Compounds and methods targeting interleukin-34

Abstract

This invention relates to IL-34 antibodies, compositions comprising such antibodies, and methods of using such antibodies and / or compositions to treat immune-mediated diseases, such as neurodegenerative diseases, like Alzheimer's disease or tau proteinosis.

Description

Compounds and methods for targeting interleukin-34 This invention relates to compounds, pharmaceutical compositions, and methods, including antibodies against human interleukin-34 (IL-34), which are intended for use in the field of neuroinflammatory diseases and acute or chronic inflammatory disorders. Specifically, the embodiments are intended for therapeutic and / or diagnostic applications related to Alzheimer's disease and other tau protein disorders. Alzheimer's disease (AD), a leading cause of dementia, occurs in 1% of people aged 65 to 69, increasing to 40-50% in those aged 95 and older. AD patients present with hallmark clinical symptoms, including cognitive impairment and memory deficits. In these patients, the presence of AD is confirmed by post-mortem histopathological examination revealing a heavy burden of senile plaques and neurofibrillary tangles (NFTs) in the cerebral cortex. Mature senile plaques consist of extracellular β-amyloid peptides derived from enzymatically processed amyloid precursor proteins and intracellular neurofibrillary tangles (NFTs) derived from hyperphosphorylated tau proteins. Aggregates of hyperphosphorylated tau, such as those in neurofibrillary tangles, are associated with the degree of cognitive impairment in Alzheimer's disease. In AD and various other tau-related diseases, tau aggregates are found in specific brain regions and patterns associated with disease risk, onset, and / or progression, and these regions and patterns are known to those skilled in this technique. Cytokines regulate normal homeostatic tissue function, and dysregulation of these cytokine networks is associated with pathological symptoms. The central nervous system (CNS), with its minimal hematogenous circulation of immune cells, appears particularly vulnerable to dysregulated cytokine networks. In neurodegenerative diseases, resident CNS cells are major producers of pro-inflammatory cytokines and can contribute to cytokine network dysregulation and neuroinflammation. CNS damage may involve the recruitment of circulating immune cells, leading to an innate immune response comprised of resident microglia, peripherally derived monocytes, macrophages, and dendritic cells. The activated states of microglia and macrophages are not strictly pro-inflammatory or anti-inflammatory, but may represent a range of functional states. Microglia and / or peripherally derived monocytes and macrophages can acquire an anti-inflammatory phenotype in which these cells remove debris and promote regeneration and homeostasis. Neuronal dysfunction or injury can also activate microglia to produce pro-inflammatory cytokines and recruit leukocytes from the bloodstream. Microglia activation is a common phenomenon in neurodegenerative diseases such as Alzheimer's disease (AD), reflecting a tissue response to the accumulation of extracellular β-amyloid plaques and hyperphosphorylated tau aggregates. Neuroinflammation is an important component of neurodegenerative diseases, characterized by increased production of pro-inflammatory cytokines from CNS cells (Becher, B., Spath, S. & Goverman, J.). Cytokine networks in neuroinflammation .Nat Rev Immunol 17, 49-59 (2017)). Neuroinflammation and microglial proliferation are considered potential mechanisms in neurodegenerative diseases such as plaque buildup in Alzheimer's disease, and neuronal death and dysfunction in Parkinson's disease and Huntington's disease. Microglial proliferation involves the abnormal proliferation and / or hypertrophy of microglia in response to inflammatory signals. Generally, IL-34 acts as a potent pleiotropic cytokine in the regulation of inflammatory and immune processes and is a key regulatory cytokine for the growth of resident microglia in the CNS during normal tissue homeostasis. IL-34 is expressed by neurons in the cortex, anterior olfactory nucleus, and hippocampus. IL-34 shows low sequence homology with CSF-1 but has a similar general structure, and both cytokines bind to a common receptor, CSF-1R, triggering receptor autophosphorylation and dimerization, subsequently activating multiple signaling pathways (A. Freuchet, et al. J Leukoc Biol 2021 Oct; 110(4):771-796). IL-34 is a secreted homodimeric cytokine that acts as one of the two activating ligands of CSF1R, triggering receptor autophosphorylation and dimerization, subsequently activating multiple signal transduction pathways (see, for example...). Structural basis for the dual recognition of helical cytokines IL - 34 and CSF - 1 by CSF - 1R (Structure 20, 676-687, and Felix J, De Munck S, Verstraete K, Meuris L, Callewaert N, Elegheert J. et al.). The human IL-34 polypeptide is disclosed, for example, in U.S. Patent No. 9,770,486, and consists of 242 amino acids having a leader sequence and 222 amino acids in a mature form (SEQ ID NO: 31). Anti-IL-34 antibodies have been described in this technology, and various anti-IL-34 antibodies and their potential uses are described, for example, in WO 2016 / 196679. However, to date, no antibody targeting IL-34 has been approved for medical use. Therefore, there remains an unmet need for alternative and / or improved anti-IL-34 antibodies, their pharmaceutical compositions, and methods for their use in the treatment and / or diagnostic applications related to immune-mediated diseases involving IL-34 and / or diseases that can be treated with anti-IL-34 antibodies, such as neuroinflammatory diseases and / or Alzheimer's disease. Furthermore, given at least one or more of the following characteristics, there remains an unmet need for alternative and / or modified anti-IL-34 antibodies with advantageous properties superior to prior art anti-IL-34 antibodies: 1) desirable binding and dissociation rates; 2) efficacy in neutralizing human IL-34 to achieve anti-neuroinflammatory responses and in vivo efficacy; 3) sufficient as a monotherapy to treat and / or prevent immune-mediated and / or inflammatory conditions; 4) sustained duration of action; 5) adequate limitation of induction of unwanted cytokine release; 6) acceptable low immunogenicity (i.e., sufficient non-immunogenicity in humans); 7) avoidance of adverse immune compromises; and / or 8) desirable in vivo stability, physical and chemical stability, including but not limited to thermal stability, solubility, low self-binding and pharmacokinetic characteristics, which are acceptable for development and / or use in the treatment of inflammatory or neuroinflammatory conditions such as Alzheimer's disease. Embodiments of the present invention provide novel anti-human IL-34 antibodies. According to some embodiments, the present invention provides antibodies comprising a light chain variable region (LCVR) and a heavy chain variable region (HCVR), wherein the LCVR comprises complementarity-determining regions (CDRs) LCDR1, LCDR2, and LCDR3, and the HCVR comprises CDRs HCDR1, HCDR2, and HCDR3, selected from a grouping of CDR combinations provided in Table 1. Sequence identifiers used herein are listed in Table 1 and throughout the specification, and the sequences are provided in the amino acid and nucleotide sequence listing provided herein. surface 1 Amino acid and nucleotide sequences Therefore, embodiments of the present invention provide an antibody that binds to human IL-34, wherein the antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises heavy chain complementarity-determining regions (HCDR) HCDR1, HCDR2 and HCDR3, and the VL comprises light chain complementarity-determining regions (LCDR) LCDR1, LCDR2 and LCDR3, wherein HCDR1 comprises SEQ ID NO: 5, HCDR2 comprises SEQ ID NO: 6, HCDR3 comprises SEQ ID NO: 7, LCDR1 comprises SEQ ID NO: 8, LCDR2 comprises SEQ ID NO: 9, and LCDR3 comprises SEQ ID NO: 10. Therefore, embodiments of the present invention also provide antibodies comprising LCVR having the amino acid sequence of SEQ ID NO: 4 and HCVR having the amino acid sequence of SEQ ID NO: 3. Therefore, embodiments of the present invention further provide an antibody that binds to human IL-34, wherein the antibody comprises: a heavy chain (HC) comprising SEQ ID NO: 1 and a light chain (LC) comprising SEQ ID NO: 2. According to other embodiments, the present invention also provides antibodies comprising LCVR having the amino acid sequence of SEQ ID NO: 4 and HCVR having the amino acid sequence of SEQ ID NO: 3, wherein the hinge region and Fc region of the antibodies are selected from SEQ ID NO: 32 and SEQ ID NO: 33. As used herein, "antibody 1" refers to an antibody having the HCDR1 amino acid sequence of SEQ ID NO: 5, the HCDR2 amino acid sequence of SEQ ID NO: 6, the HCDR3 amino acid sequence of SEQ ID NO: 7, the LCDR1 amino acid sequence of SEQ ID NO: 8, the LCDR2 amino acid sequence of SEQ ID NO: 9, the LCDR3 amino acid sequence of SEQ ID NO: 10, the HCVR amino acid sequence of SEQ ID NO: 3, the LCVR amino acid sequence of SEQ ID NO: 4, the HC amino acid sequence of SEQ ID NO: 1, and the LC amino acid sequence of SEQ ID NO: 2. Antibody 1 may be encoded by the HC DNA sequence of SEQ ID NO: 11 and the LC DNA sequence of SEQ ID NO: 12. Unless otherwise stated, this usage is consistent with North et al. J . Mol . Biol . The methods consistent with those used in 2011: 406: 228-256 are used to annotate the framework and CDR sequence of each antibody listed in this paper. According to other embodiments, the present invention also provides an antibody comprising LC having an amino acid sequence having at least 95% sequence homology with SEQ ID NO: 2, and HC having an amino acid sequence having at least 95% sequence homology with SEQ ID NO: 1. According to other embodiments, the present invention also provides an antibody comprising an LC having the amino acid sequence of SEQ ID NO: 2 and an HC having the amino acid sequence of SEQ ID NO: 35, which is further referred to herein as antibody 2. According to other embodiments, the present invention also provides an antibody comprising an LC having the amino acid sequence of SEQ ID NO: 2 and an HC having the amino acid sequence of SEQ ID NO: 36, which is further referred to herein as antibody 3. According to other embodiments, the present invention also provides an antibody comprising an LC having the amino acid sequence of SEQ ID NO: 2 and an HC having the amino acid sequence of SEQ ID NO: 37, which is further referred to herein as antibody 4. The carboxyl terminus of each HC defines a constant region primarily responsible for effector function, and in some embodiments of the present invention, the antibody has one or more modifications in the constant region of each HC that reduce effector function. Preferably, embodiments of the present invention are IgG4 antibodies, and therefore contain an IgG4 Fc region, or an Fc region derived from human IgG4, such as a modified IgG4 Fc region. According to some embodiments, modifications to reduce effector function and amino acid substitutions in the constant regions of the two HCs are introduced into the IgG4 hinge and Fc region. Therefore, some embodiments have modifications in the constant regions of the two HCs, including the amino acid alanine at residues 230 and 231 (exemplified in the HC of antibody 1 and SEQ ID NO: 33, respectively), and further modifications in the constant regions of the two HCs to promote stability, including the amino acid proline at residue 224 (exemplified in the HC of antibody 1 and, for example, SEQ ID NO: 32), and the deletion of the amino acid lysine at residue 443 (exemplified in the HC of SEQ ID NO. 1). The antibodies of this invention are considered to possess a combination of particularly advantageous properties superior to prior art anti-IL-34 antibodies, including but not limited to one or more of the following properties: 1) a desired binding and dissociation rate; 2) efficacy in neutralizing human IL-34 to achieve anti-neuroinflammatory responses and in vivo efficacy; 3) sufficient as a monotherapy to treat and / or prevent immune-mediated and / or inflammatory conditions; 4) a sustained duration of action; 5) adequate limitation of induction of unwanted cytokine release; 6) acceptable low immunogenicity (i.e., sufficient non-immunogenicity in humans); 7) avoidance of adverse immune compromises; and / or 8) desired in vivo stability, physical and chemical stability, including but not limited to thermal stability, solubility, low self-binding and pharmacokinetic characteristics, which are acceptable for the development and / or use in the treatment of inflammatory or neuroinflammatory conditions such as Alzheimer's disease. This application claims the benefit of U.S. Provisional Application No. 63 / 273,204, filed October 29, 2021, pursuant to 35 USC §119(e), the disclosure of which is incorporated herein by reference. Embodiments of the present invention provide compositions and methods for preventing, downregulating, or improving inflammatory and / or neuroinflammatory-related conditions, and offer significant advancements over prior art by using pharmacologically advantageous anti-human IL-34 antibodies provided in the embodiments described herein to neutralize IL-34. The anti-human IL-34 antibodies of the present invention can improve immune and / or inflammatory pathology, or restore immune homeostasis, preferably by directly altering the underlying disease pathology through inhibition of the innate arm of the immune response and / or elimination of microglial proliferation or activation and / or proliferation of other mononuclear globulin / macrophage lineage cells. The use of these antibodies can clinically lead to durable long-term improvement in the treated disease. Furthermore, there is a need for diagnostic anti-human IL-34 antibodies that are specific for human IL-34, have improved binding affinity, exhibit enhanced sensitivity in human IL-34 assays, and provide improved enzyme-linked immunosorbent assay (ELISA) conditions resulting in minimal interference and broad dilution linearity. According to some embodiments of the invention, anti-human IL-34 antibodies are provided, including human IL-34 neutralizing antibodies, which bind to human IL-34 as given in SEQ ID NO: 31. Interleukin 34 (IL-34; also known as the uncharacterized protein C16orf77) is secreted as a homodimer composed of 39 kDa monomers. It belongs to an unknown family of interleukins. Human IL-34 is synthesized as a 242-amino acid (AA) precursor containing 20 AA signal sequences, yielding a mature chain of 222 AAs. As used herein, IL-34 refers to the mature chain. The mature chain contains a potential site for N-linked glycosylation. IL-34 is found in a variety of tissues, including the heart, brain, liver, kidneys, spleen, thymus, testes, ovaries, small intestine, prostate, and large intestine, with the highest concentration in the spleen. When used herein to refer to the IL-34 polypeptide, “h IL-34” or “human IL-34” refers to wild-type human IL-34, preferably having the amino acid sequence shown in SEQ ID NO: 31, which is mature IL-34 with the leader sequence removed. (See, for example, Lin et al., Science (2008) Vol. 320, No. 5877, pp. 807-811). An example of human IL-34 (SEQ ID NO:31) has the following amino acid sequence: As used herein, "human anti-IL34 antibody" or "anti-human IL-34 antibody" refers to an antibody that binds to human IL-34. Preferably, administration of the "human anti-IL34 antibody" or "anti-human IL-34 antibody" in vitro or in vivo results in a neutralization and / or blocking response of IL-34 activity, such as a significant reduction in at least one desired activity, for example, demonstrated by changes in IL-34 reactive molecules or cellular markers as evidence of a desired reduction in IL-34 signaling. For example, the number, density, or phenotype of microglia in the CNS are possible examples of IL-34 reactive molecules or cellular effects. As used herein, when the terms "signal transduction," "signal transduction," and "IL-34-mediated" refer to IL-34, they mean cellular and / or intercellular responses induced by the activity of IL-34. As used herein, the term "antibody" refers to an immunoglobulin molecule that binds to an antigen. Examples of antibodies include monoclonal antibodies, polyclonal antibodies, human antibodies, humanized antibodies, chimeric antibodies, or binding antibodies. These antibodies can be of any class (e.g., IgG, IgE, IgM, IgD, IgA) and any subclass (e.g., IgG1, IgG2, IgG3, IgG4). An exemplary antibody is an immunoglobulin G (IgG) type antibody composed of four polypeptide chains: two heavy chains (HC) and two light chains (LC) cross-linked via interchain disulfide bonds. The LCs are classified as κ or λ, each characterized by a specific constant region. Embodiments of the present invention may comprise IgG1, IgG2, or IgG4 antibodies, and further comprise κ or λ light chains. Preferably, the antibodies of the present invention comprise a light chain constant region, which is a κ constant region. HCs are classified as γ, μ, α, δ, or ε, and antibody isotypes are defined as IgG, IgM, IgA, IgD, or IgE, respectively. The amino-terminal portion of each of the four polypeptide chains includes a variable region primarily responsible for antigen recognition, containing approximately 100 to 125 or more amino acids. The carboxyl-terminal portion of each of the four polypeptide chains contains a constant region primarily responsible for effector function. Each heavy chain consists of a heavy chain variable region (VH) and a heavy chain constant region. The heavy chain constant region contains CH1, CH2, and CH3 domains. CH1 appears after HCVR; CH1 and HCVR form the heavy chain portion of the antigen-binding (Fab) fragment, which is the portion of the antibody that binds one or more antigens. CH2 appears after the hinge region and before CH3. CH3 appears after CH2 and is located at the carboxyl terminus of the heavy chain. The light chain constant region contains a CL domain. CL appears after LCVR; CL and LCVR form the light chain portion of the Fab. The antibodies of this invention comprise IgG HCs that can be further subdivided into, for example, subclasses such as IgG1, IgG2, IgG3, and IgG4, and embodiments of the invention may include one or more modifications in the constant regions of each HC, such as modifications that enhance or reduce effector function. As used herein, the term "Fc region" refers to the region of the antibody containing the CH2 and CH3 domains of the antibody heavy chain. Where appropriate, the Fc region may include a portion or the entire hinge region of the antibody heavy chain. IgG1 is known to induce antibody-dependent cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), and the Fc mutations described herein can reduce aggregation, decrease or enhance ADCC or CDC activity (or other functions), and / or modify the pharmacokinetics of the antibody. Embodiments of the anti-human IL-34 antibody described herein reduce binding to the FcγR and C1q receptors, thereby reducing or eliminating cytotoxicity induced by antibodies having the wild-type IgG Fc region. Therefore, according to some embodiments, mutations are introduced into the Fc region at the locations described herein. Patient safety can be improved by sufficiently reducing or eliminating the effector function of these anti-human IL-34 antibodies containing the modified Fc region, and, combined with other characteristics described herein, provides a modified profile of useful activity for the therapeutic agent while avoiding unwanted activity. When expressed in certain biological systems, antibodies undergo glycosylation in the Fc region. Typically, glycosylation occurs in the antibody Fc region at highly conserved N-glycosylation sites. The N-glycan is usually linked to aspartic acid. Glycosylation can also occur at other sites. The present invention relates to monoclonal antibodies. Monoclonal antibody systems are derived from a single copy or include, for example, any eukaryotic, prokaryotic, or phage pure line, and are not limited by their production method. Monoclonal antibodies can be produced, for example, by fusion tumor technology, recombinant technology, phage presentation technology, synthetic techniques such as CDR-grafting, or combinations of these techniques, or other techniques known in this field. The present invention encompasses the human or humanized antibodies of the present invention. In the case of monoclonal antibodies, the terms "human" and "humanized" are well known to those skilled in the art (Weiner LJ, J. Immunother. 2006; 29: 1-9; Mallbris L et al., J. Clin. Aesthet. Dermatol. 2016; 9: 13-15). Exemplary embodiments of the antibodies of the present invention also include antibody fragments or antigen-binding fragments that at least contain the portion of the antibody that retains the ability to specifically interact with the antigen, such as Fab, Fab', F(ab')2, Fv fragments, scFv antibody fragments, disulfide-linked Fv (sdFv), Fd fragments, and linear antibodies. The amino-terminal regions of each LC and HC protein contain variable regions of approximately 100 to 120 amino acids. These variable regions are primarily responsible for recognizing antigens via the CDRs they contain. The VH and VL regions can be further subdivided into hypervariable regions called complementarity-determining regions (CDRs), interspersed with more conserved regions called framework regions (FRs). CDRs are exposed on the protein surface and are crucial regions for antibody antigen-binding specificity. Each VH and VL protein consists of three CDRs and four FRs arranged from the amino-terminus to the carboxyl-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In this paper, the three CDRs of the heavy chain are referred to as "HCDR1, HCDR2, and HCDR3," and the three CDRs of the light chain are referred to as "LCDR1, LCDR2, and LCDR3." CDRs contain most of the residues that form specific interactions with antigens. The functional ability of an antibody to bind to a specific antigen is largely influenced by the six CDRs. Assigning amino acid residues to the CDR can be done according to well-known protocols, including those described in: Kabat (Kabat et al., "Sequences of Proteins of Immunological Interest", National Institutes of Health, Bethesda, Md. (1991)), Chothia (Chothia et al., "Canonical structures for the hypervariable regions of immunoglobulins", Journal of Molecular Biology, 196, 901-917 (1987); Al-Lazikani et al., "Standard conformations for the canonical structures of immunoglobulins", Journal of Molecular Biology, 273, 927-948 (1997)), North (North et al., "A New Clustering of Antibody CDR Loop Conformations", Journal of Molecular Biology, 406, 228-256 (2011)), or IMGT. (The international ImMunoGeneTics database is available at www.imgt.org; see Lefranc et al., Nucleic Acids Res. 1999; 27:209-212). For the purposes of this invention, and unless otherwise stated, the North CDR definition is used for the anti-IL-34 antibody described herein, and for the CDR domains that partition amino acids into the LCVR and HCVR regions. Table 2 below provides the CDR sequences of antibody 1 and / or the antibodies of this invention, generated using Benchling information software based on the rules of North, Kabat, Chothia, and / or IMGT, respectively. surface 2 : The antibody embodiments of the present invention possess a combination of pharmacologically useful and important activities and properties, and are capable of binding human IL-34 with high affinity and high specificity in a single state, as well as other useful properties. Unless otherwise specified, the term "bind" as used herein is intended to mean the ability of a protein or molecule to form an attractive interaction with another protein or molecule, as determined by commonly known methods in this art, which causes the two proteins or molecules to approach each other. Unless otherwise specified, the phrase "specific binding" as used herein regarding the affinity of anti-IL-34 antibodies for human IL-34 preferably means less than about 1 × 10⁻⁶. - 10 M, or even better, is between approximately 1 × 10 - 10 M and approximately 1 × 10 - 12 K between M D This is determined using commonly known methods within this technology, including solution equilibrium titration (SET) measured using an SPR (surface plasma resonance) biosensor and / or an MSD (Meso Scale Discovery) instrument, essentially as described herein. The phrase "specific binding" also refers to the relative affinity of anti-IL-34 antibodies for human IL-34 compared to other antigens, where this affinity for human IL-34 leads to specific recognition of human IL-34. The antibody embodiments of the present invention can be manifested and generated from constructs containing the sequences of the embodiments of the present invention using various techniques known in this art. The terms "nucleic acid" or "polynucleotide," used interchangeably herein, refer to polymers incorporating natural, modified, and / or nucleotide analogs of nucleotides, including single-stranded and / or double-stranded nucleotide-containing molecules such as DNA, cDNA, and RNA molecules. The polynucleotides of the present invention may also include acceptors incorporated therein, for example, by DNA or RNA polymerases or synthetic reactions. The DNA molecules of the present invention are DNA molecules comprising non-naturally occurring polynucleotide sequences that encode polypeptides (e.g., heavy chains, light chains, variable heavy chains, and variable light chains) having the amino acid sequence of at least one polypeptide of the antibodies of the present invention. A separated DNA encoding an HCVR or LCVR region can be converted into a full-length heavy chain gene, forming a heavy chain or light chain, by operatively linking the corresponding HCVR or LCVR-encoding DNA to another DNA molecule encoding a heavy chain or light chain constant region. The sequences of heavy chain constant region genes in humans and other mammals are known in this technique. DNA fragments covering these regions can be obtained, for example, by standard PCR amplification. After the sequence has been operatively ligated to the expression control sequence, the polynucleotide of the present invention can be expressed in host cells. Expression vectors can typically replicate in the host organism either in a free genomic body or as a whole portion of the host chromosomal DNA. Typically, expression vectors will contain selection markers, such as tetracycline, neomycin, and dihydrofolate reductase, to allow detection of cells transformed with the desired DNA sequence. Vectors containing the polynucleotide sequence of interest (e.g., a polynucleotide encoding a polypeptide of an antibody and an expression control sequence) can be transferred into host cells using well-known methods that vary depending on the type of cell host. The antibodies of this invention can be readily produced in mammalian cells, non-limiting examples of which include CHO, NSO, HEK293, or COS cells. Host cells are cultured using techniques well known in this art. Mammal expression of the antibody typically results in glycosylation. Antibody glycosylation is typically N-linked or O-linked. N-linked glycosylation refers to the linking of a carbohydrate moiety to a side chain of an aspartic acid residue. O-linked glycosylation refers to the linking of a sugar, such as N-acetylglucosamine, galactose, or xylose, to a hydroxylamine amino acid. Typically, glycosylation occurs at highly conserved N-glycosylation sites in the antibody Fc region (e.g., position 297 in IgG1 according to the IMGT or EU index number). Glycosylation sites can be modified to alter glycosylation (e.g., blocking or reducing glycosylation or altering the amino acid sequence to produce additional or diversified glycosylation). Mammal expression of antibodies from the IgG subclass can result in the cleavage of one or two C-terminal amino acids in the heavy chain; for example, with IgG1 antibodies, one or two C-terminal amino acids may be removed. For IgG1 antibodies, if a C-terminal lysine is present, it can be cleaved or truncated from the heavy chain during expression. Additionally, the subterminal glycine can also be cleaved or truncated from the heavy chain. The mammalian expression of antibodies can also lead to the modification of N-terminal amino acids. For example, when the N-terminal amino acid of the heavy or light chain is glutamic acid, it can be modified into pyroglutamic acid. The antibodies of this invention, or pharmaceutical compositions comprising them, can be administered via non-enteral routes, including subcutaneous and intravenous administration as non-limiting examples. The antibodies of this invention can be administered to patients in single or multiple doses using pharmaceutically acceptable carriers, diluents, or excipients. The pharmaceutical compositions of this invention can be prepared by methods well known in the art (e.g., Remington: The Science and Practice of Pharmacy, 22nd ed. (2012), A. Loyd et al., Pharmaceutical Press) and comprise the antibodies as disclosed herein and one or more pharmaceutically acceptable carriers, diluents, or excipients. Use of the antibody examples of the present invention According to some embodiments, the anti-IL-34 antibody of the present invention can be used to treat immune-mediated diseases. As used herein, the terms "immune-mediated disease" or "inflammatory disease or condition" are used interchangeably and refer to adverse conditions caused by inappropriate or excessive immune responses, wherein IL-34 inhibition leads to a greater homeostatic response and a less pathological response. The terms "immune-mediated disease" or "inflammatory condition" are intended to include such conditions, whether they are mediated by microglial or macrophage cellular immune responses or by cellular immune responses mediated by similar tissue-resident cell types such as histiocytes, Kupffer cells, alveolar macrophages, intestinal macrophages, macrophage-like synovial cells, or Langerhans cells. Examples of diseases for which the antibody therapy of the present invention described herein is intended to be used include Alzheimer's disease; Tau disease; Sjogren's syndrome (SS); rheumatoid arthritis (RA); inflammatory bowel disease (IBD), atopic dermatitis, nephropathy, sepsis, amyotrophic lateral sclerosis (ALS) and / or non-alcoholic fatty liver disease (NAFLD). In some more specific embodiments, the immune-mediated disease is Alzheimer's disease (AD). According to other embodiments of the invention, anti-IL-34 antibodies can be used for diagnostic applications in immune-mediated diseases. In some embodiments, the immune-mediated disease is at least one of AD; Hughley's syndrome (SS); rheumatoid arthritis (RA); inflammatory bowel disease (IBD), atopic dermatitis, nephropathy, sepsis, and / or non-alcoholic fatty liver disease (NAFLD). The present invention further provides a pharmaceutical composition comprising the anti-IL-34 antibody of the present invention and one or more pharmaceutically acceptable carriers, diluents, or excipients. Furthermore, the present invention provides a method for treating immune-mediated diseases such as Alzheimer's disease (AD); Hughley's syndrome (SS); rheumatoid arthritis (RA); inflammatory bowel disease (IBD), atopic dermatitis, nephropathy, sepsis, and / or non-alcoholic fatty liver disease (NAFLD), comprising administering the pharmaceutical composition of the present invention to a patient in need. In addition, the present invention provides a method for treating immune-mediated diseases. More specifically, the present invention provides a method for treating immune-mediated diseases including Alzheimer's disease (AD); Hugh Grant's syndrome (SS); rheumatoid arthritis (RA); inflammatory bowel disease (IBD), atopic dermatitis, nephropathy, sepsis, and / or non-alcoholic fatty liver disease (NAFLD), comprising administering an effective amount of the anti-IL-34 antibody of the present invention to a patient in need. This invention also provides the anti-IL-34 antibody of this invention for therapeutic purposes. More specifically, this invention provides the anti-IL-34 antibody of this invention for the treatment of immune-mediated diseases including Alzheimer's disease (AD); Hugh Grant's syndrome (SS); rheumatoid arthritis (RA); inflammatory bowel disease (IBD), atopic dermatitis, nephropathy, sepsis, and / or non-alcoholic fatty liver disease (NAFLD). In some embodiments, the present invention provides the use of the anti-IL-34 antibody of the present invention for the manufacture of a medicament for the treatment of one or more immune-mediated diseases, including Alzheimer's disease (AD); Hughley's syndrome (SS); rheumatoid arthritis (RA); inflammatory bowel disease (IBD), atopic dermatitis, nephropathy, sepsis, and / or non-alcoholic fatty liver disease (NAFLD). The antibodies of this invention can be used to identify immune-mediated diseases in which IL-34 may contribute to the pathogenesis of the disease. In other embodiments, this invention provides a method for treating a patient with an immune-mediated disease. These methods include the steps of: contacting a patient sample with an anti-IL-34 antibody and detecting the binding between human IL-34 and the antibody in the patient sample; and diagnosing the patient as having, being at risk of, requiring treatment, and / or at risk of symptoms associated with an immune-mediated disease (see, for example, Xie, HH, et al.) when the presence of IL-34 in the patient sample is detected to be higher than a reference value observed in unaffected individuals. Elevated Serum Interleukin - 34 Level in Patients with Systemic Lupus Erythematosus Is Associated with Disease Activity. Sci Rep 8, 3462 (2018). According to some more specific embodiments of the treatment methods provided herein, these methods further include the steps of: determining a reference value, which includes the further step of contacting a control standard with a first antibody that binds to the same IL-34 first antigenic determinant region used to contact the patient sample; contacting the control standard with a second antibody having a detectable label and binding to the same IL-34 second antigenic determinant region used to contact the patient sample; and detecting a signal provided by the detectable signal. In some specific embodiments, the anti-IL-34 antibody comprises a combination of LC and HC CDRs provided in Table 1. In other embodiments, the second antibody comprises a combination of LCVR and HCVRs provided in Table 1. According to some embodiments, the reference value is approximately 10-30 pg / mL, for example, from CNS tissue degradation products. In some embodiments, the immune-mediated disease is one of AD; Hughley's syndrome (SS); rheumatoid arthritis (RA); inflammatory bowel disease (IBD), atopic dermatitis, nephropathy, sepsis, and / or non-alcoholic fatty liver disease (NAFLD). In some embodiments, the patient sample is one of CSF, blood, serum, tissue breakdown products, or plasma. According to some embodiments, the method further includes the steps of: contacting the patient sample with a second anti-IL-34 antibody that binds to the second antigenic determinant region of IL-34 and has a detectable label; and detecting a signal provided by the detectable signal. In other embodiments, the second antibody comprises a combination of LC and HC CDR provided in Table 1. In other embodiments, the second antibody comprises a combination of LCVR and HCVR provided in Table 1. According to some embodiments, the first and second anti-IL-34 antibodies are not bound together. According to some embodiments, the present invention provides a method for detecting IL-34 in a patient sample, comprising the steps of: contacting the patient sample with a first antibody that binds to a first antigenic determinant region of IL-34; contacting the patient sample with a second antibody that binds to a second antigenic determinant region of IL-34 and has a detectable label; and detecting a signal provided by the detectable label. In some embodiments, the patient sample is one of blood, serum, tissue breakdown products, or plasma. According to some more specific embodiments, the first antigenic determinant region of IL-34 and the second antigenic determinant region of IL-34 partially overlap. Furthermore, in some embodiments, the steps of contacting the first and second antibodies occur simultaneously. In some specific embodiments, the first antibody comprises a combination of LC and HC CDR provided in Table 1. In other embodiments, the first antibody comprises a combination of LCVR and HCVR provided in Table 1. According to some embodiments of the present invention, a method for quantifying IL-34 in a patient sample is provided. The method includes the steps of: contacting the patient sample with a first antibody that binds to a first antigenic determinant region of IL-34; contacting the patient sample with a second antibody that binds to a second antigenic determinant region of IL-34 and has a detectable label; and detecting a signal provided by the detectable label; contacting a control standard with a first antibody that binds to the same (e.g., the first antigenic determinant region of IL-34 used for contacting the patient sample); contacting the control standard with a second antibody that binds to the same (e.g., the second antigenic determinant region of IL-34 used for contacting the patient sample) and has a detectable label; and detecting a signal provided by the detectable label. In some embodiments, the patient sample is one of blood, serum, plasma, or tissue breakdown products. According to some more specific embodiments, the first antigenic determinant region of IL-34 and the second antigenic determinant region of IL-34 partially overlap. Furthermore, in some embodiments, the steps of contacting the first and second antibodies occur simultaneously. In some specific embodiments, the first antibody comprises a combination of LC and HC CDR provided in Table 1. In other embodiments, the first antibody comprises a combination of LCVR and HCVR provided in Table 1. In some specific embodiments, the second antibody comprises a combination of LC and HCVR provided in Table 1 or herein. In other embodiments, the second antibody comprises a combination of LCVR and HCVR provided in Table 1. According to some embodiments, methods for diagnosing immune-mediated diseases are provided. These methods include the steps of contacting a patient sample with an anti-IL-34 antibody and detecting the binding between IL-34 and the antibody in the patient sample. According to some specific embodiments, the diagnostic method includes diagnosing a patient as having; being at risk; requiring treatment; and / or at risk of symptoms associated with an immune-mediated disease when the presence of IL-34 in the patient sample is detected to be above a reference value. According to some more specific embodiments, these methods further include the steps of: determining a reference value, which includes contacting a control standard with a first antibody that binds to the same IL-34 first antigenic determinant region used to contact the patient sample; contacting the control standard with a second antibody having a detectable label and binding to the same IL-34 second antigenic determinant region used to contact the patient sample; and detecting a signal provided by the detectable signal. In some embodiments, the first antibody comprises a combination of LC and HC CDR provided in Table 1. Some embodiments of the methods for diagnosing immune-mediated diseases provided herein further include the steps of: contacting a patient sample with a second anti-IL-34 antibody that binds to the second antigenic determinant region of IL-34 and has a detectable label; and detecting a signal provided by the detectable label. In some specific embodiments, the anti-IL-34 antibody comprises a combination of LC and HC CDRs provided in Table 1. In other embodiments, the antibody comprises a combination of LCVR and HCVRs provided in Table 1. According to a specific embodiment, the first antigenic determinant region of IL-34 partially overlaps with the second antigenic determinant region of IL-34. According to some embodiments, the first and second antibodies are not bound together. According to other embodiments, the reference value is in the range of approximately 10-30 pg / mL, derived from CNS tissue degradation products, and / or a suitable reference set and sample source determined by a person skilled in the art. In other embodiments, the immune-mediated disease is one of AD; tau proteinosis; Hughley's syndrome (SS); rheumatoid arthritis (RA); inflammatory bowel disease (IBD), atopic dermatitis, nephropathy, sepsis, and / or non-alcoholic fatty liver disease (NAFLD). In one embodiment, the present invention provides a method for determining the content of human IL-34 in body fluids, comprising: (a) contacting the body fluids with a diagnostic monoclonal antibody against human IL-34 or an antigen-binding fragment thereof, the antibody or antigen-binding fragment thereof specifically binding to human IL-34, such as that composed of the amino acid sequence in SEQ ID NO: 31, the antibody or antigen-binding fragment thereof comprising: light chain complementarity-determining regions LCDR1, LCDR2 and LCDR3 comprising amino acid sequences (SEQ ID NO: 8), (SEQ ID NO: 9) and (SEQ ID NO: 10), respectively, and heavy chain complementarity-determining regions HCDR1, HCDR2 and HCDR3 comprising amino acid sequences (SEQ ID NO: 5), (SEQ ID NO: 6) and (SEQ ID NO: 7), respectively; (b) removing any non-specifically binding monoclonal antibody or antigen-binding fragment thereof as appropriate; and (c) detecting and / or quantifying the amount of monoclonal antibody or antigen-binding fragment thereof specifically binding to human IL-34. Preferably, the fluid is blood, serum or plasma, or cerebrospinal fluid, and the contact occurs outside the body. Tau protein disorders include, but are not limited to, Alzheimer's disease (AD), Pick's disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), auricolic granulomatosis, Down syndrome, chronic traumatic encephalopathy (CTE), traumatic brain injury (TBI), frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17), Guam Parkinson's disease-dementia complex, Niemann-Pick type C disease, and tonic dystrophy (see Li, C., Götz, J.). Tau - based therapies in neurodegeneration : opportunities and Challenges .Nat Rev Drug Discov 16, 863-883 (2017)). In embodiments of the present invention, the patient is a human being diagnosed with a medical risk, symptom, or condition such as that described herein, requiring treatment with the antibody described herein. In cases where the condition treatable by the method of the present invention is known by established and accepted classifications, such as Alzheimer's disease; tau proteinosis; Hughley's syndrome (SS); rheumatoid arthritis (RA); inflammatory bowel disease (IBD), atopic dermatitis, nephropathy, sepsis, and / or non-alcoholic fatty liver disease (NAFLD), their classifications can be found in various well-known medical texts. For example, the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) currently provides diagnostic tools for identifying certain conditions described herein. Furthermore, the International Classification of Diseases, Tenth Revision (ICD-10) provides classifications for certain conditions described herein. Those familiar with this technique will recognize that there are alternative nomenclatures, disease classifications, and classification systems for the diseases and symptoms described herein, including those described in DSM-5 and ICD-10, and that terminology and classification systems have evolved with the development of medical science. The term "treating" (or "treatment") refers to slowing down, interrupting, halting, alleviating, stopping, reducing, or reversing the progression or severity of existing symptoms, ailments, conditions, or diseases in an individual. The term "individual" refers to a human being. The terms "human individual" and "patient" are used interchangeably in this invention. As used herein, "treatment method" also applies to the use of the composition in treating the disease or condition described herein and / or the composition used and / or in the manufacture of a medicament for treating the disease or condition described herein. The term "preventing / prevention" refers to the preventive administration of the antibody of this invention to asymptomatic individuals or individuals with preclinical Alzheimer's disease to prevent the onset or progression of the disease. As used in this article, the term "delayed progression" means delaying or inhibiting the progression of a disease or its symptoms within an individual. The terms "diseases characterized by Aβ deposition" or "diseases characterized by Aβ deposits" are used interchangeably and refer to diseases pathologically characterized by Aβ deposits in the brain or cerebral vascular structures. This includes diseases such as Alzheimer's disease, Down syndrome, and amyloid angiopathy. The clinical diagnosis, staging, or progression of Alzheimer's disease can be easily determined by the attending physician or healthcare professional, if proficient in this technique, using known techniques and observational results. This typically includes brain plaque imaging, mental or cognitive assessments (e.g., Clinical Dementia Rating - Summary of Boxes (CDR-SB), Mini-Mental State Exam (MMSE), or Alzheimer's Disease Assessment Scale - Cognitive (ADAS-Cog)) or functional assessments (e.g., Alzheimer's Disease Cooperative Study - Activities of Daily Living). Living; ADCS-ADL). Cognitive and functional assessments can be used to determine cognitive changes (e.g., cognitive decline) and functional changes (e.g., functional decline) in patients. Therefore, according to the techniques described herein, an individual can be identified as having "slowly progressive" cognitive decline. In one illustrative embodiment, "slowly progressive" cognitive decline can be identified by iADRS, where an individual's iADRs decline by less than about 20 over a given time period (e.g., 6, 12, 18, or 24 months). In another illustrative embodiment, "slowly progressive" cognitive decline can be identified by APOE-4 genotyping, where the individual is APOE-4 homozygous negative or AP... OE-4 heterozygous. In another illustrative embodiment, "slowly progressive" cognitive decline can be identified by MMSE, where an individual is identified as having an MMSE of approximately 27 or a decline in MMSE of less than approximately 3 over a given time period (e.g., 6, 12, 18, or 24 months). As used herein, "clinical Alzheimer's disease" refers to the diagnostic stage of Alzheimer's disease. It includes symptom diagnosis of prodromal Alzheimer's disease, mild Alzheimer's disease, moderate Alzheimer's disease, and severe Alzheimer's disease. The term "preclinical Alzheimer's disease" refers to the stage prior to clinical Alzheimer's disease, where measurable changes in biomarkers (such as CSF Aβ42 levels or deposited brain plaques obtained via amyloid PET) indicate the earliest signs in a patient with Alzheimer's pathology that progress to clinical Alzheimer's disease. This typically occurs before symptoms such as memory loss and confusion become identifiable.Preclinical Alzheimer's disease also includes pre-existing autosomal dominant carriers and patients with a higher risk of developing AD due to carrying one or both APOE e4 paired genes. The reduction or slowing of cognitive decline can be measured using cognitive assessments such as the Clinical Dementia Rating Scale-Box Sum, the Brief Mental State Test, or the Alzheimer's Disease Rating Scale-Cognition. The reduction or slowing of functional decline can be measured using functional assessments such as the ADCS-ADL. As used herein, "mg / kg" refers to the amount of antibody or drug administered to an individual, expressed in milligrams, based on their body weight in kilograms. A single dose is given. For example, for an individual weighing 70 kg, a 10 mg / kg dose of antibody would be equivalent to a single 700 mg dose of antibody administered in a single dosing. Similarly, for an individual weighing 70 kg, a 20 mg / kg dose of antibody would be equivalent to a single 1400 mg dose of antibody administered in a single dosing. As used in this article, if based on 18 Quantitative analysis of flortaucipir (F-fluorocyclopyr) showed that a tau load less than 1.10 SUVr (<1.10 SUVr) indicates a "very low tau" load in human individuals. Quantitative analysis refers to calculating SUVr, where SUVr represents the tau load relative to the reference region (parametric estimation of reference signal intensity or PERSI; see Southekal et al., "Flortaucipir F 18 Quantitation Using Parametric Estimation of Reference Signal Intensity"). J . Nucl . Med When comparing .59:944-951 (2018)), specific target attention regions in the brain (multi-block centroid discriminant analysis or MUBADA, see Devous et al., "Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir F18"), J . Nucl . Med Counts within .59:937-943 (2018)). As used herein, if based on 18 Quantitative analysis of F-fluroxepirine showed that a tau load less than or equal to 1.46 SUVr (i.e., ≤1.46 SUVr) indicates a human individual with a "very low to moderate tau" load. Quantitative analysis refers to calculating SUVr, where SUVr represents the load relative to the reference zone (PERSI; see Southekal et al., "Flortaucipir F 18 Quantitation Using Parametric Estimation of Reference Signal Intensity"). J . Nucl . Med When comparing the target-specific attention area (MUBADA) in the brain (see Devous et al., "Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir F18"), .59:944-951 (2018) J . Nucl . Med The counts within .59:937-943 (2018)). As used in this article, if based on 18 Quantitative analysis of F-fluroxepirine showed that individuals with a tau load greater than or equal to 1.10 and less than or equal to 1.46 (i.e., ≥1.10 SUVr to ≤1.46 SUVr) had a "low to moderate tau" load. Quantitative analysis refers to calculating SUVr, where SUVr represents the load relative to the reference zone (PERSI; see Southekal et al., "Flortaucipir F 18 Quantitation Using Parametric Estimation of Reference Signal Intensity"). J . Nucl . Med When comparing the target-specific attention area (MUBADA) in the brain (see Devous et al., "Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir F18"), .59:944-951 (2018) J . Nucl . Med The counts are within .59:937-943 (2018). Human individuals with a "low to moderate tau" load can also be described as having a "moderate" tau load. As used in this article, if based on 18 Quantitative analysis of F-fluroxepirine showed that a tau load greater than 1.46 SUVr (i.e., >1.46 SUVr) indicates a "high tau" load in human individuals. Quantitative analysis refers to calculating SUVr, where SUVr represents the tau load relative to the reference zone (PERSI; see Southekal et al., "Flortaucipir F 18 Quantitation Using Parametric Estimation of Reference Signal Intensity"). J . Nucl . Med When comparing the target-specific attention area (MUBADA) in the brain (see Devous et al., "Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir F18"), .59:944-951 (2018) J . Nucl . Med The counts within .59:937-943 (2018)). As used in this article, the term "about" means up to ±10%. As used in this article, the term "innate immunity" includes the arm of the immune response that is opposite to the arm of the acquired immune response, which is required to initiate and maintain the acquired immune response (antibody and T cell response). "Effective amount" means the amount that a therapeutic healthcare professional is seeking to elicit a biological or medical response or desired therapeutic effect in a tissue, system, or human body from the anti-human IL-34 antibody of the present invention or a pharmaceutical composition containing the antibody. As used herein, the term "effective response" or "patient responsiveness to treatment" refers to the clinical or therapeutic benefit accrued to a patient upon administration of the antibody of the present invention. The effective amount of an antibody may vary depending on factors such as an individual's disease condition, age, sex, and weight, as well as the antibody's ability to elicit a desired response in the individual. An effective amount is also an amount in which a therapeutically beneficial effect outweighs any toxic or damaging effects of the antibody. This benefit includes any one or more of the following: reduced levels of inflammation or immune activation; stabilization of immune-mediated diseases or conditions; or improvement of signs or symptoms of immune-mediated diseases. Alternatively, this benefit includes any one or more of the following: increased immune tolerance to transplanted organs; stabilization of autoimmune diseases or conditions; or improvement of signs or symptoms of autoimmune diseases. The potential benefits of the methods disclosed herein include significant and / or long-term remissions in patients with immune-mediated or neuroinflammatory conditions, with an acceptable safety profile, including acceptable tolerability, toxicity, and / or adverse events, thereby enabling patients to benefit overall from the treatment. The efficacy of the treatments of this invention can be measured using various indicators commonly used to assess treatments for various immune-mediated conditions. Other methods for determining the efficacy of any particular therapy of this invention may be employed, including, for example, markers of immune cell activation, inflammation assays, cell cycle-dependent biomarker assays and observations, and / or measurement of response using various inflammatory, immune, or tissue-specific biomarkers. The effective dose can be readily determined by a person skilled in the art using known techniques and by observations obtained under similar conditions. The effective dose of the anti-human IL-34 antibody of the present invention can be administered in a single dose or multiple doses. Furthermore, the effective dose of the antibody of the present invention can be administered in multiple doses, the amount being less than the effective dose if not administered more than once. When determining the effective dose for a patient, the attending physician will consider several factors, including but not limited to: the patient's body type (e.g., weight or mass), body surface area, age, and general health status; the specific disease or condition involved; the degree, involvement, or severity of the disease or condition; the individual patient's response; the specific compound administered; the administration method; the bioavailability characteristics of the administered formulation; the chosen dosing regimen; the use of concomitant medications; and other relevant circumstances known to the physician. The weekly, bi-weekly, monthly, or quarterly non-enteral (including but not limited to subcutaneous, intramuscular, and / or intravenous) dose may be from about 0.5 mg / kg to about 50 mg / kg. As used herein, the term "month" or its derivatives refer to a period of time comprising 28 to 31 consecutive days. The potential benefits of the methods disclosed herein include significant and / or long-term remission in patients with immune-mediated diseases or neuroinflammatory diseases, with an acceptable safety profile, including acceptable tolerability, toxicity, and / or adverse events, thereby enabling patients to benefit overall from the treatment. More specifically, the antibodies of this invention will provide effective treatment while avoiding clinically unwanted immunosuppression and / or immune-related adverse events such as "cytokine storm" or significant cytokine release. The antibodies of this invention can be used to treat cytokine storms or other adverse cytokine releases. As used herein, "significant cytokine release" refers to a significant increase in measurable cytokines that can be detected by methods known to those skilled in the art. For example, significant cytokine release in human blood samples can be detected by ELISA, in which the cytokine content in unstimulated blood is compared with the cytokine content in blood cultured with the antibody. For example, in some of these studies, significant cytokine release can be detected if the levels of IL-6, IL-8, or IFN-γ in antibody-cultured blood are at least three times higher than those in unstimulated blood. Preferably, treatment for immune-mediated diseases as described in the embodiments herein will occur, in which the patient will not experience significant cytokine release. Antibody 1 Combined uses The present invention further provides the antibody of the present invention, specifically antibody 1, and the simultaneous, separate, or sequential combination of anti-N3pGlu Aβ antibody, and methods of using such combinations to treat diseases such as AD characterized by amyloid β (Aβ) deposition. Some known anti-Aβ antibodies that can be used in the combinations of the present invention include donanemab, bapineuzumab, gantenerumab, aducanumab, GSK933776, solanezumab, crenezumab, ponezumab, and lecanemab (BAN2401). The present invention further provides a simultaneous, separate, or sequential combination of antibody 1 and doneemab (CAS No. 1931944-80-7, SEQ ID NO: 38 and 39), and a method of using such combinations to treat diseases such as Alzheimer's disease characterized by amyloid β (Aβ) deposition (Donanemab in early Alzheimer's disease, Mintun, MA et al., New England Journal of Medicine (2021), 384(18), 1691-1704). Preferably, the combination provides for the continuous use of antibody 1 after treatment with doneemab. As used herein, the interchangeable terms "anti-N3pGlu Aβ antibody," "anti-N3pG antibody," or "anti-N3pE antibody" refer to antibodies that preferentially bind to N3pGlu Aβ relative to Aβ1-40 or Aβ1-42. Those skilled in the art will understand and recognize that "anti-N3pGlu Aβ antibody" and certain specific antibodies, including "hE8L," "B12L," and "R17L," are identified and disclosed in U.S. Patent No. 8,679,498 B2 (which is incorporated herein by reference in its entirety) (along with methods of manufacturing and using such antibodies). See, for example, Table 1 of U.S. Patent No. 8,679,498 B2. Each of the antibodies disclosed in U.S. Patent No. 8,679,498 B2, including the "hE8L", "B12L", and "R17L" antibodies, can be used as the anti-N3pGlu Aβ antibody of the present invention or as a substitute for the anti-N3pGlu Aβ antibodies described in the various embodiments of the present invention. The anti-N3pGlu Aβ antibody system of the combination method of the present invention comprises the HC and LC antibodies of SEQ ID NO: 40 and 41, respectively. Other representative species of anti-N3pGlu Aβ antibodies include, but are not limited to, the antibodies disclosed below: U.S. Patent No. 8,961,972; U.S. Patent No. 10,647,759; U.S. Patent No. 9,944,696; WO 2010 / 009987A2; WO 2011 / 151076A2; WO 2012 / 136552A1, and their equivalents, such as according to 35 USC 112(f). Those skilled in the art will understand and recognize that "anti-N3pGlu Aβ antibody" and certain specific antibodies are identified and disclosed in the following (together with methods of manufacturing and using such antibodies): U.S. Patent No. 8,961,972 (incorporated herein by reference in its entirety); U.S. Patent No. 10,647,759 (incorporated herein by reference in its entirety); and U.S. Patent No. 9,944,696 (incorporated herein by reference in its entirety). Any of the anti-N3pGlu Aβ antibodies disclosed in U.S. Patent Nos. 8,961,972, 9,944,696, and 10,647,759 may be used as the anti-N3pGlu Aβ antibody of the present invention or as a substitute for the anti-N3pGlu Aβ antibodies described in various embodiments of the present invention. Those skilled in the art will understand and recognize that "anti-N3pGlu Aβ antibody" and several specific antibodies, including "antibody VI", "antibody VII", "antibody VIII" and "antibody IX", are identified and disclosed in WO2010 / 009987A2 (which is incorporated herein by reference in its entirety) (along with methods of manufacturing and using such antibodies). Each of these four antibodies (e.g., "antibody VI", "antibody VII", "antibody VIII" and "antibody IX") can be used as the anti-N3pGlu Aβ antibody of the present invention or as a substitute for the anti-N3pGlu Aβ antibodies described in various embodiments of the present invention. Those skilled in the art will understand and recognize that "anti-N3pGlu Aβ antibody" and certain specific antibodies, including "antibody X" and "antibody XI," are identified and disclosed in WO 2011 / 151076A2 (which is incorporated herein by reference in its entirety) (along with methods of manufacturing and using such antibodies). Each of these two antibodies (e.g., "antibody X" and "antibody XI") can be used as the anti-N3pGlu Aβ antibody of the present invention or as a substitute for the anti-N3pGlu Aβ antibodies described in various embodiments of the present invention. Those skilled in the art will understand and recognize that "anti-N3pGlu Aβ antibody" and certain specific antibodies, including "antibody XII" and "antibody XIII," are identified and disclosed in WO 2012 / 136552A1 (which is incorporated herein by reference in its entirety) (along with methods of manufacturing and using such antibodies). Each of these two antibodies (e.g., "antibody XII" and "antibody XIII") can be used as the anti-N3pGlu Aβ antibody of the present invention or as a substitute for the anti-N3pGlu Aβ antibodies described in various embodiments of the present invention. This invention provides a method for treating diseases characterized by Aβ deposition in an individual using a combination of the antibody of this invention, specifically antibody 1, and an anti-N3pGlu Aβ antibody, specifically donenemab, wherein the individual is selected based on: i) the tau content / burden (global tau) in their whole brain, ii) the tau content / burden in a region of their brain (e.g., different lobes), and / or the presence of one or two APOE e4 pairs in the individual's genome. Diseases that can be treated or prevented using the combination method disclosed herein include, for example, Alzheimer's disease (AD), Down syndrome, and amyloid angiopathy (CAA). This invention also relates to using the combination provided herein to slow disease progression in individuals with early-symptom Alzheimer's disease (AD) in the presence of moderate brain tau burden. Anti-N3pGlu Aβ systems are known in this art and are described herein. For example, U.S. Patent No. 8,679,498 (which is incorporated herein by reference in its entirety, including the anti-N3pGlu Aβ antibody disclosed therein) discloses anti-N3pGlu Aβ antibodies and methods of treating diseases such as Alzheimer's disease with these antibodies. Passive immunization, by long-term continuous administration of antibodies against Aβ, including N3pGlu Aβ, found in deposits, has been shown to disrupt Aβ aggregates and promote plaque clearance in the brains of various animal models. Donemumab (disclosed in U.S. Patent No. 8,679,498, see also CAS No. 1931944-80-7) is a pyroglutamic acid-modified antibody against the third amino acid of the amyloid β (N3pGlu Aβ) antigenic determinant, which is found only in amyloid plaques in the brain. Donemumab's mechanism of action is to target and remove existing amyloid plaques, a key pathological marker of AD. The second neuropathological marker of Alzheimer's disease (AD) is the presence of intracellular neurofibrillary tangles containing hyperphosphorylated tau protein. Aβ may trigger tau pathology, with a more complex and synergistic interaction between Aβ and tau manifesting in later stages and driving disease progression (Busche et al., "Synergy Between Amyloid-β and Tau in Alzheimer's disease"). Nature Neuroscience23:1183-93 (2020)). Administration of Aβ antibodies has led to adverse events in humans, such as amyloid-associated imaging abnormalities (ARIA), signs of angioedema and sulcus effusion (ARIA-E), microbleeds and hemosiderin deposition (ARIA-H), infusion site reactions, and immunogenicity risks. See, e.g., Piazza and Winblad, "Amyloid-Related Imaging Abnormalities (ARIA) in Immunotherapy Trials for Alzheimer's Disease: Need for Prognostic Biomarkers?" Journal of Alzheimer's Disease, 52:417-420 (2016); Sperling et al., "Amyloid-related Imaging Abnormalities in Patients with Alzheimer's Disease Treated with Bapineuzumab: A Retrospective Analysis," The Lancet Neurology 11.3: 241-249 (2012); Brashear et al., "Clinical Evaluation of Amyloid-related Imaging Abnormalities in Bapineuzumab Phase III Studies", J. of Alzheimer's Disease 66.4:1409-1424 (2018); Budd et al., "Clinical Development of Aducanumab, an Anti-Aβ Human Monoclonal Antibody Being Investigated for the Treatment of Early Alzheimer's Disease", The Journal of Prevention of Alzheimer's Disease 4.4: 255 (2017). The combination therapy strategy of donenemab and antibody 1 in this invention includes targeting N3pGlu Aβ, which is specific to amyloid plaques in early symptomatic AD patients with pre-existing cerebral amyloid burden, and targeting neuroinflammation in these patients. This basic principle is based on the amyloid hypothesis of AD, which suggests that the production and deposition of Aβ are early and necessary events in the pathogenesis of AD. See, for example, Selkoe, "The Origins of Alzheimer Disease: A is for Amyloid". JAMA 283:1615-1617 (2000). Clinical support for this hypothesis comes from the following arguments: parenchymal Aβ levels increase before the onset of AD symptoms, and this is supported by AD gene variants that overproduce brain Aβ and gene variants that prevent Aβ production. See, for example, Jonsson et al., "A Mutation in APP Protects Against Alzheimer's Disease and Age-related Cognitive Decline". Nature488 (7409):96-99 (2012) and Fleisher et al., "Associations Between Biomarkers and Age in the Presenilin 1 E280A Autosomal Dominant Alzheimer Disease Kindred: A Cross-sectional Study", JAMA Neurol .72:316-24 (2015). Therefore, there is a need for improved drug combinations to treat individuals without causing or increasing problematic adverse events. Neuroinflammation is an important component of neurodegenerative diseases and is characterized by increased production of pro-inflammatory cytokines by CNS cells. Neuroinflammation and microglial proliferation are considered potential mechanisms of Alzheimer's disease and / or neuronal cell death and dysfunction. Microglial proliferation involves the abnormal proliferation and / or hypertrophy of microglia in response to inflammatory signals. IL-34 acts as a potent pleiotropic cytokine in the regulation of inflammatory and immune processes and is expressed by neurons in the cortex, anterior olfactory nucleus, and hippocampus. Treatment with antibody 1 and N3pGlu Aβ antibody, specifically donepemumab, concurrently, alone, or preferably continuously after N3pGlu Aβ antibody therapy, aims to improve the impact of neuroinflammation and / or microglial proliferation on the pathogenesis of AD and to slow or prevent the progression of neurodegenerative processes in these patients. One aspect of this invention is based on the concept that Alzheimer's patients with low or moderate tau, very low to moderate tau, or no high tau respond to combination therapy with an anti-N3pGlu Aβ antibody, such as donepemab, and an antibody of the present invention, such as antibody 1. Another aspect of this invention is based on the concept that Alzheimer's patients with one or two APOE e4 paired genes respond to treatment with an anti-N3pGlu Aβ antibody. Yet another aspect of this invention is based on the concept that Alzheimer's patients with one or two APOE e4 paired genes and low or moderate tau, very low to moderate tau, or no high tau respond to combination therapy with an anti-N3pGlu Aβ antibody, such as donepemab, and an antibody of the present invention, such as antibody 1. Some aspects of this invention pertain to patient-based neuropathology-based diagnosis and treatment. Patient selection based on neuropathology not only provides a more homogeneous population in clinical trials but also ensures accurate identification of AD stages and progression. Correctly identifying the stage of AD also allows for, for example, timely referral to a memory clinic, accurate and early diagnosis of AD, initiation of symptomatic treatment, future planning, and initiation of disease remission therapy using combination therapy with anti-N3pGlu Aβ antibodies such as donepemab and antibodies of the present invention such as antibody 1. Some embodiments of the present invention provide combined embodiments for treating human individuals suffering from a disease characterized by Aβ deposits in the individual's brain, wherein the individual is first administered an anti-N3pGlu Aβ antibody, such as donepemab, in two steps, and then treated simultaneously, separately, or consecutively with an antibody of the present invention, such as antibody 1. In the first step, the human individual is administered one or more first doses of about 100 mg to about 700 mg of anti-N3pGlu Aβ antibody, wherein each first dose is administered approximately every 4 weeks. Approximately four weeks after the administration of one or more first doses, in the second step, the human individual is administered one or more second doses greater than 700 mg to about 1400 mg, wherein each second dose is administered every 4 weeks. Preferably, the anti-N3pGlu Aβ system is donepemab. The treatment with antibody 1 and donepemab is administered simultaneously, separately, or consecutively after the treatment. Preferably, antibody 1 is administered consecutively after the treatment with donepemab. Some approaches to combination therapy are based on identifying the stage / progression of AD in patients based on: i) the total or overall tau load in the individual brain, or ii) the spread of tau in the individual brain or its regions or parts. In some embodiments, patients may be stratified / identified / selected / treated based on the amount of tau present in an individual's brain (e.g., the whole brain or a part of the brain). In some embodiments, patients may be stratified / identified / selected / treated based on the amount of tau present in an individual's brain (e.g., the whole brain or a part of the brain) and the presence of one or two APOE e4 paired genes. In other embodiments, patients are stratified / identified / selected / treated based on the stage of AD progression (e.g., based on the spread of tau in the brain). For example, during some stages, the tau load in AD patients is isolated to areas of the frontal or temporal lobes that do not include the posterolateral temporal lobe (PLT). Another stage of AD is in which the tau load in AD patients is limited to the posterolateral temporal lobe (PLT) or occipital lobe. Yet another stage of AD is when the tau load in AD patients is present in the parietal or precuneus or frontal lobe, accompanied by tau load in the PLT or occipital lobe. In some embodiments, patients may be stratified / identified / selected / treated based on the stage of AD progression (e.g., based on the spread of tau in the brain) and the presence of one or both APOE e4 paired genes. Stratification of patients based on the amount of tau in the brain, the progression of Alzheimer's disease (AD) in a specific part of the brain, and / or the presence of one or two APOE e4 pairs can be used to determine, for example, whether a patient will respond to combination therapy with an anti-N3pGlu Aβ antibody such as donepemab and an antibody of the present invention such as antibody 1. Stratification / selection of patient populations based on the amount of tau in the brain, the progression of AD in a specific part of the brain, and / or the presence of one or two APOE e4 pairs also helps address patient heterogeneity and reproducibility issues encountered during the design and execution of clinical trials added to treatment. Other embodiments of the invention provide for the treatment or prevention of a disease characterized by amyloid β (Aβ) deposits in the brain of a human individual, in response to a combination of an anti-N3pGlu Aβ antibody, such as donepemab, and an antibody of the present invention, such as antibody 1. In some embodiments of this embodiment, the reactive human individual includes a human individual with low to moderate tau load, very low to moderate tau load, and / or one or two APOE e4 pairs. In some embodiments of this embodiment, the reactive human individual does not include a human individual with high tau load. In some embodiments of this embodiment, the reactive human individual does not include a human individual with high tau load and / or one or two APOE e4 pairs. In some embodiments, administration of a combination of an anti-N3pGlu Aβ antibody, such as donepemab, and an antibody of the present invention, such as antibody 1, to a reactive human individual is used for the treatment or prevention of a disease characterized by amyloid β (Aβ) deposits in the brain of a human individual. In one embodiment, the present invention relates to the use of an anti-N3pGlu Aβ antibody, specifically donenemab, and the antibody of the present invention, specifically antibody 1, for the simultaneous, separate, or sequential treatment or prevention of a disease in a human individual characterized by Aβ deposits in the brain. The treatment or prevention comprises: i) administering to the human individual one or more first doses of about 100 mg to about 700 mg of the anti-N3pGlu Aβ antibody, wherein each first dose is administered approximately every 4 weeks; and ii) approximately four weeks after administering one or more first doses, administering to the human individual one or more second doses of the anti-N3pGlu Aβ antibody greater than 700 mg to about 1400 mg, wherein each second dose is administered approximately every 4 weeks, wherein the anti-N3pGlu Aβ antibody comprises donenemab, and administering to the human individual the antibody of the present invention, specifically antibody 1. Preferably, antibody 1 is administered sequentially after the donenemab treatment. To date, the clinical focus for donepemab treatment has been specific to early-symptom Alzheimer's disease (AD) patients with pre-existing cerebral amyloid burden. However, a second neuropathological marker of AD is the presence of intracellular neurofibrillary tangles containing hyperphosphorylated tau protein. Current disease models suggest that Aβ triggers tau pathology, with a more complex and synergistic interaction between Aβ and tau manifesting in later stages and driving disease progression (Busche et al., "Synergy Between Amyloid-β and Tau in Alzheimer's disease"). Nature Neuroscience23:1183-93 (2020)). Currently, there is no disease-reducing treatment for Alzheimer's disease (AD). Therefore, there is a need for improved methods to treat individuals with AD characterized by Aβ deposition. These methods should be designed to help identify patients based on their potential for therapeutic benefit from the treatment. Furthermore, these treatments and methods should not be associated with increased cytotoxicity or other known adverse events. This invention satisfies one or more of these needs. Doody et al., "Phase 3 Trials of Solanezumab for Mild-to-Moderate Alzheimer's Disease," NEJM, 370; 4, 311-321 (2014) states that "no significant difference in therapeutic efficacy was observed between APOE ε4 carriers and non-carriers." Administration of anti-N3pGlu Aβ antibody and the antibody of the present invention to human individuals possessing one or more APOE e4 counterpart genes (e.g., APOE e4 carriers) is intended to provide unexpected efficacy compared to non-carriers of one or more of those counterpart genes. Therefore, embodiments of the present invention include administering simultaneous, separate, or sequential doses of anti-N3pGlu Aβ antibody, specifically donenemab, and the antibody of the present invention, specifically antibody 1, to patients possessing one or more APOE e4 counterpart genes as a means of mitigating cognitive decline in those patients. According to specific embodiments, the present invention provides a method for treating or preventing a disease characterized by amyloid β (Aβ) deposits in the brain of human individuals identified as having high neurological tau burden, comprising administering simultaneously, separately, or consecutively therapeutically effective amounts of an anti-Aβ antibody, particularly donepemab, and a therapeutically effective amount of the antibody of the present invention, particularly antibody 1. Additionally, according to specific embodiments, the present invention provides a combined method for treating or preventing a disease characterized by Aβ deposits in the brain of human individuals identified as having posterolateral temporal lobe tau burden, comprising administering simultaneously, separately, or consecutively therapeutically effective amounts of an anti-Aβ antibody, particularly donepemab, and a therapeutically effective amount of the antibody of the present invention, particularly antibody 1. According to specific embodiments, the present invention provides a combined method for treating or preventing a disease characterized by amyloid β (Aβ) deposits in the brain of human individuals identified as having high neurological tau burden and possessing one or more lipoprotein E ε-4 paired genes (hereinafter referred to as APOE e4 or APOE4), comprising administering simultaneously, separately, or sequentially therapeutically effective amounts of an anti-Aβ antibody, particularly donepemab, and a therapeutically effective amount of the antibody of the present invention, particularly antibody 1. Additionally, according to specific embodiments, the present invention provides a method for treating or preventing a disease characterized by Aβ deposits in the brain of human individuals identified as having posterolateral temporal lobe tau burden, comprising administering simultaneously, separately, or sequentially therapeutically effective amounts of an anti-Aβ antibody, particularly donepemab, and a therapeutically effective amount of the antibody of the present invention, particularly antibody 1. According to some embodiments, the present invention provides an anti-Aβ antibody, and particularly donepemab, for simultaneous, separate, or sequential use with the antibody of the present invention, and particularly antibody 1, to treat or prevent a disease characterized by Aβ deposits in the brain of a human individual identified as having a high neurological tau load. This treatment or prevention comprises administering a therapeutically effective amount of the anti-Aβ antibody, and particularly donepemab, in simultaneous, separate, or sequential doses, and a therapeutically effective amount of the antibody of the present invention, and particularly antibody 1. In some embodiments, the human individual has been identified as having a high neurological tau load and possessing one or both APOE e4 paired genes. In some embodiments, the present invention provides an anti-Aβ antibody, particularly donepemab, for simultaneous, separate, or sequential use with the antibody of the present invention, particularly antibody 1, to treat or prevent a disease characterized by Aβ deposits in the brain of a human individual identified as having posterolateral temporal lobe tau load. In some embodiments, the human individual has been identified as having posterolateral temporal lobe tau load and possessing one or both APOE e4 paired genes. In some embodiments, the present invention provides an anti-Aβ antibody, particularly donepemab, for simultaneous, separate, or sequential use with the antibody of the present invention, particularly antibody 1, to treat, prevent, or slow the progression of Alzheimer's disease (AD). In some embodiments, the present invention provides an anti-Aβ antibody, particularly donepemab, for simultaneous, separate, or sequential use with the antibody of the present invention, particularly antibody 1, to treat, prevent, or slow the progression of Alzheimer's disease (AD) in human individuals identified with slowly progressive Alzheimer's cognitive decline. Some embodiments of the present invention provide an anti-Aβ antibody, particularly donepemab, for simultaneous, separate, or sequential use with the antibody of the present invention, particularly antibody 1, to treat, prevent, or slow the progression of Alzheimer's disease (AD) in human individuals identified with slowly progressive Alzheimer's cognitive decline and one or both APOE e4 paired genes. Furthermore, according to some embodiments, the present invention provides the use of an anti-Aβ antibody, specifically donenemab, in combination with the antibody of the present invention, particularly antibody 1, simultaneously, separately, or sequentially, for the manufacture of a medicament for the treatment or prevention of Alzheimer's disease. Furthermore, according to some embodiments, the present invention provides the use of an anti-Aβ antibody, particularly donenemab, in combination with the antibody of the present invention, particularly antibody 1, simultaneously, separately, or sequentially, for the manufacture of a medicament for the treatment or prevention of a disease characterized by Aβ deposits in the brain of a human individual identified as having i) high neurological tau burden or ii) high neurological tau burden and one or both APOE e4 paired genes. In some embodiments, the present invention provides the use of an anti-Aβ antibody, specifically donenemab, in combination with the antibody of the present invention, particularly antibody 1, simultaneously, separately, or sequentially, for the manufacture of a medicament for the treatment or prevention of a disease characterized by Aβ deposits in the brain of a human individual identified as having i) posterolateral temporal lobe tau burden or ii) posterolateral temporal lobe tau burden and one or both APOE e4 pairs. In other embodiments, the present invention provides the use of an anti-Aβ antibody, specifically donenemab, in combination with the antibody of the present invention, particularly antibody 1, simultaneously, separately, or sequentially, for the manufacture of a medicament for the treatment, prevention, or delay of Alzheimer's disease (AD) in a human individual identified as having i) slowly progressive AD cognitive decline or ii) one or both APOE e4 pairs and slowly progressive AD cognitive decline. According to one portion of the embodiments provided herein, human individuals have been identified as having posterolateral temporal and occipital tau load. In some embodiments, human individuals have been identified as having posterolateral temporal, occipital, and parietal tau load. In some embodiments, human individuals have been identified as having posterolateral temporal, occipital, parietal, and frontal tau load. In some embodiments, by neurological PET imaging, human individuals have been identified as having one or more of the posterolateral temporal, occipital, parietal, and / or frontal tau loads. In some embodiments, one or more of the posterolateral temporal, occipital, parietal, and / or frontal tau loads correspond to a neurological tau load greater than 1.46 SUVr. In one part of the embodiments provided by the present invention, human individuals have been identified as having one or two APOE e4 pairs and tau load in the posterolateral temporal and occipital lobes. In some embodiments, human individuals have been identified as having one or two APOE e4 pairs and tau load in the posterolateral temporal, occipital, and parietal lobes. In some embodiments, human individuals have been identified as having one or more of the tau load in the posterolateral temporal, occipital, parietal, and / or frontal lobes as determined by neurological PET imaging, and one or two APOE e4 pairs. In some embodiments, one or more of the tau load in the posterolateral temporal, occipital, parietal, and / or frontal lobes corresponds to a neurological tau load greater than 1.46 SUVr. According to other embodiments, the present invention provides a method for treating, preventing, or delaying the progression of Alzheimer's disease (AD) in a human individual identified as having slowly progressive AD cognitive decline, comprising administering simultaneously, separately, or sequentially a therapeutically effective amount of an anti-Aβ antibody, particularly donepemab, and a therapeutically effective amount of the antibody of the present invention, particularly antibody 1. According to some embodiments, the human individual has been identified as having a high neurological tau load. According to some embodiments, the human individual has been identified as having one or two APOE e4 pairs. In some embodiments, the human individual has been identified as having a posterolateral temporal lobe tau load. In some embodiments, the human individual has been identified as having a posterolateral temporal lobe and occipital lobe tau load. In some embodiments, the human individual has been identified as having a posterolateral temporal lobe, occipital lobe, and parietal lobe tau load. In some embodiments, the human individual has been identified as having a posterolateral temporal lobe tau load and one or two APOE e4 pairs. In some embodiments, the human individual has been identified as having one or two APOE e4 pairs and tau load in the posterolateral temporal and occipital lobes. In some embodiments, the human individual has been identified as having one or two APOE e4 pairs and tau load in the posterolateral temporal, occipital, and parietal lobes. In some embodiments, the human individual has been identified as having one or two APOE e4 pairs and tau load in the posterolateral temporal, occipital, parietal, and frontal lobes. According to embodiments of the invention provided herein, human individuals have been identified as having slowly progressive Alzheimer's disease (AD) cognitive decline by one or more of ADAS-Cog, iADL, CDR-SB, MMSE, APOE-4 genotyping, and / or iADRS. In some embodiments, human individuals have been identified as having slowly progressive AD cognitive decline by iADRS. In some embodiments, the iADRS decline is less than 20. In some embodiments, the iADRS decline is less than 20 over a 6-month period. In some embodiments, the iADRS decline is less than 20 over a 12-month period. In some embodiments, the iADRS decline is less than 20 over an 18-month period. In some embodiments, the iADRS decline is less than 20 over a 24-month period. In some embodiments, human individuals have been identified as having slowly progressive AD cognitive decline by APOE-4 genotyping. In some embodiments, human individuals have been identified as APOE-4 alloconjugating. In some embodiments, human individuals have been identified as APOE-4 homoconjugating negative. In some embodiments, human individuals have been identified as having slowly progressive AD cognitive decline by MMSE. In some embodiments, human individuals have been identified as having an MMSE greater than 27. In some embodiments, the MMSE decline is less than 3. In some embodiments, the MMSE decline is less than 3 over a 6-month period. In some embodiments, the MMSE decline is less than 3 over a 12-month period. In some embodiments, the MMSE decline is less than 3 over an 18-month period. In some embodiments, the MMSE decline is less than 3 over a 24-month period. According to embodiments of the invention provided herein, human individuals have been identified as having a high neurological tau load by neurological PET imaging. In some embodiments, human individuals have been identified as having a high neurological tau load greater than 1.46 SUVr by neurological PET imaging. In some embodiments, human individuals have been identified as having a high neurological tau load by quantification of human tau ("hTau-pT217"), which is phosphorylated by threonine at residue 217. In some embodiments, hTau-pT217 is quantified in a biological sample from the human individual. In some embodiments, the biological sample is cerebrospinal fluid. In some embodiments, the biological sample is one of blood, plasma, or serum. For the purposes of this invention, the tau content or load of a human individual (which may be used interchangeably herein) can be determined using techniques or methods for detecting or quantifying i) neurological or brain tau deposits, ii) tau in blood, serum, and / or plasma, or iii) tau in cerebrospinal fluid. In some embodiments, neurological tau load (whether determined via PET or via blood, serum, plasma, or cerebrospinal fluid analysis) can be used to stratify individuals based on neurological tau load (e.g., low, moderate, or high neurological tau load). Neurological tau burden can be determined using methods such as tau imaging with radiolabeled PET compounds (Leuzy et al., "Diagnostic Performance of RO948 F18 Tau Positron Emission Tomography in the Differentiation of Alzheimer Disease from Other Neurodegenerative Disorders"). JAMA Neurology77.8:955-965 (2020); Ossenkoppele et al., “Discriminative Accuracy of [ 18 F]-flortaucipir Positron Emission Tomography for Alzheimer Disease vs Other Neurodegenerative Disorders", JAMA 320, 1151-1162, doi:10.1001 / jama.2018.12917 (2018), which is incorporated herein by reference in its entirety, and these compounds include [ 18 [F]-Fluoroxepirine, a PET ligand. It can be used, for example, by the disclosed method (Pontecorvo et al., "A Multicentre Longitudinal Study of Flortaucipir (18F) in Normal Ageing, Mild Cognitive Impairment and Alzheimer's Disease Dementia"). Brain142:1723-35 (2019); Devous et al., "Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir F18", Journal of Nuclear Medicine59:937-43 (2018); Southekal et al., "Flortaucipir F18 Quantitation Using Parametric Estimation of Reference Signal Intensity", J . Nucl . Med .59:944-51 (2018), which is incorporated herein by reference in its entirety) Quantitative assessment of PET tau images to estimate SUVr (standardized uptake ratio), and / or visual assessment of patients, for example, to determine whether a patient has an AD pattern (Fleisher et al., "Positron Emission Tomography Imaging With [ 18 F]-flortaucipir and Postmortem Assessment of Alzheimer Disease Neuropathologic Changes", JAMA Neurology 77:829-39 (2020), which is incorporated herein by reference in its entirety. Lower SUVr values ​​indicate less tau load, while higher SUVr values ​​indicate higher tau load. In one embodiment, quantitative assessment by fluoxetine scanning is performed via methods such as Southekal et al., "Flortaucipir F18 Quantitation Using Parametric Estimation of Reference Signal Intensity". J . Nucl . Med The automated image processing pipeline described in .59:944-951 (2018) is incorporated herein by reference in its entirety. In some embodiments, the counting of specific target areas of interest in the brain (e.g., multi-block centroid discriminant analysis or MUBADA, see Devous et al., "Test-Retest Reproducibility for the Tau PET Imaging Agent Flortaucipir F18") is performed. J . Nucl . Med .59:937-943 (2018), which is incorporated herein by reference in its entirety, was compared with a reference region, which could be, for example, the whole cerebellum, the cerebellar GM, atlas-based white matter (atlasWM), or individual-specific white matter (ssWM), for example, using parametric estimation of reference signal intensity (PERSI), see Southekal et al., "Flortaucipir F18 Quantitation Using Parametric Estimation of Reference Signal Intensity". J . Nucl . Med .59:944-951 (2018), which is incorporated herein by reference in its entirety. An exemplary method for determining tau load is quantitative analysis reported by standardized uptake ratio (SUVr), which represents the count in a specific target attention area (e.g., MUBADA) in the brain when compared with a reference area (e.g., using PERSI). In some embodiments, for the purposes of this invention, phosphorylated tau (P-tau; phosphorylated at threonine 181 or 217 or a combination thereof) can be used to measure tau burden / load (Barthelemy et al., "Cerebrospinal Fluid Phospho-tau T217 Outperforms T181 as a Biomarker for the Differential Diagnosis of Alzheimer's Disease and PET Amyloid-positive Patient Identification"). Alzheimer ' s Res . Ther .12, 26, doi:10.1186 / s13195-020-00596-4 (2020); Mattsson et al., "Aβ Deposition is Associated with Increases in Soluble and Phosphorylated Tau that Precede a Positive Tau PET in Alzheimer's Disease", Science Advances 6, eaaz2387 (2020), which is incorporated herein by reference in its entirety. In one particular embodiment, an antibody against human tau phosphorylated at residue 217 (threonine) can be used to measure tau burden / load in an individual (see International Patent Application Publication WO 2020 / 242963, which is incorporated herein by reference in its entirety). In some embodiments, the invention includes using the anti-tau antibody disclosed in WO 2020 / 242963 to measure tau burden / load in an individual. The anti-tau antibody system disclosed in WO 2020 / 242963 targets isoforms of human tau expressed in the CNS (e.g., recognizing isoforms expressed in the CNS but not isoforms of human tau expressed exclusively outside the CNS). When amyloid is detected in the brain by methods such as amyloid imaging using radiolabeled PET compounds or by using diagnostic agents that detect Aβ or Aβ biomarkers, the individual is positive for amyloid deposits. Exemplary methods that can be used to measure brain amyloid burden / load include, for example, flubetapiril (Carpenter et al., "The Use of the Exploratory IND in the Evaluation and Development of...). 18 F-PET Radiopharmaceuticals for Amyloid Imaging in the Brain: A Review of One Company's Experience", The Quarterly Journal of Nuclear Medicine and Molecular Imaging 53.4:387 (2009), which is incorporated herein by reference in its entirety; Flurbetaben (Syed et al., "[ 18 F]Florbetaben: A Review in β-Amyloid PET Imaging in Cognitive Impairment", CNS Drugs 29, 605-613 (2015), which is incorporated herein by reference in its entirety; and flumethamol (Heurling et al., "Imaging β-amyloid Using [ 18 F] Flutemetamol Positron Emission Tomography: From Dosimetry to Clinical Diagnosis", European Journal of Nuclear Medicine and Molecular Imaging 43.2: 362-373 (2016), which is incorporated herein by reference in its entirety. 18 F]-Fluorbetapyr can provide qualitative and quantitative measurements of brain plaque burden in patients, including those with pre-AD or mild AD dementia, and can also be used to assess the reduction of amyloid plaques from the brain. In addition, β-amyloid burden / load can be measured using analyses based on cerebrospinal fluid or plasma. For example, Aβ42 can be used to measure brain amyloid (Palmqvist, S. et al., "Accuracy of Brain Amyloid Detection in Clinical Practice Using Cerebrospinal Fluid Beta-amyloid 42: a Cross-validation Study Against Amyloid Positron Emission Tomography"). JAMA Neurol71, 1282-1289 (2014, which is incorporated herein by reference in its entirety). In some embodiments, the ratio of Aβ42 / Aβ40 or Aβ42 / Aβ38 can be used as a biomarker for amyloid β (Janelidze et al., "CSF Abeta42 / Abeta40 and Abeta42 / Abeta38 Ratios: Better Diagnostic Markers of Alzheimer Disease"). Ann Clin Transl Neurol 3, 154-165 (2016, which is incorporated herein by reference in its entirety). In some embodiments, brain amyloid plaques or Aβ deposited in CSF or plasma can be used to stratify individuals based on amyloid burden / load. Further examples of combined uses and methods of using the antibodies of the present invention are provided below. A combined example may refer to antibody 1; however, the examples further include similar methods, uses, and all limitations described herein with respect to the antibodies of the present invention as described herein. A combined example may refer to "anti-N3pG Aβ antibody," which refers to each of the anti-N3pG Aβ antibodies described herein; however, for clarity, these examples further include similar methods, uses, and all limitations described herein with respect to each of the anti-N3pG Aβ antibodies individually, and, for example, preferably, combined uses of donepemab. Further examples of the invention are provided below, which are numbered and include internal references to other numbered examples. For clarity, these examples will be read separately and / or together with the numbered examples they refer to. The examples described below begin with number 26. The term "treatment process" refers to a particular patient or individual, the listed antibodies, the listed doses, the listed frequency and / or duration, the listed order, and any other limitations, within the scope described in the examples. Other combinations of embodiments of the present invention include: 26. A method for treating or preventing a disease in a human individual characterized by amyloid β (Aβ) deposits in the brain, comprising administering an effective amount of anti-N3pG Aβ antibody to the human individual in need, simultaneously, separately or in combination with an effective amount of antibody 1. 27. The method of Example 26, wherein the anti-N3pG Aβ anti-system donepemab. 28. The method of Example 26, wherein the disease is Alzheimer's disease. 29. The method of Example 26, wherein the anti-N3pG Aβ anti-system donepemab and the disease is Alzheimer's disease. 30. The method of Example 29, wherein antibody 1 is administered continuously after donepemab treatment. 31. A method for treating or preventing a disease in a human individual characterized by amyloid β (Aβ) deposits in the brain, comprising: i) administering to the human individual a first dose of one or more anti-N3pG Aβ antibodies of about 100 mg to about 700 mg, wherein each first dose is administered about once every four weeks; and ii) administering to the human individual a second dose of one or more anti-N3pG Aβ antibodies greater than 700 mg to about 1400 mg about four weeks after administering the one or more first doses, wherein each second dose is administered about once every four weeks, wherein the anti-N3pGlu Aβ anti-system donepemab; and iii) administering to the human individual an effective amount of antibody 1 simultaneously, separately or consecutively. 32. The method of Example 31, wherein the human individual is given a first dose of donepemab once, twice, or three times, followed by a second dose. 33. The method of Example 31 or 32, wherein the human individual is given a first dose of about 700 mg of donepemab. 34. The method of any one of Examples 31 to 33, wherein the human individual is given one or more second doses of donepemab of about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg or about 1400 mg. 35. The method of any one of Examples 31 to 34, wherein the human individual is given one or more second doses of donepemab, approximately 1400 mg. 36. The method of any one of Examples 31 to 35, wherein the human individual is administered the anti-N3pGlu Aβ antibody for a treatment duration of up to 72 weeks or until normal amyloid levels are achieved. 37. The method of any one of Examples 31 to 36, wherein the anti-N3pGlu Aβ antibody is administered to the human individual until the amyloid plaque content of the patient is about 25 percent or less. 38. The method of any one of Examples 31 to 36, wherein the anti-N3pGlu Aβ antibody is administered to the human individual during the treatment process until, for two consecutive PET imaging scans, the amyloid plaque content of the human individual is about 25 percent or less, wherein, where the two consecutive PET imaging scans are at least 6 months apart, or for a single PET imaging scan, the amyloid content is about 11 percent or less. 39. The method of any one of Examples 31 to 36, wherein the human individual is given a first dose of donepemab at 700 mg every four weeks, followed by a second dose of 1400 mg every four weeks, for a treatment duration of up to 72 weeks. 40. The method of any one of Examples 31 to 36, wherein the human individual is given three first doses of 700 mg every four weeks, followed by a second dose of 1400 mg every four weeks, until the amyloid plaque content of the individual is about 25 percent amyloid or lower. 41. The method of any one of Examples 31 to 36, wherein the human individual is given a first dose of 700 mg donepemab three times every four weeks, followed by a second dose of 1400 mg every four weeks, until, for two consecutive PET imaging scans, the individual has an amyloid plaque content of about 25 percent or less, where the two consecutive PET imaging scans are at least 6 months apart, or for a single PET imaging scan, an amyloid content of about 11 percent or less. 42. The method of any one of Examples 31 to 41, wherein the second dose of donepemab is administered to the human individual for a duration sufficient to treat or prevent the disease. 43. The method of any one of Examples 31 to 42, wherein the treatment or prevention of the disease causes i) a reduction in Aβ deposits in the brain of the human individual and / or ii) a slowing of cognitive or functional decline in the human individual. 44. The method of Example 43, wherein the reduction in Aβ deposits in the brain of the human individual is determined by amyloid PET brain imaging or by diagnosis of biomarkers for detecting Aβ. 45. The method of Example 43 or 44, wherein the second dose is administered to the human individual until the Aβ deposits in the human individual’s brain are reduced by about 20% to 100%. 46. ​​The method of Example 45, wherein the Aβ deposits in the brain of the human individual are reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 75%, or about 100%. 47. The method of any one of Examples 31 to 44, wherein a second dose of donepemab is administered to the human individual until the Aβ deposits in the human individual’s brain are reduced by i) about an average of about 25 percent amyloid to about 100 percent amyloid, ii) about an average of about 50 percent amyloid to about 100 percent amyloid, iii) about 100 percent amyloid, or iv) about 84 percent amyloid. 48. The method of any one of Examples 31 to 47, wherein the human individual is characterized by a disease in which Aβ deposits are selected from preclinical Alzheimer's disease (AD), clinical AD, prodromal AD, mild AD, moderate AD, severe AD, Down syndrome, clinical amyloidosis, or preclinical amyloidosis. 49. The method of any one of Examples 31 to 48, wherein the human individual is a patient with early symptomatic AD. 50. The method of Example 49, wherein the human individual suffers from pre-AD and mild dementia attributable to AD. 51. The method of any one of Examples 26 to 50, wherein the human individual has: i) very low to moderate tau load or has been identified as having very low to moderate tau load, ii) low to moderate tau load or has been identified as having low to moderate tau load, iii) very low to moderate tau load or has been identified as having very low to moderate tau load and one or two APOE e4 pairs, iv) low to moderate tau load or has been identified as having low to moderate tau load and one or two APOE e4 pairs, or v) one or two APOE e4 pairs. 52. The method of Example 51, wherein the human individual has i) a very low to moderate tau load if the tau load measured by PET brain imaging is ≤1.46 SUVr, or ii) a low to moderate tau load if the tau load measured by PET brain imaging is between 1.10 SUVr and 1.46 SUVr. 53. The method of any one of Examples 26 to 50, wherein the human individual i) does not have a high tau load or has been determined not to have a high tau load, or ii) carries one or both of the APOE e4 pairs and does not have a high tau load or has been determined not to have a high tau load. 54. The method of Example 53, wherein if the tau load measured by PET brain imaging is higher than 1.46 SUVr, the human individual has a high tau load. 55. The method of Example 51 or 53, wherein the tau load of the human individual is determined using PET brain imaging or a diagnosis that detects biomarkers of tau. 56. Use of an anti-N3pGlu Aβ antibody and antibody 1, either simultaneously, separately, or in a continuous combination, to manufacture a medicament for treating or preventing a disease in a human individual characterized by Aβ deposits in the brain, wherein one or more first doses of the anti-N3pGlu Aβ antibody, ranging from about 100 mg to about 700 mg, are administered, wherein each first dose is administered approximately every 4 weeks, followed by one or more second doses, ranging from about 700 mg to about 1400 mg, administered four weeks after the administration of the one or more first doses, wherein each second dose of the anti-N3pGlu Aβ antibody is administered approximately every 4 weeks, and wherein the anti-N3pGlu Aβ antibody is a donenemab. 57. As used in Example 56, wherein the human individual is given a first dose of donepemab once, twice, or three times, followed by a second dose of donepemab. 58. As used in Examples 56 or 57, wherein the human individual is given a first dose of three doses of about 700 mg donepemab. 59. The use as described in any of Examples 56 to 58, wherein a second dose of donepemab of about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg or about 1400 mg is administered to the human individual. 60. As used in any of Examples 56 to 59, wherein the human individual is given one or more second doses of donepemab, approximately 1400 mg. 61. The use as described in any of Examples 56 to 60, wherein the human individual is administered anti-N3pGlu Aβ antibody for a duration of up to 72 weeks or until normal amyloid levels are achieved. 62. As used in any of Examples 56 to 61, wherein the anti-N3pGlu Aβ antibody is administered to the human individual until the patient’s amyloid plaque content is about 25 percent amyloid or lower. 63. As used in any of Examples 56 to 61, wherein the human individual is administered an anti-N3pGlu Aβ antibody until, for two consecutive PET imaging scans, the patient has an amyloid plaque content of about 25 percent or less, where the two consecutive PET imaging scans are at least 6 months apart, or for a single PET imaging scan, an amyloid content of about 11 percent or less. 64. As used in any of Examples 56 to 61, wherein the human individual is given a first dose of donepemab at 700 mg every four weeks, followed by a second dose of donepemab at 1400 mg every four weeks, for a duration of up to 72 weeks. 65. As used in any of Examples 56 to 61, wherein the human individual is given a first dose of donepemab at 700 mg every four weeks, followed by a second dose of donepemab at 1400 mg every four weeks, until the patient’s amyloid plaque content is about 25 percent amyloid or lower. 66. As used in any of Examples 56 to 61, wherein the human individual is given a first dose of 700 mg donepemab three times every four weeks, followed by a second dose of 1400 mg donepemab every four weeks, until, for two consecutive PET imaging scans, the patient has an amyloid plaque content of about 25 percent or less, where the two consecutive PET imaging scans are at least 6 months apart, or for a single PET imaging scan, an amyloid content of about 11 percent or less. 67. As used in any of Examples 56 to 66, wherein the second dose of donepemab administered to the human individual is sustained for a duration sufficient to treat or prevent the disease. 68. The use of any one of Examples 56 to 67, wherein the treatment or prevention of the disease causes i) a reduction in Aβ deposits in the brain of the human individual and / or ii) a slowing of cognitive or functional decline in the human individual. 69. As used in Example 68, wherein the reduction in Aβ deposits in the brain of the human individual is determined by amyloid PET brain imaging or by diagnosis of biomarkers for detecting Aβ. 70. As used in Examples 68 or 69, wherein a second dose of donepemab is administered to the human individual until the Aβ deposits in the human individual’s brain are reduced by approximately 20% to 100%. 71. As used in Example 70, wherein Aβ deposits in the brain of the human individual are reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 75%, or about 100%. 72. As used in Examples 70 or 71, wherein Aβ deposits in the patient's brain are reduced by 100%. 73. As used in any of Examples 56 to 72, wherein a second dose of donepemab is administered to the human individual until the Aβ deposits in the human individual’s brain are reduced by i) about an average of about 25 percent amyloid to about 100 percent amyloid, ii) about an average of about 50 percent amyloid to about 100 percent amyloid, iii) about 100 percent amyloid, or iv) about 84 percent amyloid. 74. The use as described in any of Examples 56 to 73, wherein the disease characterized by Aβ deposits in the brain of the human individual is selected from preclinical Alzheimer's disease, clinical AD, prodromal AD, mild AD, moderate AD, severe AD, Down syndrome, clinical amyloidosis, or preclinical amyloidosis. 75. The use as described in any of Examples 56 to 74, wherein the human individual is a patient with early symptomatic AD, or wherein the human individual has pre-AD or mild dementia attributable to AD. 76. As used in any of Examples 56 to 75, wherein the human individual has: i) very low to moderate tau load or has been identified as having very low to moderate tau load, ii) low to moderate tau load or has been identified as having low to moderate tau load, iii) very low to moderate tau load or has been identified as having very low to moderate tau load and one or two APOE e4 pairs, iv) low to moderate tau load or has been identified as having low to moderate tau load and one or two APOE e4 pairs, or v) one or two APOE e4 pairs. 77. As used in Example 76, wherein the human individual has i) a very low to moderate tau load if the tau load measured by PET brain imaging is ≤1.46 SUVr, or ii) a low to moderate tau load if the tau load measured by PET brain imaging is between 1.10 SUVr and 1.46 SUVr. 78. As used in any of Examples 56 to 75, wherein the human individual i) does not have a high tau load or has been determined not to have a high tau load, or ii) carries one or both of the APOE e4 pairs and does not have a high tau load or has been determined not to have a high tau load. 79. As used in Example 78, wherein if the tau load measured by PET brain imaging is higher than 1.46 SUVr, then the human individual has a high tau load. 80. As used in Examples 76 or 78, wherein the tau load of the human individual is determined using tau PET brain imaging or a diagnosis that detects biomarkers of tau. 81. A method for treating or preventing a disease in a human individual characterized by amyloid β (Aβ) deposits in the brain, the human individual being identified as having i) very low to moderate tau load or low to moderate tau load or ii) very low to moderate tau load or low to moderate tau load and one or two APOE e4 pairs, the method comprising: i) administering to the human individual one or more first doses of donepemab, from about 100 mg to about 700 mg, wherein each first dose of donepemab is administered about every 4 weeks; and ii) four weeks after administering the one or more first doses, administering to the human individual one or more second doses of donepemab, from about 700 mg to about 1400 mg, wherein each second dose is administered about every 4 weeks; and concurrently, separately or in combination with an effective amount of antibody 1. 82. A method for treating or preventing a disease in a human individual characterized by amyloid β (Aβ) deposits in the brain, comprising: determining whether the human individual has a tau load in the temporal, occipital, parietal, or frontal lobe of the brain, and if the human individual has a tau load in the temporal, occipital, parietal, or frontal lobe of the brain, then: i) administering to the human individual one or more first doses of about 100 mg to about 700 mg of anti-N3pGlu Aβ antibody, wherein each first dose is administered about once every four weeks; and ii) about four weeks after administering the one or more first doses, administering to the human individual one or more second doses of anti-N3pGlu Aβ antibody greater than 700 mg to about 1400 mg, wherein each second dose is administered about once every four weeks, simultaneously, separately, or in combination with an effective amount of antibody 1. 83. The method of Example 82, wherein the human individual has tau load in the posterolateral temporal lobe or temporal lobe of the brain. 84. The method of Example 82, wherein the human individual has a tau load in the occipital lobe of the brain. 85. The method of Example 82, wherein the human individual has a tau load in the parietal lobe of the brain. 86. The method of Example 82, wherein the human individual has a tau load in the frontal lobe of the brain. 87. The method of Example 82, wherein the human individual has tau load in the posterior lateral temporal lobe (PLT) and / or occipital lobe of the brain. 88. The method of any one of Examples 82 to 87, wherein the human individual has tau load in i) the parietal or precuneus region or ii) the frontal lobe region of the brain, and tau load in the PLT or occipital lobe region. 89. The method of any one of Examples 82 to 86, wherein the human individual has tau load in a region of the brain i) isolated to the frontal lobe or ii) the temporal lobe excluding the posterolateral temporal lobe (PLT). 90. The method of any one of Examples 82 to 88, wherein the human individual has tau load in the posterolateral temporal lobe, occipital lobe and parietal lobe of the brain. 91. The method of any one of Examples 82 to 88, wherein the human individual has tau load in the posterolateral temporal lobe, occipital lobe, parietal lobe and frontal lobe of the brain. 92. The method of any one of Examples 82 to 88, wherein the human individual has tau load in the posterolateral temporal lobe, occipital lobe, parietal lobe and / or frontal lobe of the brain. 93. The method of any one of Examples 82 to 92, wherein the first dose is administered to the human individual once, twice, or three times, followed by the administration of the second dose. 94. The method of any one of Examples 82 to 93, wherein a first dose of about 700 mg is administered to the human individual. 95. The method of any one of Examples 82 to 94, wherein the human individual is given one or more second doses of about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg or about 1400 mg. 96. The method of any one of Examples 82 to 95, wherein one or more second doses of about 1400 mg are administered to the human individual. 97. The method of any one of Examples 82 to 96, wherein the human individual is administered the anti-N3pGlu Aβ antibody for a duration of up to 72 weeks or until normal amyloid levels are achieved. 98. The method of any one of Examples 82 to 97, wherein the anti-N3pGlu Aβ antibody is administered to the human individual until the amyloid plaque content of the patient is about 25 percent amyloid or lower. 99. The method of any one of Examples 82 to 98, wherein the human individual is administered the anti-N3pGlu Aβ antibody until, for two consecutive PET imaging scans, the amyloid plaque content of the human individual is about 25 percent or less, wherein, where the two consecutive PET imaging scans are at least 6 months apart, or for a single PET imaging scan, the amyloid content is about 11 percent or less. 100. The method of any one of Examples 82 to 99, wherein the human individual is given three first doses of 700 mg every four weeks, followed by a second dose of 1400 mg every four weeks, for a duration of up to 72 weeks. 101. The method of any one of Examples 82 to 100, wherein the human individual is given three first doses of 700 mg every four weeks, followed by a second dose of 1400 mg every four weeks, until the amyloid plaque content of the individual is about 25 percent amyloid or lower. 102. The method of any of Examples 82 to 101, wherein the human individual is given three first doses of 700 mg every four weeks, followed by a second dose of 1400 mg every four weeks, until, for two consecutive PET imaging scans, the individual has an amyloid plaque content of about 25 percent or less, where the two consecutive PET imaging scans are at least 6 months apart, or for a single PET imaging scan, an amyloid content of about 11 percent or less. 103. The method of any one of Examples 82 to 102, wherein the second dose is administered to the human individual for a duration sufficient to treat or prevent the disease. 104. The method of any one of Examples 82 to 103, wherein the treatment or prevention of the disease causes i) a reduction in Aβ deposits in the brain of the human individual and / or ii) a slowing of cognitive or functional decline in the human individual. 105. The method of Example 97, wherein the reduction in Aβ deposits in the brain of the human individual is determined by amyloid PET brain imaging or by diagnosis of biomarkers for detecting Aβ. 106. The method of Example 97 or 98, wherein the second dose is administered to the human individual until the Aβ deposits in the human individual’s brain are reduced by about 20% to 100%. 107. The method of Example 106, wherein the Aβ deposits in the brain of the human individual are reduced by about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 75%, or about 100%. 108. The method of any one of Examples 82 to 107, wherein a second dose is administered to the human individual until the Aβ deposits in the human individual’s brain are reduced by i) about an average of about 25 percent amyloid to about 100 percent amyloid, ii) about an average of about 50 percent amyloid to about 100 percent amyloid, iii) about 100 percent amyloid, or iv) about 84 percent amyloid. 109. The method of any one of Examples 82 to 108, wherein the human individual is characterized by a disease in which Aβ deposits are selected from preclinical Alzheimer's disease (AD), clinical AD, prodromal AD, mild AD, moderate AD, severe AD, Down syndrome, clinical amyloidosis, or preclinical amyloidosis. 110. The method of any one of Examples 82 to 109, wherein the human individual is a patient with early symptomatic AD. 111. The method of Example 109, wherein the human individual suffers from pre-AD and mild dementia attributable to AD. 112. The method of any one of Examples 82 to 111, wherein the human individual has: i) very low to moderate tau load or has been determined to have very low to moderate tau load, or ii) low to moderate tau load or has been determined to have low to moderate tau load. 113. The method of Example 112, wherein the human individual has i) a very low to moderate tau load if the tau load measured by PET brain imaging is ≤1.46 SUVr, or ii) a low to moderate tau load if the tau load measured by PET brain imaging is between 1.10 SUVr and 1.46 SUVr. 114. The method of any one of Examples 82 to 113, wherein the human individual does not have a high tau load or has been determined not to have a high tau load. 115. The method of Example 114, wherein if the tau load measured by PET brain imaging is higher than 1.46 SUVr, the human individual has a high tau load. 116. The method of Example 114 or 115, wherein the tau load of the human individual is determined using PET brain imaging or a diagnosis that detects biomarkers of tau. 117. The method of any one of Examples 82 to 116, wherein the anti-N3pGlu Aβ antibody comprises donepemab. 118. The method of any one of Examples 82 to 117, wherein the patient has one or two APOE e4 pairs. 119. A method for reducing / preventing further increase in tau load or slowing the rate of tau accumulation in the temporal, occipital, parietal, or frontal lobes of a human brain, comprising administering an anti-N3pGlu Aβ antibody to the human individual, simultaneously, separately, or in combination with an effective amount of antibody 1. Example The following examples are provided for illustration, but do not limit the claimed invention. The results of the following analysis show that exemplary monoclonal antibodies of the present invention, such as antibody 1, bind to and / or neutralize IL-34, and are therefore useful for the treatment of the immune-mediated and inflammatory diseases described herein. Example 1 : Antibody generation, expression, and purification: A panel of human anti-IL-34 antibodies was obtained using a complete human yeast display library, and screening was conducted to identify reagents that could be effective human IL-34 neutralizing antibodies. Mutations were systematically introduced into the individual complementarity-determining regions (CDRs) of each antibody, and the resulting collection of libraries underwent multiple rounds of selection, decreasing antigen concentration and / or increasing dissociation time to isolate pure lines with modified affinity. The sequences of individual variants were determined and used to construct combinatorial libraries, which underwent another round of selection with increased stringency to identify additive or cooperative mutation pairings between individual CDR regions. Individual combinatorial pure lines were sequenced, and binding characteristics were determined. To further increase affinity for IL-34, additional rounds of single and combinatorial mutagenesis could be performed on these combinatorial pure lines. This screening could be performed against human or rhesus macaque IL-34 to increase affinity for the selected species. Selected antibodies could also be mutagenized to repair post-translational modifications such as isomerization while retaining binding affinity for IL-34. In addition, the antibody can be restructured (FW) or replaced with a CDR to restore the sequence to its germline state, thereby reducing the potential risk of immunogenicity. Engineered and / or optimized anti-IL-34 antibodies, referred to herein as antibody 1, are obtained. These antibodies have amino acid sequences of the variable regions of the heavy and light chains, and complete heavy and light chain amino acid sequences, as well as nucleotide sequences encoding them, listed in the section entitled "List of Amino Acid and Nucleotide Sequences" below. The SEQ ID NOs corresponding to these sequences are shown in Table 1, along with the CDR amino acid sequences of the light and heavy chains. The exemplary anti-IL-34 antibody of the present invention can be expressed and purified in essentially the following way. It can be transiently or stably transfected into suitable host cells such as HEK 293, NSO or CHO using an expression system for secreting antibodies, with an optimal predetermined HC:LC vector ratio (such as 1:3 or 1:2 or 1:1) or a single vector system encoding both HC and LC. The phenotype contains, for example, DNA encoding the LC and HC sequences of antibody 1 (the DNA sequence encoding the HC sequence of exemplary antibody 1, SEQ ID NO: 11, and the DNA sequence encoding the LC amino acid sequence of exemplary antibody 1, SEQ ID NO: 12); and is expressed by a commonly used and suitable construct for this purpose. Pure line-derived cell lines are amplified and screened for antibody 1 production, and pure line-derived cell lines are selected and established. These cell lines are generated without any material containing animal components and are used for production. The clarified culture medium secreted into which the antibody is dissolved can be purified using conventional techniques such as a mixed-mode approach involving ion exchange and hydrophobic interaction chromatography. For example, conventional methods can be used to apply the culture medium to and dissociate it from a protein A or G column; a mixed-mode approach involving ion exchange and hydrophobic interaction chromatography can also be used. Soluble aggregates and polymers can be effectively removed using common techniques, including size exclusion, hydrophobic interaction, ion exchange, or hydroxyapatite chromatography. The exemplary anti-IL-34 antibody of this invention is concentrated and / or aseptically filtered using common techniques. The purity of the exemplary antibody after these chromatographic steps is greater than 95%. The exemplary anti-IL-34 antibody of this invention can be immediately frozen at -70°C or stored at 4°C for several months. Example 2 : anti- IL - 34 Antibody characterization For humans and stone crab macaques IL - 34 Binding Affinity: The binding affinity of the anti-IL-34 monoclonal antibody of this invention to human and / or cynomolgus monkey (IL-34) can be determined by methods known in this art. In short, the binding affinity and kinetics of the antibody are assessed using a BIAcore™ 8K (Cytiva) at 37°C via surface plasma resonance. Binding affinity is measured as follows: The anti-IL-34 antibody is immobilized on a BIAcore™ Sensor Chip Protein A (Cytiva), and human or cynomolgus monkey IL-34 is flowed, starting at 25 nM or 12.5 nM, and serially diluted 2-fold in HBS-EP+ buffer (Teknova). For each cycle, 200 µL of IL-34 is flowed through the immobilized antibody at 100 µL / min, followed by dissociation for 20 min. The chip surface is regenerated with 50 µL of pH 1.5 glycine buffer at a flow rate of 100 µL / min. Data fitted to a 1:1 Langmiur combined model to derive k on, k off, and calculate K D Table 3 shows the average values ​​of at least three human and rhesus monkey IL-34 assays for exemplary antibody 1. surface 3 : Antibody - Humans and stone crab macaques IL - 34 complex in 37 ℃ The following are the combined affinity ( K D ) Example 3 : Anti-human IL - 34 In vitro functional characterization of the antibodies was performed to assess their ability to neutralize IL-34 binding and / or activity. The neutralization of IL-34 binding and / or activity by the antibodies of this invention can be evaluated by one or more IL-34 / CSF1R receptor binding assays and IL-34-based cellular activity assays, as described below. Antibody 1 since CSF1R Replacement IL - 34 Analysis of neutralizing antibodies capable of binding to IL-34 / CSF1R can be performed using enzymatic assays. These assays utilize recombinantly expressed CSF1R extracellular domain proteins capable of binding to IL-34. These proteins can be bound to an ELISA disc to capture soluble IL-34. Subsequently, IL-34 can be detected by biotinylation of the antigen and by peroxidase or phosphatase detection via streptavidin / neutravidin binding. These neutralization assays involve pre-incubating (e.g., for 1 hour) the antibody to be evaluated with labeled IL-34 before adding it to the binding assay (and control samples not involving antibodies targeting IL-34). CSF1R extracellular domain protein (available from R&D as hCSF1R_Fc, catalog number 329-MR, Lithocarpus macaque CSF1R ECD-Fc (AAA lineage CSF1R extracellular domain linker to Fc) (SEQ ID NO: 34)) can bind to an ELISA plate at a concentration of 30 nM to capture soluble biotinylated IL-34 and allow binding for one hour. After rinsing and blocking the plate, biotinylated IL-34 can be added, followed by detection by streptavidin-bound peroxidase. The binding level is close to 80% (EC50). 80 A concentration of labeled IL-34 (3.7 nM) was used in combination with a range of antibody concentrations (0-100 nM) to determine the antibody concentration required to displace IL-34 from CSF1R. After a 1-hour incubation, IL-34 bound to CSF1R was detected by streptavidin-binding peroxidase. Antibodies (n=2) were analyzed, and the mean and standard deviation of each concentration were calculated. The efficacy of the antibody in displacing IL-34 from CSF1R was reported as IC50. 50 (nM), and the confidence interval (CI) is calculated in Tables 4 and 5. surface 4 : Humans IL - 34 From human beings CSF1R Replacement surface 5 : Stone crab macaque IL - 34 From stone crab macaque CSF1R Replacement IL-34 binds to human CSF1R with an affinity of approximately 50-100 pM, requiring high-affinity antibodies for effective neutralization of this interferon in the CNS. The results in Table 4 show that antibody 1 has a high affinity for human IL-34 and can displace IL-34 from human CSF1R, with an IC50 value of [missing value]. 50 The result was 0.06567 nM. The results in Table 4 show that antibody 1 has a high affinity for human IL-34, and specifically, the affinity of antibody 1 for human IL-34 is comparable to that of hCSF1R, thus enabling it to effectively neutralize IL-34 binding in vivo. It is believed that blocking IL-34 provides a useful disease-modifying approach while avoiding the safety issues associated with some existing immunomodulatory therapies. Therefore, neutralizing IL-34-mediated signaling represents a therapeutic approach for managing neuroinflammation, microglial proliferation, and neurodegenerative diseases such as Alzheimer's disease and other tau protein diseases and inflammatory diseases. (See, for example, Lelios, I. et al. Emerging roles of IL-34 in health and disease, J Exp Med (2020) 217 ​​(3): e20190290). In vitro inhibition IL - 34 The IL-34 neutralizing activity of the antibody of the present invention can be assessed by one or more IL-34-based cell assays, such as those described below. The ability of the antibody of the present invention to neutralize human IL-34-induced luciferase reporter activity can be assessed in 293 hCSF1R SRE cells transfected with cDNA to express human CSF1R (registration: NP_001275634.1). For example, 293 / SRE cells stably overexpressing human CSF1R (hCSF1R) were dissociated in 0.05% trypsin-PBS and seeded at 70,000 cells per 100 μl in tissue culture-treated 96-well plates. The next day, the growth medium was removed, and the cells were starved with DMEM-F12 (Dulbecco's Modified Eagle Medium: Nutrient Mixture F-12) supplemented with heat-inactivated 1% FBS (fetal bovine serum). Twenty-four hours after starvation, cells were treated for 6 hours with 100 ng / ml human IL-34 and multiple concentrations of hCSF1R-Fc or antibody 1. After culturing, cells were treated with 50 μl Promega TM Glo TM Lysis buffer (Promega) TM (E266A) Gently stir to lyse cells for 5 minutes. Add 50 ml of BrightGlo TM Promega luminescent reagent TM E2620) and cultured on lysed cells for 2 minutes. Perkin Elmer Wallac 1420 Victor2 TM The luminescence was read on a microplate reader. The reduction in relative fluorescent units (RFU) shown in Table 7 and Figure 1 reflects the ability of antibody 1 to neutralize human IL-34-induced luciferase activity. Antibody 1 was used to neutralize the half-maximal inhibitory concentration (IC50) of hIL-34. 50 The value was 0.05326 μg / ml. Human CSF1R-Fc was used as a positive control in this analysis with an IC50 value of 0.09603 μg / ml. 50 Inhibits luciferase activity. surface 7 : Performance hCSF1R Of 293 SRE Human cells IL - 34 Neutralization of induced luciferase reporter activity Anti-drug analysis using flow cytometry technology IL34 Antibody inhibits human mononuclear globulins IL - 34 Inducing CD163 Performance ability IL-34 neutralization can also be assessed by measuring the expression of the cell surface antigen CD163 in human monocytes after IL-34 treatment using flow cytometry (see, for example, Boulagriba, S.). And others. IL - 34 and CSF - 1 display an equivalent macrophage differentiation ability but a different polarization potential . Sci Rep 8, 256 (2018). CD14-positive mononuclear globules were treated with IL-34 for 6 days, and CD163 expression was assessed by flow cytometry after staining with CD163 antibody. Changes in the number of CD163-expressing cells indicated that IL-34 treatment increased the expression of this antigen in mononuclear globules. The increase in CD163 expression was inhibited by adding antibody 1. Isotype-matched IgG4 antibody was used as a negative control in this experiment. CD14+ human mononuclear globules differentiated into macrophages by the addition of IL-34 (100 ng / ml). The macrophage marker CD163 was used to monitor the degree of differentiation. This differentiation into macrophages could be inhibited by the addition of anti-IL-34 antibody. CD14+ human mononuclear globules were seeded in 6-well plates with or without IL-34. Cells were treated with 15 μg / ml of anti-IL-34 antibody, such as antibody 1, or IgG4 PAA for a total of 6 days, with a refresh treatment on day 3. On day 6, cells were removed from the plates with non-enzymatic cell dissociation buffer, collected, and washed in FACS buffer (PBS + 2% FBS + 0.1% sodium azide + 2% EDTA). Cells were blocked for 30 minutes with TruStain FcX (catalog number 422302) as recommended by the manufacturer. After blocking, cells were washed in FACS buffer and stained with anti-CD163-PE or IgGk isotype control-PE at 4°C for 1 hour. At the end of culture, cells were washed and flow cytometry was performed on Accuri using a minimum of 10,000 events. The median PE-A level for each treatment was collected. The results are shown in Table 10. surface 10 : Inhibition of human mononuclear globulins by flow cytometry analysis IL - 34 Inducing CD163 Performance The inhibition of CD163 expression in human monocytes by antibody 1 in response to IL-34 demonstrates the ability of the antibody of the present invention to regulate the response of monocyte / macrophage numbers and / or phenotypic differentiation to IL-34, and supports the use of the antibody of the present invention for the treatment of immune-mediated diseases such as neuroinflammation and other inflammatory conditions (see, for example, Lelios, I. et al.). Emerging roles of IL - 34 in health and disease, J Exp Med (2020) 217 ​​(3): e20190290). Example 4 : Antibody 1 Characterization of immunogenic potential dendritic cells ( DC ) Internalization analysis Single-core ball derivative DC nourish ( MDDC CD14+ mononuclear globules were isolated from peripheral blood mononuclear cells (PBMCs) and cultured and differentiated into dendritic cells (DCs) according to standard protocols. In short, PBMCs were isolated from LRS-WBCs using density gradient centrifugation with Ficoll (#17-1440-02, GE Healthcare) and Sepmate 50 (#15450, STEMCELL Technologies). CD14+ mononuclear globules were isolated from LRS-WBCs using a positive-selection CD14+ microbead kit (#130-050-201, Miltenyi Biotec) according to the manufacturer's instructions. Cells were then cultured at 1 million / ml with 1000 units / ml GM-CSF and 600 units / ml IL-4 for 6 days in RPMI medium (hereinafter referred to as complete RPMI medium or medium, purchased from Life Technologies) containing L-glutamic acid and 25 mM HEPES, supplemented with 10% FBS, 1 mM sodium pyruvate, 1× penicillin-streptomycin, 1× non-essential amino acids and 55 μM 2-mercaptoethanol to drive immature dendritic cells (MDDCs). The medium was changed twice, on days 2 and 5. On day 6, cells were gently collected with a cell scraper and used for experiments. The dendritic morphology of MDDCs was characterized by microscopic observation, and the expression of CD14, CD11c, and HLA-DR was characterized by flow cytometry. The upregulation of CD80, CD83, and CD86 by flow cytometry confirmed their responsiveness to LPS treatment. Fab - TAMRA - QSY7 The F(ab')2 fragment of goat anti-human IgG (Jackson ImmunoResearch) was double-labeled with QSY7-NHS and TAMRA-SE (Molecular Probes) to obtain Fab-TAMRA-QSY7 as a universal probe for tracking sample internalization. Each vial of F(ab')2 (approximately 1 ml, 1.3 mg / ml) was concentrated to approximately 2 mg / ml by centrifugation at 14,000 rcf for 2 min using an Amico Ultra-0.5 centrifuge filter (#UFC501096, Millipore). The pH was adjusted to alkaline (> pH 8) with 10% (v / v) 1 M sodium bicarbonate, and 6.8 µl of QSY-NHS was added to a 10 mM stock solution in DMSO and mixed. The reaction vials were kept in the dark at room temperature for 30 min. The intermediate product Fab-QSY7 was purified using a Zeba Spin desalting column (#89890, Thermo Scientific) by centrifugation at 1000 rcf for 2 min. The concentration and degree of labelling (DOL) were calculated by measuring the absorbance at 280 nm and 560 nm using a NanoDrop (ThermoFisher). Fab-QSY7 was then concentrated to approximately 2 mg / mL by centrifugation again at 14,000 rcf for 2 min using an Amico Ultra-0.5 centrifuge filter. After pH adjustment with 10% (v / v) 1 M sodium bicarbonate, 4.3 µl of TAMRA-SE in 15 mM stock solution in DMSO was added and mixed. After 30 min, the final product Fab-TAMRA-QSY7 was purified and collected using a Zeba Spin desalting column by centrifugation at 1000 rcf for 2 min. The concentration and DOL were again quantified by reading the absorbance at 280 nm, 555 nm, and 560 nm using a NanoDrop Spectrophotometer. Using this method, approximately 300 µl of Fab-TAMRA-QSY7 at a concentration of approximately 1.5 mg / ml was obtained, with approximately two QSY7 and two TAMRA per F(ab')2. By FACS For standardized internalization studies, individual test molecules were normalized to 1 mg / ml using PBS and subsequently further diluted to 8 µg / ml in intact RPMI medium. Fab-TAMRA-QSY7 was diluted to 5.33 µg / ml in intact RPMI medium. The antibody and Fab-TAMRA-QSY7 were mixed in equal volumes and incubated in the dark at 4°C for 30 min for complex formation. MDDC was resuspended in intact RPMI medium at 4 million / ml and seeded at 50 µl / well in 96-well discs, with 50 µl of the antibody / probe complex added to each well. Cells were then cultured in CO2. Cells were incubated at 37°C for 24 h in an incubator. Cells were washed with 2% FBS PBS and resuspended in 100 µl of 2% FBS PBS containing Cytox Green live / dead dye. Data were collected on a BD LSR Fortessa X-20 and analyzed in FlowJo. Viable single cells were gated, and the percentage of TAMRA-positive cells was recorded as a reading. Data presentation and statistical analysis: Molecules were tested in duplicate or triplicate on three or more donors. The percentage of TAMRA-positive individuals was considered for each donor. To allow for comparison of molecules with data from different donors, a standardized internalization index (NII) was used. The internalization signal was normalized to IgG1 isotype (NII = 0) and internal positive control PC (NII = 100) using the following formula: Where X TAMRA ,IgG1 isotype TAMRA and PC TAMRA The percentages of TAMRA-positive individuals for tested molecules X, IgG1 isotypes, and PCs are shown. Data were analyzed in JMP® 14.1.0 or Graphpad Prism 8.1.2. The mean percentage of TAMRA-positive individuals and the NII are calculated and reported. Increased internalization of antigen-presenting cells, such as dendritic cells (DCs), is associated with an increased risk of immunogenicity. The geometric mean of the duplicate assays for antibody 1 is shown in Table 11. surface 11 . DC Internalization results (See, e.g., Wen, Y., Cahya, S., Zeng, W. et al. Development of a FRET-Based Assay for Analysis of mAbs Internalization and Processing by Dendritic Cells in Preclinical Immunogenicity Risk Assessment. AAPS J22, 68 (2020) MAPP analyze ( MHC Related peptide proteomics ) method Primary human dendritic cells from 10 normal human donors were prepared from skin-colored blood cells as described below: CD-14 positive cells were isolated and subjected to treatment at 37°C and 5% CO2. 2. Cells were cultured for 3 days in intact RPMI medium containing 5% Serum Replacement (Thermo Fisher Scientific, catalog number A2596101) with 20 ng / ml IL-4 and 40 ng / ml GM-CSF to differentiate into immature dendritic cells (Knierman et al., "The Human Leukocyte Antigen Class II Immunopeptidome of the SARS-CoV-2 Spike Glycoprotein", Cell Reports, 33, 108454 (2020)). On day 4, three micromoles of test antibody were added to approximately 5 × 10⁻⁶. 6 Cells were cultured for 5 hours, and the medium was replaced with fresh medium containing 5 µg / ml LPS to transform the cells into mature dendritic cells. The next day, mature cells were lysed in 1 ml of RIPA buffer containing protease inhibitors and DNase. The lysates were stored at 80°C until sample analysis. HLA-II molecules were isolated from the lysate of a biotinylated anti-pan-HLA class II antibody (pure Tu39) using an automated liquid handling system after thawing. The bound receptor-peptide complex was dissociated using 5% acetic acid and 0.1% TFA. The dissociated MHC-II peptide was pre-washed through a 10k MWCO filter to remove high molecular weight proteins. The separated MHC-II peptide was analyzed by nano-LC / MS using a Thermo easy 1200 nLC-HPLC system equipped with a Thermo LUMOS mass spectrometer. Separation was performed using a 75µm × 7 cm YMC-ODS C18 column with a 65-minute gradient at a flow rate of 250 nL / min, with 0.1% formic acid aqueous solution as solvent A and 80% acetonitrile containing 0.1% formic acid as solvent B. Mass spectrometry was run at a full scan mode at 240,000 resolution, followed by a 3-second data-correlated MS / MS cycle consisting of rapid scans using an ion trap with HCD and EThcD fragmentation. Peptide identification was generated using a variety of search algorithms within the internal proteomics pipeline (Higgs et al., "Label-free LC-MS method for the identification of biomarkers", Methods in Molecular Biology, 428, 209-230 (2008)), without enzyme search parameters for bovine / human databases containing test antibody sequences. The KNIME workflow was used to process the identification profiles of the samples. Peptides identified in the test samples were aligned with parental sequences. A summary was created for all donors, with annotations showing the percentage of donors with non-germinal residues, the number of different regions displaying peptides with non-germinal residues, and the depth of peptide display in each region with non-germinal residues. Increased display of non-germinal peptides was associated with increased immunogenicity risk. Results for antibody 1 are shown in Table 12. surface 12 : MAPP result T Cell proliferation analysis: This analysis assesses the ability of test candidates or their MAPP-derived peptide clusters to activate CD4+ T cells by inducing cell proliferation (Walsh et al., "Post-hoc assessment of the immunogenicity of three antibodies reveals distinct immune stimulatory mechanisms", mAbs, 12, 1764829 (2020)). Cryopreserved PBMCs from 10 healthy donors were used, with CD8+ T cells depleted from the PBMCs and labeled with 1 µM carboxyfluorescein diacetate succinimide (CFSE). PBMCs were plotted in 4 × 10⁻⁶ cells / mL. 6 10 cells / ml / well seeded in a solution containing 5% CTS TM The test was performed in triplicate in 2.0 mL of AIM-V medium (Life Technologies, catalog number 12055-083) containing different test samples, DMSO control, medium control, and keyhole hemocyanin (KLH; positive control). Cells were cultured at 37°C and 5% CO2. 2. Incubate for 7 days. On day 7, samples were stained with the following cell surface markers: anti-CD3, anti-CD4, anti-CD14, anti-CD19, and DAPI, and then sampled using a BD LSRFortessa equipped with a High Throughput Sampler (HTS). TM Viability was detected using flow cytometry. Data was analyzed using FlowJo® software (FlowJo, LLC, TreeStar), and the Cellular Division Index (CDI) was calculated. In short, viability was determined by analyzing the proliferating CFSE cells in the stimulated wells. dim The percentage of CD4+ T cells divided by the number of CFSE cells proliferating in unstimulated wells dim The CDI for each tested molecule was calculated based on the percentage of CD4+ T cells. A CDI ≥ 2.5 was considered a positive response. The percentage of donors present in all donors was assessed. Results for antibody 1 are shown in Table 13. surface 13 . CD4 + T Incidence of cellular response Example 5 : Antibody pharmacokinetics in Lithops macaques: A single intravenous (IV) dose of antibody 1 at 3 mg / kg was administered to Lithops macaques in 1 mL / kg PBS (pH 7.4). For pharmacokinetic characterization, blood was collected from two animals / time points at 1, 3, 6, 24, 48, 72, 96, 120, 168, 240, 336, 408, 504, and 672 hours post-administration and processed into serum. Serum concentrations of antibody 1 were determined by qualified immunoaffinity liquid chromatography-mass spectrometry. Antibody 1 and human antibody internal standard (stable isotope-labeled human IgG) were extracted from 100% Lithops macaque serum using biotinylated goat anti-human IgG antibody, followed by quantification of trypsin substitute peptides using a Q-Exactive™ Orbitrap® mass spectrometer. Pharmacokinetic parameters for each animal (N=2) were calculated using non-compartmental analysis (NCA), and the parameters were summarized by average. NCA and summary statistics were performed using Phoenix. As shown in Table 14, antibody 1 exhibits an expanded pharmacokinetic profile in stone crab macaques. surface 14 : To the stone crab macaque in one go 3 mg / kg IV Antibody after dosage 1 Plasma pharmacokinetic parameters. Heavy chain of antibody 1 (SEQ ID NO: 1) Antibody 1 Light chain ; Antibody 2 Of LC ( SEQ ID NO : 2 ) Antibody 1 Of HCVR ( SEQ ID NO : 3 ) Antibody 1 Of LCVR ; Antibody 2 Of LCVR ( SEQ ID NO : 4 ) Antibody 1: HCDR1 (SEQ ID NO: 5) Antibody 1, HCDR2 (SEQ ID NO: 6) Antibody 1 HCDR3 (SEQ ID NO: 7) LCDR1 of Antibody 1 and Antibody 2 (SEQ ID NO: 8) LCDR2 of antibody 1 and antibody 2 (SEQ ID NO: 9) LCDR3 of Antibody 1 and Antibody 2 (SEQ ID NO: 10) Encoding antibody 1 The heavy chain DNA ( SEQ ID NO : 11 ) DNA encoding the light chain of antibody 1 (SEQ ID NO: 12) Antibody 1: HCDR1 (Kabat) (SEQ ID NO: 13) Antibody 1: HCDR2 (Kabat) (SEQ ID NO: 14) Antibody 1: HCDR3 (Kabat) (SEQ ID NO: 15) Antibody 1: LCDR1 (Kabat) (SEQ ID NO: 16) Antibody 1: LCDR2 (Kabat) (SEQ ID NO: 17) Antibody 1: LCDR3 (Kabat) (SEQ ID NO: 18) Antibody 1: HCDR1 (Chothia) (SEQ ID NO: 19) Antibody 1: HCDR2 (Chothia) (SEQ ID NO: 20) Antibody 1: HCDR3 (Chothia) (SEQ ID NO: 21) Antibody 1: LCDR1 (Chothia) (SEQ ID NO: 22) Antibody 1, LCDR2 (Chothia) (SEQ ID NO: 23) Antibody 1: LCDR3 (Chothia) (SEQ ID NO: 24) Antibody 1: HCDR1 (IMGT) (SEQ ID NO: 25) Antibody 1 HCDR2 (IMGT) (SEQ ID NO: 26) Antibody 1 HCDR3 (IMGT) (SEQ ID NO: 27) Antibody 1: LCDR1 (IMGT) (SEQ ID NO: 28) Antibody 1's LCDR2 (IMGT) (SEQ ID NO: 29) Antibody 1's LCDR3 (IMGT) (SEQ ID NO: 30) Humans IL - 34 ( SEQ ID NO : 31 ) IgG4PAA hinge region (SEQ ID NO: 32) IgG4PAA Fc district ( SEQ ID NO : 33 ) Stone crab macaque CSF1R ECD - Fc Of sequence ( SEQ ID NO : 34 ) Antibody 2 heavy chain ( SEQ ID NO : 35 ) Antibody 3 heavy chain ( SEQ ID NO : 36 ) Antibody 4 heavy chain ( SEQ ID NO : 37 ) Donemazan heavy chain ( SEQ ID NO : 38 ) Donaseonine light chain ( SEQ ID NO : 39 ) anti- N3pG antibody heavy chain ( SEQ ID NO : 40 ) anti- N3pG antibody light chain ( SEQ ID NO : 41 ) picture 1 shows that antibody 1 neutralizes the activity of human IL-34-induced luciferase reporter in 293 SRE cells expressing hCSF1R. TW202334211A_111141269_SEQL.xml

Claims

1. An antibody that binds to human IL-34, wherein the antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises heavy chain complementarity-determining regions (HCDR) HCDR1, HCDR2 and HCDR3, and the VL comprises light chain complementarity-determining regions (LCDR) LCDR1, LCDR2 and LCDR3, wherein HCDR1 comprises SEQ ID NO: 5, HCDR2 comprises SEQ ID NO: 6, HCDR3 comprises SEQ ID NO: 7, LCDR1 comprises SEQ ID NO: 8, LCDR2 comprises SEQ ID NO: 9, and LCDR3 comprises SEQ ID NO:

10.

2. The antibody as claimed in claim 1, wherein the VH contains SEQ ID NO: 3 and the VL contains SEQ ID NO:

4.

3. The antibody as claimed in claim 1 or 2, wherein the antibody comprises: a heavy chain (HC) comprising SEQ ID NO: 1 and a light chain (LC) comprising SEQ ID NO:

2.

4. A vector comprising a first nucleic acid sequence encoding SEQ ID NO: 11 and a second nucleic acid sequence encoding SEQ ID NO:

12.

5. A composition comprising: a first vector comprising a nucleic acid sequence encoding SEQ ID NO: 11 and a second vector comprising a nucleic acid sequence encoding SEQ ID NO:

12.

6. A cell comprising the vector as claimed in claim 4.

7. The cell in claim 6, wherein the cell is a mammalian cell.

8. A method for producing an antibody, comprising culturing cells as claimed in claim 7 under conditions that allow the antibody to be expressed, and recovering the expressed antibody from the culture medium.

9. A pharmaceutical composition comprising an antibody as claimed in any one of claims 1 to 3 and a pharmaceutically acceptable excipient, diluent or carrier.

10. Use of an antibody as claimed in any one of claims 1 to 3 or a pharmaceutical composition as claimed in claim 9, for the manufacture of a medicament for treating immune-mediated diseases involving IL-34.

11. As claimed in claim 10, wherein the immune-mediated disease is selected from the group consisting of: Alzheimer's disease; tau protein disease; Hughley's syndrome (SS); rheumatoid arthritis (RA); inflammatory bowel disease (IBD), atopic dermatitis, nephropathy, sepsis and / or non-alcoholic fatty liver disease (NAFLD).

12. As requested in claim 11, wherein the immune-mediated disease is Alzheimer's disease.

13. An in vitro method for determining the content of human IL-34 in a body fluid, comprising: (a) contacting the body fluid with a diagnostic monoclonal antibody against human IL-34 specifically bound to human IL-34 composed of an amino acid sequence of SEQ ID NO: 31, or an antigen-binding fragment thereof, the antibody or antigen-binding fragment comprising: light chain complementarity-determining regions LCDR1, LCDR2 and LCDR3 comprising amino acid sequences (SEQ ID NO: 8), (SEQ ID NO: 9) and (SEQ ID NO: 10), respectively, and heavy chain complementarity-determining regions HCDR1, HCDR2 and HCDR3 comprising amino acid sequences (SEQ ID NO: 5), (SEQ ID NO: 6) and (SEQ ID NO: 7), respectively; (b) removing any non-specifically bound monoclonal antibody or antigen-binding fragment thereof as appropriate; and (c) detecting and / or quantifying the amount of monoclonal antibody or antigen-binding fragment thereof specifically bound to human IL-34.

14. The method of claim 13, wherein the bodily fluid is blood, serum or plasma, or cerebrospinal fluid, and the contact occurs outside the body.

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