable domain comprises: a CDR-L1 having the sequence RSSQSIVHSNGNTYLE (SEQ ID NO: 1), or optionally having one or two conservative substitutions relative to the sequence of SEQ ID NO: 1, a CDR-L2 having the sequence KVSNRFS (SEQ ID NO: 2), or optionally having one or two conservative substitutions relative to the sequence of SEQ ID NO: 2, a CDR-L3 having the sequence FQGSXVPPT (SEQ ID NO: 3), wherein X is leucine (L) or arginine (R), or optionally having one or two conservative substitutions relative to the sequence of SEQ ID NO: 3, a valine at position 3, a threonine at position 7, a threonine at position 14, a proline or leucine at position 15, an aspartate or glutamine at position 17, a glutamine or proline at position 18, a glutamine at position 45, a lysine at position 74, a valine at position 83, a valine at position 85, a glutamine at position 100, and a valine at position 104, wherein the positions are according to Chothia / Martin numbering; and (b) a heavy chain variable domain comprising: a CDR-H1 having the sequence SFGMH (SEQ ID NO: 4), or optionally having one or two conservative substitutions relative to the sequence of SEQ ID NO: 4, a CDR-H2 having the sequence YISSGSSTIYYGDTVKG (SEQ ID NO: 5), or optionally having one or two conservative substitutions relative to the sequence of SEQ ID NO: 5, and9 LEGAL02 / 46562464v1a CDR-H3 having the sequence EGGYYYGRSYXTMDY (SEQ ID NO: 6), or optionally having one or two conservative substitutions relative to the sequence of SEQ ID NO: 6, wherein X is tyrosine, asparagine, or glutamine.

[0041] In some embodiments, the CDR-L3 comprises FQGSLVPPT (SEQ ID NO: 59).

[0042] In some embodiments, the CDR-L3 comprises FQGSRVPPT (SEQ ID NO: 60).

[0043] In some embodiments, the light chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a leucine at position 15. In some embodiments, the CDR-L3 comprises FQGSLVPPT (SEQ ID NO: 59). In some embodiments, the CDR-L3 comprises FQGSRVPPT (SEQ ID NO: 60).

[0044] In some embodiments, the light chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a proline at position 15. In some embodiments, the CDR-L3 comprises FQGSLVPPT (SEQ ID NO: 59). In some embodiments, the CDR-L3 comprises FQGSRVPPT (SEQ ID NO: 60).

[0045] In some embodiments, the light chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises an aspartate at position 17. In some embodiments, the CDR-L3 comprises FQGSLVPPT (SEQ ID NO: 59). In some embodiments, the CDR-L3 comprises FQGSRVPPT (SEQ ID NO: 60).

[0046] In some embodiments, the light chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a glutamine at position 17. In some embodiments, the CDR-L3 comprises FQGSLVPPT (SEQ ID NO: 59). In some embodiments, the CDR-L3 comprises FQGSRVPPT (SEQ ID NO: 60).

[0047] In some embodiments, the light chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a glutamine at position 18. In some embodiments, the CDR-L3 comprises FQGSLVPPT (SEQ ID NO: 59). In some embodiments, the CDR-L3 comprises FQGSRVPPT (SEQ ID NO: 60).

[0048] In some embodiments, the light chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a proline at position 18. In some embodiments, the CDR-L3 comprises FQGSLVPPT (SEQ ID NO: 59). In some embodiments, the CDR-L3 comprises FQGSRVPPT (SEQ ID NO: 60).

[0049] In some embodiments, the light chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a leucine at position 15, an aspartate position 17, and a proline at position 18. In some embodiments, the CDR-L3 comprises FQGSLVPPT (SEQ ID NO: 59). In some embodiments, the CDR-L3 comprises FQGSRVPPT (SEQ ID NO: 60).10 LEGAL02 / 46562464v1

[0050] In some embodiments, the light chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a leucine at position 15, an aspartate position 17, and a glutamine at position 18. In some embodiments, the CDR-L3 comprises FQGSLVPPT (SEQ ID NO: 59). In some embodiments, the CDR-L3 comprises FQGSRVPPT (SEQ ID NO: 60).

[0051] In some embodiments, the light chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a leucine at position 15, a glutamine position 17, and a proline at position 18. In some embodiments, the CDR-L3 comprises FQGSLVPPT (SEQ ID NO: 59). In some embodiments, the CDR-L3 comprises FQGSRVPPT (SEQ ID NO: 60).

[0052] In some embodiments, the light chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a leucine at position 15, a glutamine position 17, and a glutamine at position 18. In some embodiments, the CDR-L3 comprises FQGSLVPPT (SEQ ID NO: 59). In some embodiments, the CDR-L3 comprises FQGSRVPPT (SEQ ID NO: 60).

[0053] In some embodiments, the light chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a proline at position 15, an aspartate position 17, and a proline at position 18. In some embodiments, the CDR-L3 comprises FQGSLVPPT (SEQ ID NO: 59). In some embodiments, the CDR-L3 comprises FQGSRVPPT (SEQ ID NO: 60).

[0054] In some embodiments, the light chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a proline at position 15, an aspartate position 17, and a glutamine at position 18. In some embodiments, the CDR-L3 comprises FQGSLVPPT (SEQ ID NO: 59). In some embodiments, the CDR-L3 comprises FQGSRVPPT (SEQ ID NO: 60).

[0055] In some embodiments, the light chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a proline at position 15, a glutamine position 17, and a proline at position 18. In some embodiments, the CDR-L3 comprises FQGSLVPPT (SEQ ID NO: 59). In some embodiments, the CDR-L3 comprises FQGSRVPPT (SEQ ID NO: 60).

[0056] In some embodiments, the light chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a proline at position 15, a glutamine position 17, and a glutamine at position 18. In some embodiments, the CDR-L3 comprises FQGSLVPPT (SEQ ID NO: 59). In some embodiments, the CDR-L3 comprises FQGSRVPPT (SEQ ID NO: 60).

[0057] In some embodiments, the heavy chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a CDR-H3 having the sequence11 LEGAL02 / 46562464v1EGGYYYGRSYYTMDY (SEQ ID NO: 7). In some embodiments, the CDR-L3 comprises FQGSLVPPT (SEQ ID NO: 59). In some embodiments, the CDR-L3 comprises FQGSRVPPT (SEQ ID NO: 60).

[0058] In some embodiments, the heavy chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a CDR-H3 having the sequence EGGYYYGRSYNTMDY (SEQ ID NO: 8). In some embodiments, the CDR-L3 comprises FQGSLVPPT (SEQ ID NO: 59). In some embodiments, the CDR-L3 comprises FQGSRVPPT (SEQ ID NO: 60).

[0059] In some embodiments, the heavy chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a CDR-H3 having the sequence EGGYYYGRSYQTMDY (SEQ ID NO: 9). In some embodiments, the CDR-L3 comprises FQGSLVPPT (SEQ ID NO: 59). In some embodiments, the CDR-L3 comprises FQGSRVPPT (SEQ ID NO: 60).

[0060] In some embodiments, the light chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a leucine at position 15, an aspartate position 17, and a proline at position 18; and the heavy chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a CDR-H3 having the sequence EGGYYYGRSYYTMDY (SEQ ID NO: 7). In some embodiments, the CDR-L3 comprises FQGSLVPPT (SEQ ID NO: 59). In some embodiments, the CDR-L3 comprises FQGSRVPPT (SEQ ID NO: 60).

[0061] In some embodiments, the light chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a leucine at position 15, an aspartate position 17, and a proline at position 18; and the heavy chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a CDR-H3 having the sequence EGGYYYGRSYNTMDY (SEQ ID NO: 8). In some embodiments, the CDR-L3 comprises FQGSLVPPT (SEQ ID NO: 59). In some embodiments, the CDR-L3 comprises FQGSRVPPT (SEQ ID NO: 60).

[0062] In some embodiments, the light chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a leucine at position 15, an aspartate position 17, and a proline at position 18; and the heavy chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a CDR-H3 having the sequence EGGYYYGRSYQTMDY (SEQ ID NO: 9). In some embodiments, the CDR-L3 comprises FQGSLVPPT (SEQ ID NO: 59). In some embodiments, the CDR-L3 comprises FQGSRVPPT (SEQ ID NO: 60).12 LEGAL02 / 46562464v1

[0063] In some embodiments, the light chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a leucine at position 15, an aspartate position 17, and a glutamine at position 18; and the heavy chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a CDR-H3 having the sequence EGGYYYGRSYYTMDY (SEQ ID NO: 7). In some embodiments, the CDR-L3 comprises FQGSLVPPT (SEQ ID NO: 59). In some embodiments, the CDR-L3 comprises FQGSRVPPT (SEQ ID NO: 60).

[0064] In some embodiments, the light chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a leucine at position 15, an aspartate position 17, and a glutamine at position 18; and the heavy chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a CDR-H3 having the sequence EGGYYYGRSYNTMDY (SEQ ID NO: 8). In some embodiments, the CDR-L3 comprises FQGSLVPPT (SEQ ID NO: 59). In some embodiments, the CDR-L3 comprises FQGSRVPPT (SEQ ID NO: 60).

[0065] In some embodiments, the light chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a leucine at position 15, an aspartate position 17, and a glutamine at position 18; and the heavy chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a CDR-H3 having the sequence EGGYYYGRSYQTMDY (SEQ ID NO: 9). In some embodiments, the CDR-L3 comprises FQGSLVPPT (SEQ ID NO: 59). In some embodiments, the CDR-L3 comprises FQGSRVPPT (SEQ ID NO: 60).

[0066] In some embodiments, the light chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a leucine at position 15, a glutamine position 17, and a proline at position 18; and the heavy chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a CDR-H3 having the sequence EGGYYYGRSYYTMDY (SEQ ID NO: 7). In some embodiments, the CDR-L3 comprises FQGSLVPPT (SEQ ID NO: 59). In some embodiments, the CDR-L3 comprises FQGSRVPPT (SEQ ID NO: 60).

[0067] In some embodiments, the light chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a leucine at position 15, a glutamine position 17, and a proline at position 18; and the heavy chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a CDR-H3 having the sequence EGGYYYGRSYNTMDY (SEQ ID NO: 8). In some embodiments, the CDR-L3 comprises13 LEGAL02 / 46562464v1FQGSLVPPT (SEQ ID NO: 59). In some embodiments, the CDR-L3 comprises FQGSRVPPT (SEQ ID NO: 60).

[0068] In some embodiments, the light chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a leucine at position 15, a glutamine position 17, and a proline at position 18; and the heavy chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a CDR-H3 having the sequence EGGYYYGRSYQTMDY (SEQ ID NO: 9). In some embodiments, the CDR-L3 comprises FQGSLVPPT (SEQ ID NO: 59). In some embodiments, the CDR-L3 comprises FQGSRVPPT (SEQ ID NO: 60).

[0069] In some embodiments, the light chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a leucine at position 15, a glutamine position 17, and a glutamine at position 18; and the heavy chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a CDR-H3 having the sequence EGGYYYGRSYYTMDY (SEQ ID NO: 7). In some embodiments, the CDR-L3 comprises FQGSLVPPT (SEQ ID NO: 59). In some embodiments, the CDR-L3 comprises FQGSRVPPT (SEQ ID NO: 60).

[0070] In some embodiments, the light chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a leucine at position 15, a glutamine position 17, and a glutamine at position 18; and the heavy chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a CDR-H3 having the sequence EGGYYYGRSYNTMDY (SEQ ID NO: 8). In some embodiments, the CDR-L3 comprises FQGSLVPPT (SEQ ID NO: 59). In some embodiments, the CDR-L3 comprises FQGSRVPPT (SEQ ID NO: 60).

[0071] In some embodiments, the light chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a leucine at position 15, a glutamine position 17, and a glutamine at position 18; and the heavy chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a CDR-H3 having the sequence EGGYYYGRSYQTMDY (SEQ ID NO: 9). In some embodiments, the CDR-L3 comprises FQGSLVPPT (SEQ ID NO: 59). In some embodiments, the CDR-L3 comprises FQGSRVPPT (SEQ ID NO: 60).

[0072] In some embodiments, the light chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a proline at position 15, an aspartate position 17, and a proline at position 18; and the heavy chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a CDR-H3 having the sequence14 LEGAL02 / 46562464v1EGGYYYGRSYYTMDY (SEQ ID NO: 7). In some embodiments, the CDR-L3 comprises FQGSLVPPT (SEQ ID NO: 59). In some embodiments, the CDR-L3 comprises FQGSRVPPT (SEQ ID NO: 60).

[0073] In some embodiments, the light chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a proline at position 15, an aspartate position 17, and a proline at position 18; and the heavy chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a CDR-H3 having the sequence EGGYYYGRSYNTMDY (SEQ ID NO: 8). In some embodiments, the CDR-L3 comprises FQGSLVPPT (SEQ ID NO: 59). In some embodiments, the CDR-L3 comprises FQGSRVPPT (SEQ ID NO: 60).

[0074] In some embodiments, the light chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a proline at position 15, an aspartate position 17, and a proline at position 18; and the heavy chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a CDR-H3 having the sequence EGGYYYGRSYQTMDY (SEQ ID NO: 9). In some embodiments, the CDR-L3 comprises FQGSLVPPT (SEQ ID NO: 59). In some embodiments, the CDR-L3 comprises FQGSRVPPT (SEQ ID NO: 60).

[0075] In some embodiments, the light chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a proline at position 15, an aspartate position 17, and a glutamine at position 18; and the heavy chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a CDR-H3 having the sequence EGGYYYGRSYYTMDY (SEQ ID NO: 7). In some embodiments, the CDR-L3 comprises FQGSLVPPT (SEQ ID NO: 59). In some embodiments, the CDR-L3 comprises FQGSRVPPT (SEQ ID NO: 60).

[0076] In some embodiments, the light chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a proline at position 15, an aspartate position 17, and a glutamine at position 18; and the heavy chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a CDR-H3 having the sequence EGGYYYGRSYNTMDY (SEQ ID NO: 8). In some embodiments, the CDR-L3 comprises FQGSLVPPT (SEQ ID NO: 59). In some embodiments, the CDR-L3 comprises FQGSRVPPT (SEQ ID NO: 60).

[0077] In some embodiments, the light chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a proline at position 15, an aspartate position 17, and a glutamine at position 18; and the heavy chain variable domain of the anti-Aβ antibody,15 LEGAL02 / 46562464v1or the antigen binding fragment thereof, comprises a CDR-H3 having the sequence EGGYYYGRSYQTMDY (SEQ ID NO: 9). In some embodiments, the CDR-L3 comprises FQGSLVPPT (SEQ ID NO: 59). In some embodiments, the CDR-L3 comprises FQGSRVPPT (SEQ ID NO: 60).

[0078] In some embodiments, the light chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a proline at position 15, a glutamine position 17, and a proline at position 18; and the heavy chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a CDR-H3 having the sequence EGGYYYGRSYYTMDY (SEQ ID NO: 7). In some embodiments, the CDR-L3 comprises FQGSLVPPT (SEQ ID NO: 59). In some embodiments, the CDR-L3 comprises FQGSRVPPT (SEQ ID NO: 60).

[0079] In some embodiments, the light chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a proline at position 15, a glutamine position 17, and a proline at position 18; and the heavy chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a CDR-H3 having the sequence EGGYYYGRSYNTMDY (SEQ ID NO: 8). In some embodiments, the CDR-L3 comprises FQGSLVPPT (SEQ ID NO: 59). In some embodiments, the CDR-L3 comprises FQGSRVPPT (SEQ ID NO: 60).

[0080] In some embodiments, the light chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a proline at position 15, a glutamine position 17, and a proline at position 18; and the heavy chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a CDR-H3 having the sequence EGGYYYGRSYQTMDY (SEQ ID NO: 9). In some embodiments, the CDR-L3 comprises FQGSLVPPT (SEQ ID NO: 59). In some embodiments, the CDR-L3 comprises FQGSRVPPT (SEQ ID NO: 60).

[0081] In some embodiments, the light chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a proline at position 15, a glutamine position 17, and a glutamine at position 18; and the heavy chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a CDR-H3 having the sequence EGGYYYGRSYYTMDY (SEQ ID NO: 7). In some embodiments, the CDR-L3 comprises FQGSLVPPT (SEQ ID NO: 59). In some embodiments, the CDR-L3 comprises FQGSRVPPT (SEQ ID NO: 60).

[0082] In some embodiments, the light chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a proline at position 15, a glutamine position 17,16 LEGAL02 / 46562464v1and a glutamine at position 18; and the heavy chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a CDR-H3 having the sequence EGGYYYGRSYNTMDY (SEQ ID NO: 8). In some embodiments, the CDR-L3 comprises FQGSLVPPT (SEQ ID NO: 59). In some embodiments, the CDR-L3 comprises FQGSRVPPT (SEQ ID NO: 60).

[0083] In some embodiments, the light chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a proline at position 15, a glutamine position 17, and a glutamine at position 18; and the heavy chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a CDR-H3 having the sequence EGGYYYGRSYQTMDY (SEQ ID NO: 9). In some embodiments, the CDR-L3 comprises FQGSLVPPT (SEQ ID NO: 59). In some embodiments, the CDR-L3 comprises FQGSRVPPT (SEQ ID NO: 60).

[0084] In some embodiments, the light chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises: a CDR-L1 having the sequence RSSQSIVHSNGNTYLE (SEQ ID NO: 1), or optionally having one or two conservative substitutions relative to the sequence of SEQ ID NO: 1, a CDR-L2 having the sequence KVSNRFS (SEQ ID NO: 2), or optionally having one or two conservative substitutions relative to the sequence of SEQ ID NO: 2, a CDR-L3 having the sequence FQGSXVPPT (SEQ ID NO: 3) wherein X is L or R, or optionally having one or two conservative substitutions relative to the sequence of SEQ ID NO: 3, a valine at position 3, a threonine at position 7, a threonine at position 14, a proline or leucine at position 15, an aspartate or glutamine at position 17, a glutamine or proline at position 18, a glutamine at position 45, a lysine at position 74, a valine at position 83, a valine at position 85, a glutamine at position 100, and a valine at position 104, wherein the positions are according to Chothia / Martin numbering; wherein the light chain variable domain comprises an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 38. In some embodiments, the CDR-L3 comprises FQGSLVPPT (SEQ ID NO: 59). In some embodiments, the CDR-L3 comprises FQGSRVPPT (SEQ ID NO: 60).

[0085] In some embodiments, the light chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises: a CDR-L1 having the sequence RSSQSIVHSNGNTYLE (SEQ ID NO: 1), or optionally having one or two conservative substitutions relative to the sequence of SEQ ID NO: 1, a CDR-L2 having the sequence KVSNRFS (SEQ ID NO: 2), or optionally having one or two conservative substitutions relative to the sequence of SEQ ID NO: 2, a CDR-L3 having the sequence FQGSXVPPT (SEQ ID NO:17 LEGAL02 / 46562464v13) wherein X is L or R, or optionally having one or two conservative substitutions relative to the sequence of SEQ ID NO: 3, a valine at position 3, a threonine at position 7, a threonine at position 14, a proline or leucine at position 15, an aspartate or glutamine at position 17, a glutamine or proline at position 18, a glutamine at position 45, a lysine at position 74, a valine at position 83, a valine at position 85, a glutamine at position 100, and a valine at position 104, wherein the positions are according to Chothia / Martin numbering; wherein the light chain variable domain comprises an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 10, 11, 12, 13, 14, 15, 16, 17, 51, 52, 53, 54, 55, 56, 57, or 58. In some embodiments, the CDR-L3 comprises FQGSLVPPT (SEQ ID NO: 59). In some embodiments, the CDR-L3 comprises FQGSRVPPT (SEQ ID NO: 60).

[0086] In some embodiments, the light chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises SEQ ID NO: 38.

[0087] In some embodiments, the light chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises SEQ ID NO: 10, 11, 12, 13, 14, 15, 16, 17, 51, 52, 53, 54, 55, 56, 57, or 58.

[0088] In some embodiments, the heavy chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a CDR-H1 having the sequence SFGMH (SEQ ID NO: 4), or optionally having one or two conservative substitutions relative to the sequence of SEQ ID NO: 4, a CDR-H2 having the sequence YISSGSSTIYYGDTVKG (SEQ ID NO: 5), or optionally having one or two conservative substitutions relative to the sequence of SEQ ID NO: 5, and a CDR-H3 having the sequence EGGYYYGRSYXTMDY (SEQ ID NO: 6), or optionally having one or two conservative substitutions relative to the sequence of SEQ ID NO: 6, wherein X is tyrosine, asparagine, or glutamine; wherein the heavy chain variable domain comprises an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 26.

[0089] In some embodiments, the heavy chain variable domain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a CDR-H1 having the sequence SFGMH (SEQ ID NO: 4), or optionally having one or two conservative substitutions relative to the sequence of SEQ ID NO: 4, a CDR-H2 having the sequence YISSGSSTIYYGDTVKG (SEQ ID NO: 5), or optionally having one or two conservative substitutions relative to the sequence of SEQ ID NO: 5, and a CDR-H3 having the sequence EGGYYYGRSYXTMDY (SEQ ID NO: 6), or optionally having one or two conservative substitutions relative to the sequence of SEQ ID NO: 6, wherein X is tyrosine, asparagine, or glutamine; wherein the heavy chain variable18 LEGAL02 / 46562464v1domain comprises an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 27, 28, or 29.

[0090] In some embodiments, an anti-Aβ antibody, or antigen binding fragment thereof, having affinity for amyloid beta (Aβ), comprises a light chain variable domain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 38 and a heavy chain variable domain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 26; wherein the light chain variable domain comprises a CDR-L1 having the sequence RSSQSIVHSNGNTYLE (SEQ ID NO: 1), or optionally having one or two conservative substitutions relative to the sequence of SEQ ID NO: 1, a CDR-L2 having the sequence KVSNRFS (SEQ ID NO: 2), or optionally having one or two conservative substitutions relative to the sequence of SEQ ID NO: 2, a CDR-L3 having the sequence FQGSXVPPT (SEQ ID NO: 3) wherein X is L or R, or optionally having one or two conservative substitutions relative to the sequence of SEQ ID NO: 3, positions 3, 7, 14, 15, 17, 18, 45, 74, 83, 85, 100, and 104 (according to Chothia / Martin numbering) in the light chain are as indicated in SEQ ID NO: 38, and wherein the heavy chain variable domain comprises a CDR-H1 having the sequence SFGMH (SEQ ID NO: 4), or optionally having one or two conservative substitutions relative to the sequence of SEQ ID NO: 4, a CDR-H2 having the sequence YISSGSSTIYYGDTVKG (SEQ ID NO: 5), or optionally having one or two conservative substitutions relative to the sequence of SEQ ID NO: 5, and a CDR-H3 having the sequence EGGYYYGRSYXTMDY (SEQ ID NO: 6), or optionally having one or two conservative substitutions relative to the sequence of SEQ ID NO: 6, wherein X is tyrosine, asparagine, or glutamine. In some embodiments, the CDR-L3 comprises FQGSLVPPT (SEQ ID NO: 59). In some embodiments, the CDR-L3 comprises FQGSRVPPT (SEQ ID NO: 60).

[0091] In some embodiments, an anti-Aβ antibody, or antigen binding fragment thereof, having affinity for amyloid beta (Aβ), comprises a light chain variable domain and a heavy chain variable domain wherein: (a) the light chain variable domain comprises an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 10 or 51 and the heavy chain variable domain comprises an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 27; (b) the light chain variable domain comprises an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID19 LEGAL02 / 46562464v1NO: 10 or 51 and the heavy chain variable domain comprises an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 28; (c) the light chain variable domain comprises an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 10 or 51 and the heavy chain variable domain comprises an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 29; (d) the light chain variable domain comprises an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 11 or 52 and the heavy chain variable domain comprises an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 27; (e) the light chain variable domain comprises an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 11 or 52 and the heavy chain variable domain comprises an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 28; (f) the light chain variable domain comprises an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 11 or 52 and the heavy chain variable domain comprises an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 29; (g) the light chain variable domain comprises an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 12 or 53 and the heavy chain variable domain comprises an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 27; (h) the light chain variable domain comprises an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 12 or 53 and the heavy chain variable domain comprises an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 28;20 LEGAL02 / 46562464v1(i) the light chain variable domain comprises an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 12 or 53 and the heavy chain variable domain comprises an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 29; (j) the light chain variable domain comprises an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 13 or 54 and the heavy chain variable domain comprises an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 27; (k) the light chain variable domain comprises an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 13 or 54 and the heavy chain variable domain comprises an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 28; (l) the light chain variable domain comprises an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 13 or 54 and the heavy chain variable domain comprises an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 29; (m) the light chain variable domain comprises an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 14 or 55 and the heavy chain variable domain comprises an amino acid sequence at least 95% identical to SEQ ID NO: 27; (n) the light chain variable domain comprises an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 14 or 55 and the heavy chain variable domain comprises an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 28; (o) the light chain variable domain comprises an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 14 or 55 and the heavy chain variable domain comprises an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 29;21 LEGAL02 / 46562464v1(p) the light chain variable domain comprises an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 15 or 56 and the heavy chain variable domain comprises an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 27; (q) the light chain variable domain comprises an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 15 or 56 and the heavy chain variable domain comprises an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 28; (r) the light chain variable domain comprises an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 15 or 56 and the heavy chain variable domain comprises an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 29; (s) the light chain variable domain comprises an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 16 or 57 and the heavy chain variable domain comprises an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 27; (t) the light chain variable domain comprises an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 16 or 57 and the heavy chain variable domain comprises an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 28; (u) the light chain variable domain comprises an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 16 or 57 and the heavy chain variable domain comprises an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 29. (v) the light chain variable domain comprises an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 17 or 58 and the heavy chain variable domain comprises an amino acid sequence at least22 LEGAL02 / 46562464v190%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 27; (w) the light chain variable domain comprises an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 17 or 58 and the heavy chain variable domain comprises an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 28; or (x) the light chain variable domain comprises an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 17 or 58 and the heavy chain variable domain comprises an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 29; wherein the light chain variable domain comprises CDR-L1, CDR L2, and CDR3 sequences as present in SEQ ID NO: 38, positions 3, 7, 14, 15, 17, 18, 45, 74, 83, 85, 100, and 104 (according to Chothia / Martin numbering) in the light chain are as indicated in SEQ ID NO: 38, and wherein the heavy chain variable domain comprises CDR-H1, CDR-H2, and CDR-H3 sequences as present in SEQ ID NO: 26.

[0092] In some embodiments, the anti-Aβ antibody, or antigen binding fragment thereof, comprises a Fab, a Fab′, a F(ab′)2, a scFab, a Fv, or a scFv. In some embodiments, the anti-Aβ antigen binding fragment comprises a scFv. In some embodiments, the anti-Aβ antigen binding fragment comprises a Fab.

[0093] In some embodiments, the light chain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises: a CDR-L1 having the sequence RSSQSIVHSNGNTYLE (SEQ ID NO: 1), or optionally having one or two conservative substitutions relative to the sequence of SEQ ID NO: 1, a CDR-L2 having the sequence KVSNRFS (SEQ ID NO: 2), or optionally having one or two conservative substitutions relative to the sequence of SEQ ID NO: 2, a CDR- L3 having the sequence FQGSXVPPT (SEQ ID NO: 3) wherein X is L or R, or optionally having one or two conservative substitutions relative to the sequence of SEQ ID NO: 3, a valine at position 3, a threonine at position 7, a threonine at position 14, a proline or leucine at position 15, an aspartate or glutamine at position 17, a glutamine or proline at position 18, a glutamine at position 45, a lysine at position 74, a valine at position 83, a valine at position 85, a glutamine at position 100, and a valine at position 104, wherein the positions are according to Chothia / Martin numbering; wherein the light chain comprises an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to23 LEGAL02 / 46562464v1SEQ ID NO: 39, 61, or 62. In some embodiments, the CDR-L3 comprises FQGSLVPPT (SEQ ID NO: 59). In some embodiments, the CDR-L3 comprises FQGSRVPPT (SEQ ID NO: 60).

[0094] In some embodiments, the light chain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises: a CDR-L1 having the sequence RSSQSIVHSNGNTYLE (SEQ ID NO: 1), or optionally having one or two conservative substitutions relative to the sequence of SEQ ID NO: 1, a CDR-L2 having the sequence KVSNRFS (SEQ ID NO: 2), or optionally having one or two conservative substitutions relative to the sequence of SEQ ID NO: 2, a CDR- L3 having the sequence FQGSXVPPT (SEQ ID NO: 3) wherein X is L or R, or optionally having one or two conservative substitutions relative to the sequence of SEQ ID NO: 3, a valine at position 3, a threonine at position 7, a threonine at position 14, a proline or leucine at position 15, an aspartate or glutamine at position 17, a glutamine or proline at position 18, a glutamine at position 45, a lysine at position 74, a valine at position 83, a valine at position 85, a glutamine at position 100, and a valine at position 104, wherein the positions are according to Chothia / Martin numbering; wherein the light chain variable domain comprises an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 18, 19, 20, 21, 22, 23, 24, 25, 63, 64, 65, 66, 67, 68, 69, or 70. In some embodiments, the CDR-L3 comprises FQGSLVPPT (SEQ ID NO: 59). In some embodiments, the CDR-L3 comprises FQGSRVPPT (SEQ ID NO: 60).

[0095] In some embodiments, the light chain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises SEQ ID NO: 39, 61, or 62.

[0096] In some embodiments, the light chain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises SEQ ID NO: 18, 19, 20, 21, 22, 23, 24, 25, 63, 64, 65, 66, 67, 68, 69, or 70.

[0097] In some embodiments, the Fab heavy chain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a CDR-H1 having the sequence SFGMH (SEQ ID NO: 4), or optionally having one or two conservative substitutions relative to the sequence of SEQ ID NO: 4, a CDR-H2 having the sequence YISSGSSTIYYGDTVKG (SEQ ID NO: 5), or optionally having one or two conservative substitutions relative to the sequence of SEQ ID NO: 5, and a CDR-H3 having the sequence EGGYYYGRSYXTMDY (SEQ ID NO: 6), or optionally having one or two conservative substitutions relative to the sequence of SEQ ID NO: 6, wherein X is tyrosine, asparagine, or glutamine; wherein the heavy chain variable domain comprises an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 30.24 LEGAL02 / 46562464v1

[0098] In some embodiments, a Fab heavy chain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises a CDR-H1 having the sequence SFGMH (SEQ ID NO: 4), or optionally having one or two conservative substitutions relative to the sequence of SEQ ID NO: 4, a CDR-H2 having the sequence YISSGSSTIYYGDTVKG (SEQ ID NO: 5), or optionally having one or two conservative substitutions relative to the sequence of SEQ ID NO: 5, and a CDR-H3 having the sequence EGGYYYGRSYXTMDY (SEQ ID NO: 6), or optionally having one or two conservative substitutions relative to the sequence of SEQ ID NO: 6, wherein X is tyrosine, asparagine, or glutamine; wherein the heavy chain variable domain comprises an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 31, 32, or 33.

[0099] In some embodiments, a Fab heavy chain of the anti-Aβ antibody, or the antigen binding fragment thereof, comprises SEQ ID NO: 30, 31, 32, or 33.

[0100] In some embodiments, an anti-Aβ antibody, or antigen binding fragment thereof, having affinity for amyloid beta (Aβ), comprises a light chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 39, 61, or 62 and a heavy chain Fab comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 30; wherein the light chain variable domain comprises a CDR- L1 having the sequence RSSQSIVHSNGNTYLE (SEQ ID NO: 1), or optionally having one or two conservative substitutions relative to the sequence of SEQ ID NO: 1, a CDR-L2 having the sequence KVSNRFS (SEQ ID NO: 2), or optionally having one or two conservative substitutions relative to the sequence of SEQ ID NO: 2, a CDR-L3 having the sequence FQGSXVPPT (SEQ ID NO: 3) wherein X is L or R, or optionally having one or two conservative substitutions relative to the sequence of SEQ ID NO: 3, positions 3, 7, 14, 15, 17, 18, 45, 74, 83, 85, 100, and 104 (according to Chothia / Martin numbering) in the light chain are as indicated in SEQ ID NO: 39, 61, or 62, and wherein the heavy chain variable domain comprises a CDR-H1 having the sequence SFGMH (SEQ ID NO: 4), or optionally having one or two conservative substitutions relative to the sequence of SEQ ID NO: 4, a CDR-H2 having the sequence YISSGSSTIYYGDTVKG (SEQ ID NO: 5), or optionally having one or two conservative substitutions relative to the sequence of SEQ ID NO: 5, and a CDR-H3 having the sequence EGGYYYGRSYXTMDY (SEQ ID NO: 6), or optionally having one or two conservative substitutions relative to the sequence of SEQ ID NO: 6, wherein X is tyrosine, asparagine, or glutamine. In some embodiments, the CDR-L3 comprises FQGSLVPPT (SEQ ID NO: 59). In some embodiments, the CDR-L3 comprises FQGSRVPPT (SEQ ID NO: 60).25 LEGAL02 / 46562464v1

[0101] In some embodiments, the anti-Aβ antibody, or the antigen binding fragment thereof, comprises: (a) a light chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 18 or 63, and a Fab heavy chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 31; (b) a light chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 18 or 63, and a Fab heavy chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 32; (c) a light chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 18 or 63, and a Fab heavy chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 33; (d) a light chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 19 or 64, and a Fab heavy chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 31; (e) a light chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 19 or 64, and a Fab heavy chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 32; (f) a light chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 19 or 64, and a Fab heavy chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 33; (g) a light chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 20 or 65, and a Fab heavy chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 31; (h) a light chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 20 or 65, and a Fab heavy chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 32;26 LEGAL02 / 46562464v1(i) a light chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 20 or 65, and a Fab heavy chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 33; (j) a light chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 21 or 66, and a Fab heavy chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 31; (k) a light chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 21 or 66, and a Fab heavy chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 32; (l) a light chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 21 or 66, and a Fab heavy chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 33; (m) a light chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 22 or 67, and a Fab heavy chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 31; (n) a light chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 22 or 67, and a Fab heavy chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 32; (o) a light chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 22 or 67, and a Fab heavy chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 33; (p) a light chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 23 or 68, and a Fab heavy chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 31; (q) a light chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 23 or 68, and27 LEGAL02 / 46562464v1a Fab heavy chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 32; (r) a light chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 23 or 68, and a Fab heavy chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 33; (s) a light chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 24 or 69, and a Fab heavy chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 31; (t) a light chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 24 or 69, and a Fab heavy chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 32; (u) a light chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 24 or 69, and a Fab heavy chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 33; (v) a light chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 25 or 70, and a Fab heavy chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 31; (w) a light chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 25 or 70, and a Fab heavy chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 32; or (x) a light chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 25 or 70, and a Fab heavy chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 33; wherein the light chain comprises CDR-L1, CDR L2, and CDR3 sequences as present in SEQ ID NO: 39, 61, or 62, positions 3, 7, 14, 15, 17, 18, 45, 74, 83, 85, 100, and 104 (according to Chothia / Martin numbering) in the light chain are as indicated in SEQ ID NO: 39,28 LEGAL02 / 46562464v161, or 62, and wherein the heavy chain variable domain comprises CDR-H1, CDR-H2, and CDR-H3 sequences as present in SEQ ID NO: 30.

[0102] In some embodiments, the anti-Aβ antibody, or antigen binding fragment thereof, comprises an immunoglobulin. The immunoglobulin can be, but is not limited to, an IgG isotype, an IgE isotype, an IgA isotype, an IgD isotype, or an IgM isotype. The IgG immunoglobulin can, but is not limited to, an IgG1or an IgG4.

[0103] In some embodiments, the anti-Aβ antibody, comprises: a light chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 39, 61, or 62, and a heavy chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 34 or 47; wherein the light chain comprises a CDR-L1 having the sequence RSSQSIVHSNGNTYLE (SEQ ID NO: 1), or optionally having one or two conservative substitutions relative to the sequence of SEQ ID NO: 1, a CDR-L2 having the sequence KVSNRFS (SEQ ID NO: 2), or optionally having one or two conservative substitutions relative to the sequence of SEQ ID NO: 2, a CDR-L3 having the sequence FQGSXVPPT (SEQ ID NO: 3) wherein X is L or R, or optionally having one or two conservative substitutions relative to the sequence of SEQ ID NO: 3, positions 3, 7, 14, 15, 17, 18, 45, 74, 83, 85, 100, and 104 (according to Chothia / Martin numbering) in the light chain are as indicated in SEQ ID NO: 39, 61, or 62, and wherein the heavy chain comprises a CDR-H1 having the sequence SFGMH (SEQ ID NO: 4), or optionally having one or two conservative substitutions relative to the sequence of SEQ ID NO: 4, a CDR-H2 having the sequence YISSGSSTIYYGDTVKG (SEQ ID NO: 5), or optionally having one or two conservative substitutions relative to the sequence of SEQ ID NO: 5, and a CDR-H3 having the sequence EGGYYYGRSYXTMDY (SEQ ID NO: 6), or optionally having one or two conservative substitutions relative to the sequence of SEQ ID NO: 6, wherein X is tyrosine, asparagine, or glutamine. In some embodiments, the CDR-L3 comprises FQGSLVPPT (SEQ ID NO: 59). In some embodiments, the CDR-L3 comprises FQGSRVPPT (SEQ ID NO: 60).

[0104] In some embodiments, an anti-Aβ antibody, comprises: (a) a light chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 18 or 63, and a Fab heavy chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 35 or 48;29 LEGAL02 / 46562464v1(b) a light chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 18 or 63, and a Fab heavy chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 36 or 49; (c) a light chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 18 or 63, and a Fab heavy chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 37 or 50; (d) a light chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 19 or 64, and a Fab heavy chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 35 or 48; (e) a light chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 19 or 64, and a Fab heavy chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 36 or 49; (f) a light chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 19 or 64, and a Fab heavy chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 37 or 50; (g) a light chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 20 or 65, and a Fab heavy chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 35 or 48; (h) a light chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 20 or 65, and a Fab heavy chain comprising an amino acid sequence at least 90%, at least 95%, at30 LEGAL02 / 46562464v1least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 36 or 49; (i) a light chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 20 or 65, and a Fab heavy chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 37 or 50; (j) a light chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 21 or 66, and a Fab heavy chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 35 or 48; (k) a light chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 21 or 66, and a Fab heavy chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 36 or 49; (l) a light chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 21 or 66, and a Fab heavy chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 37 or 50; (m) a light chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 22 or 67, and a Fab heavy chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 35 or 48; (n) a light chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 22 or 67, and a Fab heavy chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 36 or 49; (o) a light chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 22 or31 LEGAL02 / 46562464v167, and a Fab heavy chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 37 or 50; (p) a light chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 23 or 68, and a Fab heavy chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 35 or 48; (q) a light chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 23 or 68, and a Fab heavy chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 36 or 49; (r) a light chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 23 or 68, and a Fab heavy chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 37 or 50; (s) a light chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 24 or 69, and a Fab heavy chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 35 or 48; (t) a light chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 24 or 69, and a Fab heavy chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 36 or 49; (u) a light chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 24 or 69, and a Fab heavy chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 37 or 50;32 LEGAL02 / 46562464v1(v) a light chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 25 or 70, and a Fab heavy chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 35 or 48; (w) a light chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 25 or 70, and a Fab heavy chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 36 or 49; or (x) a light chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 25 or 70, and a Fab heavy chain comprising an amino acid sequence at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 37 or 50; wherein the light chain comprises CDR-L1, CDR L2, and CDR3 sequences as present in SEQ ID NO: 39, 61, or 62, positions 3, 7, 14, 15, 17, 18, 45, 74, 83, 85, 100, and 104 (according to Chothia / Martin numbering) in the light chain are as indicated in SEQ ID NO: 39, 61, or 62, and wherein the heavy chain variable domain comprises CDR-H1, CDR-H2, and CDR-H3 sequences as present in SEQ ID NO: 34 or 47.

[0105] In some embodiments, the described anti-Aβ antibodies, or antigen binding fragments thereof, have increased affinity for Aβ and improved pharmacokinetic properties relative to Ab158 and lecanemab (US8858949 and US9573994).

[0106] In some embodiments, the described anti-Aβ antibodies have improved pharmacokinetics (PK) relative to known anti-Aβ antibodies (e.g., lecanemab). In some embodiments, the described anti-Aβ antibodies have increase circulation time or decreased plasma clearance relative to known anti-Aβ antibodies (e.g., lecanemab). PK can be measured as described in Example 1 below.

[0107] In some embodiments, the described anti-Aβ antibodies have improved affinity for Aβ relative to known anti-Aβ antibodies (e.g., lecanemab). Affinity for Aβ can be measured, for example by surface plasmon resonance (SPR) using a Biacore 8K instrument (See Example 1).

[0108] In some embodiments, the described anti-Aβ antibodies have improved affinity for variant forms of Aβ (variant Aβ species). In some embodiments, the described anti-Aβ33 LEGAL02 / 46562464v1antibodies exhibit improved engagement of variant Aβ species. Variant Aβ species include, but are not limited to, monomeric Aβ, soluble Aβ, Aβ oligomer, plaque form Aβ, Aβ protofibril, Aβ fibrils (amyloid fibrils), Aβ40, Aβ42 (Aβ1-42), AβE3-40, AβpE3-42, non-metal-dependent Aβ aggregates, and metal-dependent Aβ aggregates.

[0109] In some embodiments, the described anti-Aβ antibodies exhibit reduced immunogenicity risks relative to known anti-Aβ antibodies (e.g., lecanemab). Immunogenicity may be evaluated according to known methods, e.g., Pineda et al. (BioDrugs. 2016; 30: 195– 206).

[0110] Any of the described anti-Aβ antibodies, or an antigen binding fragment thereof, can comprise one or more modifications known in the art to increase serum stability, modulate effector function, influence glycosylation, reduce immunogenicity in humans, facilitate heterodimerization (e.g., knob and hole mutations), or facilitate attachment of a molecule (such as, but not limited to, a therapeutic agent).

[0111] Exemplary antibody modifications known in the art to increase serum stability include: a M428L substitution; a N434S substitution; a M428L substitution and a N434S substitution; a N434A substitution; or a M252Y substitution, a S254T substitution, and a T256E substitution.

[0112] Exemplary antibody modifications known in the art to modulate effector function include: a K322A substitution, a L234A substitution and a L235A substitution (LALA substitution); a P329G substitution; a L234A substitution, a L235A substitution, a P329G substitution (LALA-PG substitution), or a L234A substitution, a L235A substitution, a P329S substitution (LALA-PS substitution) (according to EU numbering scheme). In some embodiments, the anti-Aβ antibody comprises a K322A substitution. In some embodiments, the anti-Aβ antibody comprises a LALA substitution. In some embodiments, the anti-Aβ antibody comprises a LALA-PG substitution. . In some embodiments, the anti-Aβ antibody comprises a LALA-PS substitution. In some embodiments, the anti-Aβ antibody comprises a K322A substitution and a LALA substitution. In some embodiments, the anti-Aβ antibody comprises a K322A substitution and a LALA-PG substitution. In some embodiments, the anti- Aβ antibody comprises a K322A substitution and a LALA-PS substitution. In some embodiments, the K322A substitution decreases or eliminates C1 binding.

[0113] An exemplary knob mutation known in the art includes: a T366W substitution (according to EU numbering scheme). Exemplary hole mutations known in the art include: T366S, L368A, and Y407V substitutions (according to EU numbering scheme). Exemplary34 LEGAL02 / 46562464v1antibody modifications known in the art to facilitate attachment of a molecule include: cysteine substitutions.

[0114] Exemplary antibody modifications that facilitate attachment of a molecule include various cysteine substitutions, wherein one or more amino acids in a constant domain of an antibody are mutated to a cysteine residue. Cysteine substitutions include, but are not limited to, S124C, S239C, S442C, A330C, and T289C (EU numbering) and A114C (Kabat numbering) in the heavy chain and K149C, K156C, S165C, and S168C (Kabat numbering), in the light chain.

[0115] In some embodiments, an anti-Aβ antibody or antigen binding fragment thereof—as described herein—may comprise one or more functionally inconsequential amino acid substitutions, deletions, or insertions.

[0116] In some embodiments, an anti-Aβ antibody or antigen binding fragment thereof—as described herein—may comprise one or more conservative substitutions. Conservative substitutions include substituting a specified amino acid at a given location for another amino acid in the same charge grouping, hydrophobicity grouping, side chain ring structure grouping (e.g., aromatic amino acids), size grouping, and / or polar or non-polar grouping. In some embodiments, conservative substitutions can involve the exchange of a member of one of these classes for another member of the same class. In some embodiments, conservative substitutions can involve the exchange of a member of one of these classes for another member of the same subclass (as indicated below).

[0117] The term “conservative substitution” or “conservative mutation” refers to an alteration that results in the substitution of an amino acid with another amino acid that can be categorized as having a similar feature. Examples of categories of conservative amino acid groups defined in this manner can include: (a) a “charged / polar group” including Glu (Glutamic acid or E), Asp (Aspartic acid or D), Asn (Asparagine or N), Gln (Glutamine or Q), Lys (Lysine or K), Arg (Arginine or R), His (Histidine or H), Ser (Serine or S), Thr (Threonine or T) and optionally Cys (Cysteine or C); (b) an “aromatic or cyclic group” including Phe (Phenylalanine or F), Tyr (Tyrosine or Y), Trp (Tryptophan or W), Pro (Proline or P), and (Histidine or H); (c) an “aliphatic group” including Gly (Glycine or G), Ala (Alanine or A), Val (Valine or V), Leu (Leucine or L), Ile (Isoleucine or I), Met (Methionine or M), Ser (Serine or S), Thr (Threonine or T), and Cys (Cysteine or C), and (d) a “non-polar (hydrophobic) group” including Gly (glycine or G), Ala (alanine or A), Val (valine or V), Leu (leucine or L), Ile (isoleucine or I), Phe (phenylalanine or F), Met (methionine or M), Tyr (Tyrosine or Y), and Trp (tryptophan or W). Within each group, subgroups can also be identified. For example, the group of charged35 LEGAL02 / 46562464v1or polar amino acids can be sub-divided into subgroups including: a “positively-charged subgroup” comprising Lys, Arg, and His; a “negatively-charged subgroup” comprising Glu and Asp; and a “polar subgroup” comprising Asn and Gln. The aromatic or cyclic group can be subdivided into subgroups including: a “nitrogen ring subgroup” comprising Pro, His, and Trp; and a “phenyl or aromatic subgroup” comprising Phe, Trp, and Tyr. In another example, the aliphatic group can be subdivided into subgroups, e.g., an “aliphatic non-polar subgroup” comprising Val, Leu, Gly, and Ala; and an “aliphatic slightly-polar subgroup” comprising Met, Ser, Thr, and Cys. Examples of categories of conservative mutations include amino acid substitutions of amino acids within the subgroups above, such as, but not limited to: Lys for Arg or vice versa, such that a positive charge can be maintained; Glu for Asp or vice versa, such that a negative charge can be maintained; Ser for Thr or vice versa, such that a free −OH can be maintained; and Gln for Asn or vice versa, such that a free −NH2can be maintained. In some embodiments, conservative substitutions can involve the exchange of an amino acid of one group of subgroup for another amino acid of the same group or subgroup. Additions subgroups include: Subgroup I (hydrophobic side chains): Met, Ala, Val, Leu, Ile; Subgroup II (neutral hydrophilic side chains): Cys, Ser, Thr; Subgroup III (acidic side chains): Asp, Glu; Subgroup IV (basic side chains): Asn, Gln, His, Lys, Arg; Subgroup V (residues influencing chain orientation): Gly, Pro; and Subgroup VI (aromatic side chains): Trp, Tyr, Phe.

[0118] An anti-Aβ antibody, or antigen binding fragment thereof, as described herein, can be, but is not limited to, a monospecific antibody, a bispecific antibody, a F(ab′)2, a bispecific F(ab′)2, a Fab, a single chain Fab (scFab), a Fv fragment, or a single chain variable fragment (scFv).

[0119] Any of the described anti-Aβ antibodies, or antigen binding fragments thereof, can be formed as a multispecific anti-Aβ antibody (e.g., a bispecific antibody or a trispecific antibody), wherein the antibody comprises at least one Aβ binding fragment as described herein and at least one second antigen binding fragment having affinity for a second target protein or antigen. As used herein, a multispecific anti-Aβ antibody includes bispecific immunoglobulins as well and molecules having a first anti-Aβ antibody antigen binding fragment and a second antigen binding fragment having affinity for a second target protein or antigen.

[0120] In some embodiments, a multispecific anti-Aβ antibody comprises an anti-Aβ immunoglobulin linked to a second antigen binding fragment having affinity for a second target36 LEGAL02 / 46562464v1protein or antigen. The second antigen binding fragment can be, but is not limited to, an antibody, a F(ab′)2, a Fab, a scFab, a Fv fragment, or a scFv.

[0121] In some embodiments, a multispecific anti-Aβ antibody comprises or consists of a bispecific immunoglobulin having an anti-Aβ Fab arm and a second Fab arm having affinity for a second target protein or antigen. The bispecific immunoglobulin can be, but is not limited to, an IgG, an IgM, an IgA, an IgD, or an IgE. The IgG can be, but is not limited to, an IgG2, and an IgG4.

[0122] In some embodiments, a multispecific anti-Aβ antibody comprises a F(ab′)2or bispecific F(ab′)2. A multispecific anti-Aβ antibody can comprise an anti-Aβ F(ab′)2 linked to a second antigen binding fragment having affinity for a second target protein or antigen. The second antigen binding fragment can be, but is not limited to, an antibody, a F(ab′)2, a Fab, a scFab, a Fv fragment, or a scFv.

[0123] In some embodiments, a multispecific anti-Aβ antibody comprises an anti-Aβ Fab linked to a second antigen binding fragment having affinity for a second target protein or antigen. The second antigen binding fragment can be, but is not limited to, an antibody, a F(ab′)2, a Fab, a scFab, a Fv fragment, or a scFv.

[0124] In some embodiments, a multispecific anti-Aβ antibody comprises an anti-Aβ scFab linked to a second antigen binding fragment having affinity for a second target protein or antigen. The second antigen binding fragment can be, but is not limited to, an antibody, a F(ab′)2, a Fab, a scFab, a Fv fragment, or a scFv.

[0125] In some embodiments, a multispecific anti-Aβ antibody comprises an anti-Aβ Fv fragment linked to a second antigen binding fragment having affinity for a second target protein or antigen. The second antigen binding fragment can be, but is not limited to, an antibody, a F(ab′)2, a Fab, a scFab, a Fv fragment, or a scFv.

[0126] In some embodiments, a multispecific anti-Aβ antibody comprises an anti-Aβ scFv linked to a second antigen binding fragment having affinity for a second target protein or antigen. The second antigen binding fragment can be, but is not limited to, an antibody, a F(ab′)2, a Fab, a scFab, a Fv fragment, or a scFv.

[0127] Any of the described anti-Aβ antibodies, multispecific anti-Aβ antibodies, F(ab′)2s, bispecific F(ab′)2s, Fabs, scFabs, Fv fragments, or scFvs can be linked to one or more of: a polypeptide, non-polypeptide scaffold or carrier, a targeting ligand, and a drug (e.g., a second pharmaceutical compound). The polypeptide can be, but is not limited to, an antibody, and antibody fragment, a protein, or a polypeptide scaffold. The antibody fragment can be, but is not limited to, an Fc polypeptide dimer or a Fc polypeptide. An anti-Aβ antibody, multispecific37 LEGAL02 / 46562464v1anti-Aβ antibody, F(ab′)2, bispecific F(ab′)2, Fab, scFab, Fv fragment, or scFv linked to a polypeptide can be provided as a fusion protein. III. NUCLEIC ACIDS, VECTORS, HOST CELLS, and METHODS OF MANUFACTURE

[0128] The anti-Aβ antibodies, or antigen binding fragments thereof, as described herein can be prepared using recombinant methods. Accordingly, isolated nucleic acids comprising sequences encoding any of the anti-Aβ antibodies, or antigen binding fragments thereof described herein or portions thereof are readily generated using methods available in the art. Host cells into which the nucleic acids are introduced and that can be used to replicate the polypeptide-encoding nucleic acids and / or to express the polypeptides are also available in the art. A host cell can be, but is not limited to, a prokaryotic cell or a eukaryotic. The eukaryotic cell be, but is not limited to, a yeast cell, an insect cell, or a mammalian cell (e.g., a human cell).

[0129] A nucleic acid(s) encoding an anti-Aβ antibody, or an antigen binding fragment thereof, can be DNA, RNA, cDNA, mRNA, single-stranded, double-stranded, linear, or circular.

[0130] An anti-Aβ antibody, or an antigen binding fragment thereof, may comprise two or more polypeptides (e.g., a light chain polypeptide and a heavy chain polypeptide), each of which may be encoded by a separate nucleic sequence. The separate nucleic acid sequences may be present on the same plasmid or vector or different plasmids or vectors. If present on the same plasmid or vector, the separate nucleic acid sequences may be expressed from a single promoter or from different promoters. Method of expressing nucleic acids encoding separate polypeptides from a single promoter are known in the art and include, but are not limited to, the use of 2A elements and internal ribosome entry sites.

[0131] A nucleic acid encoding an anti-Aβ antibody, or an antigen binding fragment thereof, can be provided in a plasmid or vector. The plasmid or vector can be used to replicate the nucleic acid or facilitate expression of the nuclei acid. A plasmid or vector can be, but is not limited to, a viral vector, a phagemid, a yeast chromosomal vector, or a non-episomal mammalian vector.

[0132] In some embodiments, the nucleic acid(s) encoding an anti-Aβ antibody, or an antigen binding fragment thereof, is(are) operably linked to one or more regulatory sequences in one or more expression constructs. The expression constructs can be adapted for expression of the polypeptide(s) in a system that produces the anti-Aβ antibody, or the antigen binding fragment thereof. Such a system can be, but is not limited to, a mammalian cell expression system, an38 LEGAL02 / 46562464v1insect cell expression system, a yeast cell expression system, or a bacterial cell expression system.

[0133] Expression vehicles for production of a recombinant polypeptide include plasmids and other vectors. For instance, suitable vectors include plasmids of the following types: pBR322-derived plasmids, pEMBL-derived plasmids, pEX-derived plasmids, pBTac-derived plasmids, and pETC-derived plasmids for expression in prokaryotic cells, such as E. coli. The pcDNAI / amp, pcDNAEneo, pRc / CMV, pSV2gpt, pSV2neo, pSV2-dhfr, pTk2, pRSVneo, pMSG, pSVT7, pko-neo, and pHyg-derived vectors are examples of mammalian expression vectors suitable for transfection of eukaryotic cells. Alternatively, derivatives of viruses such as the bovine papilloma virus (BPV-l), or Epstein-Barr virus (pHEBo, pREP-derived, and p205) can be used for transient expression of polypeptides in eukaryotic cells. In some embodiments, it may be desirable to express the recombinant polypeptide by the use of a baculovirus expression system. Examples of such baculovirus expression systems include pVL-derived vectors (such as pVLl392, pVLl393, and pVL94l), pAcUW-derived vectors (such as pAcUWl), and pBlueBac-derived vectors. Additional expression systems include adenoviral, adeno-associated virus, and other viral expression systems.

[0134] An expression vector for expressing an anti-Aβ antibody, or an antigen binding fragment thereof, or a portion thereof, or a plasmid or vector containing the nucleic acid can be transformed, transfected, or transduced into a host cell. The host cell can be, but is not limited to, a mammalian cell, a yeast cell, an insect cell, prokaryotic cell, Chinese hamster ovary (CHO) cell, a baby hamster kidney (BHK) cell, a NSO cell, a YO cell, a HEK293 cell, a COS cell, a Vero cell, or a HeLa cell. The host cell containing the expression vector or expression vectors can be cultured under appropriate conditions to allow expression of the anti- Aβ antibody, or the antigen binding fragment thereof.

[0135] An anti-Aβ antibody, or an antigen binding fragment thereof, can be manufactured by culturing a host cell comprising one or more nucleic acids encoding the anti-Aβ antibody, or the antigen binding fragment thereof, expressing the anti-Aβ antibody, or the antigen binding fragment thereof, and isolating the expressed anti-Aβ antibody, or the antigen binding fragment thereof, from the culture, using methods available in the art for producing proteins from host cells. The host cell can be a bacterial cell, a eukaryotic cell, an insect cell, or a mammalian cell. IV. FORMULATIONS

[0136] Any of the described anti-Aβ antibodies, or antigen binding fragments thereof, can be prepared, provided, or formulated as a salt, mixed salt, or a free acid. Suitable pharmaceutically39 LEGAL02 / 46562464v1acceptable salts include, but are not limited to, sodium, potassium, calcium, and magnesium salts.

[0137] Any of the described anti-Aβ antibodies, or antigen binding fragments thereof, can be provided in or formulated in a pharmaceutical composition. A pharmaceutical composition or medicament includes a pharmaceutically effective amount of at least one of the described anti- Aβ antibodies, or antigen binding fragments thereof, and optionally one or more pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients (excipients) are substances other than the Active Pharmaceutical ingredient (API, therapeutic product (e.g., an anti-Aβ antibody, or an antigen binding fragment thereof)) that are intentionally included in the pharmaceutical composition. Excipients do not exert or are not intended to exert a therapeutic effect at the intended dosage. Excipients may act to (a) aid in processing of the API during manufacture, (b) protect, support, or enhance stability, bioavailability, or patient acceptability of the API, (c) assist in product identification, and / or (d) enhance any other attribute of the overall safety, effectiveness, or delivery of the API during storage or use. A pharmaceutically acceptable excipient may or may not be an inert substance.

[0138] Excipients include, but are not limited to: absorption enhancers, anti-adherents, anti- foaming agents, anti-oxidants, binders, buffering agents, carriers, coating agents, colors, delivery enhancers, delivery polymers, dextran, dextrose, diluents, disintegrants, emulsifiers, extenders, fillers, flavors, glidants, humectants, lubricants, oils, polymers, preservatives, saline, salts, solvents, sugars, suspending agents, sustained release matrices, sweeteners, thickening agents, tonicity agents, vehicles, water-repelling agents, and wetting agents.

[0139] The carrier can be, but is not limited to, a solvent or dispersion medium containing, for example, water, saline, phosphate buffered saline, Ringer’s solution, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. A carrier may also contain adjuvants or additives such as preservatives, wetting agents, emulsifying agents, and dispersing agents. A carrier may also contain isotonic agents, such as sugars, polyalcohols, sodium chloride, and the like.

[0140] The pharmaceutical compositions can contain other additional components commonly found in pharmaceutical compositions. Such additional components can include, but are not limited to, anti-pruritics, astringents, local anesthetics, or anti-inflammatory agents (e.g., antihistamine, diphenhydramine, etc.).

[0141] Pharmaceutically acceptable refers to those properties and / or substances which are acceptable to the subject from a pharmacological / toxicological point of view. The phrase pharmaceutically acceptable refers to molecular entities, compositions, and properties that are40 LEGAL02 / 46562464v1physiologically tolerable and do not typically produce an allergic or other untoward or toxic reaction when administered to a subject. In some embodiments, a pharmaceutically acceptable compound is approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals and more particularly in humans.

[0142] In some embodiments, the pharmaceutical compositions further comprise one or more additional active ingredients. The additional active pharmaceutical ingredient can be, but is not limited to, a small molecule drug.

[0143] An anti-Aβ antibody, or an antigen binding fragment thereof, or pharmaceutical composition containing the anti-Aβ antibody, or the antigen binding fragment thereof, can be formulated as a liquid formulation or as a solid formulation (including a powder or lyophilized formulation; e.g., a lyophilized cake or powder).

[0144] In some embodiments, the pharmaceutical compositions described herein can be formulated for administration to a subject.

[0145] As disclosed above, an anti-Aβ antibody, or an antigen binding fragment thereof, or pharmaceutical composition containing the anti-Aβ antibody, or the antigen binding fragment thereof, can be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. For injection, the anti-Aβ antibody, or the antigen binding fragment thereof, can be formulated into preparations by dissolving, suspending, or emulsifying them in an aqueous or nonaqueous solvent, such as vegetable or other similar oils, synthetic aliphatic acid glycerides, esters of higher aliphatic acids or propylene glycol; and if desired, with conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers, and preservatives. In some embodiments, polypeptides can be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer. Formulations for injection can be presented in unit dosage form, e.g., in ampules or in multi-dose containers, with an added preservative. The compositions can take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing, and / or dispersing agents.

[0146] Typically, a pharmaceutical composition for use in in vivo administration is sterile. Sterilization can be accomplished according to methods known in the art, e.g., heat sterilization, steam sterilization, sterile filtration, or irradiation.41 LEGAL02 / 46562464v1

[0147] Dosages and desired drug concentration of pharmaceutical compositions of the invention may vary depending on the particular use envisioned. The determination of the appropriate dosage or route of administration is well within the skill of one in the art.

[0148] In some embodiments, the anti-Aβ antibody, or the antigen binding fragment thereof, is formulated with one or more additional therapeutic agents.

[0149] In some embodiments, the anti-Aβ antibody, or the antigen binding fragment thereof, is linked to one or more additional therapeutic agents. The anti-Aβ antibodies, or antigen binding fragments thereof can be linked, directly or indirectly, to a therapeutic agent to form an antibody-drug conjugate (ADC). The therapeutic agent can be, but is not limited to, a drug, a cytotoxic agent, a DNA or RNA molecule, or a chemical moiety.

[0150] In some embodiments, an anti-Aβ antibody, or an antigen binding fragment thereof, or a pharmaceutical composition containing the anti-Aβ antibody, or the antigen binding fragment thereof, is formulated for subcutaneous administration, intravascular (e.g., intravenous) administration, intrathecal administration, intracerebroventricular administration, intraperitoneal administration, transdermal administration, intradermal administration, or intranasal administration. In some embodiments, an anti-Aβ antibody, or an antigen binding fragment thereof, or a pharmaceutical composition containing the anti-Aβ antibody, or the antigen binding fragment thereof, is formulated for administration by an auto-injector. An auto- injector can be, but is not limited to, a prefilled, single-dose, auto-injector. V. KITS

[0151] In some embodiments, kits comprising an anti-Aβ antibody, or an antigen binding fragment thereof, as described herein are provided. In some embodiments, the kits are for use in preventing or treating a neurological disorder condition of the central nervous system (CNS).

[0152] The described anti-Aβ antibodies, or antigen binding fragments thereof and pharmaceutical compositions comprising anti-Aβ antibodies, or antigen binding fragments thereof disclosed herein may be packaged or included in a kit, container, pack, or dispenser. The anti-Aβ antibodies, or antigen binding fragments thereof and pharmaceutical compositions comprising the anti-Aβ antibodies, or antigen binding fragments thereof may be packaged in pre-filled syringes or vials. Any of the anti-Aβ antibodies, or antigen binding fragments thereof or pharmaceutical compositions containing anti-Aβ antibodies, or antigen binding fragments thereof described herein can be formulated or packaged in single-dose or multi-dose format. Any of the anti-Aβ antibodies, or antigen binding fragments thereof or pharmaceutical42 LEGAL02 / 46562464v1compositions containing the anti-Aβ antibodies, or antigen binding fragments thereof described identified herein can be formulated for repeat dosing.

[0153] In some embodiments, the kit further comprises one or more additional therapeutic agents. For example, in some embodiments, the kit comprises an anti-Aβ antibody, or an antigen binding fragment thereof, as described herein and further comprises one or more additional therapeutic agents for use in the treatment of a neurological disorder or condition of the CNS.

[0154] The kit or package may further contain instructions for use. Instructions include documents describing relevant materials or methodologies pertaining to the kit. The instructions may include one or more of: background information, list of components and their availability information (purchase information, etc.), brief or detailed protocols for using the kit, trouble-shooting guidance, references, technical support, indications, usage, dosage, administration, contraindications, and / or warnings concerning the use of the drug, and any other related documents. Instructions can be supplied with the kit or as a separate member component, either as a paper form or an electronic form. The instructions may include a notice in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration. VI. THERAPEUTIC METHODS

[0155] The terms “treat,” “treatment,” and the like, mean the methods or steps taken to provide relief from, or amelioration or alleviation of the number, severity, adverse effect, and / or frequency of one or more symptoms or pathological consequences of a disease, disorder, or condition in a subject. Treatment can be prophylactic in terms of preventing or partially preventing a disease, or a symptom or condition of the disease. Preventing includes providing prophylaxis with respect to the occurrence or recurrence of a disease in a subject that may be predisposed to the disease but has not yet been diagnosed with the disease. Preventing also includes providing prophylaxis with respect to the occurrence or recurrence of a symptom or pathological consequence of a disease in a subject that may be predisposed to the symptom or pathological consequence of the disease but has not yet been diagnosed with the symptom or pathological consequence of the disease. Treatment can also be prophylactic in terms of delaying onset of a disease, or a symptom or condition of the disease. Delaying development of a disease or symptom or pathological consequence of the disease indicates deferring, hindering, slowing, retarding, stabilizing, suppressing, and / or postponing development of the43 LEGAL02 / 46562464v1disease or symptom or pathological consequence of the disease. The delay can be of varying lengths of time, depending on the history of the disease and / or individual being treated. Treating can include inhibiting the disease, disorder, or condition, e.g., impeding its progress; and relieving the disease, disorder, or condition, e.g., causing regression of the disease, disorder, and / or condition. Treatment can also mean prolonging survival as compared to expected survival in the absence of treatment. Treatment can be therapeutic in terms of a partial or complete cure of a disease, condition, symptom, or adverse effect attributed to the disease, disorder, or condition. The term treatment can include: (a) preventing the disease from occurring in a subject who may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., mitigating or ameliorating the disease and / or its symptoms or conditions. Treating can refer to both therapeutic treatment alone, prophylactic treatment alone, or both therapeutic and prophylactic treatment. Those in need of treatment (subjects in need thereof) can include those previously diagnosed with a disease, disorder, or condition, or those identified as being at risk of developing a disease, disorder, or condition. Treating the disease, disorder, or condition can include ameliorating at least one symptom of the particular disease, disorder, or condition, even if the underlying pathophysiology is not affected.

[0156] The term “pharmaceutically acceptable excipient” refers to a non-active pharmaceutical ingredient that is biologically or pharmacologically compatible for use in humans or animals, such as but not limited to a buffer, carrier, or preservative.

[0157] An “effective amount” of an agent, e.g., an anti-Aβ antibody or antigen binding fragment thereof, in the context of administration, refers to an amount effective, at dosages / amounts and for periods of time necessary, to achieve a desired result, such as a therapeutic or prophylactic result.

[0158] A “therapeutically effective amount” of an agent, e.g., an anti-Aβ antibody or antigen binding fragment thereof, refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result, such as for treatment of a disease, condition, or disorder, and / or pharmacokinetic or pharmacodynamic effect of the treatment. The therapeutically effective amount may vary according to factors such as the disease state, age, sex, and weight of the subject, and the populations of cells administered.

[0159] A “prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. A prophylactically effective amount may be less than the therapeutically effective amount of the same drug (e.g., anti-Aβ antibody or antigen binding fragment thereof).44 LEGAL02 / 46562464v1

[0160] A “dose,” “unit dose,” or “dosage” refers to physically discrete units suitable for use in a subject, each unit containing a predetermined quantity of active pharmaceutical ingredient and / or a pharmaceutical composition.

[0161] A “subject” refers to an animal that is the object of treatment, observation, or experiment. “Animal” includes cold- and warm-blooded vertebrates and invertebrates such as fish, shellfish, reptiles and, in particular, mammals. In some embodiments, the subject is a mammal. Mammal includes, but is not limited to, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates, such as monkeys, chimpanzees, and apes, and humans. In some embodiments, the subject is a human.

[0162] The term “administer” refers to a method of delivering agents, compounds, or compositions to the desired site of biological action. These methods include, but are not limited to, topical delivery, parenteral delivery, intravenous delivery, intradermal delivery, intramuscular delivery, intrathecal delivery, colonic delivery, rectal delivery, or intraperitoneal delivery. In one embodiment, the compositions described herein are administered intravenously. A molecule that is “administered peripherally” means that the molecule is not administered directly to CNS (e.g., not administered intrathecally or directly into the brain, such as intracerebroventricularly).

[0163] The described anti-Aβ antibodies, or antigen binding fragments thereof, can be administered to a subject to treat a neurological disease or condition of the brain or CNS. The neurological disorder or condition of the CNS can be, but is not limited to, a neurodegenerative disease. In some embodiments, the described anti-Aβ antibodies, or antigen binding fragments thereof, can be administered to a subject to treat a neurodegenerative disease or condition associated with Aβ protein aggregation comprising administering to the subject an anti-Aβ antibodies, or an antigen binding fragments thereof, as described herein. The neurodegenerative disease or condition can be, but is not limited to: Alzheimer's disease, cognitive impairment associated with Aβ oligomers, traumatic brain injury (TBI), Lewy body dementia (LBD), Downs syndrome (DS), Amyotrophic lateral sclerosis (ALS), frontotemporal dementia, a tauopathy, a systemic amyloidosis, atherosclerosis, or Parkinson's disease dementia (PDD).

[0164] Described are methods of treating neurological disorder or condition of the CNS comprising, administering to the subject an effective amount of anti-Aβ antibody, or the antigen binding fragment thereof, as described herein. In some embodiments, the subject has or has been diagnosed with a neurological disorder or condition of the CNS or is at increased risk of developing a neurological disorder or condition of the CNS. The neurological disorder or45 LEGAL02 / 46562464v1condition of the CNS can be, but is not limited to, a neurodegenerative disease. The neurodegenerative disease can be, but is not limited to, a neurodegenerative disease or condition associated with Aβ protein aggregation, Alzheimer's disease, cognitive impairment associated with Aβ oligomers, traumatic brain injury (TBI), Lewy body dementia (LBD), Downs syndrome (DS), Amyotrophic lateral sclerosis (ALS), frontotemporal dementia, a tauopathy, a systemic amyloidosis, atherosclerosis, or Parkinson's disease dementia (PDD).

[0165] Described are methods of reducing, delaying, or preventing one or more symptoms or pathological conditions associated with a neurological disorder or condition of the CNS in a subject comprising administering to the subject an anti-Aβ antibody, or an antigen binding fragment thereof. The neurological disorder or condition can be, but is not limited to, a neurodegenerative disease or condition or a neurodegenerative disease or condition associated with Aβ protein aggregation.

[0166] Described are methods of reducing Aβ accumulation in a subject comprising administering to the subject an anti-Aβ antibody, or an antigen binding fragment thereof, as described herein.

[0167] Described are methods of preventing Aβ accumulation in a subject comprising administering to the subject an anti-Aβ antibody, or an antigen binding fragment thereof, as described herein.

[0168] Described are methods of reducing or preventing β-Amyloid plaque formation (i.e., neuritic or senile plaque, beta-amyloid protein deposits, plaque formed as a result of clumping, assembly, and deposition of Aβ protein pieces in the brain) in a subject comprising administering to the subject an anti-Aβ antibody, or an antigen binding fragment thereof, as described herein.

[0169] Described are methods of reducing or preventing Aβ amyloid fibril formation in a subject comprising administering to the subject an anti-Aβ antibody, or an antigen binding fragment thereof, as described herein.

[0170] Described are methods of reducing or preventing Aβ protofibrils in a subject comprising administering to the subject an anti-Aβ antibody, or an antigen binding fragment thereof, as described herein.

[0171] Described are methods of reducing or preventing Aβ-mediated synaptic toxicity in a subject comprising administering to the subject an anti-Aβ antibody, or an antigen binding fragment thereof, as described herein.

[0172] For any of the above methods of treatment, administering an anti-Aβ antibody, or an antigen binding fragment thereof, includes, administering a composition (e.g., a46 LEGAL02 / 46562464v1pharmaceutical composition) comprising the anti-Aβ antibody, or the antigen binding fragment thereof.

[0173] A pharmaceutical composition containing an anti-Aβ antibody, or an antigen binding fragment thereof, or a pharmaceutical composition containing the anti-Aβ antibody, or the antigen binding fragment thereof, can be administered by a variety of methods known in the art. Any appropriate route of administration may be employed, including for example, but not limited to, subcutaneous administration, intravascular (e.g., intravenous) administration, intrathecal administration, intracerebroventricular administration, intraperitoneal administration, transdermal administration, intradermal administration, or intranasal administration. Administration can be by bolus injection, infusion, or a combination thereof. In some embodiments, the anti-Aβ antibody, or the antigen binding fragment thereof, or a pharmaceutical composition containing the anti-Aβ antibody, or the antigen binding fragment thereof, is administered subcutaneously. In some embodiments, the anti-Aβ antibody, or the antigen binding fragment thereof, or a pharmaceutical composition containing the anti-Aβ antibody, or the antigen binding fragment thereof, is administered using an auto-injector.

[0174] In some embodiments, the anti-Aβ antibody, or the antigen binding fragment thereof, is administered in combination with one or more additional therapeutic agents. In some embodiments, the anti-Aβ antibody, or the antigen binding fragment thereof, is administered in combination with one or more additional therapies.

[0175] The additional therapeutic can be, but is not limited to, a neuroprotective agent (e.g., an anticholinergic agent, a dopaminergic agent, a glutamatergic agent, a histone deacetylase (HDAC) inhibitor, a cannabinoid, a caspase inhibitor, melatonin, an anti-inflammatory agent, a hormone (e.g., estrogen or progesterone), a vitamin), or an agent for use in treating a cognitive or behavioral symptom of a neurological disorder (e.g., an antidepressant, a dopamine agonist, or an anti-psychotic).

[0176] Also described are methods of detecting Aβ protein aggregation in a subject comprising contacting a sample from the subject with any of the described anti-Aβ antibodies or antigen binding fragments thereof and measuring an amount of the anti-Aβ antibody or antigen binding fragment bound to aggregated Aβ protein in the sample. Measuring the amount of the anti-Aβ antibody or the antigen binding fragment bound to aggregated Aβ protein in the sample can be used to determine a level of Aβ protein aggregation in the subject. Determining a level of Aβ protein aggregation in the subject can be used to diagnose Alzheimer's disease or risk of developing Alzheimer's disease. In some embodiments, if the level of aggregated Aβ protein detected in the sample is greater than a control level of aggregated Aβ protein, then the47 LEGAL02 / 46562464v1subject is determined to have or be at risk of developing Alzheimer's disease. The sample can be, but is not limited to, a cerebrospinal fluid sample or a blood sample. Detecting or determining a level of a protein or aggregate in a sample using antibody or an antigen binding fragment thereof, can be done using methods known in the art.

[0177] Described are methods of treating Alzheimer's disease in a subject comprising (a) contacting a sample from the subject with any of the described anti-Aβ antibodies antigen binding fragment thereof; (b) determining a level of aggregated Aβ protein in the sample by measuring an amount of the anti-Aβ antibody or antigen binding fragment bound to aggregated Aβ protein in the sample; and if the level of aggregated Aβ protein detected in the sample is greater than a control level of aggregated Aβ protein, then treating the subject for Alzheimer's disease. Treating the subject for Alzheimer's disease can include administering to the subject any of the described anti-Aβ antibodies or antigen binding fragments thereof.

[0178] Also described are methods of detecting Aβ protofibrils in a subject comprising contacting a sample from the subject with any of the described anti-Aβ antibodies or antigen binding fragments thereof and measuring an amount of the anti-Aβ antibody or antigen binding fragment bound to Aβ protofibrils in the sample. Measuring the amount of the anti-Aβ antibody or the antigen binding fragment bound to the Aβ protofibrils in the sample can be used to determine a level of Aβ protofibrils in the subject. Determining a level of Aβ protofibrils in the subject can be used to diagnose Alzheimer's disease or risk of developing Alzheimer's disease. In some embodiments, if the level of Aβ protofibrils detected in the sample is greater than a control level of Aβ protofibrils, then the subject is determined to have or be at risk of developing Alzheimer's disease. The sample can be, but is not limited to, a cerebrospinal fluid sample or a blood sample.

[0179] Described are methods of treating Alzheimer's disease in a subject comprising (a) contacting a sample from the subject with any of the described anti-Aβ antibodies antigen binding fragment thereof; (b) determining a level of Aβ protofibrils in the sample by measuring an amount of the anti-Aβ antibody or antigen binding fragment bound to the Aβ protofibrils in the sample; and if the level of Aβ protofibrils detected in the sample is greater than a control level of Aβ protofibrils, then treating the subject for Alzheimer's disease. Treating the subject for Alzheimer's disease can include administering to the subject any of the described anti-Aβ antibodies or antigen binding fragments thereof.48 LEGAL02 / 46562464v1EXAMPLES Example 1.

[0180] (A) Anti-Aβ light chain engineering. In order provide an anti-Aβ antibody with improved pharmacokinetics, engineering of SEQ ID NO: 40 (lecanemab light chain) was conducted. The VL from mAB158 LC (SEQ ID NO: 41) was aligned with the human VL kappa II (VLKII) consensus sequence, and CDR L1, CDR L2, and CDR L3 residues of mAB158 were engineered into VLKII acceptor framework to generate re-humanized LC framework. In addition to mAB158 LC CDRs, Vernier position residues that were identified as required to maintain Aβ binding and pharmacokinetics of the parental antibody were grafted to VLKII framework to generate engineered LC variants. Engineered VL variant sequences were synthesized (Integrated DNA Technologies) and cloned into mammalian expression vectors for recombinant antibody production for pharmacokinetics and Aβ binding evaluation.

[0181] (B) Affinity maturation. For Aβ binding affinity maturation, a total of six phage libraries containing changes in hypervariable regions (CDRs) were generated in the background of the parental anti-Aβ antibody sequence. Sequence diversity was introduced at selected CDR residues using NNK randomized libraries, positions in the hypervariable region were each fully randomized one at a time to all possible 20 amino acids using oligonucleotides encoding NNK. Oligos for positions located in the same hypervariable region were pooled and one library for each CDR loop was generated. For phage library screening, phage aliquots (0.5 mL) were thawed and mixed with 0.5 mL 10% BSA in PBS to block. The phage were added to an aliquot of 200 μL M280-streptavidin (M280SA) beads (Thermoscientific, 11206D) and incubated at room temperature with gentle rotation for 1 h. Meanwhile, biotinylated Aβ 1- 16 peptide (Anaspec, AS-62136) was added to a second aliquot of 200 μL M280SA beads and incubated at room temperature with gentle rotation for 30 minutes. The beads were then washed with PBS with 1% BSA (PBSA) three times, using a magnet to separate the beads between each wash. After a 1 h incubation with gentle rotation, the beads were washed four times with PBS containing 0.1% BSA and 0.05% Tween®20, each wash lasting 5 minutes. Bound phage were eluted from the beads using 0.1 M glycine (pH 2.7) for 30 minutes. The eluted phage solution was then neutralized with 1 M Tris (pH 7.5). The eluted phage were used to infect 10 mL TG1 E. coli grown to mid-log phase (OD600 approximately 0.5) at 37°C for 30 minutes without shaking, followed by 30 min with shaking.2XYT media (Teknova, Y0166) was added (40 mL volume), and the cultures were grown for 1-2 h at 37°C with shaking. At this point, the cultures were at OD600of 0.5 or lower, and were infected with M13K07 helper phage at an MOI of approximately 10. After infection, 50 µg / mL kanamycin was added and the cultures49 LEGAL02 / 46562464v1were grown overnight at 30°C with shaking. For the second and third panning rounds, phage were precipitated once with PEG / NaCl and concentrated 20×, then the same protocol as above was followed, except that more stringent washing was performed. After the third panning round, infected TG1 cells were spread onto 2XYT plates for picking of single colonies for sequencing and recombinant antibody production for Aβ binding evaluation.

[0182] (C) Recombinant antibody production. Expression plasmids consisting of the heavy and light chains of anti-Aβ antibody variants were co-transfected in Expi293 or ExpiCHO cells. Recombinant antibody variants were subsequently purified from conditioned media by loading supernatant over a protein A column (Cytiva, 11003494). The column was washed with 10 column volumes of PBS, pH 7.4. Antibodies were eluted with 50 mM sodium citrate, pH 3.0 containing 150 mM NaCl, and immediately neutralized with 200 mM arginine, 137 mM succinic acid, pH 5.0 and were further purified by size-exclusion chromatography (Cytiva, 28989335) using 200 mM arginine, 137 mM succinic acid, pH 5.0 as running buffer. Antibody purities were confirmed by SDS-PAGE and analytical HPLC-SEC.

[0183] (D) Aβ binding measurement. Aβ 1-16 peptide binding affinities of engineered Aβ antibodies were measured by surface plasmon resonance (SPR) using a Biacore 8K instrument (Cytiva). Antibodies were captured on Biacore™ Series S CM5 sensor chips (Cytiva, 29149603) immobilized with human Fab capture kit (Cytiva, 29234601) followed by injections of serial 3-fold dilutions of Aβ 1-16 peptide at a flow rate of 30 µL / min. Each sample was analyzed using a 3-minute association followed by a 10-minute dissociation. After each injection, the sensor chip was regenerated using a 50 mM glycine pH2.0 regeneration buffer. A 1:1 Languir model of simultaneous fitting of kon and koff was used for kinetics analysis.

[0184] (E) Pharmacokinetic analysis. Wild-type 6-8 week old male C57Bl6 mice (n=3 / group) were intravenously dosed with 10 mg / kg of anti-Aβ antibody variants. In-life bleeds were taken at 30 min, 1 day, 4 days, and 7 days post-dose via submandibular bleeds. Blood was collected in EDTA plasma tubes and spun at 14,000 rpm for 5 min. Plasma was then isolated for subsequent pharmacokinetic analysis. Plasma antibody concentrations were quantified using a generic human IgG assay following the manufacturer’s protocol. Dosing solutions were also analyzed on the same plate to confirm the correct dosage. The standard curve, 0.78–200 ng / mL IgG, was fit using a four-parameter logistic regression.

[0185] (F) FcγR binding assay. Binding affinities for Fc gamma receptors (FcγRs) were measured using biolayer interferometry on Octet Red384 instrument (Sartorius). Recombinant biotinylated human FcγRIIIa, human FcγRIIa, mouse FcγRIII, and mouse FcγRIV proteins (Acros Biosystems) were captured at 1 μg / mL on streptavidin biosensors in PBS buffer, pH50 LEGAL02 / 46562464v17.4, with 1× kinetics buffer (Sartorius). Binding association measurements were carried out with antibody titrations in 1:3-fold serial dilution series, followed by dissociation measurements. Octet data analysis software (version 12.0) was used to calculate steady state affinities (KD) from a nonlinear fit based on the 1:1 binding kinetic model of the data.

[0186] (G) C1q binding assay. BLI experiments were performed on an Octet Red384. Biotinylated Abeta 1-16 was immobilized on streptavidin biosensors at 20 μg / mL followed by subsequent immobilization of anti-Aβ antibodies at 20 μg / mL. Association and dissociation were monitored with human and mouse and human C1q proteins (Complement Technology) with concentrations ranging from 0.37 to 30 nM in kinetics buffer. Binding responses were globally fitted with a 1:1 binding model using the Octet Data Analysis software. Example 2. Pharmacokinetic Analysis of lecanemab

[0187] Pharmacokinetic (PK) analysis of lecanemab and a control IgG was performed as described above. As shown in Table 1, the lecanemab antibody exhibits high clearance in WT mice relative of a control IgG. Table 1. Pharmacokinetic analysis of lecanemab. C0AUCinfCL T1 / 2(μM) (μM·h) (mL / d / kg) (d)Example 3. Lecanemab light chain causes poor PK.

[0188] Various hybrid anti-Aβ antibodies were generated to analyze the effects of various regions of the lecanemab antibody on PK. (a) Lec_LC / mAb158ch_HC contained the lecanemab antibody light chain (SEQ ID NO: 43) and the mAb158ch heavy chain (SEQ ID NO: 45) (containing a non- humanized mAb158 VH and human IgG constant regions). (b) mAb158_LC / Lec_HC contained the mAb158_LC (SEQ ID NO: 44) and the lecanemab heavy chain (SEQ ID NO: 42). (c) mAb158ch contained the mAb158ch light chain (SEQ ID NO: 44) and the mAb158ch heavy chain (SEQ ID NO: 45). Pharmacokinetic (PK) analysis of hybrid anti-Aβ antibodies and a control IgG was performed as described above. As shown in Table 1, the lecanemab antibody light chain was identified as causing poor PK in mice.51 LEGAL02 / 46562464v1Table 2. Pharmacokinetic analysis of hybrid anti-Aβ antibodies Antibody C0AUCinfCL (μM) (μM·h) (mL / d / kg) Control I G 125 ±033 187 ±53 955 ±314 a. . e, average AUCinf was 241 μM·h and CL was 6.96, which are within range of a well- behaved IgG. Example 3. Engineered anti-Aβ – PK enhancement.

[0189] Because the lecanemab light chain was identified as causing decreased PK, framework substitutions were made in the light chain to generate an engineered anti-Aβ antibody with improved performance. Amino acid substitutions, relative to SEQ ID NO: 40, at positions 7 and 15-18 (framework region 1); 37, 39, 45 (framework region 2); 74 and 85 (framework region 3), and 100 and 104 (framework region 4) were analyzed for the effect on PK. Antibodies with the following substitutions relative to lecanemab VL domain were generated. (a) Aβ-1 substitutions: P15L, L37Q, K39Q, R74K, I85V, P100Q, (b) Aβ-2 substitutions: S7T, A17Q, K45Q, R74K, I85V, P100Q, and L104V Pharmacokinetic (PK) analysis of engineered anti-Aβ antibodies and a control IgG was performed as described above. As shown in Table 3 and FIG.1, Aβ-1 and Aβ-2 variants showed improved PK properties compared to clinical lecanemab. Table 3. Pharmacokinetic analysis of engineered anti-Aβ antibodies. C0AUCinfCL (μM) (μM·h) (mL / d / kg)

[0190] Aβ-2 was selected for additional engineering to further reduce clearance rate. Amino acid substitutions in framework regions 2, 3, and 4 (Aβ-FW2, Aβ-FW3, and Aβ-FW4, respectively) wherein compared against lecanemab variants AL-1 and AL2, and did not improve pharmacokinetics of anti-Aβ antibodies (FIG.2). Additional amino acid substitutions52 LEGAL02 / 46562464v1were made in framework region 1. Specifically, amino acid substitutions were made at positions 15-18 (relative to SEQ ID NO: 40). Position 15 was left unchanged or changed to leucine (i.e., P or L). Position 17 was changed to aspartate (D) or glutamine (Q) (i.e., D or Q). Position 18 was changed left unchanged or changed to glutamine (Q) (i.e., P or Q). As shown in Table 4 and FIG.2, engineered antibodies Aβ-3, Aβ-6, and Aβ-9 showed PK properties similar to the control well-behaved IgG. Table 4. Amino acid substitutions in engineered anti-Aβ antibodies and effects on PK. AntibodyFramework region 1 positionAβ affinity15 16 17 18 (μM) PKe a a yses s o e a e a a s e e co o a o a y s able and exhibited acceptable hydrophobicity by HIC (Table 5). Table 5. eDA analyses of engineered anti-Aβ antibodies. 9953 9954 9955 9956 9957 9958 9959 Acceptance 3 0 6 3 4 6 2Example 4. Engineered anti-Aβ antibodies with improved affinity.

[0192] Amino acid substitutions were made in the heavy chain CDR3 to improve affinity for Aβ. Specifically Y100N and Y100Q mutations were made relative to SEQ ID NO: 43. The following engineered anti-Aβ antibodies were made: (a) mAb158_H93L / Lec_HC (SEQ ID NOs: 46 and 42)

[10466] (b) mAb158_H93L / Lec_HC_Y100Q (SEQ ID NOs: 46 and 37)

[10484] 53 LEGAL02 / 46562464v1(c) mAb158_LC / Lec_HC_Y100Q (SEQ ID NOs: 44 and 37)

[10485] (d) mAb158_LC / Lec_HC_Y100N (SEQ ID NOs: 44 and 36)

[10475] (e) Lec LC / Lec HC (SEQ ID NOs: 59 and 42)

[8999] (f) mAb158_LC / Lec_HC (SEQ ID NOs: 44 and 42)

[9290] Modifying the heavy chain CDR3 in combination with the light chain framework substitutions, resulted in up to a 30-fold increase in observed Aβ peptide binding affinity.

[0193] The engineered anti-Aβ antibodies were then analyzed for developability. eDA analyses showed that the variants were conformationally stable by DSF and exhibited acceptable hydrophobicity by HIC (Table 6). Table 6. eDA analyses of engineered anti-Aβ antibodies. 10466 10484 10485 10475 8999 9290 Assay Measurement Acceptance 6 5 5xampe . an a n y o an - β an o es

[0194] Various anti-Aβ antibodies and components thereof (light chain or heavy chain) were analyzed for PK and affinity as described in Example 1. Affinity variants with a non- humanized light chain framework were generated to assess the impact of affinity engineering to peripheral clearance of the IgG variants. The results are shown in Table 7 and FIG. 3. mAb158_LC_H93L / Lec_HC_Y100Q and mAb158_LC_H93L / Lec_HC_Y100N demonstrated profiles outside of the expected typical IgG-like kinetics. The results further demonstrate the affinity anti-Aβ antibodies C-G of Table 7 show IgG-like PK. Thus, the affinity engineering did not compromise the PK properties of these variants. Table 7. Noncompartmental analysis (NCA) of PK parameters in WT mice. anti-αAβ antibody C0Cmax AUCinf CL ( M) ( M) ( M·h) (mL / d / kg)54 LEGAL02 / 46562464v1Example 6. Plaque binding.

[0195] Anti-AbetaY100N, anti-AbetaH93L, and anti-AbetaH93L_Y100N bind plaques in human AD brain.

[0196] Human fresh-frozen brain sections premounted on slides were fixed with acetone for 10 min at −20 °C and then washed with PBST (PBS containing Tween 20) 3× for 10 min. Slides were then blocked for 1 h at room temperature followed by primary antibody incubation over night at 4 °C. The human anti-Abeta primary antibodies listed above were used at a final concentration of 0.1 μg / ml in addition to the rabbit anti-abeta (IBL America, 18584) at a 1:500 dilution. Slides were then washed 3× with PBSR at room temperature followed by secondary antibody treatment with donkey anti-human A647 (Jackson 709-606-149) and donkey anti- rabbit A568 (Biotium 20098) for 1 h at room temperature and then 3× 10 min washes in PBST. Slides were then mounted and imaged at 20× magnification using a widefield epifluorescence slide scanner (Axio Scan Z1; Carl Zeiss; 20× / 0.8 NA air objective; each channel was acquired independently with the appropriate filter cube for that fluorophore) (FIG.8A). Colocalization of Lecanemab with amyloid beta is shown in FIG.4. Table 8. huIgG intensity in total Plaques (10 mpk dose) day 7 day 14 antibody fold foldTable 9. Sequences Sequence SEQ ID NO:55 LEGAL02 / 46562464v1DVVMTQTPLSLPVTLGDQASISCRSSQSIVHSNGNTYLEWYLQKPGQSPQLLIYKVSNRFSGVP DRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSLVPPTFGQGTKVEIK11DVVMTQTPLSLPVTLGDQASISCRSSQSIVHSNGNTYLEWYLQKPGQSPQLLIYKVSNRFSGVP 5256 LEGAL02 / 46562464v1DVVMTQTPLSLPVTLGQPASISCRSSQSIVHSNGNTYLEWYLQKPGQSPQLLIYKVSNRFSGVP DRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSLVPPTFGQGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYE 2057 LEGAL02 / 46562464v1DVVMTQTPLSLPVTPGQPASISCRSSQSIVHSNGNTYLEWYLQKPGQSPQLLIYKVSNRFSGVP DRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSLVPPTFGQGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYE 2558 LEGAL02 / 46562464v1GPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSV VTVPSSSLGTQTYICNVNHKPSNTKVDKKV EVQLVESGGGLVQPGGSLRLSCSASGFTFSSFGMHWVRQAPGKGLEWVAYISSGSSTIYYGDTV59 LEGAL02 / 46562464v1VTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKD TLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDW LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDI60 LEGAL02 / 46562464v1

Claims

Claims:

1. An antibody or antigen binding fragment having affinity for amyloid beta (Aβ), comprising a light chain variable domain and a heavy chain variable domain, wherein: (a) the light chain variable domain comprises: a CDR-L1 having the sequence RSSQSIVHSNGNTYLE (SEQ ID NO: 1), a CDR-L2 having the sequence KVSNRFS (SEQ ID NO: 2), a CDR-L3 having the sequence FQGSXVPPT (SEQ ID NO: 3) wherein X is leucine or arginine, a valine at position 3, a threonine at position 7, a threonine at position 14, a proline or leucine at position 15, an aspartate or glutamine at position 17, a glutamine or proline at position 18, a glutamine at position 45, a lysine at position 74, a valine at position 83, a valine at position 85, a glutamine at position 100, and a valine at position 104, wherein the positions are according to Chothia / Martin numbering; and (b) a heavy chain variable domain comprising: a CDR-H1 having the sequence SFGMH (SEQ ID NO: 4), a CDR-H2 having the sequence YISSGSSTIYYGDTVKG (SEQ ID NO: 5), and a CDR-H3 having the sequence EGGYYYGRSYXTMDY (SEQ ID NO: 6), wherein X is tyrosine, asparagine, or glutamine.

2. The antibody or antigen binding fragment of claim 1, wherein CDR-L3 comprises: (i) FQGSLVPPT (SEQ ID NO: 59); or (ii) FQGSRVPPT (SEQ ID NO: 60).61 LEGAL02 / 46562464v13. The antibody or antigen binding fragment of claim 1 or 2, wherein light chain variable domain comprises a leucine at position 15.

4. The antibody or antigen binding fragment of claim 1 or 2, wherein light chain variable domain comprises a proline at position 15.

5. The antibody or antigen binding fragment of any one of claims 1-4, wherein light chain variable domain comprises an aspartate at position 17.

6. The antibody or antigen binding fragment of any one of claims 1-4, wherein light chain variable domain comprises a glutamine at position 17.

7. The antibody or antigen binding fragment of any one of claims 1-6, wherein light chain variable domain comprises a glutamine at position 18.

8. The antibody or antigen binding fragment of any one of claims 1-6, wherein light chain variable domain comprises a proline at position 18.

9. The antibody or antigen binding fragment of claim 1 or 2, wherein light chain variable domain comprises: (a) a leucine at position 15, an aspartate position 17, and a proline at position 18; (b) a leucine at position 15, an aspartate position 17, and a glutamine at position 18; (c) a leucine at position 15, a glutamine position 17, and a proline at position 18; (d) a leucine at position 15, a glutamine position 17, and a glutamine at position 18; (e) a proline at position 15, an aspartate position 17, and a proline at position 18; (f) a proline at position 15, an aspartate position 17, and a glutamine at position 18 (g) a proline at position 15, a glutamine position 17, and a proline at position 18; or (h) a proline at position 15, a glutamine position 17, and a glutamine at position 18.

10. The antibody or antigen binding fragment of any one of claim 1-9, wherein the heavy chain variable domain comprises a CDR-H3 having the sequence EGGYYYGRSYYTMDY (SEQ ID NO: 7).

11. The antibody or antigen binding fragment of any one of claim 1-9, wherein the heavy chain variable domain comprises a CDR-H3 having the sequence EGGYYYGRSYNTMDY (SEQ ID NO: 8).62 LEGAL02 / 46562464v112. The antibody or antigen binding fragment of any one of claim 1-9, wherein the heavy chain variable domain comprises a CDR-H3 having the sequence EGGYYYGRSYQTMDY (SEQ ID NO: 9).

13. The antibody or antigen binding fragment of claim 1 or 2, wherein the light chain variable domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 10, 11, 12, 13, 14, 15, 16, 17, 51, 52, 53, 54, 55, 56, 57, or 58.

14. The antibody or antigen binding fragment of claim 13, wherein the heavy chain variable domain comprises an amino acid sequence at least 95% identical to SEQ ID NO: 27, 28, or 29.

15. The antibody or antigen binding fragment of claim 14, wherein: (a) the light chain variable domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 10 or 51 and the heavy chain variable domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 27; (b) the light chain variable domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 10 or 51 and the heavy chain variable domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 28; (c) the light chain variable domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 10 or 51 and the heavy chain variable domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 29; (d) the light chain variable domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 11 or 52 and the heavy chain variable domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 27; (e) the light chain variable domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 11 or 52 and the heavy chain variable domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 28; (f) the light chain variable domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 11 or 52 and the heavy chain variable domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 29; (g) the light chain variable domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 12 or 53 and the heavy chain variable domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 27;63 LEGAL02 / 46562464v1(h) the light chain variable domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 12 or 53 and the heavy chain variable domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 28; (i) the light chain variable domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 12 or 53 and the heavy chain variable domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 29; (j) the light chain variable domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 13 or 54 and the heavy chain variable domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 27; (k) the light chain variable domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 13 or 54 and the heavy chain variable domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 28; (l) the light chain variable domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 13 or 54 and the heavy chain variable domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 29; (m) the light chain variable domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 14 or 55 and the heavy chain variable domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 27; (n) the light chain variable domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 14 or 55 and the heavy chain variable domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 28; (o) the light chain variable domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 14 or 55 and the heavy chain variable domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 29; (p) the light chain variable domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 15 or 56 and the heavy chain variable domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 27; (q) the light chain variable domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 15 or 56 and the heavy chain variable domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 28; (r) the light chain variable domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 15 or 56 and the heavy chain variable domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 29;64 LEGAL02 / 46562464v1(s) the light chain variable domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 16 or 57 and the heavy chain variable domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 27; (t) the light chain variable domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 16 or 57 and the heavy chain variable domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 28; or (u) the light chain variable domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 16 or 57 and the heavy chain variable domain comprises an amino acid sequence at least 90% identical to SEQ ID NO:

29. (v) the light chain variable domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 17 or 58 and the heavy chain variable domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 27; (w) the light chain variable domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 17 or 58 and the heavy chain variable domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 28; or (x) the light chain variable domain comprises an amino acid sequence at least 90% identical to SEQ ID NO: 17 or 58 and the heavy chain variable domain comprises an amino acid sequence at least 90% identical to SEQ ID NO:

29.

16. The antibody or antigen binding fragment of any one of claims 1-15, wherein the antigen binding fragment comprises a scFv, a Fab, or a scFab.

17. The antibody or antigen binding fragment of any one of claims 1-15, wherein the antibody or antigen binding fragment comprises: (a) a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 18 or 63, and a Fab heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 31; (b) a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 18 or 63, and a Fab heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 32; (c) a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 18 or 63, and a Fab heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 33;65 LEGAL02 / 46562464v1(d) a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 19 or 64, and a Fab heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 31; (e) a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 19 or 64, and a Fab heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 32; (f) a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 19 or 64, and a Fab heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 33; (g) a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 20 or 65, and a Fab heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 31; (h) a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 20 or 65, and a Fab heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 32; (i) a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 20 or 65, and a Fab heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 33; (j) a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 21 or 66, and a Fab heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 31; (k) a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 21 or 66, and a Fab heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 32; (l) a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 21 or 66, and a Fab heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 33; (m) a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 22 or 67, and a Fab heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 31; (n) a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 22 or 67, and a Fab heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 32;66 LEGAL02 / 46562464v1(o) a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 22 or 67, and a Fab heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 33; (p) a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 23 or 68, and a Fab heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 31; (q) a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 23 or 68, and a Fab heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 32; (r) a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 23 or 68, and a Fab heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 33; (s) a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 24 or 69, and a Fab heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 31; (t) a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 24 or 69, and a Fab heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 32; (u) a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 24 or 69, and a Fab heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 33; (v) a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 25 or 70, and a Fab heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 31; (w) a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 25 or 70, and a Fab heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 32; or (x) a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 25 or 70, and a Fab heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO:

33.

18. The antibody or antigen binding fragment any one of claims 1-17, wherein the antibody or antigen binding fragment comprises an immunoglobulin.67 LEGAL02 / 46562464v119. The antibody or antigen binding fragment of claim 18, wherein the immunoglobulin comprises an IgG isotype immunoglobulin, optionally wherein the IgG comprises an IgG1or an IgG4.

20. The antibody or antigen binding fragment of claim 19, wherein the immunoglobulin comprises (a) a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 18 or 63, and a Fab heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 35 or 48; (b) a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 18 or 63, and a Fab heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 36 or 49; (c) a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 18 or 63, and a Fab heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 37 or 50; (d) a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 19 or 64, and a Fab heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 35 or 48; (e) a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 19 or 64, and a Fab heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 36 or 49; (f) a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 19 or 64, and a Fab heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 37 or 50; (g) a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 20 or 65, and a Fab heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 35 or 48; (h) a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 20 or 65, and a Fab heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 36 or 49; (i) a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 20 or 65, and a Fab heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 37 or 50;68 LEGAL02 / 46562464v1(j) a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 21 or 66, and a Fab heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 35 or 48; (k) a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 21 or 66, and a Fab heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 36 or 49; (l) a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 21 or 66, and a Fab heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 37 or 50; (m) a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 22 or 67, and a Fab heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 35 or 48; (n) a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 22 or 67, and a Fab heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 36 or 49; (o) a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 22 or 67, and a Fab heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 37 or 50; (p) a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 23 or 68, and a Fab heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 35 or 48; (q) a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 23 or 68, and a Fab heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 36 or 49; (r) a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 23 or 68, and a Fab heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 37 or 50; (s) a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 24 or 69, and a Fab heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 35 or 48; (t) a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 24 or 69, and a Fab heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 36 or 49;69 LEGAL02 / 46562464v1(u) a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 24 or 69, and a Fab heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 37 or 50; (v) a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 25 or 70, and a Fab heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 35 or 48; (w) a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 25 or 70, and a Fab heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 36 or 49; or (x) a light chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 25 or 70, and a Fab heavy chain comprising an amino acid sequence at least 90% identical to SEQ ID NO: 37 or 50.

21. The antibody or antigen binding fragment of any one of claims 18-20, wherein the immunoglobulin comprises at least one modification to increase serum stability, modulate effector function, influence glycosylation, reduce immunogenicity in humans, and / or facilitate heterodimerization.

22. The antibody or antigen binding fragment of claim 21, wherein the at least one modification comprises one or more of: (a) a L234A substitution and a L235A substitution; a P329G substitution; or a L234A substitution, a L235A substitution, and a P329G substitution; (b) a M428L substitution; a N434S substitution; a M428L substitution and a N434S substitution; a N434A substitution; or a M252Y substitution, a S254T substitution, and a T256E substitution; (c) a deletion of a carboxy terminal lysine; (d) knob and hole mutations; optionally wherein the knob mutation comprises a T366W substitution in a first heavy chain of the immunoglobulin and the hole mutation comprises a Y407V substitution and optionally a T366S substitution and a L368A substitution in a second heavy chain of the immunoglobulin; 23. The antibody or antigen binding fragment of any one of claims 18-22 wherein the immunoglobulin comprises: an alanine at position 322, according to EU numbering, of the heavy chain.70 LEGAL02 / 46562464v124. The antibody or antigen binding fragment of any one of claims 18-23, wherein the antibody or antigen binding fragment is divalent; optionally wherein the antibody or antigen binding fragment is monospecific.

25. The antibody or antigen binding fragment of any one of claims 1-24, wherein antibody or antigen binding fragment has increase affinity to Aβ, improved PK, improved affinity for one or more variant Aβ species, and / or reduced immunogenicity relative to lecanamab.

26. A multi-specific antibody comprising the antigen binding fragment of any one of claims 1-24 and a second antigen binding fragment having affinity for a second epitope.

27. A pharmaceutical composition comprising the antibody or antigen binding fragment of any one of claims 1-25 or the multi-specific antibody of claim 26 and a pharmaceutically acceptable excipient.

28. A combination comprising a first nucleic acid sequence and a second nucleic acid sequence wherein the first and second nucleic acid sequences encode the light chain variable domain and the heavy chain variable domain of any one of claims 1-25 or the multi-specific antibody of claim 26.

29. The combination of claim 28, wherein the first and second nucleic acid sequences are provided on a single expression vector or a pair of nucleic acid sequences.

30. A host cell comprising the nucleic acid sequences of claim 28 or 29.

31. A host expressing the antibody or antigen binding fragment of any one of claims 1-25 or the multi-specific antibody of claim 26.

32. A method of manufacturing the antibody or antigen binding fragment of any one of claims 1-25 or the multi-specific antibody of claim 26 comprising: (a) culturing a host cell comprising one or more nucleic acids encoding the antibody or antigen binding fragment or the multi-specific antibody under conditions in which the antibody or antigen binding fragment or the multi-specific antibody encoded by the nucleic acid is expressed; and (b) isolating the antibody or antigen binding fragment or the multi-specific antibody from the culture.71 LEGAL02 / 46562464v133. A method of treating a neurodegenerative disease or condition associated with Aβ protein aggregation in a subject comprising administering to the subject the antibody or antigen binding fragment of any one of claims 1-25, the multi-specific antibody of claim 26, or the pharmaceutical composition of claim 27.

34. The method of claim 33, wherein the neurodegenerative disease or condition associated with Aβ protein aggregation comprises: Alzheimer's disease, cognitive impairment associated with Aβ oligomers, traumatic brain injury (TBI), Lewy body dementia (LBD), Downs syndrome (DS), Amyotrophic lateral sclerosis (ALS), Frontotemporal dementia, tauopathies, systemic amyloidoses, atherosclerosis, or Parkinson's disease dementia (PDD).

35. The method of claim 33 or 34, wherein treating comprises reducing, delaying, or preventing the neurodegenerative disease or condition associated with Aβ protein aggregation or one or more symptoms associated with the neurodegenerative disease or condition associated with Aβ protein aggregation.

36. Method for reducing or preventing Aβ accumulation, β-Amyloid plaque formation (i.e., neuritic or senile plaque, beta-amyloid protein deposits, plaque formed as a result of clumping, assembly, and deposition of Aβ protein pieces in the brain) Aβ amyloid fibril formation, Aβ-mediated synaptic toxicity, or Aβ protofibrils in a subject comprising administering to the subject the antibody or antigen binding fragment of any one of claims 1-25, the multi-specific antibody of claim 25, or the pharmaceutical composition of claim 27.72 LEGAL02 / 46562464v137. A method for diagnosis of Alzheimer's disease or risk of developing Alzheimer's disease in a subject comprising: contacting a sample from the subject with the antibody or antigen binding fragment of any one of claims 1-25 and measuring the amount of said antibody or antigen binding fragment bound to aggregated Aβ protein.

38. The method of claim 37, wherein if the level of aggregated Aβ protein detected in the sample is greater than a control level of aggregated Aβ protein, then treating the subject with the pharmaceutical composition of claim 27.

39. A method for measuring the amount of Aβ protofibrils and / or aggregated Aβ protein in a subject comprising: contacting a sample from the subject with the antibody or antigen binding fragment of any one of claims 1-27 and measuring the amount of said antibody or antigen binding fragment bound to Aβ protofibrils and / or aggregated Aβ protein.

40. The method of any one of claims 37-39, wherein the sample comprises a cerebrospinal fluid sample or a blood sample.73 LEGAL02 / 46562464v1

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