TREM2 STABILIZING ANTIBODIES

Abstract

The present invention provides antibodies that bind to and stabilize the Human Activation Receptor Expressed on Myeloid Cells 2 (TREM2) protein, and methods for using these antibodies.

Description

This application contains a sequence listing that has been submitted electronically in ASCII format, and which is incorporated by reference in its entirety. That ASCII copy, created on September 16, 2019, is named PAT058251_ST25.txt, and is 147,551 bytes in size. TECHNICAL FIELD The present invention provides antibodies that bind to and stabilize the Myeloid Cell-Expressed Human Activation Receptor 2 (TREM2) protein, and methods of using these antibodies. BACKGROUND Activation receptors expressed on myeloid cells or TREMs are a group of transmembrane glycoproteins that are expressed on different types of myeloid cells, such as macrophages, dendritic cells, osteoclasts, microglia, mast cells, monocytes, lung epithelial cells, skin Langerhans cells. , Kupffer cells and neutrophils (Takaki, R. et al, Immunol. Rev., 2006, 214: 118-29). TREMs have an immunoglobulin (Ig)-like fold in their extracellular domain and therefore belong to the immunoglobulin superfamily (IgSF). TREM receptors contain a short intracellular domain, but lack docking motifs for signaling mediators, and require adapter proteins such as DAP12 (12 kDa DNAX activating protein) for cellular activation. Two members of TREM have been reported: TREMI and TREM2, both of which play important roles in immune and inflammatory responses. The genes encoding human TREMs map to chromosome 6p21.1, which contains a cluster of genes encoding TREMI, TREM2, TREM3, TREM4, and TREM5, as well as TREM-like genes. TREM2 is a glycoprotein of around 40 kDa, which is reduced to 26 kDa after N-deglycosylation. The entire TREM2 protein consists of a leader signal peptide (amino acids 1-18), a single V-type IgSF extracellular region (amino acids 19-132), a stem region (amino acids 133-172), a positively charged transmembrane domain ( amino acids 173197) and a cytosolic tail (amino acids 198-230) (Kober et al., Elite 5 (2016); Kober et aL, J. Mol. BioL 429 (2017) 1607-1629). The extracellular region, encoded by exon 2, is composed of a single IgSF type V domain, containing three potential N-glycosylation sites. The putative transmembrane region contains a charged lysine residue. The cytoplasmic tail of TREM2 lacks signaling motifs and is thought to signal via the signaling adapter molecule DAP12 / TRYROBP. TREM2 physically associates with DAP12, which acts as a signaling adapter protein for TREM2 and a number of other cell surface receptors. The cytoplasmic n / ztznn / i ζπζ / β / υιλι domain of DAP12 contains an immunoreceptor tyrosine activation motif (ITAM) (Wunderlich, J. Biol. Chem. 288, 33027-33036, 2013 ). Following activation of the interacting receptor, DAP12 undergoes phosphorylation at conserved ITAM tyrosine residues, by Src kinases. Subsequent recruitment and activation of Syk protein kinase triggers downstream signaling pathways, including activation of mitogen-activated protein kinase (MAPK), PI3K, NFkB, and phospholipase Cy (PLCy). TREM2 can be activated by lipopolysaccharide (LPS), heat shock protein 60, neuritic remnants, bacteria, apolipoprotein E, and a wide range of anionic and zwitterionic lipids, e.g., phosphatidic acid (PA), phosphatidylglycerol (PG), phosphatidylserine (PS ), phosphatidylinositol (Pl), phosphatidylcholine (PC), cardiolipin, and sphingomyelin. TREM2 activation increases the phagocytic capacity of microglia and macrophages, reduces the release of proinflammatory cytokines, and limits TLR (Toll-like receptor) signaling. TREM2 maintains microglial survival through synergy with CSF-1 receptor signaling. Furthermore, TREM2 interacts with Plexin-A1 in order to regulate cell adhesion and motility. TREM2 is also enriched in regions of the cell surface of microglia that contact Αβ plaques or neuronal debris (Yuan et al., Neuron 90 (2016) 724-739). Some of the ligands detected by TREM2 in this environment have recently been identified, for example phospholipids and myelin lipids (Poliani et al., J. Clin. Invest. 125 (2015): 2161-2170), as well as ApoE (Atagi et al. al., J. Biol. Chem. 290 (2015): 26043-26050; Bailey et al., J. Biol. Chem. 290 (2015): 2603326042). Other ligands could be Αβ and plaque-associated neuronal debris, as TREM2 contributes to Αβ uptake into microglia (Xiang et al., EMBO Mol. Med. 8 (2016): 9921004). TREM2 has also been shown to play a role in the clearance of apoptotic cells (Takahashi et al, J. Exp. Med. 201 (2005), 647-657), myelin debris (Poliani et al, J. Clin. Invest 125 (2015): 2161-2170) and bacterial beads (Cen et al, Am. J. Respir. 188 (2013) 201-212). TREM2 signaling facilitates the degradation of ingested prey and is crucial for lipid metabolism, myelin uptake, and intracellular breakdown. TREM2 undergoes sequential proteolytic processing via ectodomain detachment and intramembrane proteolysis (Wunderlich, J. Biol. Chem. 288, 33027-33036, 2013). During ectodomain detachment, the TREM2 ectodomain is released by proteases such as members of the ADAM family (a disintegrin and metalloproteinase domain-containing protein) or the BACE family (beta site APP-cleaving enzyme, according to its acronym in English) (Kleinberger, Sci. Trans. Med. 2014; 6 (243): 243ra86). After removal of the ectodomain, the remaining membrane-retained fragment is further processed by γ-secretase-mediated intramembranous proteolysis. n / ztznn / i ζπζ / β / υιλι soluble fragments of TREM2 (sTREM2) produced by detachment of the ectodomain have been observed in culture supernatants of dendritic cells, as well as in plasma and CSF (cerebrospinal fluid) samples from patients with diseases non-inflammatory neurological diseases and multiple sclerosis (Kleinberger, 2014). The shed ectodomain of TREM2, i.e., sTREM2, in human CSF has been evaluated as a potential biomarker of Alzheimer's disease (AD), and has been shown to be increased during aging in general. (Suarez-Calvet, EMBO Mol. Med. 8, 466-476, 2016). Detailed analysis during the course of AD revealed that sTREM2 rises early in AD before clinical symptoms appear, peaks in MCI-AD, and remains elevated, but at lower levels compared to the MCI stage. -AD, in AD dementia (Suarez-Calvet, 2016). Increased TREM2 expression at the peak of disease drives resolution (eg, peritonitis, wound healing) (Turnbull, 2006; Gawish, 2015). Under chronic inflammatory conditions, such as neuroinflammation, TREM2 is constantly shed, and is unable to exert its signaling function in microglia and macrophages. Therefore, stabilization and / or prevention of TREM2 shedding at the cell surface will restore functional expression of TREM2 with signaling capabilities in microglia and macrophages. Human genetic studies indicate that loss of surface TREM2 rather than lack of sTREM2 leads to disease risk. For example, an amino acid mutation at position 47 from R to H in the TREM2 protein, eg in SEQ ID NO: 1, causes slightly reduced cell surface expression (Kleinberger 2014) and reduced ligand binding capacity. from TREM2 (Wang 2015, Atagi 2015, Bailey 2015). The T66M amino acid mutation in TREM2 results in a lack of TREM2 expression on the cell surface (Kleinberger 2014) and therefore no soluble TREM2 is generated. A TREM2 cleavage site mutation: H157Y, enhances sTREM2 expression and reduces full-length membrane-bound TREM2, and is associated with increased risk of AD (Thornton 2017, Schlepckow 2017). Therefore, these genetic studies suggest that it is desirable to stabilize TREM2 on the cell surface, both to reduce sTREM2 and to increase TREM2 bound to the plasma membrane. Haass et al. (WO18015573) generated antibodies that bind to a 10 amino acid peptide (AHVEHSISRS SEQ ID NO: 132) spanning amino acids 152-161 located in the TREM2 stem region and that inhibits TREM2 cleavage. Such antibodies prevent TREM2 cleavage by directly binding and thus blocking the cleavage site. Schwabe et al (WO17062672) describe antibodies that bind to TREM2. However, no stabilizing effect is indicated for any of the described antibodies. In contrast, for some of the antibodies described in WO17062672, a destabilizing effect is reported (Example 15). Therefore, there is a need to identify and develop antibodies against hTREM2 that stabilize TREM2 and activate and / or facilitate TREM2-related functions, that have good developmental characteristics, and that are suitable for the treatment of patients suffering from a neurodegenerative disease for which which stabilization of TREM2 is beneficial. BRIEF DESCRIPTION OF THE INVENTION The published literature has targeted the stem region of TREM2 to generate antibodies that stabilize TREM2 since the cleavage site for ADAM17 resides within the stem region. In fact, a large molecule such as an antibody (or a binding fragment of the antibody) is expected to spherically prevent a sheddase from accessing the relatively small region of the stem (amino acids 133-172). Therefore, it is not surprising that previous efforts to generate stabilizing antibodies against TREM2 have been directed at the stem region of TREM2. The IgSF region of TREM2 (amino acids 19-132 of any of SEQ ID NO: 1, 2 or 3 lies furthest from the cleavage site (H157), and is part of the ectodomain. So far, the IgSF region has not been found. has been considered a potential target for antibodies that would stabilize TREM2, since antibodies against the IgSF region of TREM2 would not be expected to spherically prevent access of a sheddase to the TREM2 cleavage site. Surprisingly, we found that antibodies as described herein bind to the IgSF region and are capable of efficiently stabilizing TREM2 on the cell surface. We have also shown that such antibodies can display downstream functional effects, such as the facilitation of TREM2-dependent phagocytosis in human M2A macrophages. In addition, such antibodies can also enhance TREM2-dependent functions in vivo, for example, by increasing the phagocytic capacity of microglia or macrophages in the brain. Accordingly, provided herein are antibodies or antigen-binding fragments of antibodies, eg, monoclonal antibodies or antigen-binding fragments thereof, that specifically bind to the IgSF domain of human TREM2 (hTREM2) and stabilize the protein. hTREM2. Such an antibody is referred to herein as an hTREM2 antibody or its antigen-binding fragment. These hTREM2 antibodies or antigen-binding fragments thereof can (i) reduce or inhibit shedding of the TREM2 ectodomain; (ii) stabilizing the TREM2 protein on the cell surface; and / or (ii) maintaining or increasing functions of TREM2, such as binding to its cognate ligands, intracellular signalling, increased phagocytosis, facilitation of degradation of phagocytic material, and promotion of TREM2-dependent downstream regulatory functions. Since dysfunctional TREM2 or surface-absent TREM2 is associated with human neurodegenerative n / ztznn / i ζπζ / ε / υιλι neuroinflammatory pathologies, the hTREM2 antibody or its antigen-binding fragment described herein can be used to treat, prevent, or diagnose a neuroinflammatory or neurodegenerative disease such as Alzheimer's disease, frontotemporal dementia, Parkinson's disease, amyotrophic lateral sclerosis, NasuHakola disease, multiple sclerosis, ALS, antibody encephalitis anti-NMDA receptor, autism, cerebral lupus (NP-SLE), chemoinduced peripheral neuropathy (CIPN), postherpetic neuralgia, chronic inflammatory demyelinating polyneuropathy (CIDP) acronym), epilepsy, Guillain-Barré syndrome (GBS), inclusion body myositis, lysosomal storage diseases, e.g. eg, sphingomyelinlipidose (Niemann-Pick C) and mucopolysaccharide II / IIIB, metachromatic leukodystrophy, multifocal motor neuropathy, myasthenia gravis, Neuro-Behcet's disease, neuromyelitis optica (NIMIO), optic neuritis, polymyositis, dermatomyositis, Rasmussen's encephalitis, syndrome of Rett, stroke, transverse myelitis, traumatic brain injury, spinal cord injury, viral encephalitis, or bacterial meningitis. The hTREM2 antibodies or an antigen-binding fragment thereof described herein are also suitable for treating, preventing, or diagnosing autoimmune, inflammatory, or malignant disorders mediated or associated with extensive proteolytic cleavage of TREM2 or cells expressing aberrant or mutated variants. of the TREM2 receptor. In some preferred embodiments, the hTREM2 antibody or an antigen-binding fragment as described herein can be used to treat, prevent, or diagnose a disease selected from Alzheimer's disease, frontotemporal dementia, Parkinson's disease, lateral sclerosis. amyotrophic or Nasu-Hakola disease. Also provided herein are methods for diagnosing and / or treating TREM2-associated diseases using the TREM2-binding antibodies or antigen-binding fragments thereof described herein. In one aspect, provided herein are antibodies or antigen-binding fragments thereof that specifically bind to the IgSF domain of the TREM2 protein and stabilize the TREM2 protein. In some preferred embodiments, these antibodies or their antigen-binding fragments stabilize the TREM2 protein on the cell surface of a TREM2-expressing cell such as macrophages, dendritic cells, osteoclasts, microglia, mast cells, monocytes, lung epithelial cells, cells Langerhans cell, Kupffer cells, neutrophils, or hepatocarcinoma cells. In some embodiments, these antibodies or antigen-binding fragments thereof reduce proteolytic detachment of the TREM2 protein ectodomain. n / ztznn / i ζπζ / ε / υιλι In some embodiments, antibodies or antigen-binding fragments thereof that specifically bind to the IgSF domain of human TREM2 are provided herein. For example, said antibodies or antigen-binding fragments thereof bind to the IgSF domain of human TREM2 comprising amino acid residues 19 to 132 of SEQ ID NO: 1, amino acid residues 19 to 132 of SEQ ID NO : 2, or amino acid residues 19 to 132 of SEQ ID NO: 3. In some embodiments, the TREIVI2 antibodies are human or humanized antibodies. In some embodiments, the antigen-binding fragment is a Fab, F(ab')2, Fv fragments, scFv, minibody, or a diabody. In some embodiments, the TREM2 antibody is a bispecific antibody. In some embodiments, the bispecific antibody specifically binds human TREM2 and DAP12. In some embodiments, the TREM2 antibody comprises an Fc region. In some embodiments, the Fc region is a modified lgG1 Fc region that has one or more mutations and has reduced antibody-dependent cellular cytotoxicity (ADCC) activity. or complement-dependent cytotoxicity (CDC) compared to the parental antibody. In some embodiments, the Fe region is selected from an IgG2 Fe region, an IgG4 Fe region, or an IgG2 / IgG4 hybrid Fe region. In some embodiments, the hTREM2 antibodies or their antigen-binding fragments are monoclonal. Provided herein are nucleic acids encoding such monoclonal antibodies or antigen-binding fragments thereof, and vectors and host cells comprising nucleic acid encoding such monoclonal antibodies or antigen-binding fragments thereof. In another aspect, provided herein is pharmaceutical compositions comprising one or more of the TREM2 antibodies or antigen-binding fragments thereof described herein, or nucleic acid encoding such antibodies or antigen-binding fragments thereof, or cells comprising said nucleic acids, and a pharmaceutically acceptable carrier. In another aspect, provided herein are methods of treating a disease associated with TREM2 loss of function in a subject in need thereof, by administering to the subject a therapeutically effective amount of any of the TREM2 antibodies or binding fragments thereof. to antigen described in this document. Such methods may include one or more of the following steps: (1) assaying the level of cell surface TREM2 in a sample obtained from a subject; (2) select a subject whose cell surface TREM2 level is below a reference level, where the reference level njztznn / i ζπζ / ε / υιλι is the cell surface TREM2 level in a sample obtained from a healthy subject; and (3) administering to the subject a therapeutically effective amount of an antibody or antigen-binding fragment thereof that specifically binds to the IgSF domain of the TREM2 protein and stabilizes the TREM2 protein. In some embodiments, such methods further include administering a second agent to the subject. The level of cell surface TREM2 in a sample can be determined by an assay selected from flow cytometry, immunohistochemistry, Western blotting, immunofluorescent assay, radioimmunoassay (RIA), enzyme-linked immunosorbent assay (ELISA). ), homogeneous time-resolved fluorescence (HTRF), or positron emission tomography (PET). In some embodiments, the sample comprises cerebrospinal fluid and its cellular components. In some embodiments, the disease associated with the loss of function of TREM2 is a neuroinflammatory or neurodegenerative disease such as Alzheimer's disease, frontotemporal dementia, Parkinson's disease, amyotrophic lateral sclerosis, Nasu-Hakola disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS), anti-NMDA receptor encephalitis, autism, cerebral lupus (NP-SLE), chemoinduced peripheral neuropathy (CIPN), postherpetic neuralgia, chronic inflammatory demyelinating polyneuropathy (CIDP), epilepsy, Guillain-Guillain syndrome Barré (GBS), Inclusion Body Myositis, Lysosomal Storage Diseases, p. eg, sphingomyelinlipidose (Niemann-Pick C) and mucopolysaccharide II / IIIB, metachromatic leukodystrophy, multifocal motor neuropathy, myasthenia gravis, Neuro-Behcet's disease, neuromyelitis optica (NMO), optic neuritis, polymyositis, dermatomyositis, Rasmussen's encephalitis, syndrome of Rett, stroke, transverse myelitis, traumatic brain injury, spinal cord injury, viral encephalitis, or bacterial meningitis. In some preferred embodiments, the disease associated with TREM2 loss of function is a neurodegenerative disease selected from Alzheimer's disease, frontotemporal dementia, Parkinson's disease, amyotrophic lateral sclerosis, or Nasu-Hakola disease. In a further preferred embodiment, the disease is Alzheimer's disease. In some embodiments, TREM2 antibodies or their antigen-binding fragments stabilize TREM2 protein on the cell surface of a TREM2-expressing cell selected from a macrophage, dendritic cell, osteoclast, microglia, mast cell, monocyte, lung epithelial cell, skin Langerhans cells, Kupffer cells, neutrophils, or hepatocarcinoma cells. In some embodiments, the TREM2 antibody or its antigen-binding fragment is administered to the subject via an oral, intravenous, intracranial, intrathecal, subcutaneous, or intranasal route. n / ztznn / i ζπζ / ε / υιλι In another aspect, antibodies to TREM2 or antigen-binding fragments thereof are provided herein for use in treating a disease associated with TREM2 loss of function. In some preferred embodiments, these antibodies or antigen-binding fragments thereof specifically bind to the IgSF domain of the TREM2 protein (i.e., amino acid residues 19 to 132 of SEQ ID NO: 1, amino acid residues 19 to 132 of SEQ ID NO: 2, or amino acid residues 19 to 132 of SEQ ID NO: 3) and stabilize the TREM2 protein. In some preferred embodiments, the antibodies or their antigen-binding fragments stabilize the TREM2 protein on the cell surface of a TREM2-expressing cell selected from a macrophage, dendritic cell, osteoclast, microglia, mast cell, monocyte, lung epithelial cell, skin Langerhans cells, Kupffer cells, neutrophils, or hepatocarcinoma cells. In some embodiments, the disease associated with the loss of TREM2 function is a neuroinflammatory or neurodegenerative disease such as Alzheimer's disease, frontotemporal dementia, Parkinson's disease, amyotrophic lateral sclerosis, NasuHakola disease, multiple sclerosis, amyotrophic lateral sclerosis ( ALS), NMDA receptor antibody encephalitis, autism, cerebral lupus (NP-SLE), chemoinduced peripheral neuropathy (CIPN), postherpetic neuralgia, chronic inflammatory demyelinating polyneuropathy (CIDP), epilepsy, Guillain-Barré syndrome (GBS) , inclusion body myositis, lysosomal storage diseases, e.g. eg, sphingomyelinlipidose (Niemann-Pick C) and mucopolysaccharide II / IIIB, metachromatic leukodystrophy, multifocal motor neuropathy, myasthenia gravis, Neuro-Behcet's disease, neuromyelitis optica (NMO), optic neuritis, polymyositis, dermatomyositis, Rasmussen's encephalitis, syndrome of Rett, stroke, transverse myelitis, traumatic brain injury, spinal cord injury, viral encephalitis, or bacterial meningitis. In some preferred embodiments, the disease associated with the loss of TREM2 function is a neurodegenerative disease selected from Alzheimer's disease, frontotemporal dementia, Parkinson's disease, amyotrophic lateral sclerosis, or Nasu-Hakola disease. In a further preferred embodiment, the disease is Alzheimer's disease. In some embodiments, TREM2 antibodies or their antigen-binding fragments stabilize TREM2 protein on the cell surface of a TREM2-expressing cell selected from a macrophage, dendritic cell, osteoclast, microglia, mast cell, monocyte, lung epithelial cell, skin Langerhans cells, Kupffer cells, neutrophils, or hepatocarcinoma cells. BRIEF DESCRIPTION OF THE DRAWINGS FIG 1A shows an exemplary alignment of the amino acid sequences of human TREM2 isoform 1 (SEQ ID NO: 1), isoform 2 (SEQ ID NO: 2) and isoform 3 (SEQ ID NO: 3). . n / ztznn / i ζπζ / ε / υιλι FIG 1B illustrates the structure of TREM2 and its interaction with the signaling adapter protein DAP12. Mature TREM2 includes a single immunoglobulin domain (IgSF), a stem region, a transmembrane (TM) domain, and a cytoplasmic domain. FIG 2 shows the stabilization of TREM2 in CHO-hDAP12-hTREM2 cells by antibody treatment. FIG 3 shows the binding of TREM2 antibodies to human M2A macrophages before and after PMA treatment. FIG 4 shows the binding of antibodies to the chimeric proteins WT-TREM2 (4A) and TREM2TREM1 expressed recombinantly in CHO-hDAP12 cells (4B, C). FIG 5 shows the stabilization of TREM2 on the hM2A cell surface by TREM2 antibodies. FIG 6 (A,B) shows that antibodies that stabilize TREM2 on the cell surface also increase the phagocytic capacity of human M2A. Statistics were calculated using Student's t-test, *Pval <0.05, **Pval <0.01, ***Pval <0.001 compared to isotype control. FIG 7 (A,B) shows the determination of the lowest effective dose in the hM2A phagocytosis assay. Statistics were calculated using Student's t-test, *Pval <0.05, **Pval <0.01, *“ Pval <0.001 compared to isotype control. FIG 8 shows that TREM2 antibodies bound to the plate induce TREM2-dependent NFAT promoter-dependent gene transcription. FIG 9 (A,B) shows that TREM2 antibodies increase Syk phosphorylation in human M2A macrophages. (B) indicates the quantification of pSyk under different conditions in correlation with total Syk from the western blot shown in (A). FIG 10 shows the phagocytosis of S. aureus bioparticles 0-3 h by human M2A macrophages. FIG 11 shows phagocytosis of SH-SY5Y cells 3-12 h by human M2A macrophages. FIG 12 shows that TREM2 antibodies facilitate chemotaxis of human M2A macrophages. FIG 13 shows that TREM2 antibodies facilitate phagocytosis in human iPS-derived microglia using apoptotic pHrodo-tagged SH-SY5Y cells and cumulative phagocytosis as read-out. FIG 14 shows that TREM2 antibodies facilitate chemotaxis of human iPS-derived microglia. FIG 15 (A-E) shows the results of prophylactic / concomitant and therapeutic treatment with TREM2 antibody in the cuprizone model. njztznn / i ζπζ / ε / υιλι FIG 16 shows the results of image analysis (A) of the MPTP model in humanized TREM2 mice and a representative microscopy image for each group (B). FIG 17 (A-C) shows the results of cross-blocking experiments of MOR041877, MOR041895 and MOR042596 Fab with full length MOR041877, MOR41895, MOR042596, MOR044698 and MOR03207 IgG in CHO-hDAP12-hTREM2 cells. FIG 18 shows the increase in phagocytic capacity of hM2A after treatment with MOR042596. FIG 19 shows the TREM2 binding epitope to MOR042596 as determined by X-ray crystallography. The TREM2 protein backbone is shown in the drawing representation, and the side chains of TREM2 residues within a distance of 5 Á of the FAb are shown as bars. The Fab heavy chain is shown as a dark gray surface and the light chain as a light gray surface. FIG 20 shows a close-up view of the TREM2-Fab interface (see Figure 19), comparing MOR042596 (crystal structure) and MOR044698 (homology pattern). TREM2 residues within 5 Á of the Fabs are shown as bars, and residues proximal to LCDR3 (D39-K42) are marked. The heavy chain (dark gray, top right) as well as LCDR1 and LCDR2 of the light chain (light gray, top left) are identical for both Fabs. LCDR3 has several shared key residues (positions 90, 93, 95) keeping the backbone-loop conformation of LCDR3 the same for both Fabs. There are changes at positions 89, 91, 92, 94, 96, and there is an additional insert at MOR044698 (S95a). The general epitope is conserved between MOR042596 and MOR044698. FIG 21 shows the TREM2 binding epitope to MOR041877 as determined by X-ray crystallography. The TREM2 protein backbone is shown in the drawing representation, and the side chains of TREM2 residues within a distance of 5 Á of the Fab are shown as bars. The Fab heavy chain is shown as a dark gray surface and the light chain as a light gray surface. FIG 22 (A,B) shows the cerebral cortex of hTREM2-KI mice treated with cuprizone and either MOR044698-mu or isotype control antibody, along with naïve mice as controls, stained for TREM2 and Iba1 (A). . A quantitative analysis of the normalized area positive for hTREM2 is provided (B). DETAILED DESCRIPTION Provided herein are antibodies and their antigen-binding fragments that specifically bind to the extracellular domain of human TREM2 and stabilize the TREM2 protein. Those TREM2 antibodies and their antigen-binding fragments can reduce or inhibit shedding of the TREM2 ectodomain; they can stabilize the TREM2 protein on the cell surface n / ztznn / i ζπζ / ε / υιλι; and may optionally maintain or enhance functions of TREM2, such as binding to its cognate ligands, intracellular signalling, increased phagocytosis, and facilitation of degradation of phagocytic material. Since dysfunctional TREM2 or surface absent TREM2 is associated with human neuroinflammatory and neurodegenerative pathologies, the TREM2 stabilizing antibodies and antigen-binding fragments thereof described herein can be used to treat, prevent or diagnose neuroinflammatory or neurodegenerative diseases such as Alzheimer's disease, frontotemporal dementia, Parkinson's disease, amyotrophic lateral sclerosis, NasuHakola disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS), NMDA receptor encephalitis, autism, cerebral lupus (NP-SLE), chemoinduced peripheral neuropathy (CIPN), postherpetic neuralgia, chronic inflammatory demyelinating polyneuropathy (CIDP), epilepsy, Guillain-Barré syndrome (GBS), inclusion body myositis, lysosomal storage diseases, e.g. eg, sphingomyelinlipidose (Niemann-Pick C) and mucopolysaccharide II / IIIB, metachromatic leukodystrophy, multifocal motor neuropathy, myasthenia gravis, Neuro-Behcet's disease, neuromyelitis optica (NMO), optic neuritis, polymyositis, dermatomyositis, Rasmussen's encephalitis, syndrome of Rett, stroke, transverse myelitis, traumatic brain injury, spinal cord injury, viral encephalitis, or bacterial meningitis. The TREM2-binding antibodies and their antigen-binding fragments described herein are also suitable for treating, preventing, or diagnosing autoimmune, inflammatory, or malignant disorders mediated or associated with extensive proteolytic cleavage of TREM2 or cells expressing aberrant or variant variants. TREM2 receptor mutations. In some preferred embodiments, the hTREM2 antibody or an antigen-binding fragment as described herein can be used to treat, prevent, or diagnose a disease selected from Alzheimer's disease, frontotemporal dementia, Parkinson's disease, lateral sclerosis. amyotrophic or Nasu-Hakola disease. Also provided herein are methods for diagnosing and / or treating TREM2-associated diseases using the TREM2-binding antibodies and their antigen-binding fragments described herein. TREM2 mediates nonphlogistic phagocytosis of bacteria and dying cells, and dampens inflammatory responses. Homozygous loss of function of TREM2 causes Nasu-Hakola disease (polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, PLOSL) or frontotemporal dementia (FTD) syndrome, diseases characterized by bone cysts, neuroinflammation, progressive neurodegeneration and presenile dementia. A heterozygous R47H loss-of-function mutation of TREM2 is also an important risk factor for njztznn / i ζπζ / ε / υιλι late-onset Alzheimer's disease (AD), with an effect size similar to that of the apolipoprotein E allele ε4. TREM2 is expressed in microglia found in the white matter, hippocampus, and neocortex, which is in part consistent with reported pathologic features in AD brains, supporting possible involvement of TREM2 in AD pathogenesis. . Genetic screens have now also identified heterozygous missense mutations in TREM2 as risk factors for Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD), in addition to AD (Kleinberger, Sci Transi). Med. 2014 Jul 2;6(243):243ra86). Thus, functional TREM2 is required to protect against age-related neuroinflammatory and neurodegenerative diseases that cause severe cognitive impairment and dementia. Due to alternative splicing, three TREM2 isoforms are present in humans, with isoform 1 being the longest isoform. Alignment of the amino acid sequences of human TREM2 isoform 1 (SEQ ID NO: 1), human TREM2 isoform 2 (SEQ ID NO: 2) and human TREM2 isoform 3 (SEQ ID NO: 3) are presented in Figure 1A. Figure 1B illustrates the structure of TREM2 and its interaction with the signaling adapter protein DAP12. Definitions. As used throughout the specification and claims, the singular forms a, an, and the include plural references, unless the context clearly indicates otherwise. For example, the term a cell includes a plurality of cells, including mixtures thereof. All numerical designations, eg, pH, temperature, time, concentration, and molecular weight, including ranges, are approximations that vary (+) or (-) in 0.1 increments. It should be understood, though not always explicitly stated, that all numerical designations are preceded by the term around. The term around in relation to a numerical value X means, for example, X ± 15%, including all values ​​within this range. It should also be understood, although not always explicitly stated, that the reagents described herein are merely exemplary, and that their equivalents are known in the art. Throughout this specification and the claims that follow, unless the context otherwise requires, the word comprises, and variations such as comprising and comprising, are used herein in their open and non-limiting sense, unless otherwise stated. When used herein, consisting of excludes any element, step, or ingredient not specified in the aspect element, embodiment, and / or claim. When used in this document, which consists essentially of does not exclude n / ztznn / i ζπζ / ε / υιλι materials or steps that do not materially affect the basic and novel features of appearance, embodiment and / or claim. As used herein, TREM2 (also known as myeloid cell-expressed activation receptor 2, TREM2, TREM2a, TREM2b or TREM2c) refers to a transmembrane glycoprotein belonging to the immunoglobulin superfamily (IgSF). The entire TREM2 protein (SEQ ID NO: 1) consists of a signal leader peptide (amino acids 1-18), a single V-type IgSF extracellular region (amino acids 19-132), a stem region (amino acids 133-172), a positively charged transmembrane domain (amino acids 173-197) and a cytosolic tail (amino acids 198-230) (Feuerbach et al., Neurosci. Lett. 660 (2017): 109-114). The human TREM2 gene maps to chromosomal location 6p21.1, and the genomic sequence of the TREM2 gene can be found in GenBank (Gen ID: 54209). Due to alternative splicing, three TREM2 isoforms are present in humans (protein sequences available from ENSEMBL under the IDs ENSP00000362205, ENSP00000342651 and ENSP00000362214). The term TREM2 is used to collectively refer to all TREM2 isoforms. The protein and mRNA sequences for the longer human TREM2 isoform are: Activation receptor expressed in myeloid cells 2 precursor isoform 1 precursor [Homo sapiens] (NP_061838.1) ME PLRLLILLFVTEL SGAHNTTVFQGVAGQSLQVSCPY DSMKHWGRRKAWCRQLGEKGPCQRWST HN LWLLSFLRRWNGSTAITDDTLGGTLTITLRbTLQPHDAGLYQCQSLHGSEADTLRKVLVEVLA^ DAGDLWFPGESE SFEDAHVEHSISRSLLEGEIPFP PTSILLLLACI ELIKILAASALWA AAWHGQKPG ΤΗP PSE LDCGHDPGYQLQTLPGLRDT (SEQ ID NO: 1) Homo sapiens activation receptor expressed on myeloid cells 2 (TREM2), transcript variant 1, mRNA (NCBI Reference Sequence: NM 018965.3) n / ztznn / i ζπζ / ε / υιλι gggcagcgcc tgcacaaggc tgctcatctt gagtqgcqgg ggcgcaaggc c gcacaactt acgataccct gtctctacca t g g a g g t g c t agtctgagag gagaaatcca agattctagc atccacccag ggatgagaga gaccagccca ag agactact gagtggggag caaataaatc tgacatgcct actctgottc actcttttgtc ccagtccctg ctggtgccgc gtggetgctg gggtggcact gtgccagagc ggcagacccc cttcgaqgar cttccccaccc ίΛ vj G G 3 G f .g a a o t g g a g cacgtgaagg q o c t g c a t a c ctqcctgaac gtggtaagaa caagactgto gatcctctat tqcccttggc a c a g a g c t g t caggtgtctt cagctgggag tccttcGtga ctcaccatta ctcca tggc to ctggateacc gcccatgtgg acttcca tcc Gtctgggctg tgtggcGatg aagatgatgg ttqacacttg actgcttctc c a c c t g a c a a atatttagct c t c t c c g c a g t £$$g<3aaggg ccggagccca g c G o c t a t g a agaagggccc ggaggtggaa cgctgcggaa gtgaggctga gggatgctgg L.· ttCtCCtGCt cagcctggca a o c c a g q g t a Q'iSCJQ:¿i¿i^.3Cí G Q C C el C C 3 CJ CJ 3 ctggaccctg cttctgaata jgataaaaaa tcaaggggaaa tggcatggag C 3 3 O el C C 3 G 3 ctccatgaag atgccagcgt tgg gagcaca tctacaaccc cacGGtcagg agatctctgg ctcaaggagc ggcctgcahc tggacagaag tcagGtcGaa ccaggagaag ctccttqttc gaagcaggga ttggacattt gaagagatct cctctccggc gtqttccagg cactggggga gtggtcagca gccatcacag catgatgcgg aaggtcctgg ttccccgggg ctcttggaag tttctcatca GCGQ' Q CJ 3 C3 G actctgcGag teocaceagg tgctctgqca atggttgagg t a a a c a c 11 a &33&33 n / ztznn / i znz / E / v (SEQ ID NO: 133) The amino acid sequences of human TREM2 isoform 2 (SEQ ID NO: 2) and isoform 3 (SEQ ID NO: 3) are shown in FIG 1 A. As used herein, human TREM2 protein in addition encompasses proteins that are at least about 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82 over their full length %, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to any of SEQ ID No: 1, 2, or 3, where such proteins still have ligand binding, intracellular signalling, facilitation of phagocytosis and degradation of phagocytic material, and others regulatory functions of TREM2. Sequences of murine, macaque (cyno) and other animal TREM2 proteins are known in the art (eg, NP_112544.1 and NP 001259007.1 for murine TREM2 protein). The term "extracellular domain" refers to the portion of a transmembrane protein that is exposed on the extracellular side of a lipid bilayer of a cell. Methods for determining the ectodomain of a protein are known in the art (Singer (1990); High et al (1993) and McVector software, Oxford Molecular). For example, the extracellular domain of the human TREM2 protein can include amino acid residues 19 to 172 of SEQ ID NO: 1. The term TREM2 ectodomain refers to a portion of the TREM2 extracellular domain that is released after sheddase cleavage. The cleavage site is reported to be between amino acid H157 and S158 (Feuerbach et al, Neurosci. Lett. 660 (2017): 109-114). Therefore, the hTREM2 ectodomain will consist of amino acids 19-157 of any of SEQ ID NO: 1, 2 or 3. The term IgSF domain refers to a part of the extracellular domain of TREM2 that contains an immunoglobulin (Ig)-like fold and therefore belongs to the immunoglobulin superfamily. In humans, for example, the IgSF domain consists of amino acid residues 19 to 132 of any of SEQ ID NO: 1, 2 and 3. The term TREM2 stem region refers to a portion of the TREM2 extracellular domain that connects the immunoglobulin type V (IgSF) domain and the transmembrane domain. For example, the stem region of the human TREM2 isoform 1 protein may include amino acid 133172 of SEQ ID NO: 1. The term "transmembrane domain" refers to the portion of a transmembrane protein that spans the lipid bilayer of a cell. Methods for determining the transmembrane domain of a protein are known in the art (Elofsson et al., Annu. Rev. Biochem. 76 (2007): 125-140; Bernsel et al., Protein Science 14 (2005): 1723 -1728). The terms cytoplasmic domain and cytoplasmic tail are used interchangeably and refer to the portion of a transmembrane protein that is on the cytoplasmic side of a cell's lipid bilayer. Methods for determining the cytoplasmic tail of a protein are known in the art (Elofsson et al. (2007) and Bernsel et al. (2005)). The term "stabilize," as used herein, refers to maintaining, restoring, or increasing the cell surface level of TREM2 in a TREM2-expressing cell, for example, to the TREM2 level in a corresponding TREM2-expressing cell in a healthy subject without inflammation or neurodegenerative disease. This can be achieved, for example, by reducing or inhibiting shedding of the TREM2 ectodomain, or by increasing TREM2 expression on the cell surface. The cell surface level of TREM2 can be assessed by flow cytometry / FACS (fluorescence assisted cell sorting), or by cell surface immunoprecipitation of TREM2, or by reduction of soluble TREM2 along weather. TREM2 cell surface expression can also be detected by enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), bioassays (eg, increased phagocytosis), Western blot assay, flow cytometry, immunohistochemistry , immunofluorescent assay, homogeneous time-resolved fluorescence (HTRF), or positron emission tomography (PET). The term "activate" as used herein refers to the initiation or preservation of downstream TREM2 signaling expressed on the cell surface, for example, in TREM2-expressing cells in healthy subjects or individuals with inflammatory or neurodegenerative diseases where TREM2-dependent activities appropriate TREM2 are impaired. This can be achieved, without limitation, by TREM2-associated phosphorylation of DAP12 or DAP10, leading via different intracellular signaling cascades to enhancement of Syk phosphorylation, phagocytosis, n / ztznn / i ζπζ / ε / υιλι increased target-directed cell motility (chemotaxis), increased cell survival, modulation of cytokine or chemokine release from TREM2-expressing cells, increased degradation of intracellular phagocytosed material, or changes in gene expression. TREM2-dependent increased phosphorylation of DAP12 or Syk can be assessed by Western blotting, ELISA, or flow cytometry / FACS. Directed cell motility, eg chemotaxis, can be assessed by bioassays. Modulation of cytokine release can be assessed by enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), or flow cytometry / FACS. Changes in gene expression can be assessed by quantitative RT-PCR (real-time polymerase chain reaction) at the mRNA level, or by Western blotting or flow cytometry, in the protein level. The term "facilitate" herein refers to the enhancement or restoration of TREM2-dependent activities impaired by the disease. These activities may include phagocytosis, increased target-directed cell motility (chemotaxis), increased cell survival, modulation of cytokine or chemokine release from TREM2-expressing cells, increased degradation of intracellular phagocytosed material, modulation of cellular responses from neighboring cells (astrocytes / neurons) or changes in gene expression. The term "antibody", as used herein, refers to a protein or polypeptide sequence derived from an immunoglobulin molecule that specifically binds to an antigen. Antibodies can be polyclonal or monoclonal, single or multiple chain or intact immunoglobulins, and can be derived from natural sources or from recombinant sources. A natural antibody is a glycoprotein comprising at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each heavy chain is composed of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region is composed of three domains, CH1, CH2, and CH3. Each light chain is composed of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region is composed of one domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is composed 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. The variable regions of the heavy and light chains contain a binding domain that interacts with an antigen. The constant regions of antibodies can mediate the binding of immunoglobulin to host tissues or factors, including various cells of the immune system (eg, effector cells) and the first component (C1 q) of the classical complement system. An antibody can be a monoclonal antibody, a human antibody, a humanized n / ztznn / i ζπζ / ε / υιλι antibody, a camelized antibody or a chimeric antibody. Antibodies can be of any isotype (eg, IgG, IgE, IgM, IgD, IgA, and IgY), class (eg, IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), or subclass. Throughout this document, the term antibody or antibody molecule also includes any of its fragments and any of its derivatives, unless the context indicates otherwise. The term "antibody fragment" or "antigen-binding fragment" refers to at least a portion of an antibody, which retains the ability to specifically interact (eg, by binding, steric hindrance, stabilization / destabilization, spatial distribution) with an epitope. of an antigen. Examples of antibody fragments include, without limitation, Fab, Fab', F(ab')2, Fv fragments, scFv, disulfide-linked Fv (sdFv) antibody fragments, an Fd fragment consisting of the VH and CH1 domains , linear antibodies, single domain antibodies such as sdAb (VL or VH), camelid VHH domains, multispecific antibodies formed from antibody fragments such as a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region , and an isolated CDR or other epitope-binding fragment of an antibody. An antigen-binding fragment can also be incorporated into single domain, maxibody, minibody, nanobody, intrabody, diabody, triabody, tetrabody, v-NAR and bis-scFv domain antibodies (see, for example, Hollinger and Hudson, Nature Biotechnology 23 : 1126-1136,2005). Antigen-binding fragments can also be grafted onto polypeptide-based scaffolds such as fibronectin type III (Fn3) (see US Patent No. 6,703,199, which describes fibronectin polypeptide minibodies). The term scFv refers to a fusion protein comprising at least one antibody fragment comprising a light chain variable region and at least one antibody fragment comprising a heavy chain variable region, wherein the regions The light and heavy chain variables are contiguously linked, eg, via a synthetic linker, eg, a short, flexible polypeptide linker, and capable of expression as a single-chain polypeptide, and where the scFv retains the specificity of the scFv. intact antibody from which it is derived. Unless specified, as used herein, a scFv may have the VL and VH variable regions in any order, for example, with respect to the N-terminus and C-terminus of the polypeptide, the scFv may comprise VL-connector-VH or can comprise VH-connector-VL. The terms complementarity determining region or CDR, as used herein, refer to the amino acid sequences within antibody variable regions that confer antigen specificity and binding affinity. For example, in general, there are three CDRs in each heavy chain variable region (eg, HCDR1, HCDR2, and HCDR3) and three CDRs in each light chain variable region (LCDR1, LCDR2, and LCDR3). The precise boundaries of the amino acid sequence of a given CDR can be determined using any of several well known njztznn / i ζπζ / ε / υιλι schemes, including those described by Kabat et al. (1991), “Sequences of Proteins of Immunological Interest,” 5thEd. Public Health Service, National Institutes of Health, Bethesda, MD (Kabat numbering scheme), Al-Lazikani et al., (1997) JMB 273,927-948 (Chothia numbering scheme), or a combination of the above, and ImMunoGenTics numbering (IMGT) (Lefranc, M.-P., The Immunologist, 7,132-136 (1999); Lefranc, M.-P. etal., Dev. Comp. Immunol., 27, 55-77 (2003); Lefranc et aL, (2015) Nucleic Acids Res. 43, D413-422) (IMGT numbering scheme). In a combined Kabat and Chothia numbering scheme for a given CDR region (eg, HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, or LCDR3), in some embodiments, the CDRs correspond to amino acid residues that are defined as part of the Kabat CDR, together with the amino acid residues that are defined as part of the Chothia CDR. As used in this document, CDRs defined according to the Chothia numbering scheme are also sometimes called hypervariable loops. Under IMGT, the CDR regions of an antibody can be determined using the IMGT / DomainGap Align program. Generally, unless specifically indicated, the antibody molecules can include any combination of one or more Kabat CDRs and / or Chothia CDRs. The term "epitope" includes any protein determinant capable of specifically binding to an immunoglobulin or otherwise interacting with a molecule. Epitopic determinants generally consist of clusters of chemically active surface molecules such as amino acids or carbohydrate or sugar side chains, and may have specific three-dimensional structural features, as well as specific charge features. An epitope can be linear or conformational. Conformational and linear epitopes are distinguished, for example, in that binding to the former but not to the latter is lost in the presence of denaturing solvents. Binds same epitope meaning the ability of an antibody, antibody fragment, or other antigen-binding moiety to bind to a specific antigen and to bind to the same epitope as the exemplified antibody when using the same epitope mapping technique for comparison the antibodies. The epitopes of the exemplified antibody and other antibodies can be determined using epitope mapping techniques. Epitope mapping techniques are well known in the art. For example, conformational epitopes are readily identified by determining the spatial conformation of amino acids, eg, by hydrogen / deuterium exchange, X-ray crystallography, and two-dimensional nuclear magnetic resonance. In another embodiment, the present disclosure relates to an antibody or antibody fragment that cross competes with an antibody described in Table 1. In one embodiment, the present disclosure relates to an antibody or antibody fragment, wherein said antibody or antibody fragment cross-competes with a n / 7bnn / i ζπζ / ε / υιλι antibody or antibody fragment comprising 6 CDRs defined by any of the combined Kabat, Chothia, IMGT, or Kabat / Chothia methods, of one or more of the antibodies in Table 1. In another embodiment, the present disclosure relates to an antibody or antibody fragment that binds (eg, by binding and / or stabilizing) to the same epitope as one of the antibodies in Table 1. In a further embodiment, said antibody or antigen-binding fragment thereof binds (eg, by binding and / or stabilization) to an epitope that overlaps with the epitope of an antibody or antibody fragment comprising 6 CDRs defined by any of the combined Kabat, Chothia, IMGT, or Kabat / Chothia methods of any of the antibodies in Table 1. The term "monovalent antibody" as used herein refers to an antibody that binds to a single epitope on a target molecule. The term "bivalent antibody" as used herein refers to an antibody that binds to two epitopes on at least two identical target molecules. The bivalent antibody can also cross-link the target molecules with each other. A bivalent antibody also refers to an antibody that binds to two different epitopes on at least two identical target molecules. The term "multivalent antibody" refers to a single binding molecule with more than one valency, where valency is described as the number of antigen-binding moieties present per molecule of an antibody construct. Thus, the single binding molecule can bind to more than one binding site on a target molecule. Examples of multivalent antibodies include, but are not limited to, bivalent antibodies, trivalent antibodies, tetravalent antibodies, pentavalent antibodies, and the like, as well as bispecific antibodies and biparatopic antibodies. For example, for TREM2, the multivalent antibody (eg, a TREM2 biparatopic antibody) has a binding moiety for two TREM2 domains, respectively. The term "multivalent antibody" also refers to a single binding molecule that has more than one antigen-binding moiety for two separate target molecules. For example, an antibody that binds TREM2 and a second non-TREM2 target molecule. In one embodiment, a multivalent antibody is a tetravalent antibody that has four epitope binding domains. A tetravalent molecule can be bispecific and bivalent for each binding site on that target molecule. The term "bispecific antibody" as used herein refers to an antibody that binds to two or more different epitopes. In some embodiments, a bispecific antibody binds to two different targets. In some embodiments, a bispecific antibody binds to two different epitopes on a single target molecule. An antibody that binds n / ztznn / i ζπζ / ε / υιλι to two different epitopes on a single target molecule is also known as a biparatopic antibody. The phrases "monoclonal antibody" or "monoclonal antibody composition" as used herein refer to polypeptides, including antibodies, bispecific antibodies, etc., that have a substantially identical amino acid sequence or are derived from the same genetic source. This term also includes preparations of antibody molecules of unique molecular composition. A monoclonal antibody composition displays a unique binding affinity and specificity for a particular epitope. The phrase human antibody, as used herein, includes antibodies that have variable regions in which both the framework region and the CDR are derived from sequences of human origin. The constant region is also derived from human sequences, eg, human germline sequences, or mutated versions of human germline sequences, or antibody containing consensus framework sequences derived from human framework sequence analysis, eg, as is described in Knappik, et al. (2000. J Mol Biol 296, 57-86). The structures and locations of immunoglobulin variable domains, eg, CDRs, can be defined using well-known numbering schemes, eg, the Kabat numbering scheme, the Chothia numbering scheme, or a combination of Kabat numbering and Chothia, and ImMunoGenTics (IMGT) (see, for example, Sequences of Proteins of Immunological Interest, U. S. Department of Health and Human Services (1991), eds. Kabat et al.; Al Lazikani et al., (1997) J. Mol Bio. 273:927-948); Kabat et al, (1991) Sequences of Proteins of Immunological Interest, 5thedit., NIH Publication no. 91-3242 U.S. Department of Health and Human Services; Chothia et al, (1987) J. Mol. Biol. 196:901-917; Chothia et al, (1989) Nature 342:877-883; and ΑΙ-Lazikani et al, (1997) J. Mal. Biol. 273:927-948; Lefranc, M.-P., The Immunologist, 7, 132-136 (1999); Lefranc, M.-P. et al, Dev. Comp. Immunol., 27, 55-77 (2003); Lefranc et al, (2015) Nucleic Acids Res. 43, D413-422. Human antibodies of the invention may include amino acid residues not encoded by human sequences (eg, mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo, or a conservative substitution to promote stability or manufacturing). . However, the term human antibody, as used herein, is not intended to include antibodies in which the germline-derived CDR sequences of another mammalian species, such as a mouse, have been grafted onto human framework sequences. . The phrase recombinant human antibody, as used herein, includes all human antibodies that are prepared, expressed, created, or isolated by recombinant means, such as antibodies isolated from an animal (eg, a mouse) that is transgenic or transchromosomal to human immunoglobulin genes, or a hybridoma prepared therefrom, antibodies isolated from nyztznn / i ζπζ / ε / υιλι a host cell transformed to express the human antibody, e.g. eg from a transfectome, antibodies isolated from a recombinant, combinatorial library of human antibodies, and antibodies prepared, expressed, created, or isolated by any other means that involves splicing all or a portion of a human immunoglobulin gene sequences, to other DNA sequences. Such recombinant human antibodies have variable regions in which the framework and CDR regions are derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies can be subjected to in vitro mutagenesis (or, when a transgenic animal is used for human Ig sequences, in vivo somatic mutagenesis), and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences which, while derived from and related to the human germline VH and VL sequences, may not naturally exist within the germline repertoire of human antibodies in vivo. The term Fe region as used herein refers to a polypeptide comprising the CH3, CH2, and at least a portion of the hinge region of an antibody constant domain. Optionally, an Fe region can include a CH4 domain, present in some classes of antibodies. An F region may comprise the entire hinge region of an antibody constant domain. In one embodiment, the invention comprises an Fe region and a CH1 region of an antibody. In one embodiment, the invention comprises an Fe region and a CH3 region of an antibody. In another embodiment, the invention comprises an Fe region, a CH1 region and a Ckappa / lambda region of the constant domain of an antibody. In one embodiment, a binding molecule of the invention comprises a constant region, eg, a heavy chain constant region. In one embodiment, said constant region is modified compared to a wild-type constant region. That is, the polypeptides of the invention described herein may comprise alterations or modifications to one or more of the three heavy chain constant domains (CH1, CH2 or CH3) and / or to the light chain (CL) constant region domain. Exemplary modifications include additions, deletions, or substitutions of one or more amino acids in one or more domains. Such changes may be included to optimize effector function, half-life, etc. As used herein, the term "affinity" refers to the strength of interaction between antibody and antigen at unique antigenic sites. Within each antigenic site, the variable regions of the antibody interact through weak noncovalent forces with the antigen at numerous sites; the more interactions, the stronger the affinity. As used herein, the term "high affinity" for an IgG antibody or fragment thereof (eg, a Fab fragment) refers to an antibody that has an affinity of 10-8M or less, 10-9M or less, or 10-10Μ, or 10-11M or less, or 10-12M or less, or 10-13M or less, for a target antigen. However, high affinity binding may vary for other antibody isotypes, however. For example, high affinity binding for an IgM isotype refers to an antibody that has an affinity of 10-7M or less, or 10-8M or less. As used herein, the terms Kasoc, Ka, or Kon are intended to refer to the rate of association of a particular antibody-antigen interaction, while the term Kdis, Kd, ​​or Koff is intended to refer to the rate of dissociation of a particular antigen-antibody interaction. In one embodiment, the term KD (or KD), as used herein, is intended to refer to the dissociation constant, which is derived from the ratio of Kd to Ka (ie, Kd / Ka), and it is expressed as a molar concentration (M). KD values ​​for antibodies can be determined using methods well established in the art. One method of determining the KD of an antibody is through the use of surface plasmon resonance or through a biosensor system such as a Biacore® system. As used herein, the term "avidity" refers to an informative measure of the overall stability or strength of the antibody-antigen complex. It is controlled by three main factors: affinity of the antibody epitope; the valency of both the antigen and the antibody; and the structural arrangement of the interacting parts. Ultimately, these factors define the specificity of the antibody, that is, the probability that the particular antibody will bind to a precise antigen epitope. The term "binding specificity" or "binds specifically" as used herein refers to the ability of an individual antibody combining site to react with one antigenic determinant and not a different antigenic determinant. The antibody combining site is located in the Fab portion of the molecule and is constructed from the hypervariable regions of the heavy and light chains. The binding affinity of an antibody is the strength of the reaction between a single antigenic determinant and a single combining site on the antibody. It is the sum of the forces of attraction and repulsion that operate between the antigenic determinant and the antibody combining site. The terms "treat" and "treatment" refer to therapeutic treatment, in which the goal is to slow down an unwanted physiological change or disorder. For the purpose of this invention, beneficial or desired clinical outcomes include, without limitation, alleviation of symptoms, lessening of the extent of the disease, stabilization of the disease state (i.e., no worsening), delay or slowing down the progression of the disease, improvement or palliation of the state of the disease and remission (partial or total), detectable or undetectable. Treatment may also mean prolonging survival compared to the expected survival if you do not receive treatment. n / ztznn / i ζπζ / β / υιλι The terms "prevention" and "prevent" referring to any particular disease or disorder refer to prophylactic or preventative measures such as the administration of a compound of the present invention to a subject before any symptoms of that disease or disorder are evident. The term "subject" refers to an animal, human or non-human, to whom treatment is provided in accordance with the methods of the present invention. Veterinary and non-veterinary applications are contemplated. The term includes, without limitation, mammals, eg, humans, other primates, pigs, rodents such as mice and rats, rabbits, guinea pigs, hamsters, cows, horses, cats, dogs, sheep, and goats. Typical subjects include humans, farm animals, and household pets such as cats and dogs. In some preferred embodiments, the subject is a human. An effective / effective amount refers to an amount sufficient to effect beneficial or desired results. For example, a therapeutic amount is one that achieves the desired therapeutic effect. This amount may be the same as or different from a prophylactically effective or effective amount, which is an amount necessary to prevent the onset of the disease or symptoms of the disease. An effective amount may be administered in one or more administrations, applications, or dosages. A therapeutically effective amount of a therapeutic compound (ie, an effective dosage) depends on the therapeutic compounds selected. The compositions can be administered from one or more times per day to one or more times per week; which includes once every two days. One of skill in the art will appreciate that certain factors may affect the dosage and time required to effectively treat a subject, including, but not limited to, the severity of the disease or disorder, previous treatments, general health, and / or age. of the subject, and other diseases present. Furthermore, treatment of a subject with a therapeutically effective amount of the therapeutic compounds described herein can include a single treatment or a series of treatments. The term "nucleic acid" or "polynucleotide" refers to deoxyribonucleic acids (DNA) or ribonucleic acids (RNA) and their polymers, both in single-stranded and double-stranded form. Unless specifically limited, the term encompasses nucleic acids that contain known analogs of naturally occurring nucleotides that have similar binding properties to the reference nucleic acid and are metabolized in a similar manner to naturally occurring nucleotides. Unless otherwise indicated, a particular nucleic acid sequence also implicitly encompasses its conservatively modified variants (eg, degenerate codon substitutions), alleles, orthologs, SNPs, and complementary sequences, as well as the explicitly stated sequence. Specifically, degenerate codon substitutions can be achieved by generating sequences in which the third position of one or more (or all) selected codons is replaced with residues of n / ztznn / i ζπζ / β / υιλι mixed base y / or deoxyinosine (Batzer et al., Nucleic Acid Res. 19: 5081 (1991); Ohtsuka et al., J. Biol. Chem. 260: 2605-2608 (1985); and Rossolini et al., Mol. Cell. Probes 8:91-98 (1994)). The terms peptide, polypeptide, and protein are used interchangeably and refer to a compound comprised of amino acid residues covalently linked by peptide bonds. A protein or peptide must contain at least two amino acids, and there is no limit to the maximum number of amino acids that can comprise the sequence of a protein or peptide. Polypeptides include any peptide or protein that comprises two or more amino acids linked together by peptide bonds. As used herein, the term refers to both short chains, which are also commonly referred to in the art as peptides, oligopeptides, and oligomers, for example, and longer chains, which are generally referred to in the art as proteins, of of which there are many types. Polypeptides include, for example, biologically active fragments, substantially homologous polypeptides, oligopeptides, homodimers, heterodimers, variant polypeptides, modified polypeptides, derivatives, analogs, fusion proteins, among others. A polypeptide includes a natural peptide, a recombinant peptide, or a combination thereof. The term "conservative sequence modifications" refers to amino acid modifications that do not significantly affect or alter the binding characteristics of the antibody or antibody fragment containing the amino acid sequence. Such conservative modifications include amino acid substitutions, additions, and deletions. Modifications can be introduced into an antibody or antibody fragment of the invention by standard techniques known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis. Conservative amino acid substitutions are those in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (eg, lysine, arginine, histidine), acidic side chains (eg, aspartic acid, glutamic acid), uncharged polar side chains (eg, glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan), nonpolar side chains (eg, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine), beta-branched side chains (eg, threonine, valine, isoleucine ) and aromatic side chains (eg, tyrosine, phenylalanine, tryptophan, histidine). Thus, one or more amino acid residues within an antibody or its antigen-binding fragment of the invention can be replaced with other amino acid residues from the same family of side chains, and the altered antibody or its antigen-binding fragment can be evaluated using the functional tests described in this document. The term "homologous" or "identical" refers to subunit sequence identity between two polymer molecules, for example, between two nucleic acid molecules, such as two DNA molecules or two RNA molecules, or between two polypeptide molecules. When a position of the n / ztznn / i ζπζ / β / υιλι subunit in the two molecules is occupied by the same monomeric subunit, for example, if a position in each of the two DNA molecules is occupied by adenine, then they are homologous or identical in that position. The homology between two sequences is a direct function of the number of coincident or homologous positions; For example, if half (eg, five positions in a ten subunit long polymer) of the positions in two sequences are homologous, the two sequences are 50% homologous; if 90% of the positions (eg, 9 out of 10) are coincident or homologous, the two sequences are 90% homologous. Percent sequence identity can be determined by comparing two optimally aligned sequences in a comparison window, where the fragment of the amino acid sequence in the comparison window may comprise additions or deletions (eg, gaps or overhangs) compared to the reference sequence (including no additions or deletions) for optimal alignment of the two sequences. The percentage can be calculated by determining the number of positions at which the identical amino acid residue occurs in both sequences to produce the number of matching positions, dividing the number of matching positions by the total number of positions in the comparison window, and multiplying the result by 100 to produce the percent sequence identity. The result is the percent identity of the subject sequence to the query sequence. The term isolated means altered or removed from the natural state. For example, a nucleic acid or peptide naturally present in a living animal is not isolated, but the same nucleic acid or peptide partially or completely separated from coexisting materials in its natural state is isolated. An isolated nucleic acid or protein can exist in a substantially purified form, or it can exist in a non-native environment such as, for example, a host cell. An isolated antibody is substantially free of other antibodies having different antigenic specificities (eg, an isolated antibody that specifically binds to TREM2 is substantially free of antibodies that specifically binds to antigens other than TREM2). However, an isolated antibody that specifically binds to a target molecule may cross-react with the same antigens from other species; for example, an isolated antibody that specifically binds TREM2 can bind TREM2 molecules from other species. An isolated antibody can be a monoclonal antibody. An isolated antibody can be a recombinant monoclonal antibody. Furthermore, an isolated antibody can be substantially free of other cellular material and / or chemicals. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as that commonly understood by one skilled in the art to which this invention pertains. Although methods and materials similar or equivalent to those described herein may be used to practice the invention, njztznn / i ζπζ / β / υιλι suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned in this document are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, shall control. Furthermore, the materials, methods, and examples are illustrative only, and are not intended to be limiting. Details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims. Antibodies that stabilize functional TREM2. Provided herein are antibodies and antigen-binding fragments of such antibodies that stabilize TREM2 on the cell surface. Such antibodies or their antigen-binding fragments can achieve TREM2 stabilization by interfering with TREM2 proteolytic cleavage and / or reducing shedding of the TREM2 protein ectodomain. In some preferred embodiments, said antibodies or their antigen-binding fragments specifically bind to the IgSF domain of human TREM2, eg, amino acid residues 19 to 132 of any of SEQ ID NOs: 1, 2 or 3. Because the reduction or absence of TREM2 on the cell surface is associated with human neuroinflammatory and neurodegenerative pathologies, the TREM2 stabilizing antibodies or their antigen-binding fragments described herein can be used to treat, prevent, or diagnose neuroinflammatory and neurodegenerative diseases. such as Alzheimer's disease, frontotemporal dementia, Parkinson's disease, amyotrophic lateral sclerosis, Nasu-Hakola disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS), NMDA receptor antibody encephalitis, autism, cerebral lupus (NP -SLE), chemoinduced peripheral neuropathy (CIPN), postherpetic neuralgia, chronic inflammatory demyelinating polyneuropathy (CIDP), epilepsy, Guillain-Barré syndrome (GBS), inclusion body myositis, lysosomal storage diseases, e.g. eg, sphingomyelinlipidose (Niemann-Pick C) and mucopolysaccharide II / IIIB, metachromatic leukodystrophy, multifocal motor neuropathy, myasthenia gravis, Neuro-Behcet's disease, neuromyelitis optica (NMO), optic neuritis, polymyositis, dermatomyositis, Rasmussen's encephalitis, syndrome of Rett, stroke, transverse myelitis, traumatic brain injury, spinal cord injury, viral encephalitis, or bacterial meningitis. In some preferred embodiments, the hTREM2 antibody or an antigen-binding fragment as described herein can be used to treat, prevent, or diagnose a disease selected from Alzheimer's disease, frontotemporal dementia, Parkinson's disease, lateral sclerosis. amyotrophic or Nasu-Hakola disease. Due to their pharmacological profiles, the hTREM2 antibodies or their antigen-binding fragments described herein will be useful for the treatment of diseases or conditions as diverse as n / ztznn / i ζπζ / β / υιλι related diseases, CNS-related diseases, with the PNS, systemic inflammation and other inflammation-related diseases, pain, and withdrawal symptoms caused by chemical abuse. Diseases or disorders related to the CNS include generalized anxiety disorders, cognitive disorders, learning and memory deficits and dysfunctions, Alzheimer's disease (mild, moderate and severe), attention deficit hyperactivity disorder, Parkinson's disease, dementia in Parkinson's disease, Huntington's disease, ALS, prion neurodegenerative disorders such as Creutzfeld-Jacob disease and Kuru disease, Gillies de la Tourette syndrome, psychosis, depression and depressive disorders, mania, manic depression, schizophrenia , cognitive deficits in schizophrenia, obsessive-compulsive disorders, panic disorders, eating disorders, narcolepsy, nociception, AIDS dementia, senile dementia, age-related mild cognitive impairment (MCI), mental impairment age-associated memory, autism, dyslexia, tardive dyskinesia, epilepsy and seizure disorders, post-traumatic stress disorder, transient anoxia, pseudodementia, premenstrual syndrome, late luteal phase syndrome, chronic fatigue syndrome, and jet lag syndrome. The hTREM2 antibodies or their antigen-binding fragments described herein are particularly suitable for treating, preventing, or diagnosing autoimmune, inflammatory, or malignant disorders mediated or associated with extensive proteolytic cleavage of TREM2 or cells expressing aberrant or mutated variants of the TREM2 receptor. . Examples of autoimmune diseases include, without limitation, arthritis (for example, rheumatoid arthritis, progressive chronic arthritis, and arthritis deformans) and rheumatic diseases, including inflammatory conditions and rheumatic diseases involving bone loss, inflammatory pain, spondyloarthropathies, including ankylosing spondylitis. , Reiter's syndrome, reactive arthritis, psoriatic arthritis and enteropathic arthritis, hypersensitivity (including both airway hypersensitivity and skin hypersensitivity), and allergies. Autoimmune diseases include autoimmune hematologic disorders (including, for example, hemolytic anemia, aplastic anemia, pure red cell anemia, and idiopathic thrombocytopenia), systemic lupus erythematosus, inflammatory muscle disorders, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, psoriasis, Steven-Johnson syndrome, idiopathic sprue, endocrine ophthalmopathy, Graves' disease, sarcoidosis, multiple sclerosis, primary biliary cirrhosis, juvenile diabetes (type I diabetes mellitus), uveitis (anterior and posterior), keratoconjunctivitis sicca, and keratoconjunctivitis vernal, interstitial pulmonary fibrosis, psoriatic arthritis, and glomerulonephritis (with and without nephrotic syndrome, eg, gout, Langerhans cell histiocytosis, idiopathic nephrotic syndrome, or minimal change nephropathy), tumors, n / ztznn / i ζπζ / β / disease υιλι inflammatory skin and cornea, myositis, loosening of bone implants, metabolic disorders, such as atherosclerosis, diabetes and dyslipidemia. The hTREM2 antibodies or their antigen-binding fragments described herein are also useful for the treatment, prevention, or amelioration of asthma, bronchitis, pneumoconiosis, pulmonary emphysema, and other obstructive or inflammatory airway diseases, including fibrosis. idiopathic pulmonary disease or COPD. The hTREM2 antibodies or their antigen-binding fragments described herein can be used to treat a hematopoietic or hepatopoietic malignancy such as acute myeloid leukemia, chronic myeloid leukemia, myeloproliferative disorders, myelodysplastic syndromes, multiple myeloma, paroxysmal nocturnal hemoglobinuria, anemia of Fanconi, thalassemia major, Wiskott-Aldrich syndrome, hemophagocytic lymphohistiocytosis. The hTREM2 antibodies or their antigen-binding fragments described herein can be used to treat any disease or disorder associated directly or indirectly with aberrant TREM2 activity and / or expression. TREM2-related disorders include: immunological disorders, especially related to inflammatory disorders (eg, bacterial infection, fungal infection, viral infection, protozoal or other parasitic infection, psoriasis, sepsis, cerebral malaria, inflammatory bowel disease, arthritis, such such as rheumatoid arthritis, folliculitis, impetigo, granulomas, lipoid pneumonias, vasculitis, and osteoarthritis), autoimmune disorders (eg, rheumatoid arthritis, thyroiditis such as Hashimoto's thyroiditis and Graves' disease, insulin-resistant diabetes, pernicious anemia, Addison's syndrome, pemphigus, vitiligo, ulcerative colitis, systemic lupus erythematosus (SLE), Sjogren's syndrome, multiple sclerosis, dermatomyositis, mixed connective tissue disease, scleroderma, polymyositis, graft rejection, such as allograft rejection), T-cell disorders (eg, AIDS), allergic inflammatory disorders (eg, skin and / or mucosal allergies, such as allergic rhinitis, asthma, psoriasis), neurological disorders, eye disorders, embryonic disorders, or any other disorder (eg, tumors, cancer, leukemia, myeloid diseases, and trauma) that is directly or indirectly associated with aberrant TREM2 expression and / or activity. In some embodiments, the TREM2-related disorder is selected from asthma, encephalitis, inflammatory bowel disease, chronic obstructive pulmonary disease (COPD), allergic disorders, septic shock, pulmonary fibrosis, undifferentiated spondyloarthropathy, undifferentiated arthropathy, arthritis, osteolysis inflammatory, or chronic inflammation resulting from chronic viral or bacterial infections. In some embodiments, the TREM2-related disorder is selected from dementia, frontotemporal dementia, Alzheimer's disease, vascular dementia, mixed dementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus, amyotrophic lateral sclerosis, n / ztznn / disease i ζπζ / β / υιλι Huntington's disease, tauopathies, Nasu-Hakola disease, stroke, acute trauma, chronic trauma, lupus, acute and chronic colitis, wound healing, Crohn's disease, inflammatory bowel disease, ulcerative colitis, obesity, malaria, essential tremor, lupus central nervous system, Behcet's disease, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Shy-Drager syndrome, progressive supranuclear palsy, basal cortical nodal degeneration, acute disseminated encephalomyelitis, granulomatous disorders, sarcoidosis, diseases of aging, seizures , spinal cord injury, traumatic brain injury, age-related macular degeneration, glaucoma, retinitis pigmentosa, retinal degeneration, respiratory tract infection, sepsis, eye infection, systemic infection, lupus, arthritis, multiple sclerosis, low bone density, osteoporosis, osteogenesis, osteopetrosis, Paget's disease of bone, and cancer. In some preferred embodiments, the TREM2-related disorder is selected from a list consisting of Alzheimer's disease, frontotemporal dementia, Parkinson's disease, amyotrophic lateral sclerosis, or Nasu-Hakola disease. In some preferred embodiments, the TREM2-related disorder is selected from dementia, frontotemporal dementia, Alzheimer's disease, Nasu-Hakola disease, and multiple sclerosis. In some preferred embodiments, the TREM2-related disorder is a dementia such as frontotemporal dementia, Alzheimer's disease, vascular dementia, semantic dementia, or Lewy body dementia. In a more preferred embodiment, the TREM2-related disorder is Alzheimer's disease. In another preferred embodiment, the disorder is Parkinson's disease. Antibodies and their antigen-binding fragments that specifically bind to human TREM2. In one aspect, provided herein are antibodies or antigen-binding fragments thereof, eg, monoclonal antibodies or antigen-binding fragments thereof, that specifically bind to the IgSF domain of the human TREM2 protein (hTREM2 antibodies or fragments thereof). antigen binding). Those antibodies or their antigen-binding fragments can stabilize the TREM2 protein on the cell surface and / or reduce shedding of the TREM2 protein ectodomain. In some embodiments, the hTREM2 antibodies or their antigen-binding fragments provided herein include a heavy chain CDR1 (HCDR1), a heavy chain CDR2 (HCDR2), a heavy chain CDR3 (HCDR3), and a heavy chain CDR3 (HCDR3). light chain CDR1 (LCDR1), a light chain CDR2 (LCDR2) and a light chain CDR3 (LCDR3). In some embodiments, the hTREM2 antibodies or their antigen-binding fragments provided herein include a heavy chain (VH) variable region comprising CDR1, n / ztznn / i ζπζ / β / υιλι CDR2 and CDR3 and a light chain (VL) variable region comprising CDR1, CDR2 and CDR3. In some embodiments, the hTREM2 antibodies or their antigen-binding fragments provided herein include a full-length heavy chain (HC) sequence and a full-length light chain (LC) sequence. Table 1 lists the sequences of exemplary TREM2 antibodies or antigen-binding fragments thereof that specifically bind human TREM2 protein. Throughout the text of this application, if there is a discrepancy between the text of the specification (eg, Table 1) and the sequence listing, the text of the specification will control. Table 1. Sequences of exemplary monoclonal antibodies that bind to human TREM2. n / ztznn / i ζπζ / β / υιλι MOR44698A SEQ ID NO: 4 HCDR1 (Combined) GYTFTGYHMS SEQ ID NO: 5 HCDR2 (Combined) VINPVSGNTVYAQKFQG SEQ ID NO: 6 HCDR3 (Combined) IPSYTYAFDY SEQ ID NO: 7 HCDR1 (Kabat) GYHMS SEQ ID NO: 5 HCDR2 (Kabat) VINPVSGNTVYAQKFQG SEQ ID NO: 6 HCDR3 (Kabat) IPSYTYAFDY SEQ ID NO: 8 HCDR1 (Chothia) GYTFTGY SEQ ID NO: 9 HCDR2 (Chothia) NPVSGN SEQ ID NO: 6 HCDR3 (Chothia) IPSYTYAFDY SEQ ID NO: 10 HCDR1 (IMGT) GYTFTGYH SEQ ID NO: 11 HCDR2 (IMGT) INPVSGNT SEQ ID NO: 12 HCDR3 (IMGT) ARIPSYTYAFDY SEQ ID NO: 13 VH QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYHMSWVRQAPGQGL EWMGVINPVSGNTVYAQKFQGRVTMTRDTSISTA YMELSRLRSED TAVYYCARIPSYTYAFDYWGQGTLVTVSS SEQ ID NO: 14 VH DNA CAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGT GCCAGCGTGAAAGTTAGCTGCAAAGCGTCCGGATATACCTTCACT GGTTACCATATGTCTTGGGTGCGCCAGGCCCCGGGCCAGGGCC TC GAGTGGATGGGCGTTATCAACCCGGTTTCTGGCAACACGGTTTAC GCGCAGAAATTTCAGGGCCGGGTGACCATGACCCGTGATACCAGC ATTAGCACCGCGTATATGGAACTGAGCCGTCTGCGTAGCGAAGAT ACGGCCGTGTATTATTGCGCGCGTATCCCGTCTTACACTTACGCT TTCGATTACTGGGGCCAAG GCACCCTGGTGACTGTTAGCTCA SEQ ID NO: 15 Heavy chain QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYHMSWVRQAPGQGL EWMGVINPVSGNTVYAQKFQGRVTMTRDTSISTAYMELSRLRSED TAVYYCARIPSYTYAFDYWGQGTLVTVSSASTKGPSVFPLAPSSK STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSG LYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKT HTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDW LNGKEYKCKVSNKALPAPIEKTISKAKGQPR EPQVYTLPPSREEM TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 16 DNA Heavy Chain CAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGT GCCAGCGTGAAAGTT AGCTGCAAAGCGTCCGGATATACCTTCACT GGTTACCATATGTCTTGGGTGCGCCAGGCCCCGGGCCAGGGCCTC GAGTGGATGGGCGTTATCAACCCGGTTTCTGGCAACACGGTTTAC GCGCAGAAATTTCAGGGCCGGGTGACCATGACCCGTGATACCAGC ATTAGCACCGCGTATATGGAACTGAGCCGTCTG CGTAGCGAAGAT ACGGCCGTGTATTATTGCGCGCGTATCCCGTCTTACACTTACGCT TTCGATTACTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCC TCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAG AGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGAC TACTTCCC CGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTG ACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGA CTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTG GGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAAC ACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACT CACACATGCCCACCGTGCCCAGCACCTGAAGCAGCGGGGGGACCG TCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCTCTCATGATC TCCCGGACCCCTGAGGTCACATGCGTGG TGGTGGACGTGAGCCAC GAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAG GTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGC ACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGG CTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTC CC AGCCCCCATCGAGAAAACCATTCTCCAAAGCCAAAGGGCAGCCC CGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATG ACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTAT CCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAG AACAACTACAAGACCACGCCTCCCG TGCTGGACTCCGACGGCTCC TTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAG CAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC AACCACTACACGCAGAAGAGCCTTCCCCTGTCTCCGGGTAAA SEQ ID NO: 17 LCDR1 (Combined) RASQDISNYLA SEQ ID NO: 18 LCDR2 (Combined) RASSLQS SEQ ID NO: 19 LCDR3 (Combined) FQYRHMPSQT SEQ ID NO : 17 LCDR1 (Kabat) RASQDISNYLA SEQ ID NO: 18 LCDR2 (Kabat) RASSLQS SEQ ID NO: 19 LCDR3 (Kabat) FQYRHMPSQT SEQ ID NO: 20 LCDR1 (Chothia) SQDISNY SEQ ID NO: 21 LCDR2 (Chothia) RAS SEQ ID NO : 22 LCDR3 (Chothia) YRHMPSQ SEQ ID NO: 23 LCDR1 (IMGT) QDISNY SEQ ID NO: 21 LCDR2 (IMGT) RAS SEQ ID NO: 19 LCDR3 (IMGT) FQYRHMPSQT SEQ ID NO: 24 VL DIQMTQSPSSLSASVGDRVTITCRASQDISNYLAWYQQKPGKAPK LLIYRASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCFQ YRHMPSQTFGQGTKVEIK SEQ ID NO: 25 DNA VL GATATCCAGATGACCCAGAGCCCGAGCAGCCTGAGCGCCAGCGTG GGCGATCGCGTGACCATTACCTGCAGAGCCAGCCAGGACATTTCT AACTACCTGGCTTGGTACCAGCAGAAACCGGGCAAAGCGCCGAAA CTATTAATCTACCGTGCTTCTTCTCTGCAAAGCGGCGTGCCGAGC CGCTTTAGCGGCAG CGGATCCGGCACCGATTTCACCCTGACCATT AGCTCTCTGCAACCGGAAGACTTTGCGACCTATTATTGCTTCCAG TACCGTCATATGCCGTCTCAGACCTTTGGCCAGGGCACGAAAGTT GAAATTAAA SEQ ID NO: 26 Light Chain DIQMTQSPSSLSASVGDRVTITCRASQDISNYLAWYQQKPGKAPK LLIYRASSLQSGVPS RFSGSGSGTDFTLTISSLQPEDFATYYCFQ YRHMP SQTFGQGTKVEIKRTVAAP SVFIFPP SDEQLKSGTASWC LLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTL TLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 27 DNA Light chain GATATC CAGATGACCCAGAGCCCGAGCAGCCTGAGCGCCAGCGTG GGCGATCGCGTGACCATTACCTGCAGAGCCAGCCAGGACATTTCT AACTACCTGGCTTGGTACCAGCAGAAACCGGGCAAAGCGCCGAAA CTATTAATCTACCGTGCTTCTTCTCTGCAAAGCGGCGTGCCGAGC CGCTTTAGCGGCAGCGGATCCGGCACCGATTTC ACCCTGACCATT AGCTCTCTGCAACCGGAAGACTTTGCGACCTATTATTGCTTCCAG TACCGTCATATGCCGTCTCAGACCTTTGGCCAGGGCACGAAAGTT GAAATTAAACGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCC n / ztznn / i ζηζ / ε / γ CCCAGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGC CTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAG GTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAAAGCGTCACC GAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTG ACCCTGAGCAAGGCCGACTAC GAGAAGCACAAGGTGTACGCCTGC GAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTC AACCGGGGCGAGTGT MOR44698B SEQ ID NO: 4 HCDR1 (Combined) GYTFTGYHMS SEQ ID NO: 5 HCDR2 (Combined) VINPVSGNTVYAQKFQG SEQ ID NO: 6 HCDR3 (Combined) IPSYTYAFDY SEQ ID NO: 7 HCDR1 (Kabat) GYHMS SEQ ID NO: 5 HCDR2 (Kabat) VINPVSGNTVYAQKFQG SEQ ID NO: 6 HCDR3 (Kabat) IPSYTYAFDY SEQ ID NO: 8 HCDR1 (Chothia) GYTFTGY SEQ ID NO: 9 HCDR2 (Chothia) NPVSGN SEQ ID NO: 6 HCDR3 (Chothia) IPSYTYAFDY SEQ ID NO: 10 HCDR1 (IMGT) GYTFTGYH SEQ ID NO: 11 HCDR2 (IMGT) INPVSGNT SEQ ID NO: 12 HCDR3 (IMGT) ARIPSYTYAFDY SEQ ID NO: 13 VH QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYHMSWVRQAPGQGL EWMGVINPVSGN TVYAQKFQGRVTMTRDTSISTAYMELSRLRSED TAVYYCARIPSYTYAFDYWGQGTLVTVSS SEQ ID NO: 28 VH DNA CAAGTGCAACTCGTGCAGTCAGGAGCCGAAGTCAAGAAGCCTGGA GCCTCGGTCAAGGTGTCCTGCAAGGCCAGCGGATACACTTTCACT GGATACCACATGTCGTGGGTCAGACAGG CTCCTGGCCAAGGGCTG GAGTGGATGGGCGTCATCAACCCGGTGTCGGGTAATACCGTGTAC GCCCAGAAGTTCCAGGGTCGCGTGACCATGACCCGGGATACCTCC ATTAGCACCGCGTACATGGAGCTCAGCCGGTTGAGATCCGAGGAT ACCGCCGTGTACTACTGTGCGCGGATCCCGTCCTACACTTACGCC TTCGACTATTGGGGCCAGGGGACTCTTGTCACCGTGTCCTCG SEQ ID NO: 29 Heavy Chain QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYHMSWVRQAPGQGL EWMGVINPVSGNTVYAQKFQGRVTMTRDTSISTAYME LSRLRSED TAVYYCARIPSYTYAFDYWGQGTLVTVSSASTKGPSVFPLAPSSK STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC WVDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDW LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEM TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH YTQKSLSLSPGK SEQ ID NO: 30 DNA Heavy Chain CAAGTGCAACTCGTGCAGTCAGGAGCCGAAGTCAAGAAGCCTGGA GCCTCGGTCAAGGTGTCCTGCAAGGCCAGCGGATACACTTTCACT GGATACCACATGTCGTGGGTCAGACAGGCTCCTGGCCAAGGGCTG GAGTGGATGGGCGTCATCAACCCGGTGTC GGGTAATACCGTGTAC GCCCAGAAGTTCCAGGGTCGCGTGACCATGACCCGGGATACCTCC ATTAGCACCGCGTACATGGAGCTCAGCCGGTTGAGATCCGAGGAT ACCGCCGTGTACTACTGTGCGCGGATCCCGTCCTACACTTACGCC TTCGACTATTGGGGCCAGGGGACTCTTGTCACCGTGTCCTCGGCC TCCACTAAG GGCCCAAGTGTGTTTCCCCTGGCCCCCAGCAGCAAG TCTACTTCCGGCGGAACTGCTGCCCTGGGTTGCCTGGTGAAGGAC TACTTCCCCGAGCCCGTGACAGTGTCCTGGAACTCTGGGGCTCTGACTTCCGGCGTGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGC njztznn / i ζπζ / ε / υ CTGTACAGCCTGAGCAGCGTGGTGACAGTGCCCTCCAGCTCTCTG GGAACCCAGACCTATATCTGCAACGTGAACCACAAGCCCAGCAAC ACCAAGGTGGACAAGAGAGTGGAGCCCAAGAGCTGCGACAAGACC CACACCTGCCCCCCCTGCCCAGCTCCAGAACTGCTGGGAGGGCCT TCCGTGTTCCTGTTCCCCCC CAAGCCCAAGGACACCCTGATGATC AGCAGGACCCCCGAGTGACCTGCCGTGGTGGTGGACGTGTCCCAC GAGGACCCAGAGGTGAAGTTCAACTGGTACGTGGACGGCGTGGAG GTGCACAACGCCAAGACCAAGCCCAGAGAGGAGCAGTACAACAGC ACCTACAGGGTGGTGTCCGTGCTGACCGTGCTGCACC AGGACTGG CTGAACGGCAAAGAATACAAGTGCAAAGTCTCCAACAAGGCCCTG CCAGCCCCAATCGAAAAGACAATCAGCAAGGCCAAGGGCCAGCCA CGGGAGCCCCAGGTGTACACCCTGCCCCCCAGCCGGGAGGAGATG ACCAAGAACCAGGTGTCCCTGACCTGTCTGGTGAAGGGCTTCTAC CCCAGCGATATCGCC GTGGAGTGGGAGAGCAACGGCCAGCCCGAG AACAACTACAAGACCACCCCCCCAGTGCTGGACAGCGACGGCAGC TTCTTCCTGTACAGCAAGCTGACCGTGGACAAGTCCAGGTGGCAG CAGGGCAACGTGTTCAGCTGCAGCGTGATGCACGAGGCCCTGCAC AACCACTACACCCCAGAAGTCCCTGAGCCT GAGCCCCGGCAAG SEQ ID NO: 17 LCDR1 (Combined) RASQDISNYLA SEQ ID NO: 18 LCDR2 (Combined) RASSLQS SEQ ID NO: 19 LCDR3 (Combined) FQYRHMPSQT SEQ ID NO: 17 LCDR1 (Kabat) RASQDISNYLA SEQ ID NO: 18 LCDR2 (Kabat) RASSLQS SEQ ID NO: 19 LCDR3 (Kabat) FQYRHMPSQT SEQ ID NO: 20 LCDR1 (Chothia) SQDISNY SEQ ID NO: 21 LCDR2 (Chothia) RAS SEQ ID NO: 22 LCDR3 (Chothia) YRHMPSQ SEQ ID NO: 23 LCDR1 (IMGIj QDISNY SEQ ID NO: 21 LCDR2 (IMGIj RAS SEQ ID NO: 19 LCDR3 (IMGT) FQYRHMPSQT SEQ ID NO: 24 VL DIQMTQSPSSLSASVGDRVTITCRASQDISNYLAWYQQKPGKAPK L LIYRASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCFQ YRHMPSQTFGQGTKVEIK SEQ ID NO: 31 DNA VL GACATTCAGATGACCCAGTCCCCGTCGTCCCTGTCCGCATCCGTG GGCGACAGAGTCACCATCACTTGCCGGGCCTCACAGGATATTTCC AACTACCTGGCCTGGTATCAGCAGAAGCCTGGAAAGGCCCCGAAG CTGCTGATCTACCGGGCGTCCTCCTTGCAATCGGGAGTGCCAAGC CGCTTTCTGGTTCCG GGAGCGGGACTGACTTCACCCTGACTATT AGCAGCCTGCAGCCCGAAGATTTCGCTACCTACTACTGCTTCCAG TACCGGCACATGCCCTCACAAACCTTCGGACAGGGCACCAAAGTC GAGATCAAG SEQ ID NO: 26 Light chain DIQMTQSPSSLSASVGDRVTITCRASQDISNYLAWYQQKPGKAPK LLIYRASSLQSGV PSRFSGSGSGTDFTLTISSLQPEDFATYYCFQ YRHMP SQTFGQGTKVEIKRTVAAP SVFIFPP SDEQLKSGTASWC LLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTL TLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 32 DNA Light chain GAC ATTCAGATGACCCAGTCCCCGTCGTCCCTGTCCGCATCCGTG GGCGACAGAGTCACCATCACTTGCCGGGCCTCACAGGATATTTCC AACTACCTGGCCTGGTATCAGCAGAAGCCTGGAAAGGCCCCGAAG CTGCTGATCTACCGGGCGTCCTCCTTGCAATCGGGAGTGCCAAGC CGCTTTCTGGTTCCGGGAGCGGG ACTGACTTCACCCTGACTATT AGCAGCCTGCAGCCCGAAGATTTCGCTACCTACTACTGCTTCCAGTACCGGCACATGCCCTCACAAACCTTCGGACAGGGCACCAAAGTC njztznn / i ζπζ / β / υ GAGATCAAGCGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCC CCCAGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGTGC CTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAG GTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTCACC GAGCAGGACAGCAAGGACT CCACCTACAGCCTGAGCAGCACCCTG ACCCTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGC GAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTC AACAGGGGCGAGTGC MOR44698C SEQ ID NO: 4 HCDR1 (Combined) GYTFTGYHMS SEQ ID NO: 5 HCDR 2 (Combined) VINPVSGNTVYAQKFQG SEQ ID NO: 6 HCDR3 (Combined) IPSYTYAFDY SEQ ID NO: 7 HCDR1 (Kabat) GYHMS SEQ ID NO: 5 HCDR2 (Kabat) VINPVSGNTVYAQKFQG SEQ ID NO: 6 HCDR3 (Kabat) IPSYTYAFDY SEQ ID NO: 8 HCDR1 (Chothia) GYTFTGY SEQ ID NO: 9 HCDR2 (Chothia) NPVSGN SEQ ID NO: 6 HCDR3 (Chothia) IPSYTYAFDY SEQ ID NO: 10 HCDR1 (IMGT) GYTFTGYH SEQ ID NO: 11 HCDR2 (IMGT) INPVSGNT SEQ ID NO: 12 HCDR3 (IMGT) ARIPSYTYAFDY SEQ ID NO: 13 VH QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYHMSWVRQAPGQGL EWMGVINPVS GNTVYAQKFQGRVTMTRDTSISTAYMELSRLRSED TAVYYCARIPSYTYAFDYWGQGTLVTVSS SEQ ID NO: 28 DNA VH CAAGTGCAACTCGTGCAGTCAGGAGCCGAAGTCAAGAAGCCTGGA GCCTCGGTCAAGGTGTCCTGCAAGGCCAGCGGATACACTTTCACT GGATACCACATGTCGTGGGTCAGACAG GCTCCTGGCCAAGGGCTG GAGTGGATGGGCGTCATCAACCCGGTGTCGGGTAATACCGTGTAC GCCCAGAAGTTCCAGGGTCGCGTGACCATGACCCGGGATACCTCC ATTAGCACCGCGTACATGGAGCTCAGCCGGTTGAGATCCGAGGAT ACCGCCGTGTACTACTGTGCGCGGATCCCGTCCTACACTTACGCC TTCGACTATTGGGGCCAGGGGACTCTTGTCACCGTGTCCTCG SEQ ID NO: 33 Heavy chain QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYHMSWVRQAPG QGL EWMGVINPVSGNTVYAQKFQGRVTMTRDTSISTAYMELSRLRSED TAVYYCARIPSYTYAFDYWGQGTLVTVSSASTKGPSVFPLAPSSK STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPK SCDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCWVAVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDW LNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVYTLPPSREEM TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV LDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 34 DNA Heavy Chain CAAGTGCAACTCGTGCAGTCAGGAGCCGAAGTCAAGAAGCCTGGA GCCTCGGTCAAGGTGTCCTGCAAGGCCAGCGGATACACTTTCACT GGATACCACATGTCGTGGGTCAGACAGGCTCCTGGC CAAGGGCTG GAGTGGATGGGCGTCATCAACCCGGTGTCGGGTAATACCGTGTAC GCCCAGAAGTTCCAGGGTCGCGTGACCATGACCCGGGATACCTCC ATTAGCACCGCGTACATGGAGCTCAGCCGGTTGAGATCCGAGGAT ACCGCCGTGTACTACTGTGCGCGGATCCCGTCCTACACTTACGCC TTCGACTATTGG GGCCAGGGGACTCTTGTCACCGTGTCCTCGGCC TCCACTAAGGGCCCGTCAGTGTTCCCCCCTTGCGCCATCCTCGAAG TCAACCTCCGGAGGAACTGCCGCACTGGGTTGCCTCGTGAAAGAC TATTTCCCGGAACCCGTCACTGTCTCCTGGAACTCAGGAGCGCTC n / ztznn / i ζπζ / β / υ ACCAGCGGAGTGCATACCTTTCCTGCGGTGCTGCAGTCCAGCGGC CTGTACTCCCTGAGCTCCGTCGTGACCGTCCCCTCGTCGTCCCTG GGAACCCAAACCTACATTTGCAACGTCAATCACAAGCCAAGCAAC ACTAAGGTGGACAAGAGAGTGGAGCCCAAGTCCTGCGATAAGACC CACACCTGTCCTCCCTGTCCGGCA CCTGAACTGCTTGGTGGACCT TCCGTGTTCCTGTTCCCGCCCAAGCCAAAAGACACCCTGATGATC TCCCGCACTCCGGAAGTCACTTGCGTGGTCGTGGCCGTGTCCCAC GAGGACCCCGAGGTCAAGTTTAATTGGTACGTGGACGGAGTGGAA GTGCACAACGCCAAGACCAAGCCGCGGGAAGAACAGTACAACTCC ACCTACCGCGTGGTGTCCGTCCTGACTGTGCTCCACCAGGACTGG CTGAACGGAAAGGAGTACAAGTGCAAAGTGTCCAACAAGGCACTG GCTGCCCCTATCGAAAAGACTATCTCCAAGGCCAAGGGCCAACCT AGGGAGCCCCAGGTGTACACGTTGCCTCCTTCCCGCGAAGAAATG ACTAAGAACCAGGTGTCGCT GACCTGTCTCGTGAAAGGGTTCTAC CCCTCTGACATCGCCGTGGAATGGGAGTCAAACGGACAGCCTGAG AACAACTATAAGACCACACCACCTGTCCTGGACTCCGACGGCTCC TTCTTCCTGTACTCAAAGTTGACCGTGGACAAGTCGCGGTGGCAA CAGGGCAACGTGTTCTCTTGCTCCGTGATGCACGAAGCC CTGCAC AACCACTACACCCAAAAGTCGCTCAGCCTCTCCCCCGGAAAG SEQ ID NO: 17 LCDR1 (Combined) RASQDISNYLA SEQ ID NO: 18 LCDR2 (Combined) RASSLQS SEQ ID NO: 19 LCDR3 (Combined) FQYRHMPSQT SEQ ID NO: 17 LCDR1 (Kabat) RASQDISNYLA SEQ ID NO: 18 LCDR2 (Kabat) RASSLQS SEQ ID NO: 19 LCDR3 (Kabat) FQYRHMPSQT SEQ ID NO: 20 LCDR1 (Chothia) SQDISNY SEQ ID NO: 21 LCDR2 (Chothia) RAS SEQ ID NO: 22 LCDR3 (Chothia) YRHMPSQ SEQ ID NO: 23 LCDR1 (IMGT) QDISNY SEQ ID NO: 21 LCDR2 (IMGT) RAS SEQ ID NO: 19 LCDR3 (IMGT) FQYRHMPSQT SEQ ID NO: 24 VL DIQMTQSPSSLSASVGDRVTITCRASQDISNYLAWYQQKPGK APK LLIYRASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCFQ YRHMPSQTFGQGTKVEIK SEQ ID NO: 31 DNA VL GACATTCAGATGACCCAGTCCCCGTCGTCCCTGTCCGCATCCGTG GGCGACAGAGTCACCATCACTTGCCGGGCCTCACAGGATATTTCC AACTACCTGGCCTGGTATCAGCAGAAGCCTGGAAAGGCCCCGAAG CTGCTGATCTACCGGGCGTCCTCCTTGCAATCGGGAGTGCCAAGC CGCTTTCT GGTTCCGGGAGCGGGACTGACTTCACCCTGACTATT AGCAGCCTGCAGCCCGAAGATTTCGCTACCTACTACTGCTTCCAG TACCGGCACATGCCCTCACAAACCTTCGGACAGGGCACCAAAGTC GAGATCAAG SEQ ID NO: 26 Light chain DIQMTQSPSSLSASVGDRVTITCRASQDISNYLAWYQQKPGKAPK LLIYRAS SLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCFQ YRHMP SQTFGQGTKVEIKRTVAAP SVFIFPP SDEQLKSGTASWC LLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTL TLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 32 DNA Light chain GACATTCAGATGACCCAGTCCCCGTCGTCCCTGTCCGCATCCGTG GGCGACAGAGTCACCATCACTTGCCGGGCCTCACAGGATATTTCC AACTACCTGGCCTGGTATCAGCAGAAGCCTGGAAAGGCCCCGAAG CTGCTGATCTACCGGGCGTCCTCCTTGCAATCGGGAGTGCCAAGC CGCTTTTTCTGGTTCCGG GAGCGGGACTGACTTCACCCTGACTATT AGCAGCCTGCAGCCCGAAGATTTCGCTACCTACTACTGCTTCCAG n / ztznn / i ζπζ / β / υ TACCGGCACATGCCCTCACAAACCTTCGGACAGGGCACCAAAGTC GAGATCAAGCGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCC CCCAGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGC CTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAG GTGGACAACGCCCTGCAGA GCGGCAACAGCCAGGAGAGCGTCACC GAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTG ACCCTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGC GAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTC AACAGGGGCGAGTGC MOR44698D SEQ ID NO: 4 HCDR1 (Combined) GYTFTGYHMS SEQ ID NO: 5 HCDR2 (Combined) VINPVSGNTVYAQKFQG SEQ ID NO: 6 HCDR3 (Combined) IPSYTYAFDY SEQ ID NO: 7 HCDR1 (Kabat) GYHMS SEQ ID NO: 5 HCDR2 (Kabat) VINPVSGNTVYAQKFQG SEQ ID NO: 6 HCDR3 (Kabat) IPSYTYAFDY SEQ ID NO: 8 HCDR1 (Chothia) GYTFTGY SEQ ID NO: 9 HCDR2 (Chothia) NPVSGN SEQ ID NO: 6 HCDR3 (Chothia) IPSYTYAFDY SEQ ID NO: 10 HCDR1 (IMGT) GYTFTGYH SEQ ID NO: 11 HCDR2 (IMGT) INPVSGNT SEQ ID NO: 12 HCDR3 (IMGT) ARIPSYTYAFDY SEQ ID NO: 13 VH QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYHMSWVRQAPGQGL EWMGVIN PVSGNTVYAQKFQGRVTMTRDTSISTAYMELSRLRSED TAVYYCARIPSYTYAFDYWGQGTLVTVSS SEQ ID NO: 28 VH DNA CAAGTGCAACTCGTGCAGTCAGGAGCCGAAGTCAAGAAGCCTGGA GCCTCGGTCAAGGTGTCCTGCAAGGCCAGCGGATACACTTTCACT GGATACCACATGTCGTGGGTCAG ACAGGCTCCTGGCCAAGGGCTGGAGTGGATGGGCGTCATCAACCCGGTGTCGGGTAATACCGTGTAC GCCCAGAAGTTCCAGGGTCGCGTGACCATGACCCGGGATACCTCC AT TAGCAC C GC GTACAT GGAGC TCAGCCGGTT GAGAT C C GAGGAT ACCGCCGTGTACTACTGTGCGCGGATCCCGTCCTACACTTACGCC TTCGACTATTGGGGCCAGGGGACTCTTGTCACCGTGTCCTCG SEQ ID NO: 35 Heavy Chain QV QLVQSGAEVKKPGASVKVSCKASGYTFTGYHMSWVRQAPGQGL EWMGVINPVSGNTVYAQKFQGRVTMTRDTSISTAYMELSRLRSED TAVYYCARIPSYTYAFDYWGQGTLVTVSSASTKGPSVFPLAPSSK STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVL QSSG LYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDW LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTL PPSREEM TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK SEQ ID NO: 36 DNA Heavy Chain CAAGTGCAACTCGTGCAGTCAGGAGCCGAAGTCAAGAAGCCTGGA GCCTCGGTCAAGGTGTCCTGCAAGGCCAG CGGATACACTTTCACT GGATACCACATGTCGTGGGTCAGACAGGCTCCTGGCCAAGGGCTG GAGTGGATGGGCGTCATCAACCCGGTGTCGGGTAATACCGTGTAC GCCCAGAAGTTCCAGGGTCGCGTGACCATGACCCGGGATACCTCC ATTAGCACCGCGTACATGGAGCTCAGCCGGTTGAGATCCGAGGAT AC CGCCGTGTACTACTGTGCGCGGATCCCGTCCTACACTTACGCC TTCGACTATTGGGGCCAGGGGACTCTTGTCACCGTGTCCTCGGCC TCCACTAAGGGCCCGTCAGTGTTCCCCCTTGCGCCATCCTCGAAG TCAACCTCCGGAGGAACTGCCGCACTGGGTTGCCTCGTGAAAGAC n / ztznn / i ζηζ / ε / γ TATTTCCCGGAACCCGTCACTGTCTCCTGGAACTCAGGAGCGCTC ACCAGCGGAGTGCATACCTTTCCTGCGGTGCTGCAGTCCAGCGGC CTGTACTCCCTGAGCTCCGTCGTGACCGTCCCCTCGTCGTCCCTG GGAACCCAAACCTACATTTGCAACGTCAATCACAAGCCAAGCAAC ACTAAGGTGGACAAGAGAGTGGAG CCCAAGTCCTGCGATAAGACC CACACCTGTCCTCCCTGTCCGGCACCTGAACTGCTTGGTGGACCT TCCGTGTTCCTGTTCCCGCCCAAGCCAAAAGACACCCTGATGATC TCCCGCACTCCGGAAGTCACTTGCGTGGTCGTGGACGTGTCCCAC GAGGACCCCGAGGTCAAGTTTAATTGGTACGTGGACGGAGTGGAA GT GCACAACGCCAAGACCAAGCCGCGGGAAGAACAGTACAACTCC ACCTACCGCGTGGTGTCCGTCCTGACTGTGCTCCACCAGGACTGG CTGAACGGAAAGGAGTACAAGTGCAAAGTGTCCAACAAGGCACTG CCAGCCCCTATCGAAAAGACTATCTCCAAGGCCAAGGGCCAACCT AGGGAGCCCCAGGTGTACACGTTGCC TCCTTCCCGCGAAGAAATG ACTAAGAACCAGGTGTCGCTGACCTGTCTCGTGAAAGGGTTCTAC CCCTCTGACATCGCCGTGGAATGGGAGTCAAACGGACAGCCTGAG AACAACTATAAGACCACCACCTGTCCTGGACTCCGACGGCTCC TTCTTCCTGTACTCAAAGTTGACCGTGGACAAGTCGCGGTGGCAA CAGG GCAACGTGTTCTCTTGCTCCGTGCTGCACGAAGCCCTGCAC AGCCACTACACCCAAAAGTCGCTCAGCCTCTCCCCCGGAAAG SEQ ID NO: 17 LCDR1 (Combined) RASQDISNYLA SEQ ID NO: 18 LCDR2 (Combined) RASSLQS SEQ ID NO: 19 LCDR3 (Combined) FQYRHMPSQT SEQ ID NO: 17 LCDR1 (Kabat) RASQDISNYLA SEQ ID NO: 18 LCDR2 (Kabat) RASSLQS SEQ ID NO: 19 LCDR3 (Kabat) FQYRHMPSQT SEQ ID NO: 20 LCDR1 (Chothia) SQDISNY SEQ ID NO: 21 LCDR2 (Chothia) RAS SEQ ID NO: 22 LCDR3 (Chothia) YRHMPSQ SEQ ID NO: 23 LCDR1 (IMGT) QDISNY SEQ ID NO: 21 LCDR2 (IMGT) RAS SEQ ID NO: 19 LCDR3 (IMGT) FQYRHMPSQT SEQ ID NO: 24 VL DIQMTQSPSSLSASVGDRVTITCRASQDISNYLAWYQQKP GKAPK LLIYRASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCFQ YRHMPSQTFGQGTKVEIK SEQ ID NO: 31 DNA VL GACATTCAGATGACCCAGTCCCCGTCGTCCCTGTCCGCATCCGTG GGCGACAGAGTCACCATCACTTGCCGGGCCTCACAGGATATTTCC AACTACCTGGCCTGGTATCAGCAGAAGCCTGGAAAGGCCCCGAAG CTGCTGATCTACCGGGCGTCCTCCTTGCAATCGGGAGTGCCAAGC CGCTTTT CTGGTTCCGGGAGCGGGACTGACTTCACCCTGACTATT AGCAGCCTGCAGCCCGAAGATTTCGCTACCTACTACTGCTTCCAG TACCGGCACATGCCCTCACAAACCTTCGGACAGGGCACCAAAGTC GAGATCAAG SEQ ID NO: 26 Light Chain DIQMTQSPSSLSASVGDRVTITCRASQDISNYLAWYQQKPGKAPK LLIY RASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCFQ YRHMP SQTFGQGTKVEIKRTVAAP SVFIFPP SDEQLKSGTASWC LLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTL TLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 3 2 DNA Light chain GACATTCAGATGACCCAGTCCCCGTCGTCCCTGTCCGCATCCGTG GGCGACAGAGTCACCATCACTTGCCGGGCCTCACAGGATATTTCC AACTACCTGGCCTGGTATCAGCAGAAGCCTGGAAAGGCCCCGAAG CTGCTGATCTACCGGGCGTCCTCCTTGCAATCGGGAGTGCCAAGC CGCTTTTTCTGGTTCCG GGAGCGGGACTGACTTCACCCTGACTATT n / 7bnn / i 7Π7 / β / υ AGCAGCCTGCAGCCCGAAGATTTCGCTACCTACTACTGCTTCCAG TACCGGCACATGCCCTCACAAACCTTCGGACAGGGCACCAAAGTC GAGATCAAGCGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCAGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGC CTGCTGAACAACTTCTACCCCCGG A ACAGGGGCGAGTGC MOR44698E SEQ ID NO: 4 HCDR1 (Combined) GYTFTGYHMS SEQ ID NO: 5 HCDR2 (Combined) VINPVSGNTVYAQKFQG SEQ ID NO: 6 HCDR3 (Combined) IPSYTYAFDY SEQ ID NO: 7 HCDR1 (Kabat) GYHMS SEQ ID NO: 5 HCDR2 (Kabat) VINPVSGNTVYAQKFQG SEQ ID NO: 6 HCDR3 (Kabat) IPSYTYAFDY SEQ ID NO: 8 HCDR1 (Chothia) GYTFTGY SEQ ID NO: 9 HCDR2 (Chothia) NPVSGN SEQ ID NO: 6 HCDR3 (Chothia) IPSYTYAFDY SEQ ID NO: 10 HCDR1 (IMGT) GYTFTGYH SEQ ID NO: 11 HCDR2 (IMGT) INPVSGNT SEQ ID NO: 12 HCDR3 (IMGT) ARIPSYTYAFDY SEQ ID NO: 13 VH QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYHMSWVRQAPGQ GL EWMGVTNPVSGNTVYAQKFQGRVTMTRDTSISTAYMELSRLRSED TAVYYCARTPSYTYAFDYWGQGTLVTVSS SEQ ID NO: 28 VH DNA CAAGTGCAACTCGTGCAGTCAGGAGCCGAAGTCAAGAAGCCTGGA GCCTCGGTCAAGGTGTCCTGCAAGGCCAGCGGATACACTTTCACT GGATACCACATGTC GTGGGTCAGACAGGCTCCTGGCCAAGGGCTG GAGTGGATGGGCGTCATCAACCCGGTGTCGGGTAATACCGTGTAC GCCCAGAAGTTCCAGGGTCGCGTGACCATGACCCGGGATACCTCC ATTAGCACCGCGTACATGGAGCTCAGCCGGTTGAGATCCGAGGAT ACCGCCGTGTACTACTGTGCGCGGATCCCGTCCTACACTTACGCC TTCGACTATTGGGGCCAGG GGACTCTTGTCACCGTGTCCTCG SEQ ID NO: 37 Heavy Chain QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYHMSWRQAPGQGL EWMGVINPVSGNTVYAQKFQGRVTMTRDTSISTAYMELSRLRSED TAVYYCARTPSYTYAFDYWGQGTLVTVSSASTKGPSVFPLAPSSK STSG L NGKEYKCKVSNKALAAPIEKTTSKAKGQPREPQVYTLPPSREEM TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQKSLSLSPGK SEQ ID NO: 38 DNA Heavy Chain CAAGTGCAACTCGTGCAGTCAGGAGCCGAAGTCAA GAAGCCTGGA GCCTCGGTCAAGGTGTCCTGCAAGGCCAGCGGATACACTTTCACT GGATACCACATGTCGTGGGTCAGACAGGCTCCTGGCCAAGGGCTG GAGTGGATGGGCGTCATCAACCCGGTGTCGGGTAATACCGTGTAC GCCCAGAAGTTCCAGGGTCGCGTGACCATGACCCGGGATACCTCC ATTAG CACCGCGTACATGGAGCTCAGCCGGTTGAGATCCGAGGAT ACCGCCGTGTACTACTGTGCGCGGATCCCGTCCTACACTTACGCC TTCGACTATTGGGGCCAGGGGACTCTTGTCACCGTGTCCTCGGCC TCCACTAAGGGCCCGTCAGTGTTCCCCCTTGCGCCATCCTCGAAG nyztznn / i ζηζ / Ε / γ TCAACCTCCGGAGGAACTGCCGCACTGGGTTGCCTCGTGAAAGAC TATTTCCCGGAACCCGTCACTGTCTCCTGGAACTCAGGAGCGCTC ACCAGCGGAGTGCATACCTTTCCTGCGGTGCTGCAGTCCAGCGGC CTGTACTCCCTGAGCTCCGTCGTGACCGTCCCCTCGTCGTCCCTG GGAACCCAAACCTACATTTGCA ACGTCAATCACAAGCCAAGCAAC ACTAAGGTGGACAAGAGAGTGGAGCCCAAGTCCTGCGATAAGACC CACACCTGTCCTCCCTGTCCGGCACCTGAACTGCTTGGTGGACCT TCCGTGTTCCTGTTCCCGCCCAAGCCAAAAGACACCCTGATGATC TCCCGCACTCCGGAAGTCACTTGCGTGGTCGTGGCCGTGTCCCAC G AGGACCCCGAGGTCAAGTTTAATTGGTACGTGGACGGAGTGGAA GTGCACAACGCCAAGACCAAGCCGCGGGAAGAACAGTACAACTCC ACCTACCGCGTGGTGTCCGTCCTGACTGTGCTCCACCAGGACTGGG CTGAACGGAAAGGAGTACAAGTGCAAAGTGTCCAACAAGGCACTG GCTGCCCCTATCGAAAAGACTATC TCCAAGGCCAAGGGCCAACCT AGGGAGCCCCAGGTGTACACGTTGCCTCCTTCCCGCGAAGAAATG ACTAAGAACCAGGTGTCGCTGACCTGTCTCGTGAAAGGGTTCTAC CCCTCTGACATCGCCGTGGAATGGGAGTCAAACGGACAGCCTGAG AACAACTATAAGACCACACCACCTGTCCTGGACTCCGACGGCTCC TT CTTCCTGTACTCAAAGTTGACCGTGGACAAGTCGCGGTGGCAA CAGGGCAACGTGTTCTCTTGCTCCGTGCTGCACGAAGCCCTGCAC AGCCACTACACCCAAAAGTCGCTCAGCCTCTCCCCCGGAAAG SEQ ID NO: 17 LCDR1 (Combined) RASQDISNYLA SEQ ID NO: 18 LCDR2 (Combined) RASSL QS SEQ ID NO: 19 LCDR3 (Combined) FQYRHMPSQT SEQ ID NO: 17 LCDR1 (Kabat) RASQDISNYLA SEQ ID NO: 18 LCDR2 (Kabat) RASSLQS SEQ ID NO: 19 LCDR3 (Kabat) FQYRHMPSQT SEQ ID NO: 20 LCDR1 (Chothia) SQDISNY SEQ ID NO: 21 LCDR2 (Chothia) RAS SEQ ID NO: 22 LCDR3 (Chothia) YRHMPSQ SEQ ID NO: 23 LCDR1 (IMGIj QDISNY SEQ ID NO: 21 LCDR2 (IMGIj RAS SEQ ID NO: 19 LCDR3 (IMGT) FQYRHMPSQT SEQ ID NO: 24 VL DIQMTQSPSSLSASVGDRVTITCRASQDISNYLAWYQQKP GKAPK LLIYRASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCFQ YRHMPSQTFGQGTKVEIK SEQ ID NO: 31 DNA VL GACATTCAGATGACCCAGTCCCCGTCGTCCCTGTCCGCATCCGTG GGCGACAGAGTCACCATCACTTGCCGGGCCTCACAGGATATTTCC AACTACCTGGCCTGGTATCAGCAGAAGCCTGGAAAGGCCCCGAAG CTGCTGATCTACCGGGCGTCCTCCTTGCAATCGGGAGTGCCAAGC CGCTTTCT GGTTCCGGGAGCGGGACTGACTTCACCCTGACTATT AGCAGCCTGCAGCCCGAAGATTTCGCTACCTACTACTGCTTCCAG TACCGGCACATGCCCTCACAAACCTTCGGACAGGGCACCAAAGTC GAGATCAAG SEQ ID NO: 26 Light chain DIQMTQSPSSLSASVGDRVTITCRASQDISNYLAWYQQKPGKAPK LLIYRAS SLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCFQ YRHMP SQTFGQGTKVEIKRTVAAP SVFIFPP SDEQLKSGTASWC LLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTL TLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 32 DNA Light chain GACATTCAGATGACCCAGTCCCCGTCGTCCCTGTCCGCATCCGTG GGCGACAGAGTCACCATCACTTGCCGGGCCTCACAGGATATTTCC AACTACCTGGCCTGGTATCAGCAGAAGCCTGGAAAGGCCCCGAAG CTGCTGATCTACCGGGCGTCCTCCTTGCAATCGGGAGTGCCAAGC n / ztznn / i ζπζ / β / υ CGCTTTCTGGTTCCGGGAGCGGGACTGACTTCACCCTGACTATT AGCAGCCTGCAGCCCGAAGATTTCGCTACCTACTACTGCTTCCAG TACCGGCACATGCCCTCACAAACCTTCGGACAGGGCACCAAAGTC GAGATCAAGCGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCCAGCGACGAGCAGCTGAAGAGCGG CACCGCCAGCGTGGTGTGC CTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAG GTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTCACC GAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTG ACCCTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGC G AGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTC AACAGGGGCGAGTGC MOR44698F SEQ ID NO: 4 HCDR1 (Combined) GYTFTGYHMS SEQ ID NO: 5 HCDR2 (Combined) VINPVSGNTVYAQKFQG SEQ ID NO: 6 HCDR3 (Combined) IPSYTYAFDY SE Q ID NO: 7 HCDR1 (Kabat ) GYHMS SEQ ID NO: 5 HCDR2 (Kabat) VINPVSGNTVYAQKFQG SEQ ID NO: 6 HCDR3 (Kabat) IPSYTYAFDY SEQ ID NO: 8 HCDR1 (Chothia) GYTFTGY SEQ ID NO: 9 HCDR2 (Chothia) NPVSGN SEQ ID NO: 6 HCDR3 (Chothia ) IPSYTYAFDY SEQ ID NO: 10 HCDR1 (IMGT) GYTFTGYH SEQ ID NO: 11 HCDR2 (IMGT) INPVSGNT SEQ ID NO: 12 HCDR3 (IMGT) ARIPSYTYAFDY SEQ ID NO: 13 VH QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYHMSWRQAP GQGL EWMGVINPVSGNTVYAQKFQGRVTMTRDTSISTAYMELSRLRSED TAVYYCARIPSYTYAFDYWGQGTLVTVSS SEQ ID NO: 28 VH DNA CAAGTGCAACTCGTGCAGTCAGGAGCCGAAGTCAAGAAGCCTGGA GCCTCGGTCAAGGTGTCCTGCAAGGCCAGCGGATACACTTTCACT GGATACCACATGTCGTGGGTCAGACAGGCTCCTGGCCAAGGGCTG GAGTGGATGGGCGTCATCAACCCGGTGTCGGGTAATACCGTGTAC GCCCAGAAGTTCCAGGGTCGCGTGACCATGACCCGGGATACCTCC ATTAGCACCGCGTACATGGAGCTCAGCCGGTTGAGATCCGAGGAT ACCGCCGTGTACT ACTGTGCGCGGATCCCGTCCTACACTTACGCC TTCGACTATTGGGGCCAGGGGACTCTTGTCACCGTGTCCTCG SEQ ID NO: 39 Heavy Chain QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYHMSWVRQAPGQGL EWMGVINPVSGNTVYAQKFQGRVTMTRDTSISTAYMELSRLRSED TAVYY CARIPSYTYAFDYWGQGTLVTVSSASTKGPSVFPLAPSSK STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLYITREPEVTCVWDVSH EDPEVK FNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDW LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEM TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS FFLYSKLTVDKSRWQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 40 DNA Heavy Chain CAAGTGCAACTCGTGCAGTCAGGAGCCGAAGTCAAGAAGCCTGGA GCCTCGGTCAAGGTGTCCTGCAAGGCCAGCGGATACACTTTCACT GGATACCACATGTCGTGGGTCAGACAGGCTCCTGGCCAAGGGCTG GAGTGGATGGGCGTCATCAACCCGGTGTCGGGTAATACCGTG TAC GCCCAGAAGTTCCAGGGTCGCGTGACCATGACCCGGGATACCTCC ATTAGCACCGCGTACATGGAGCTCAGCCGGTTGAGATCCGAGGAT ACCGCCGTGTACTACTGTGCGCGGATCCCGTCCTACACTTACGCC TTCGACTATTGGGGCCAGGGGACTCTTGTCACCGTGTCCTCGGCC njztznn / i ζπζ / β / υ TCCACTAAGGGCCCGTCAGTGTTCCCCCTTGCGCCATCCTCGAAG TCAACCTCCGGAGGAACTGCCGCACTGGGTTGCCTCGTGAAAGAC TATTTCCCGGAACCCGTCACTGTCTCCTGGAACTCAGGAGCGCTC ACCAGCGGAGTGCATACCTTTCCTGCGGTGCTGCAGTCCAGCGGC CTGTACTCCCTGAGCTCCGTCG TGACCGTCCCCTCGTCGTCCCTGGGAACCCAAACCTACATTTGCAACGTCAATCACAAGCCAAGCAAC ACTAAGGTGGACAAGAGAGTGGAGCCCAAGTCCTGCGATAAGACC CACACCTGTCCTCCCTGTCCGGCACCTGAACTGCTTGGTGGACCT TCCGTGTTCCTGTTCCCGCCCAAGCCAAAAGACACCCTGTATATC ACTCGC GAACCGGAAGTCACTTGCGTGGTCGTGGACGTGTCCCAC GAGGACCCCGAGGTCAAGTTTAATTGGTACGTGGACGGAGTGGAA GTGCACAACGCCAAGACCAAGCCGCGGGAAGAACAGTACAACTCC ACCTACCGCGTGGTGTCCGTCCTGACTGTGCTCCACCAGGACTGG CTGAACGGAAAGGAGTACAAGTGCAA AGTGTCCAACAAGGCACTG CCAGCCCCTATCGAAAAGACTATCTCCAAGGCCAAGGGCCAACCT AGGGAGCCCCAGGTGTACACGTTGCCTCCTTCCCGCGAAGAAATG ACTAAGAACCAGGTGTCGCTGACCTGTCTCGTGAAAGGGTTCTAC CCCTCTGACATCGCCGTGGAATGGGAGTCAAACGGACAGCCTGAG AA CAACTATAAGACCACACCACCTGTCCTGGACTCCGACGGCTCC TTCTTCCTGTACTCAAAGTTGACCGTGGACAAGTCGCGGTGGCAA CAGGGCAACGTGTTCTCTTGCTCCGTGATGCACGAAGCCCTGCAC AACCACTACACCCAAAGTCGCTCAGCCTCTCCCCCGGAAAG SEQ ID NO: 17 LCDR1 (Combined) RAS QDISNYLA SEQ ID NO: 18 LCDR2 (Combined) RASSLQS SEQ ID NO: 19 LCDR3 (Combined ) FQYRHMPSQT SEQ ID NO: 17 LCDR1 (Kabat) RASQDISNYLA SEQ ID NO: 18 LCDR2 (Kabat) RASSLQS SEQ ID NO: 19 LCDR3 (Kabat) FQYRHMPSQT SEQ ID NO: 20 LCDR1 (Chothia) SQDISNY SEQ ID NO: 21 LCDR2 (Chothia ) RAS SEQ ID NO: 22 LCDR3 (Chothia) YRHMPSQ SEQ ID NO: 23 LCDR1 (IMGT) QDISNY SEQ ID NO: 21 LCDR2 (IMGT) RAS SEQ ID NO: 19 LCDR3 (IMGT) FQYRHMPSQT SEQ ID NO: 24 VL DIQMTQSPSSLSASVGDRVTITCRASQDISNYLAWY QQKPGKAPK LLTYRASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCFQ YRHMPSQTFGQGTKVEIK SEQ ID NO: 31 ADN VL GACATTCAGATGACCCAGTCCCCGTCGTCCCTGTCCGCATCCGTG GGCGACAGAGTCACCATCACTTGCCGGGCCTCACAGGATATTTCC AACTACCTGGCCTGGTATCAGCAGAAGCCTGGAAAGGCCCCGAAG CTGCTGATCTACCGGGCGTCCTCCTTG CAATCGGGAGTGCCAAGC CGCTTTCTGGTTCCGGGAGCGGGACTGACTTCACCCTGACTATT AGCAGCCTGCAGCCCGAAGATTTCGCTACCTACTACTGCTTCCAG TACCGGCACATGCCCTCACAAACCTTCGGACAGGGCACCAAAGTC GAGATCAAG SEQ ID NO: 26 Light Chain DIQMTQSPSSLSASVGDRVTITCRASQ DISNYLAWYQQKPGKAPK LLIYRASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCFQ YRHMP SQTFGQGTKVEIKRTVAAP SVFIFPP SDEQLKSGTASWC LLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTL TLSKADYEKHKVYACEVTHQ GLSSPVTKSFNRGEC SEQ ID NO: 32 DNA light chain GACATTCAGATGACCCAGTCCCCGTCGTCCCTGTCCGCATCCGTG GGCGACAGAGTCACCATCACTTGCCGGGCCTCACAGGATATTTCC AACTACCTGGCCTGGTATCAGCAGAAGCCTGGAAAGGCCCCGAAG n / ztznn / i ζπζ / β / υ CTGCTGATCTACCGGGCGTCCTCCTTGCAATCGGGAGTGCCAAGC CGCTTTCTGGTTCCGGGAGCGGGACTGACTTCACCCTGACTATT AGCAGCCTGCAGCCCGAAGATTTCGCTACCTACTACTGCTTCCAG TACCGGCACATGCCCTCACAAACCTTCGGACAGGGCACCAAAGTC GAGATCAAGCGTACGGTGGCC GCTCCCAGCGTGTTCATCTTCCCC CCCAGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGC CTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAG GTGGACAACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTCACC GAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCT G ACCCTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGC GAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTC AACAGGGGCGAGTGC MOR44746A SEQ ID NO: 41 HCDR1 (Combined) GDSVSSSSAAWN SEQ ID NO: 42 HCDR2 (Combined) HIGYRSKW YNEYAVSVKS SEQ ID NO: 43 HCDR3 (Combined) GMYGSVPYKEGYYFDI SEQ ID NO: 44 HCDR1 ( Kabat) SSSAAWN SEQ ID NO: 42 HCDR2 (Kabat) HIGYRSKWYNEYAVSVKS SEQ ID NO: 43 HCDR3 (Kabat) GMYGSVPYKEGYYFDI SEQ ID NO: 45 HCDR1 (Chothia) GDSVSSSSA SEQ ID NO: 46 HCDR2 (Chothia) GYRSKWY SEQ ID NO: 43 HCDR3 ( Chothia) GMYGSVPYKEGYYFDI SEQ ID NO: 47 HCDR1 (IMGT) GDSVSSSSAA SEQ ID NO: 48 HCDR2 (IMGT) IGYRSKWYN SEQ ID NO: 49 HCDR3 (IMGT) ARGMYGSVPYKEGYYFDI SEQ ID NO: 50 VH QVQLQQSGPGLVKPSQTLSLT CAISGDSVSSSSAAWNWIRQSPSR GLEWLGHIGYRSKWYNEYAVSVKSRITINPDTSKNQFSLQLNSVT PEDTAVYYCARGMYGSVPYKEGYYFDIWGQGTLVTVSS SEQ ID NO: 51 VH DNA CAGGTGCAATTGCAGCAGAGCGGTCCGGGCCTGGTGAAACCGAGC CAGACCCTGAGCCTGACCTGCGCGATTTCCGGAGATAGCGTGAGC TCTTCTTCTGCTGCTTGGAACTGGATTCGTCAGAGCCCGAGCCGT GGCCTCGAGTGGCTGGGCCATATCGGTTACCGTAGCAAATGGTAC AACGAATATGCCGTGAGCGTGAAAAGCCGCATTACCATTAACCCGGATACTTCGAAAAACCAGTTTAGC CTGCAACTGAACAGCGTGACC CCGGAAGATACGGCCGTGTATTATTGCGCGCGTGGTATGTACGGT TCTGTTCCCTACAAAGAAGGTTACTACTTCGATATTTGGGGCCAA GGCACCCTGGTGACTGTTAGCTCA SEQ ID NO: 52 Heavy Chain QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSSSAAWNWIRQSPSR GLEWLGHIGYRSKWYNEYAVSVKSRITINPDTSKNQFSLQLNSVT PEDTAVYYCARGMYGSVPYKEGYYFDIWGQGTLVTVSSASTKGPS VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHT FPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHK PSNTKVDKR VEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEV TCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWS VLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEW ESNGQPENNYKTT PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQK SLSLSPGK SEQ ID NO: 53 DNA Heavy Chain CAGGTGCAATTGCAGCAGAGCGGTCCGGGCCTGGTGAAACCGAGC CAGACCCTGAGCCTGACCTGCGCGATTTCCGGAGATAGCGTGAGC TCTTCTTCTGCTGC TTGGAACTGGATTCGTCAGAGCCCGAGCCGT GGCCTCGAGTGGCTGGGCCATATCGGTTACCGTAGCAAATGGTAC AACGAATATGCCGTGAGCGTGAAAAGCCGCATTACCATTAACCCG njztznn / i ζηζ / Ε / γ GATACTTCGAAAAACCAGTTTAGCCTGCAACTGAACAGCGTGACC CCGGAAGATACGGCCGTGTATTATTGCGCGCGTGGTATGTACGGT TCTGTTCCCTACAAGAAGGTTACTACTTCGATATTTGGGGCCAA GGCACCCTGGTGACTGTTAGCTCAGCCTCCACCAAGGGTCCATCG GTCTTCCCCCTGGCACCCTCCTCCAAG AGCACCTCTGGGGGCACA GCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTG ACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACC TTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGC GTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATC TGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGC CCAGCACCTGAAGCAGCGGGGGGACCGTCAGTCTTCCTCTTCCCC CCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTC ACATGCGTGGTGGTGGACGTGAGCC ACGAAGACCCTGAGGTCAAG TTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACA AAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGGGTGGTCAGC GTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTAC AAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAA ACCA TCTCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTAC ACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGC CTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTG GAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACG CCTCCCGTGCTGGACTCCGACGGCT CCTTCTTCCTCTACAGCAAG CTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCA TGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAG AGCCTTCCCCTGTCTCCGGGTAAA SEQ ID NO: 54 LCDR1 (Combined) RASQGISSDLN SEQ ID NO: 55 LCDR2 (Combined) AAS NLQS SEQ ID NO: 56 LCDR3 (Combined) QQYTDESMT SEQ ID NO: 54 LCDR1 (Kabat) RASQGISSDLN SEQ ID NO: 55 LCDR2 (Kabat) AASNLQS SEQ ID NO: 56 LCDR3 (Kabat) QQYTDESMT SEQ ID NO: 57 LCDR1 (Chothia) SQGISSD SEQ ID NO: 58 LCDR2 (Chothia) AAS SEQ ID NO: 59 LCDR3 (Chothia) YTDESM SEQ ID NO: 60 LCDR1 (IMGT) QGISSD SEQ ID NO: 58 LCDR2 (IMGT) AAS SEQ ID NO: 56 LCDR3 (IMGT) QQYTDESMT SEQ ID NO: 61 VL DIQMTQSPSSLSASVGDRVTITCRASQGISSDLNWYQQKPGKAPK LLIYAASNLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ YTDESMTFGQGTKVEIK SEQ ID NO: 62 ADN VL GATATCCAGATGACCCAGAGCCCGAGCAGCCTGAGCGCCAGCGTG GGCGATCGCG TGACCATTACCTGCAGAGCCAGCCAGGGTATTTCT TCTGACCTGAACTGGTACCAGCAGAAACCGGGCAAAGCGCCGAAA CTATTAATCTACGCTGCTTCTAACCTGCAAAGCGGCGTGCCGAGC CGCTTTAGCGGCAGCGGATCCGGCACCGATTTCACCCTGACCATT AGCTCTCTGCAACCGGAAGACTTTGCGACCTATTATTGCCAG CAG TACACTGACGAATCTATGACCTTTGGCCAGGGCACGAAAGTTGAA ATTAAA SEQ ID NO: 63 Light Chain DIQMTQSPSSLSASVGDRVTITCRASQGISSDLNWYQQKPGKAPK LLIYAASNLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ YTDE SMTFGQGTKVEIKRTVAAP SVFIF PP SDEQLKSGTASWCL n / ztznn / i ζπζ / β / υ LNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 64 DNA Light Chain GATATCCAGATGACCCAGAGCCCGAGCAGCCTGAGCGCCAGCGTG GGCGATCGCGTGACCATTACCTGCAGAGCCAGCCAGGGTATTTCT TCT GACCTGAACTGGTACCAGCAGAAAACCGGGCAAAGCGCCGAAA CTATTAATCTACGCTGCTTCTAACCTGCAAAGCGGCGTGCCGAGC CGCTTTAGCGGCAGCGGATCCGGCACCGATTTCACCCTGACCATT AGCTCTCTGCAACCGGAAGACTTTGCGACCTATTATTGCCAGCAG TACACTGACGAATCTATGACCTTTGGCCAGGGCACG AAAGTTGAA ATTAAACGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCC AGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGCCTG CTGAACAACTTCTACCCCGGGAGGCCAAGGTGCAGTGGAAGGTG GACAACGCCCTGCAGAGCGGCAACAGCCAGGAAAGCGTCACCGAG CAGGACAG CAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACC CTGAGCAAGGCCGACTACGAGAAGCACAAGGTGTACGCCTGCGAG GTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAAC CGGGGCGAGTGT MOR44746B SEQ ID NO: 41 HCDR1 (Combined) GDSVSSSSAAWN SEQ ID NO: 42 HCDR2 (Combined) HIGYRSKWYNEYAVSVKS SEQ ID NO: 43 HCDR3 (Combined) GMYGSVPYKEGYYFDI SEQ ID NO: 44 HCDR1 (Kabat) SSSAAWN SEQ ID NO: 42 HCDR2 (Kabat) HIGYRSKWYNEYAVSVKS SEQ ID NO: 43 HCDR3 (Kabat) GMYGSVPYKEGYYFDI SEQ ID NO: 45 HCDR1 ( Chothia) GDSVSSSSA SEQ ID NO: 46 HCDR2 (Chothia) GYRSKWY SEQ ID NO: 43 HCDR3 (Chothia) GMYGSVPYKEGYYFDI SEQ ID NO: 47 HCDR1 (IMGT) GDSVSSSSAA SEQ ID NO: 48 HCDR2 (IMGT) IGYRSKWYN SEQ ID NO: 49 HCDR3 (IMGT) ARGMYGSVPY KEGYYFDI SEQ ID NO: 50 VH QVQLQSGPGLVKPSQTLSLTCAISGDSVSSSSAAWNWIRQSPSR GLEWLGHIGYRSKWYNEYAVSVKSRITINPDTSKNQFSLQLNSVT PEDTAVYYCARGMYGSVPYKEGYYFDIWGQGTLVTVSS SEQ ID NO: 65 ADN VH CAAGTGCAACTCCAGCAGTCAGGA GATACT AGCAAGAACCAGTTCAGCCTCCAGTTGAACTCCGTGACC CCGGAGGATACCGCCGTGTACTACTGTGCGCGGGGCATGTACGGA TCCGTGCCGTACAAGGAGGGATACTACTTCGACATTTGGGGCCAG GGGACTCTTGTCACCGTGTCCTCG SEQ ID NO: 66 Heavy Chain QVQLQQSGPGLVKPSQTLSLTCAISG DSVSSSSAAWNWIRQSPSR GLEWLGHIGYRSKWYNEYAVSVKSRITINPDTSKNQFSLQLNSVT PEDTAVYYCARGMYGSVPYKEGYYFDIWGQGTLVTVSSASTKGPS VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHT FPAVLQSSGLYSLSSWTVPS SSLGTQTYICNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV TCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWS VLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY TLPPSREEMTKNQV SLTCLVKGFYPSDIAVEWESNGQPENNYKTT PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQK SLSLSPGK n / ztznn / i ζπζ / ε / υ SEQ ID NO: 67 DNA Heavy Chain CAAGTGCAACTCCAGCAGTCAGGACCGGGGTTGGTCAAGCCTTCG CAGACCCTGTCCCTCACTTGCGCCATTAGCGGAGATTCGGTGTCG TCGTCGTCAGCCGCCTGGAACTGGATTAGACAGTCCCCTTCCCGA GGGCTGGAGTGGCTGGGCCACATCGGATACCGCAGCAAGTGGTAC AAC GAATACGCCGTCAGCGTGAAGTCACGCATCACCATCAACCCG GATACTAGCAAGAACCAGTTCAGCCTCCAGTTGAACTCCGTGACC CCGGAGGATACCGCCGTGTACTACTGTGCGCGGGGCATGTACGGATCCGTGCCGTACAAGGAGGGATACTACTTCGACATTTGGGGCCAG GGGACTCTTGTCACCGTGTCCTCGGCTCCCACT AAGGGCCCAAGT GTGTTTCCCCTGGCCCCCAGCAGCAAGTCTACTTCCGGCGGAACT GCTGCCCTGGGTTGCCTGGTGAAGGACTACTTCCCCGAGCCCGTG ACAGTGTCCTGGAACTCTGGGGCTCTGACTTCCGGCGTGCACACC TTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGC GTGGTGA CAGTGCCCTCCAGCTCTCTGGGAACCCAGACCTATATC TGCAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAGA GTGGAGCCCAAGAGCTGCGACAAGACCCACACCTGCCCCCCCTGC CCAGCTCCGAACTGCTGGGAGGGCCTTCCGTGTTCCTGTTCCCC CCCAAGCCCAAGGACACCCTGATGATCAGCAGGACCCCCG AGGTG ACCTGCGTGGTGGTGGACGTGTCCCACGAGGACCCAGAGGTGAAG TTCAACTGGTACGTGGACGGCGTGGAGGTGCACAACGCCAAGACC AAGCCCAGAGAGGAGCAGTACAACAGCACCTACAGGGTGGTGTCC GTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAAGAATAC AAGTG CAAAGTCTCCAACAAGGCCCTGCCAGCCCCAATCGAAAAG ACAATCAGCAAGGCCAAGGGCCAGCCACGGGAGCCCCAGGTGTAC ACCCTGCCCCCCAGCCGGGAGGAGATGACCAAGAACCAGGTGTCC CTGACCTGTCTGGTGAAGGGCTTCTACCCCAGCGATATCGCCGTG GAGTGGGAGAGCAACGGCCAGCCCG AGAACAACTACAAGACCACC CCCCCAGTGCTGGACAGCGACGGCAGCTTCTTCCTGTACAGCAAG CTGACCGTGGACAAGTCCAGGTGGCAGCAGGGCAACGTGTTCAGC TGCAGCGTGATGCACGAGGCCCTGCACAACCACTACACCCCAGAAG TCCCTGAGCCTGAGCCCCGGCAAG SEQ ID NO: 54 LCDR1 (Combined) RASQGISSDLN SEQ ID NO: 55 LCDR2 (Combined) AASNLQS SEQ ID NO: 56 LCDR3 (Combined) QQYTDESMT SEQ ID NO: 54 LCDR1 (Kabat) RASQGISSDLN SEQ ID NO: 55 LCDR2 (Kabat) AASNLQS SEQ ID NO: 56 LCDR3 (Kabat) QQYTDESMT SEQ ID NO: 57 LCDR1 (Chothia) SQGISSD SEQ ID NO: 58 LCDR2 (Chothia) AAS SEQ ID NO: 59 LCDR3 (Chothia) YTDESM SEQ ID NO: 60 LCDR1 (IMGT) QGISSD SEQ ID NO: 58 LCDR2 (IMGT) AAS SEQ ID NO: 56 LCDR3 (IMGT) QQYTDESMT SEQ ID NO: 61 VL DIQMTQSPSSLSASVGDRVTITCRASQGISSDLNWYQQKPGKAPK LLIYAASNLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ YTDESMTFGQGTKVEIK SEQ ID NO: 68 ADN VL GACATTCAGATGA CCCAGTCCCCGTCGTCCCTGTCCGCATCCGTG GGCGACAGAGTCACCATCACTTGCCGGGCCTCACAGGGAATTTCC TCCGACCTGAACTGGTATCAGCAGAAGCCTGGAAAGGCCCCGAAG CTGCTGATCTACGCCGCGTCCAACTTGCAATCGGGAGTGCCAAGC CGCTTTCTGGTTCCGGGAGCGGGACTGACTTCACCCT GACTATT AGCAGCCTGCAGCCCGAAGATTTCGCTACCTACTACTGCCAACAG n / ztznn / i ζπζ / β / υ TACACAGATGAATCCATGACCTTCGGACAGGGCACCAAAGTCGAG ATCAAG SEQ ID NO: 63 Light chain DIQMTQSPSSLSASVGDRVTITCRASQGISSDLNWYQQKPGKAPK LLIYAASNLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ YTDESMTFGQGTKVEIKRTVAAPSVFIFPPSDE QLKSGTASWCL LNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 69 DNA Light Chain GACATTCAGATGACCCAGTCCCCGTCGTCCCTGTCCGCATCCGTG GGCGACAGAGTCACCATCACTTGCCGGGGCCTCACAGG GAATTTCC TCCGACCTGAACTGGTATCAGCAGAAGCCTGGAAAGGCCCCGAAG CTGCTGATCTACGCCGCGTCCAACTTGCAATCGGGAGTGCCAAGC CGCTTTTTCTGGTTCCGGGAGCGGGACTGACTTCACCCTGACTATT AGCAGCCTGCAGCCCGAAGATTTCGCTACCTACTACTGCCAACAG TACACAGATGAATCCATGACC TTCGGACAGGGCACCAAAGTCGAG ATCAAGCGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCC AGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGCCTG CTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTG GACAACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCG TCACCGAG CAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACC CTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAG GTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAAC AGGGGCGAGTGC MOR44746C SEQ ID NO: 41 HCDR1 (Combined) GDSVSSSS AAWN SEQ ID NO: 42 HCDR2 (Combined) HIGYRSKWYNEYAVSVKS SEQ ID NO: 43 HCDR3 (Combined) GMYGSVPYKEGYYFDI SEQ ID NO: 44 HCDR1 (Kabat) SSSAAWN SEQ ID NO: 42 HCDR2 (Kabat) HIGYRSKWYNEYAVSVKS SEQ ID NO: 43 HCDR3 (Kabat) GMYGSVPYKEGYYFDI SEQ ID NO: 45 HCDR1 (Chothia) GDSVSSSSA SEQ ID NO: 46 HCDR2 (Chothia) GYRSKWY SEQ ID NO: 43 HCDR3 (Chothia) GMYGSVPYKEGYYFDI SEQ ID NO: 47 HCDR1 (IMGT) GDSVSSSSAA SEQ ID NO: 48 HCDR2 (IMGT) IGYRSKW YN SEQ ID NO: 49 HCDR3 (IMGT) ARGMYGSVPYKEGYYFDI SEQ ID NO: 50 VH QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSSSAAWNWIRQSPSR GLEWLGHIGYRSKWYNEYAVSVKSRITINPDTSKNQFSLQLNSVT PEDTAVYYCARGMYGSVPYKEGYYFDI WGQGTLVTVSS SEQ ID NO: 65 VH DNA CAAGTGCAACTCCAGCAGTCAGGACCGGGGTTGGTCAAGCCTTCG CAGACCCTGTCCCTCACTTGCGCCATTAGCGGAGATTCGGTGTCG TCGTCGTCAGCCGCCTGGAACTGGATTAGACAGTCCCCTTCCCGA GGGCTGGAGTGGCTGGGCCACATCGGATACCGCAGCAAG TGGTAC AACGAATACGCCGTCAGCGTGAAGTCACGCATCACCATCAACCCG GATACTAGCAAGAACCAGTTCAGCCTCCAGTTGAACTCCGTGACC CCGGAGGATACCGCCGTGTACTACTGTGCGCGGGGCATGTACGGA TCCGTGCCGTACAAGGAGGGATACTACTTCGACATTTGGGGCCAG GGGACTCTTGTCACCGTGTC CTCG SEQ ID NO: 70 Heavy Chain QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSSSAAWNWIRQSPSR GLEWLGHIGYRSKWYNEYAVSVKSRITINPDTSKNQFSLQLNSVT PEDTAVYYCARGMYGSVPYKEGYYFDIWGQGTLVTVSSASTKGPS VFPLAPSSKSTSGGTAALG CLVKDYFPEPVTVSWNSGALTSGVHT FPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV n / ztznn / i ζηζ / Ε / γ TCWVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWS VLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVY TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALH NHYTQK SLSLSPGK SEQ ID NO: 71 DNA Heavy chain CAAGTGCAACTCCAGCAGTCAGGACCGGGGTTGGTCAAGCCTTCG CAGACCCTGTCCCTCACTTGCGCCATTAGCGGAGATTCGGTGTCG TCGTCGTCAGCCGCCTGGAACTGGATTAGACAGTCCCCTTCCCGA GGGCTGGAGTGGCTGGGCCACATCGGATACCGCA GCAAGTGGTAC AACGAATACGCCGTCAGCGTGAAGTCACGCATCACCATCAACCCG GATACTAGCAAGAACCAGTTCAGCCTCCAGTTGAACTCCGTGACC CCGGAGGATACCGCCGTGTACTACTGTGCGCGGGGCATGTACGGA TCCGTGCCGTACAAGGAGGGATACTACTTCGACATTTGGGGCCAG GGGACTCTTGTCACCG TGTCCTCGGCCTCCACTAAGGGCCCGTCA GTGTTCCCCCTTGCGCCATCCTCGAAGTCAACCTCCGGAGGAACT GCCGCACTGGGTTGCCTCGTGAAAGACTATTTCCCGGAACCCGTC ACTGTCTCCTGGAACTCAGGAGCGCTCACCAGCGGAGTGCATACC TTTCCTGCGGTGCTGCAGTCCAGCGGCCTGTACTCCCTGAGCT CC GTCGTGACCGTCCCCTCGTCGTCCCTGGGAACCCAAACCTACATT TGCAACGTCAATCACAAGCCAAGCAACACTAAGGTGGACAAGAGA GTGGAGCCCAAGTCCTGCGATAAGACCCACACCTGTCCTCCCTGT CCGGCACCTGAACTGCTTGGTGGACCTTCCGTGTTCCTGTTCCCG CCCAAGCCAAAAGACACCCTGATGATCTC CCGCACTCCGGAAGTC ACTTGCGTGGTCGTGGCCGTGTCCCACGAGGACCCCGAGGTCAAG TTTAATTGGTACGTGGACGGAGTGGAAGTGCACAACGCCAAGACC AAGCCGCGGGAAGAACAGTACAACTCCACCTACCGCGTGGTGTCC GTCCTGACTGTGCTCCACCAGGACTGGCTGAACGGAAAGGAGTAC A AGTGCAAAGTGTCCAACAAGGCACTGGCTGCCCCTATCGAAAAG ACTATCTCCAAGGCCAAGGGCCAACCTAGGGAGCCCCAGGTGTAC ACGTTGCCTCCTTCCCGCGAAGAAATGACTAAGAACCAGGTGTCG CTGACCTGTCTCGTGAAAGGGTTCTACCCCTCTGACATCGCCGTG GAATGGGAGTCAAACGGA CAGCCTGAGAACAACTATAAGACCACA CCACCTGTCCTGGACTCCGACGGCTCCTTCTTCCTGTACTCAAAG TTGACCGTGGACAAGTCGCGGTGGCAACAGGGCAACGTGTTCTCT TGCTCCGTGATGCACGAAGCCCTGCACAACCACTACACCCAAAG TCGCTCAGCCTCTCCCCCGGAAAG SEQ ID NO: 54 LCDR1 (Combined) RASQGISSDLN SEQ ID NO: 55 LCDR2 (Combined) AASNLQS SEQ ID NO: 56 LCDR3 (Combined) QQYTDESMT SEQ ID NO: 54 LCDR1 (Kabat) RASQGISSDLN SEQ ID NO: 55 LCDR2 (Kabat) AASNLQS SEQ ID NO: 56 LCDR3 (Kabat) QQYTDESMT SEQ ID NO: 57 LCDR1 (Chothia) SQGISSD SEQ ID NO: 58 LCDR2 (Chothia) AAS SEQ ID NO: 59 LCDR3 (Chothia) YTDESM SEQ ID NO: 60 LCDR1 (IMGT) QGISSD SEQ ID NO: 58 LCDR2 (IMGT) AAS SEQ ID NO: 56 LCDR3 (IMGT) QQYTDESMT SEQ ID NO: 61 VL DIQMTQSPSSLSASVGDRVTITCRASQGISSDLNWYQQKPGKAPK LLIYAASNLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ YTDESMTFGQGTKVEIK SEQ ID NO: 68 DNA VL GACATTCAGATGACCCAGTCCCCGTCGTCCCTGTCCGCATCCGTG GGCGACAGAGTCACCATCACTTGCCGGGCCTCACAGGGAATTTCC η / ^ηη / ι ζπζ / β / υ TCCGACCTGAACTGGTATCAGCAGAAGCCTGGAAAGGCCCCGAAG CTGCTGATCTACGCCGCGTCCAACTTGCAATCGGGAGTGCCAAGC CGCTTTCTGGTTCCGGGAGCGGGACTGACTTCACCCTGACTATT AGCAGCCTGCAGCCCGAAGATTTCGCTACCTACTACTGCCAACAG TACACAGATGAATCCATGACCTTCGGA CAGGGCACCAAAGTCGAG ATCAAG SEQ ID NO: 63 Light chain DIQMTQSPSSLSASVGDRVTITCRASQGISSDLNWYQQKPGKAPK LLIYAASNLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ YTDE SMTFGQGTKVEIKRTVAAP SVFIFPP SDEQLKSGTASWCL LANNFYPREA KVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 69 DNA Light Chain GACATTCAGATGACCCAGTCCCCGTCGTCCCTGTCCGCATCCGTG GGCGACAGAGTCACCATCACTTGCCGGGCCTCACAGGGAATTTCC TCCGACCTGAACTGGTA TCAGCAGAAGCCTGGAAAGGCCCCGAAG CTGCTGATCTACGCCGCGTCCAACTTGCAATCGGGAGTGCCAAGC CGCTTTCTGGTTCCGGGAGCGGGACTGACTTCACCCTGACTATT AGCAGCCTGCAGCCCGAAGATTTCGCTACCTACTACTGCCAACAG TACACAGATGAATCCATGACCTTCGGACAGGGCACCAAAGTCGAG ATCAAGCGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCC AGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGCCTG CTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTG GACAACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTCACCGAG CAGGACAGCAAGGACTCC ACCTACAGCCTGAGCAGCACCCTGACC CTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAG GTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAAC AGGGGCGAGTGC MOR44746D SEQ ID NO: 41 HCDR1 (Combined) GDSVSSSSAAWN SEQ ID NO: 42 HCDR2 (Combined) HIGYRSKWYNEYAVSVKS SEQ ID NO: 43 HCDR3 (Combined) GMYGSVPYKEGYYFDI SEQ ID NO: 44 HCDR1 (Kabat) SSSAAWN SEQ ID NO: 42 HCDR2 (Kabat) HIGYRS KWYNEYAVSVKS SEQ ID NO: 43 HCDR3 (Kabat) GMYGSVPYKEGYYFDI SEQ ID NO: 45 HCDR1 (Chothia) GDSVSSSSA SEQ ID NO: 46 HCDR2 (Chothia) GYRSKWY SEQ ID NO: 43 HCDR3 (Chothia) GMYGSVPYKEGYYFDI SEQ ID NO: 47 HCDR1 (IMGT) GDSVSS SSAA SEQ ID NO: 48 HCDR2 (IMGT) IGYRSKWYN SEQ ID NO: 49 HCDR3 (IMGT) ARGMYGSVPYKEGYYFDI SEQ ID NO: 50 VH QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSSSAAWNWIRQSPSR GLEWLGHIGYRSKWYNEYAVSVKSRITINPDTSKNQFSLQLNSV T PEDTAVYYCARGMYGSVPYKEGYYFDIWGQGTLVTVSS SEQ ID NO: 65 DNA VH CAAGTGCAACTCCAGCAGTCAGGACCGGGGTTGGTCAAGCCTTCG CAGACCCTGTCCCTCACTTGCGCCATTAGCGGAGATTCGGTGTCG TCGTCGTCAGCCGCCTGGAACTGGATTAGACAGTCCCCTTCCCGA GGGCTGGA GTGGCTGGGCCACATCGGATACCGCAGCAAGTGGTAC AACGAATACGCCGTCAGCGTGAAGTCACGCATCACCATCAACCCG GATACTAGCAAGAACCAGTTCAGCCTCCAGTTGAACTCCGTGACC CCGGAGGATACCGCCGTGTACTACTGTGCGCGGGGCATGTACGGA TCCGTGCCGTACAAGGAGGGATACTACTTCGACAT TTGGGGCCAG GGGACTCTTGTCACCGTGTCCTCG SEQ ID NO: 72 Heavy chain QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSSSAAWNWIRQSPSR GLEWLGHIGYRSKWYNEYAVSVKSRITINPDTSKNQFSLQLNSVT n / ztznn / i ζηζ / ε / γ PEDTAVYYCARGMYGSVPYKEGYYFDIWGQGTLVTVSSASTKGPS VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHT FPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRT PEV TCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWS VLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHE ALHSHYTQK SLSLSPGK SEQ ID NO: 73 DNA Heavy Chain CAAGTGCAACTCCAGCAGTCAGGACCGGGGTTGGTCAAGCCTTCG CAGACCCTGTCCCTCACTTGCGCCATTAGCGGAGATTCGGTGTCG TCGTCGTCAGCCGCCTGGAACTGGATTAGACAGTCCCCTTCCCGA GGGCTGGAGTGGCTGGGCCACATCGGATACCG CAGCAAGTGGTAC AACGAATACGCCGTCAGCGTGAAGTCACGCATCACCATCAACCCG GATACTAGCAAGAACCAGTTCAGCCTCCAGTTGAACTCCGTGACC CCGGAGGATACCGCCGTGTACTACTGTGCGCGGGGCATGTACGGA TCCGTGCCGTACAAGGAGGGATACTACTTCGACATTTGGGGCCAG GGGACTCTTGTCAC CGTGTCCTCGGCCTCCACTAAGGGCCCCGTCA GTGTTCCCCCTTGCGCCATCCTCGAAGTCAACCTCCGGAGGAACT GCCGCACTGGGTTGCCTCGTGAAAGACTATTTCCCGGAACCCGTC ACTGTCTCCTGGAACTCAGGAGCGCTCACCAGCGGAGTGCATACC TTTCCTGCGGTGCTGCAGTCCAGCGGCCTGTACTCCCTGAG CTCC GTCGTGACCGTCCCCTCGTCGTCCCTGGGAACCCAACCTACATT TGCAACGTCAATCACAAGCCAAGCAACACTAAGGTGGACAAGAGA GTGGAGCCCAAGTCCTGCGATAAGACCCACACCTGTCCTCCCTGT CCGGCACCTGAACTGCTTGGTGGACCTTCCGTGTTCCTGTTCCCG CCCAAGCCAAAAGACACCCTGATGATC TCCCGCACTCCGGAAGTC ACTTGCGTGGTCGTGGACGTGTCCCACGAGGACCCCGAGGTCAAG TTTAATTGGTACGTGGACGGAGTGGAAGTGCACAACGCCAAGACC AAGCCGCGGGAAGAACAGTACAACTCCACCTACCGCGTGGTGTCC GTCCTGACTGTGCTCCACCAGGACTGGCTGAACGGAAAGGAGTAC A AGTGCAAAGTGTCCAACAAGGCACTGCCAGCCCCTATCGAAAAG ACTATCTCCAAGGCCAAGGGCCAACCTAGGGAGCCCCAGGTGTAC ACGTTGCCTCCTTCCCGCGAAGAAATGACTAAGAACCAGGTGTCG CTGACCTGTCTCGTGAAAGGGTTCTACCCCTCTGACATCGCCGTG GAATGGGAGTCAAACGGACA GCCTGAGAACAACTATAAGACCACA CCACCTGTCCTGGACTCCGACGGCTCCTTCTTCCTGTACTCAAAG TTGACCGTGGACAAGTCGCGGTGGCAACAGGGCAACGTGTTCTCT TGCTCCGTGCTGCACGAAGCCCTGCACAGCCACTACACCAAAAG TCGCTCAGCCTCTCCCCCGGAAAG SEQ ID NO: 54 LCDR1 (Combined) RASQGISSDLN SEQ ID NO: 55 LCDR2 (Combined) AASNLQS SEQ ID NO: 56 LCDR3 (Combined) QQYTDESMT SEQ ID NO: 54 LCDR1 (Kabat) RASQGISSDLN SEQ ID NO: 55 LCDR2 (Kabat) AASNLQS SEQ ID NO: 56 LCDR3 (Kabat) QQYTDESMT SEQ ID NO: 57 LCDR1 (Chothia) SQGISSD SEQ ID NO: 58 LCDR2 (Chothia) AAS SEQ ID NO: 59 LCDR3 (Chothia) YTDESM SEQ ID NO: 60 LCDR1 (IMGIj QGISSD SEQ ID NO : 58 LCDR2 (IMGT) AAS SEQ ID NO: 56 LCDR3 (IMGT) QQYTDESMT njztznn / i ζπζ / β / υ SEQ ID NO: 61 VL DIQMTQSPSSLSASVGDRVTITCRASQGISSDLNWYQQKPGKAPK LLIYAASNLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ YTDESMTFGQGTKVEIK SEQ ID NO: 68 ADN VL GACATTCAGATGACCCAGTCCCCGTCGTCCCTGTCCGCATCCGTG G GCGACAGAGTCACCATCACTTGCCGGGCCTCACAGGGAATTTCC TCCGACCTGAACTGGTATCAGCAGAAGCCTGGAAAGGCCCCGAAG CTGCTGATCTACGCCGCGTCCAACTTGCAATCGGGAGTGCCAAGC CGCTTTCTGGTTCCGGGAGCGGGACTGACTTCACCCTGACTATT AGC AGCC T GC AGC C C G A AGAT TTCGCTACCTAC TAC T GCC AAC AG TACACAGATGAATCCATGACCTTCGGACAGGGCACCAAAGTCGAG ATCAAG SEQ ID NO: 63 Light Chain DIQMTQSPSSLSASVGDRVTITCRASQGISSDLNWYQQKPGKAPK LLIYAASNLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ YTDESMTF GQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASWCL LNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 69 DNA Light Chain GACATTCAGATGACCCAGTCCCCGTCGTCCCTGTCCGCATCCGTG GGCGACAGAGTCACCATCACTTGCCGGGCCTCACAGGGAATTTCC TCCGACCTGAACTGGTATCAGCAGAAGCCTGGAAAGGCCCCGAAG CTGCTGATCTACGCCGCGTCCAACTTGCAATCGGGAGTGCCAAGC CGCTTTCTGG TTCCGGGAGCGGGACTGACTTCACCCTGACTATT AGCAGCCTGCAGCCCGAAGATTTCGCTACCTACTACTGCCAACAG TACACAGATGAATCCATGACCTTCGGACAGGGCACCAAAGTCGAGATCAAGCGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCC AGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGT GTGCCTG CTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTG GACAACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTCACCCGAG CAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACC CTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAG GTGACCCACCAGGGCCT GTCCAGCCCCGTGACCAAGAGCTTCAAC AGGGGCGAGTGC MOR44746E SEQ ID NO: 41 HCDR1 (Combined) GDSVSSSSAAWN SEQ ID NO: 42 HCDR2 (Combined) HIGYRSKWYNEYAVSVKS SEQ ID NO: 43 HCDR3 (Combined ) GMYGSVPYKEGYYFDI SEQ ID NO: 44 HCDR1 (Kabat) SSSAAWN SEQ ID NO: 42 HCDR2 (Kabat) HIGYRSKWYNEYAVSVKS SEQ ID NO: 43 HCDR3 (Kabat) GMYGSVPYKEGYYFDI SEQ ID NO: 45 HCDR1 (Chothia) GDSVSS SA SEQ ID NO: 46 HCDR2 (Chothia ) GYRSKWY SEQ ID NO: 43 HCDR3 (Chothia) GMYGSVPYKEGYYFDI SEQ ID NO: 47 HCDR1 (IMGT) GDSVSSSSAA SEQ ID NO: 48 HCDR2 (IMGT) IGYRSKWYN SEQ ID NO: 49 HCDR3 (IMGT) ARGMYGSVPYKEGYYFDI SEQ ID NO: 50 VH QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSSSAAWNWIRQSPSR GLEWLGHIGYRSKWYNEYAVSVKSRITINPDTSKNQFSLQLNSVT PEDTAVYYCARGMYGSVPYKEGYYFDIWGQGTLVTVSS SEQ ID NO: 65 DNA VH CAAGTGCAACTCCAGCAGTCAGGACCGGGGTTGGTCAAGCCTTCG CAGACCCTGTCCCTCACTTGCGCCATTAGCGGAGATTCGGTGTCG TCGTCGTCAGCCGCCTGGAACTGGATTAGACAGTCCCCTTCCCGA GGGCTGGA GTGGCTGGGCCACATCGGATACCGCAGCAAGTGGTAC AACGAATACGCCGTCAGCGTGAAGTCACGCATCACCATCAACCCGGATACTAGCAAGAACCAGTTCAGCCTCCAGTTGAACTCCGTGACC n / 7bnn / i 7Π7 / β / υ CCGGAGGATACCGCCGTGTACTACTGTGCGCGGGGCATGTACGGA TCCGTGCCGTACAAGGAGGGATACTACTTCGACATTTGGGGCCAG GGGACTCTTGTCACCGTGTCCTCG SEQ ID NO: 74 Heavy Chain QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSSSAAWNWIRQSPSR GLEWLGHIGY RSKWYNEYAVSVKSRITINPDTSKNQFSLQLNSVT PEDTAVYYCARGMYGSVPYKEGYYFDIWGQGTLVTVSSASTKGPS VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHT FPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKR V EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV TCVWAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWS VLTVLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVY TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEALHSHYTQK SLSLSPGK SEQ ID NO: 75 DNA Heavy Chain CAAGTGCAACTCCAGCAGTCAGGACCGGGGTTGGTCAAGCCTTCG CAGACCCTGTCCCTCACTTGCGCCATTAGCGGAGATTCGGTGTCG TCGTCGTCAGCCGCCTGGAACTGGATTAGACAGTCCCCT TCCCGA GGGCTGGAGTGGCTGGGCCACATCGGATACCGCAGCAAGTGGTAC AACGAATACGCCGTCAGCGTGAAGTCACGCATCACCATCAACCCGGATACTAGCAAGAACCAGTTCAGCCTCCAGTTGAACTCCGTGACC CCGGAGGATACCGCCGTGTACTACTGTGCGCGGGGCATGTACGGATCCGTGCCGTACAAGGAG GGATACTACTTCGACATTTGGGGCCAG GGGACTCTTGTCACCGTGTCCTCGGCTCCCACTAAGGGCCCGTCA GTGTTCCCCCTTGCGCCATCCTCGAAGTCAACCTCCGGAGGAACT GCCGCACTGGGTTGCCTCGTGAAAGACTATTTCCCGGAACCCGTC ACTGTCTCCTGGAACTCAGGAGCGCTCACCAGCGGAGTGCATACC TT TCCTGCGGTGCTGCAGTCCAGCGGCCTGTACTCCCTGAGCTCC GTCGTGACCGTCCCCTCGTCGTCCCTGGGAACCCAAACCTATCATT TGCAACGTCAATCACAAGCCAAGCAACACTAAGGTGGACAAGAGA GTGGAGCCCAAGTCCTGCGATAAGACCCACACCTGTCCTCCCTGT CCGGCACCTGAACTGCTTGGTGGACCTT CCGTGTTCCTGTTCCCG CCCAAGCCAAAAGACACCCTGATGATCTCCCGCACTCCGGAAGTC ACTTGCGTGGTCGTGGCCGTGTCCCACGAGGACCCCGAGGTCAAG TTTAATTGGTACGTGGACGGAGTGGAAGTGCACAACGCCAAGACC AAGCCGCGGGAAGAACAGTACAACTCCACCTACCGCGTGGTGTCC GTCCTGACTGTGCTCCACCAGGACTGGCTGAACGGAAAGGAGTAC AAGTGCAAAGTGTCCAACAAGGCACTGGCTGCCCCTATCGAAAAG ACTATCTCCAAGGCCAAGGGCCAACCTAGGGAGCCCCAGGTGTAC ACGTTGCCTCCTTCCCGCGAAGAAATGACTAAGAACCAGGTGTCG CTGACCTGTCTCGTGA AAGGGTTCTACCCCTCGGACATCGCCGTG GAAT GGGAG T CAAAC G GACAGC C T GAGAACAACTATAAGACCACA CCACCTGTCCTGGACTCCGACGGCTCCTTCTTCCTGTACTCAAAG TTGACCGTGGACAAGTCGCGGTGGCAACAGGGCAACGTGTTCTCT TGCTCCGTGCTGCACGAAGCCCTGCACAGCCACTA CACCCAAAAG TCGCTCAGCCTCTCCCCCGGAAAG SEQ ID NO: 54 LCDR1 (Combined) RASQGISSDLN SEQ ID NO: 55 LCDR2 (Combined) AASNLQS SEQ ID NO: 56 LCDR3 (Combined) QQYTDESMT SEQ ID NO : 54 LCDR1 (Kabat) RASQGISSDLN SEQ ID NO: 55 LCDR2 (Kabat) AASNLQS SEQ ID NO: 56 LCDR3 (Kabat) QQYTDESMT SEQ ID NO: 57 LCDR1 (Chothia) SQGISSD SEQ ID NO: 58 LCDR2 (Chothia) AAS SEQ ID NO : 59 LCDR3 (Chothia) YTDESM n / ztznn / i ζπζ / β / υ SEQ ID NO: 60 LCDR1 (IMGT) QGISSD SEQ ID NO: 58 LCDR2 (IMGT) AAS SEQ ID NO: 56 LCDR3 (IMGT) QQYTDESMT SEQ ID NO: 61 VL DIQMTQSPSSLSASVGDRVTITCRASQGISSDLNWYQQKPGKAPK LLIYAASNLQSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQ YTDESMTFGQGTKVEIK SEQ ID NO: 68 ADN VL GACATTCAGATGACCCAGTCCCCGTCGTCCCTGTCCGCATCCGTG GGCGACAGAGTCACCATCACTTGCCGGGCCTCACAGGGAATTTCC TCCGACCTGAACTGGTATCAGCAGAAGCCTGGAAAGGCCCCGAAG CTGCTGATCTACGCCGCGTC CAACTTGCAATCGGGAGTGCCAAGC CGCTTTCTGGTTCCGGGAGCGGGACTGACTTCACCCTGACTATT AGCAGCCTGCAGCCCGAAGATTTCGCTACCTACTACTGCCAACAG TACACAGATGAATCCATGACCTTCGGACAGGGCACCAAAGTCGAG ATCAAG SEQ ID NO: 63 Light Chain DIQMTQSPSSLSASVGDRVTITCRASQGISSDLNWYQQKPGKAP K LLIYAASNLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ YTDE SMTFGQGTKVEIKRTVAAP SVFIFPP SDEQLKSGTASWCL LNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO : 69 DNA Light chain GACATTCAGATGACCCAGTCCCCGTCGTCCCTGTCCGCATCCGTG GGCGACAGAGTCACCATCACTTGCCGGGCCTCACAGGGAATTTCC TCCGACCTGAACTGGTATCAGCAGAAGCCTGGAAAGGCCCCGAAG CTGCTGATCTACGCCGCGTCCAACTTGCAATCGGGAGTGCCAAGC CGCTTTTTCTGGTTCC GGGAGCGGGACTGACTTCACCCTGACTATT AGCAGCCTGCAGCCCGAAGATTTCGCTACCTACTACTGCCAACAG TACACAGATGAATCCATGACCTTCGGACAGGGCACCAAAGTCGAG ATCAAGCGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCC AGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGT GCCTG CTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTG GACAACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTCACCCGAG CAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACC CTGAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAG GTGACCCACCAGGGCCTGTC CAGCCCCGTGACCAAGAGCTTCAAC AGGGGCGAGTGC MOR44746F SEQ ID NO: 41 HCDR1 ( Combined) GDSVSSSSAAWN SEQ ID NO: 42 HCDR2 (Combined) HIGYRSKWYNEYAVSVKS SEQ ID NO: 43 HCDR3 (Combined) GMYGSVPYKEGYYFDI SEQ ID NO: 44 HCDR1 (Kabat) SSSAAWN SEQ ID NO: 42 HCDR2 (Kabat) HIGYRSKWYNEYA VSVKS SEQ ID NO: 43 HCDR3 ( Kabat) GMYGSVPYKEGYYFDI SEQ ID NO: 45 HCDR1 (Chothia) GDSVSSSSA SEQ ID NO: 46 HCDR2 (Chothia) GYRSKWY SEQ ID NO: 43 HCDR3 (Chothia) GMYGSVPYKEGYYFDI SEQ ID NO: 47 HCDR1 (IMGT) GDSVSSSSAA SEQ ID NO: 48 HCDR2 ( IMGT) IGYRSKWYN SEQ ID NO: 49 HCDR3 (IMGT) ARGMYGSVPYKEGYYFDI SEQ ID NO: 50 VH QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSSSAAWNWIRQSPSR GLEWLGHIGYRSKWYNEYAVSVKSRITINPDTSKNQFSLQLNSVT PEDTAV YYCARGMYGSVPYKEGYYFDIWGQGTLVTVSS SEQ ID NO: 65 VH DNA CAAGTGCAACTCCAGCAGTCAGGACCGGGGTTGGTCAAGCCTTCG CAGACCCTGTCCCTCACTTGCGCCATTAGCGGAGATTCGGTGTCG n / ztznn / i ζπζ / ε / υ TCGTCGTCAGCCGCCTGGAACTGGATTAGACAGTCCCCTTCCCGA GGGCTGGAGTGGCTGGGCCACATCGGATACCGCAGCAAGTGGTAC AACGAATACGCCGTCAGCGTGAAGTCACGCATCACCATCAACCCG GATACTAGCAAGAACCAGTTCAGCCTCCAGTTGAACTCCGTGACC CCGGAGGATACCGCCGTGTACTACTGTG CGCGGGGCATGTACGGA TCCGTGCCGTACAAGGAGGGATACTACTTCGACATTTGGGGCCAG GGGACTCTTGTCACCGTGTCCTCG SEQ ID NO: 76 Heavy Chain QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSSSAAWNWIRQSPSR GLEWLGHIGYRSKWYNEYAVSVKSRITINPDTSKNQ FSLQLNSVT PEDTAVYYCARGMYGSVPYKEGYYFDIWGQGTLVTVSSASTKGPS VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHT FPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKR VEPKSCDKTHTCPPCPAPELLGGPSVFLFPPK PKDTLYITREPEV TCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWS VLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVY TLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT PPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQK SLSLSPGK SEQ ID NO: 77 DNA Heavy Chain CAAGTGCAACTCCAGCAGTCAGGACCGGGGTTGGTCAAGCCTTCG CAGACCCTGTCCCTCACTTGCGCCATTAGCGGAGATTCGGTGTCG TCGTCGTCAGCCGCCTGGAACTGGATTAGACAGTCCCCTTCCCGA GGGCTGGAGTGGCTGGG CCACATCGGATACCGCAGCAAGTGGTAC AACGAATACGCCGTCAGCGTGAAGTCACGCATCACCATCAACCCG GATACTAGCAAGAACCAGTTCAGCCTCCAGTTGAACTCCGTGACC CCGGAGGATACCGCCGTGTACTACTGTGCGCGGGGCATGTACGGA TCCGTGCCGTACAAGGAGGGATACTACTTCGACATTTGGGGCCAG G GGACTCTTGTCACCGTGTCCTCGGCCTCCACTAAGGGCCCGTCA GTGTTCCCCCTTGCGCCATCCTCGAAGTCAACCTCCGGAGGAACT GCCGCACTGGGTTGCCTCGTGAAAGACTATTCCCGGAACCCGTC ACTGTCTCCTGGAACTCAGGAGCGCTCACCAGCGGAGTGCATACC TTTCCTGCGGTGCTGCAGTCCAGCGGC CTGTACTCCCTGAGCTCC GTCGTGACCGTCCCCTCGTCGTCCCTGGGAACCCAAACCTACATT TGCAACGTCAATCACAAGCCAAGCAACACTAAGGTGGACAAGAGA GTGGAGCCCAAGTCCTGCGATAAGACCCACACCTGTCCTCCCTGT CCGGCACCTGAACTGCTTGGTGGACCTTCCGTGTTCCTGTTCCCG CCCAAGCCAAAAGACACCCTGTATATCACTCGCGAACCGGAAGTC ACTTGCGTGGTCGTGGACGTGTCCCACGAGGACCCCGAGGTCAAG TTTAATTGGTACGTGGACGGAGTGGAAGTGCACAACGCCAAGACC AAGCCGCGGGAAGAACAGTACAACTCCACCTACCGCGTGGTGTCC GTCCTGACTGTGCTCCACCAGGACT GGCTGAACGGAAAGGAGTAC AAGTGCAAAGTGTCCAACAAGGCACTGCCAGCCCCTATCGAAAAG ACTATCTCCAAGGCCAAGGGCCAACCTAGGGAGCCCCAGGTGTAC ACGTTGCCTCCTTCCCGCGAAGAAATGACTAAGAACCAGGTGTCG CTGACCTGTCTCGTGAAAGGGTTCTACCCCTCTGACATCGCCGT G GAAT GGGAGT CAAACGGACAGCC TGAGAACAACTATAAGACCACA CCACCTGTCCTGGACTCCGACGGCTCCTTCTTCCTGTACTCAAAG TTGACCGTGGACAAGTCGCGGTGGCAACAGGGCAACGTGTTCTCT TGCTCCGTGATGCACGAAGCCCTGCACAACCACTACACCAAAAG TCGCTCAGCCTCTCCCCCGGAAAG SEQ ID NO: 54 LCDR1 (Combined) RASQGISSDLN SEQ ID NO: 55 LCDR2 (Combined) AASNLQS SEQ ID NO: 56 LCDR3 (Combined) QQYTDESMT SEQ ID NO : 54 LCDR1 (Kabat) RASQGISSDLN SEQ ID NO: 55 LCDR2 (Kabat) AASNLQS n / ztznn / i ζηζ / ε / γ SEQ ID NO: 56 LCDR3 (Kabat) QQYTDESMT SEQ ID NO: 57 LCDR1 (Chothia) SQGISSD SEQ ID NO: 58 LCDR2 (Chothia) AAS SEQ ID NO: 59 LCDR3 (Chothia) YTDESM SEQ ID NO: 60 LCDR1 (IMGT) QGISSD SEQ ID NO: 58 LCDR2 (IMGT) AAS SEQ ID NO: 56 LCDR3 (IMGT) QQYTDESMT SEQ ID NO: 61 VL DIQMTQSPSSLSASVGDRVTITCRASQGISSDLNWYQQKPGKAPK LLIYAASNLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ YTDESMTFGQGTKV EIK SEQ ID NO: 68 DNA VL GACATTCAGATGACCCAGTCCCCGTCGTCCCTGTCCGCATCCGTG GGCGACAGAGTCACCATCACTTGCCGGGCCTCACAGGGAATTTCC TCCGACCTGAACTGGTATCAGCAGAAGCCTGGAAAGGCCCCGAAG CTGCTGATCTACGCCGCGTCCAACTTGCAATCGGGAGTGCCAAGC CGCTT TTCTGGTTCCGGGAGCGGGACTGACTTCACCCTGACTATT AGCAGCCTGCAGCCCGAAGATTTCGCTACCTACTACTGCCAACAG TACACAGATGAATCCATGACCTTCGGACAGGGCACCAAAGTCGAG ATCAAG SEQ ID NO: 63 String light DIQMTQSPSSLSASVGDRVTITCRASQGISSDLNWYQQKPGKAPK LLIYAASNLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ YTDE SMTFGQGTKVEIKRTVAAP SVFIFPP SDEQLKSGTASWCL LNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLS STLT LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 69 DNA light chain GACATTCAGATGACCCAGTCCCCGTCGTCCCTGTCCGCATCCGTG GGC GACAGAGT CAC CATCAC TTGCCGGGCCT CACAGGGAAT T T C C TCCGACCTGAACTGGTATCAGCAGAAGCCTGGAAAGGCCCCGAAG CTGCTGATCTACGCCGCGTCCAACTTGCAATCGGGAGTGCCAAGC CGCTTTCTGGTTCCGGGAGCGGGACTGACTTCACCCTGACTATT AGCAGCCTGCAGCCCGAAGATTTCGCTACCTACTGCCAACAG TACACAGATGAATCCATGACCTTCGGACAGGGCACCAAAGTCGAGATCAAGCGTACGGTGGCCGCTCCCAG CGTGTTCATCTTCCCCCCC AGCGACGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGCCTG CTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTG GACAACGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTCACCCGAG CAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACC CT GAGCAAGGCCGACTACGAGAAGCATAAGGTGTACGCCTGCGAG GTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAAC AGGGGCGAGTGC MOR042596 SEQ ID NO: 4 HCDR1 (Combined) GYTFTGYHMS SEQ ID NO: 5 HCDR2 (Combined) VINPVSGNTVYAQKFQG SEQ ID NO: 6 HCDR3 (Combined) IPSYTYAFDY SEQ ID NO: 7 HCDR1 (Kabat) GYHMS SEQ ID NO: 5 HCDR2 (Kabat) VINPVSGNTVYAQKFQG SEQ ID NO: 6 HCDR3 (Kabat) IPSYTYAFDY SEQ ID NO: 8 HCDR1 (Chothia) GYTFTGY SEQ ID NO: 9 HCDR2 (Chothia) NPVSGN SEQ ID NO: 6 HCDR3 (Chothia) IPSYTYAFDY SEQ ID NO: 10 HCDR1 (IMGT) GYTFTGYH SEQ ID NO: 11 HCDR2 (IMGT) INPVSGNT SEQ ID NO: 12 HCDR3 (IMGT) ARIPSYTYAFDY n / ztznn / i ζηζ / Ε / γ SEQ ID NO: 13 VH QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYHMSWRQAPGQGL EWMGVINPVSGNTVYAQKFQGRVTMTRDTSISTAYMELSRLRSED TAVYYCARIPSYTYAFDYWGQGTLVTVSS SEQ ID NO: 14 VH DNA CAGGTGCAATTGGTGCAGAGCG GTGCGGAAGTGAAAAAACCGGGT GCCAGCGTGAAAGTTAGCTGCAAAGCGTCCGGATATACCTTCACT GGTTACCATATGTCTTGGGTGCGCCAGGCCCCGGGCCAGGGCCTC GAGTGGATGGGCGTTATCAACCCGGTTTCTGGCAACACGGTTTAC GCGCAGAAATTTCAGGGCCGGGTGACCATGACCCGTG ATACCAGC ATTAGCACCGCGTATATGGAACTGAGCCGTCTGCGTAGCGAAGAT ACGGCCGTGTATTATTGCGCGCGTATCCCGTCTTACACTTACGCT TTCGATTACTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCA SEQ ID NO: 15 Heavy Chain QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYHMSWVR QAPGQGL EWMGVINPVSGNTVYAQKFQGRVTMTRDTSISTAYMELSRLRSED TAVYYCARIPSYTYAFDYWGQGTLVTVSSASTKGPSVFPLAPSSK STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSG LYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDK RVEPKSCDKT HTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSH EDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDW LNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEM TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY KTTPPVLDSDGS FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO: 16 DNA Heavy Chain CAGGTGCAATTGGTGCAGAGCGGTGCGGAAGTGAAAAAACCGGGT GCCAGCGTGAAAGTTAGCTGCAAAGCGTCCGGATATACCTTCACT GGTTACCATATGTCTTGGGTGCGCCAGGCCCCGGGCCAGGGCCTC GAGTGGATGGGCGTTATCAACCCGGTTTCTGGCAACACGGTTTAC GCGCAGAAATTTCAGGGCCGGGTGACCATGACCCGTGATACCAGC ATTAGCACCGCGTATAT GGAACTGAGCCGTCTGCGTAGCGAAGAT ACGGCCGTGTATTATTGCGCGCGTATCCCGTCTTACACTTACGCT TTCGATTACTGGGGCCAAGGCACCCTGGTGACTGTTAGCTCAGCC TCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAG AGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTG GTCAAGGAC TACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTG ACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGA CTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTG GGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAAC ACCAAGGTGGACA AGAGAGTTGAGCCCAAATCTTGTGACAAAACT CACACATGCCCACCGTGCCCAGCACCTGAAGCAGCGGGGGGACCG TCAGTCTTCCTCTCTCCCCCCCAAAACCCAAGGACACCTCATGATC TCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCAC GAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGG CGTGGAG GTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGC ACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGG CTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTC CCAGCCCCCATCGAGAAAACCATTCCAAAGCCAAAGGGCAGCCC CGAGAACCACAGGTGTA CACCCTGCCCCCATCCCGGGAGGAGATG ACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTAT CCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAG AACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCC TTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGG TGGCAG CAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCAC AACCACTACACGCAGAAGAGCCTTCTCCCTGTCTCCGGGTAAA SEQ ID NO: 17 LCDR1 (Combined) RASQDISNYLA SEQ ID NO: 18 LCDR2 (Combined) RASSLQS SEQ ID NO: 78 LCDR3 (Combined) QQHGHSPTT SEQ ID NO: 17 LCDR1 (Kabat) RASQDISNYLA n / ztznn / i ζπζ / β / υ SEQ ID NO: 18 LCDR2 (Kabat) RASSLQS SEQ ID NO: 78 LCDR3 (Kabat) QQHGHSPTT SEQ ID NO: 20 LCDR1 (Chothia) SQDISNY SEQ ID NO: 21 LCDR2 (Chothia) RAS SEQ ID NO: 79 LCDR3 (Chothia) HGHSPT SEQ ID NO: 23 LCDR1 (IMGT) QDISNY SEQ ID NO: 21 LCDR2 (IMGT) RAS SEQ ID NO: 78 LCDR3 (IMGT) QQHGHSPTT SEQ ID NO: 80 VL DIQMTQSPSSLSASVGDRVTITCRASQDISNYLAWYQQKPGKAPK LLIYRASSLQSGVPSRFSGSGSGTDFTLTISSL QPEDFATYYCQQ HGHSPTTFGQGTKVEIK SEQ ID NO: 81 ADN VL GATATCCAGATGACCCAGAGCCCGAGCAGCCTGAGCGCCAGCGTG GGCGATCGCGTGACCATTACCTGCAGAGCCAGCCAGGACATTTCT AACTACCTGGCTTGGTACCAGCAGAAACCGGGCAAAGCGCCGAAA CTATTAATCTACCGTGCT TCTTCTCTGCAAAGCGGCGTGCCGAGC CGCTTTAGCGGCAGCGGATCCGGCACCGATTTCACCCTGACCATT AGC T C T C T GCAAC C GGAAGAC T T T GCGACC T AT T AT T GCC AGC AG CATGGTCATTCTCCGACTACCTTTGGCCAGGGCACGAAAGTTGAA ATTAAA SEQ ID NO: 82 Light Chain DIQMTQSPSSLSASVGDRVTITCRASQDISNY LAWYQQKPGKAPK LLIYRASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQ HGHSPTTFGQGTKVE IKRTVAAP SVFIFPPSDEQLKSGTASWCL LNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT LSKADYEKHKVYACEVTHQGLSSPVTK SFNRGEC SEQ ID NO: 83 DNA Light chain GATATCCAGATGACCCAGAGCCCGAGCAGCCTGAGCGCCAGCGTG GGCGATCGCGTGACCATTACCTGCAGAGCCAGCCAGGACATTTCT AACTACCTGGCTTGGTACCAGCAGAAACCGGGCAAAGCGCCGAAA CTATTAATCTACCGTGCTTCTTCTCTGCAAAGCGGCGTGCCGAGC CGCTTTAGCGGCAGCGGATCCGGCACCGATTTCACCCTGACCATT AGCTCTCTGCAACCGGAAGACTTTGCGACCTATTATTGCCAGCAG CATGGTCATTCTCCGACTACCTTTGGCCAGGGCACGAAAGTTGAA ATTAAACGTACGGTGGCCGCTCCCAGCGTGTTCATCTTCCCCCCC AGCGACGAGCAGCTGAAGAGCGGCACCGCCAG CGTGGTGTGCCTG CTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTG GACAACGCCCTGCAGAGCGGCAACAGCCAGGAAAGCGTCACCGAG CAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACC CTGAGCAAGGCCGACTACGAGAAGCACAAGGTGTACGCCTGCGAG GTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAAC CGGGGCGAGTGT MOR041877 SEQ ID NO: 84 HCDR1 (Combined) GFSLSTSGVGVS SEQ ID NO: 85 HCDR2 (Combined) LIFSDHDKIYSTSLKT SEQ ID NO: 86 HCDR3 (Combined) TLIDRSVYFDY SEQ ID NO: 87 HCDR1 (Kabat) TSGVGVS SEQ ID NO: 85 HCDR2 (Kabat) LIFSDHDKIYSTSLKT SEQ ID NO: 86 HCDR3 (Kabat) TLIDRSVYFDY SEQ ID NO: 88 HCDR1 (Chothia) GFSLSTSGV SEQ ID NO: 89 HCDR2 (Chothia) FSDHD SEQ ID NO: 86 HCDR3 (Chothia) TLIDRSVYFDY SEQ ID NO: 90 HCDR1 (IMGT) GFSLSTSGVG SEQ ID NO: 91 HCDR2 (IMGT) IFSDHDK SEQ ID NO: 92 HCDR3 (IMGT) ARTLIDRSVYFDY n / ztznn / i ζπζ / ε / υ SEQ ID NO: 93 VH QVQLKESGPALVKPTQTLTLTCTFSGFSLSTSGVGVSWIRQPPGK ALEWLALIFSDHDKIYSTSLKTRLTISKDTSKNQWLTMTNMDPV DTATYYCARTLIRSVYFDYWGQGTLVTVSS SEQ ID NO: 94 VH DNA CAGGTGCAATTGAAAGAAAGCGGTCCGGCG CTGGTGAAACCGACC CAGACCCTGACCCTGACGTGCACCTTTTCCGGATTCAGCCTGTCT ACTTCCGGTGTTGGTGTGAGCTGGATTCGCCAGCCGCCGGGCAAA GCGCTCGAGTGGCTGGCGCTGATCTTCTCTGACCATGACAAGATC TATAGCACCAGCCTGAAAACCCGTCTGACCATTAGCAAAGATACT TCGAAAAACCAG GTGGTGCTGACCATGACCAACATGGACCCGGTG GATACCGCGACCTATTATTGCGCGCGTACTCTGATCGACCGTTCT GTTTACTTCGATTACTGGGGCCAAGGCACCCTGGTGACTGTTAGC TCA SEQ ID NO: 95 Heavy Chain QVQLKESGPALVKPTQTLTLTCTFSGFSLSTSGVGVSWIRQPPGK ALEWLALIF SDHDKIYSTSLKTRLTISKDTSKNQWLTMTNMDPV DTATYYCARTLIRSVYFDYWGQGTLVTVSSASTKGPSVFPLAPS SKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQS SGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCD KTHTCPPCP APEAAGGPSVFLFPPKPKDTLMISRTPEVTCWVDV SHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQ DWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRE EMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD GSFFLYS KLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG K SEQ ID NO: 96 DNA Chain heavy CAGGTGCAATTGAAAGAAAGCGGTCCGGCGCTGGTGAAACCGACC CAGACCCTGACCCTGACGTGCACCTTTTCCGGATTCAGCCTGTCT ACTCCGGTGTTGGTGTGAGCTGGATTCGCCAGCCGCCGGGCAAA GCGCTCGAGTGGCTGGCGCTGATCTTCTCTGACCATGACAAGATC TATAGCACCAGCCTGAAAAC CCGTCTGACCATTAGCAAAGATACT TCGAAAAACCAGGTGGTGCTGACCATGACCAACATGGACCCGGTG GATACCGCGACCCTATTATTGCGCGCGTACTCTGATCGACCGTTCT GTTTACTTCGATTACTGGGGCCAAGGCACCCTGGTGACTGTTAGC TCAGCCTCCACCAAGGGTCCATCGGTCTTCCCCCTGGCACCCTCC TC CAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTC AAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGC GCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCC TCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGC AGCTTGGGGCACCCAGACC TACATCTGCAACGTGAATCACAAGCCC AGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGAC AAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCAGCGGGGGGACCGTCAGTCTTCCTCTCTCCCCCAAAACCCAAGGACACCCTC ATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGA CGTG AGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGC GTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTAC AACAGCACGTACCGGGTGGTCAGCGTCCTCACCGTCCTGCACCAG GAC T GGC T GAAT GGCAAGGAGTACAAGT GCAAGG TC T CCAACAAA GCCCTCCCA GCCCCCATCGAGAAAACCATTCTCCAAAGCCAAAGGG CAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAG GAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGC TTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAG CCGGAGAACAACTACAAGACCACGCCTCCCGTG CTGGACTCCGAC GGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGG TGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCT CTGCACAACCACTACACGCAGAAGAGCCTTCCCCTGTCTCCGGGT AAA SEQ ID NO: 97 LCDR1 (Combined) SGSSSNIGHHYVS SEQ ID NO: 98 LCDR2 (Combined) DNTNRPS n / ztznn / i ζπζ / β / υ SEQ ID NO: 99 LCDR3 (Combined) ATWDGLMNSIV SEQ ID NO: 97 LCDR1 (Kabat) SGSSSNIGHHYVS SEQ ID NO: 98 LCDR2 (Kabat) DNTNRPS SEQ ID NO: 99 LCDR3 (Kabat) ATWDGLMNSIV SEQ ID NO: 100 LCDR1 (Chothia) SSSNIGHHY SEQ ID NO: 101 LCDR2 (Chothia) DNT SEQ ID NO: 102 LCDR3 (Chothia) WDGLMNSI SEQ ID NO: 103 LCDR1 (IMGT) SSNIGHHY SEQ ID NO: 101 LCDR2 (IMGT) DNT SEQ ID NO: 99 LCDR3 (IMGT) ATWDGLMNSIV SEQ ID NO: 104 VL DIVLTQPPSVSGAPGQRVTISCSGSSSNIGHHYVSWYQQLPGTAP KLLIYDNTNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCA TWDGLMNSIVFGGGTKLTVL SEQ ID NO: 105 ADN VL GATATCGTGCTGACCCAGCCGCCGAGCGTGAG CGGTGCACCGGGC CAGCGCGTGACCATTAGCTGTAGCGGCAGCAGCAGCAACATTGGT CATCATTACGTGTCTTGGTACCAGCAGCTGCCGGGCACGGCGCCG AAACTGCTGATCTACGACAACACTAACCGCCCGAGCGGCGTGCCG GATCGCTTTAGCGGATCCAAAAGCGGCACCAGCGCCAGCCTGGCG ATTACCGG CCTGCAAGCAGAAGACGAAGCGGATTATTACTGCGCT ACTTGGGACGGTCTGATGAACTCTTATCGTGTTTGGCGGCGGCACG AAGTTAACCGTCCTA SEQ ID NO: 106 Light chain DIVLTQPPSVSGAPGQRVTISCSGSSSNIGHHYVSWYQQLPGTAP KLLIYDNTNRPSGVPDRFSGSKSGTSASLAITG LQAEDEADYYCA TWDGLMNSIVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKAT LVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASS YLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS SEQ ID NO: 107 DNA Light chain GATATCGTGCTGACCCAGCCGCCGAGCGTGA GCGGTGCACCGGGC CAGCGCGTGACCATTAGCTGTAGCGGCAGCAGCAGCAACATTGGT CATCATTACGTGTCTTGGTACCAGCAGCTGCCGGGCACGGCGCCG AAACTGCTGATCTACGACAACACTAACCGCCCGAGCGGCGTGCCG GATCGCTTTAGCGGATCCAAAAGCGGCACCAGCGCCAGCCTGGCG ATTACCG GCCTGCAAGCAGAAGACGAAGCGGATTATTACTGCGCT ACTTGGGACGGTCTGATGAACTCTTATCGTGTTTGGCGGCGGCACG AAGTTAACCGTCCTAGGTCAGCCCAAGGCTGCCCCCTCGGTCACT CTGTTCCCGCCCTTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACA CTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTG GCCTGGAAGGCAGATAGCA GCCCCGTCAAGGCGGGAGTGGAGACC ACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGC TATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTAC AGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTG GCCCCTACAGAATGTTCA nyztznn / i ζηζ / Ε / γ In some embodiments, the hTREM2 antibody or an antigen-binding fragment thereof comprises a VH domain having an amino acid sequence of any VH domain described in Table 1. Other suitable hTREM2 antibodies or antigen-binding fragments of they may include amino acids that have been mutated, but have at least 80, 85, 90, 95, 96, 97, 98, or 99 percent identity in the VH domain with the VH regions represented in the sequences described in Table 1 The present disclosure in certain embodiments also provides antibodies or antigen-binding fragments thereof that specifically bind to human TREM2, wherein the antibodies or antibody fragments (eg, antigen-binding fragments) comprise a VH CDR. having an amino acid sequence of any of the HCDRs listed in Table 1. In particular embodiments, the invention provides antibodies or antibody fragments (eg. antigen-binding fragments) that specifically bind to human TREM2, comprising (or alternatively, consisting of) one, two, three, four, five, or more VH CDRs having an amino acid sequence of any of the following HCDR listed in Table 1. In some embodiments, the hTREM2 antibody or antibody fragment (eg, antigen-binding fragment) comprises a VL domain having an amino acid sequence of any VL domain described in Table 1. Other antibodies or antibody fragments Suitable human antiTREM2 (eg, antigen-binding fragments) can include amino acids that have been mutated, but still have at least 80, 85, 90, 95, 96, 97, 98, or 99 percent domain identity. VL with the VL regions represented in the sequences described in Table 1. The present disclosure also provides antibodies or antibody fragments (eg, antigen-binding fragments) that specifically bind to human TREM2, the antibodies or antibody fragments (eg, antigen-binding fragments) comprise a VL CDR having an amino acid sequence from any of the LCDRs listed in Table 1. In particular, the invention provides antibodies or antibody fragments (eg, antigen-binding fragments). antigen binding) that specifically bind to human TREM2, comprising (or alternatively, consisting of) one, two, or three or more VL CDRs having an amino acid sequence of any of the LCDRs listed in Table 1. Other anti-human TREM2 antibodies or antibody fragments (eg, antigen-binding fragment) described herein include amino acids that have been mutated, but are at least 80, 85, 90, 95, 96, 97, 98 or 99 percent identity in the CDR regions with the CDR regions represented in the sequences described in Table 1. In some embodiments, includes mutant amino acid sequences in which no more than 1, 2, 3, 4 have been mutated or 5 amino acids in the CDR regions compared to the CDR regions represented in the sequence described in Table 1. n / ztznn / i ζπζ / β / υιλι Also provided herein are nucleic acid sequences encoding VH, VL, full-length heavy chain, and full-length light chain of antibodies and antigen-binding fragments thereof that specifically bind to human TREM2, for example, the nucleic acid sequences in Table 1. Such nucleic acid sequences can be optimized for expression in the desired host cells, e.g. eg, mammalian cells. Other human anti-TREM2 antibodies described herein include those in which the amino acids or nucleic acids encoding the amino acids have been mutated, but have at least 80, 85, 90, 95, 96, 97, 98, or 99 percent identity. with the sequences described in Table 1. In some embodiments, the antibodies or antigen-binding fragments thereof include mutant amino acid sequences in which no more than 1, 2, 3, 4, or 5 amino acids have been mutated. in the variable regions compared to the variable regions represented in the sequence described in Table 1, while retaining substantially the same therapeutic activity. Since each provided antibody binds human TREM2, the VH, VL, full-length light chain, and full-length heavy chain sequences (amino acid sequences and nucleotide sequences encoding the amino acid sequences) can be mixed and matched to create other TREM2 binding antibodies described herein. Such mixed and matched TREM2 binding antibodies can be tested using binding assays known in the art (eg, ELISA, assays described in the Exemplification). When strands are mixed and matched, a VH sequence from a particular VH / VL pairing must be replaced with a structurally similar VH sequence. A full-length heavy chain sequence of a particular full-length heavy chain / full-length light chain pair must be replaced by a structurally similar full-length heavy chain sequence. A VL sequence from a particular VH / VL pairing must be replaced with a structurally similar VL sequence. A full-length light chain sequence of a particular full-length heavy chain / full-length light chain pairing must be replaced by a structurally similar full-length light chain sequence. Accordingly, in one embodiment, the invention provides an isolated monoclonal antibody or antigen-binding fragment thereof having: a heavy chain (VH) variable region comprising an amino acid sequence selected from any of SEQ IDs NOT: 13 and 50; and a light chain (VL) variable region comprising an amino acid sequence selected from any of SEQ ID NO: 24 and 61; wherein the antibody specifically binds to human TREM2. njztznn / i ζπζ / ε / υιλι In another embodiment, the invention provides (i) an isolated monoclonal antibody having: a full-length heavy chain (HC) comprising an amino acid sequence selected from any of SEQ ID NO: 15, 29, 33, 35 , 37, 39, 52, 66, 70, 72, 74, 76; and a full length light chain (LC) comprising an amino acid sequence selected from any of SEQ ID NO: 26 and 63; or (ii) a functional protein comprising an antigen-binding portion thereof. In another embodiment, the present disclosure provides human TREM2 binding antibodies or antibody fragments thereof comprising CDR1, CDR2 and CDR3 heavy chain and CDR1, CDR2 and CDR3 light chain as described in Table 1, or theirs. combinations. The HCDR1 amino acid sequences of the antibodies are shown in SEQ ID NOs: 4, 7, 8, 10, 41,44, 45, 47. The HCDR2 amino acid sequences of the antibodies are shown in SEQ ID NOs: 5, 9, 11, 42, 46, 48. The HCDR3 amino acid sequences of the antibodies are shown in SEQ ID NO: 6, 12, 43, 49. The LCDR1 amino acid sequences of the antibodies are shown in SEQ ID NO: 17, 20, 23, 54, 57, 60. The amino acid sequences of the LCDR2 of the antibodies are shown in SEQ ID NO: 18, 21, 55, 58. The amino acid sequences of the LCDR3 of the antibodies are shown in SEQ ID NOs: 19, 22, 56, 59, 56. Since each of the antibodies binds to human TREM2 and antigen-binding specificity is provided primarily by the CDR1, CDR2, and CDR3 regions, the CDR1, CDR2, and CDR3 sequences of VH, and the CDR1, CDR2, and CDR3 sequences of VL can be “mixed and matched” (i.e., the CDRs of different antibodies can be mixed and matched), although each antibody must contain a VH CDR1, CDR2, and CDR3 and a VL CDR1, CDR2, and CDR3 to create other VL antibodies. binding to human TREM2 described here. Such mixed and matched TREM2 binding antibodies can be assessed using binding assays known in the art and those described in the Examples (eg ELISA). When VH CDR sequences are mixed and matched, the CDR1, CDR2 and / or CDR3 sequence of a particular VH sequence must be replaced with one or more structurally similar CDR sequences. Similarly, when VL CDR sequences are mixed and matched, the CDR1, CDR2 and / or CDR3 sequence of a particular VL sequence must be replaced with one or more structurally similar CDR sequences. It will be apparent to those skilled in the art that new VH and VL sequences can be created by substituting one or more VH and / or VL CDR region sequences with structurally similar sequences of the CDR sequences shown herein for the monoclonal antibodies of the present invention. . Accordingly, the present disclosure provides an isolated monoclonal antibody or an antigen-binding region of said antibody comprising a heavy chain CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 4, 7, 8, 10, 41, njztznn / i ζπζ / ε / υιλι 44, 45, 47; a heavy chain CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 5, 9, 11, 42, 46, 48; a heavy chain CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 6, 12, 43, 49; a light chain CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 17, 20, 23, 54, 57, 60; a light chain CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 18, 21, 55, 58; and a light chain CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 19, 22, 56, 59, 56; wherein the antibody specifically binds to human TREM2. In certain embodiments, an antibody that specifically binds to human TREM2 is an antibody or antibody fragment (eg, antigen-binding fragment) described in Table 1. In some embodiments, the antibody or antibody fragment The antigen-binding receptor thereof that specifically binds to human TREM2 comprises a heavy chain complementarity determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 4, 7, 8 or 10; a heavy chain complementarity determining region 2 (HCDR2) comprising the amino acid sequence of SEQ ID NO: 5, 9 or 11; a heavy chain complementarity determining region 3 (HCDR3) comprising the amino acid sequence of SEQ ID NO: 6 or 12; a light chain complementarity determining region 1 (LCDR1) comprising the amino acid sequence of SEQ ID NO: 17, 20 or 23; a light chain complementarity determining region 2 (LCDR2) comprising the amino acid sequence of SEQ ID NO: 18 or 21; and a light chain complementarity determining region 3 (LCDR3) comprising the amino acid sequence of SEQ ID NO: 19 or 22. In some embodiments, the antibody or the antigen-binding region thereof that specifically binds to human TREM2 comprises an HCDR1 comprising the amino acid sequence of SEQ ID NO: 41, 44, 45 or 47; a HCDR2 comprising the amino acid sequence of SEQ ID NO: 42, 46 or 48; a HCDR3 comprising the amino acid sequence of SEQ ID NO: 43 or 49; an LCDR1 comprising the amino acid sequence of SEQ ID NO: 54, 57 or 60; an LCDR2 comprising the amino acid sequence of SEQ ID NO: 55 or 58; and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 56 or 59. In some embodiments, the antibody or its antigen-binding region that specifically binds human TREM2 comprises a heavy chain (VH) variable region comprising the amino acid sequence of SEQ ID NO: 13 (or a sequence at least least about 90%, 95%, 99% or more identical to it, and / or having one, two, three or more substitutions, insertions, deletions, or modifications), and a light chain (VL) variable region that comprises the amino acid sequence of SEQ ID NO: 24 (or a sequence at least about 90%, 95%, 99% or more n / ztznn / i ζπζ / β / υιλι identical to it, and / or having a , two, three or more substitutions, insertions, deletions, or modifications). In some embodiments, the antibody or its antigen-binding region that specifically binds human TREM2 comprises a heavy chain (VH) variable region comprising the amino acid sequence of SEQ ID NO: 50 (or a sequence at least least about 90%, 95%, 99% or more identical to it, and / or having one, two, three or more substitutions, insertions, deletions, or modifications), and a light chain (VL) variable region that comprises the amino acid sequence of SEQ ID NO: 61 (or a sequence at least about 90%, 95%, 99% or more identical to it, and / or having one, two, three or more substitutions, insertions, deletions, or modifications). In some embodiments, the antibody that specifically binds human TREM2 comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 15 (or a sequence at least about 90%, 95%, 99% or more identical to it, and / or having one, two, three or more substitutions, insertions, deletions, or modifications), and a light chain comprising the amino acid sequence of SEQ ID NO: 26 (or a sequence at least around 90%, 95%, 99% or more identical to it, and / or having one, two, three or more substitutions, insertions, deletions, or modifications). In some embodiments, the antibody that specifically binds human TREM2 comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 29 (or a sequence at least about 90%, 95%, 99% or more identical to it, and / or having one, two, three or more substitutions, insertions, deletions, or modifications), and a light chain comprising the amino acid sequence of SEQ ID NO: 26 (or a sequence at least around 90%, 95%, 99% or more identical to it, and / or having one, two, three or more substitutions, insertions, deletions, or modifications). In some embodiments, the antibody that specifically binds human TREM2 comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 33 (or a sequence at least about 90%, 95%, 99% or more identical to it, and / or having one, two, three or more substitutions, insertions, deletions, or modifications), and a light chain comprising the amino acid sequence of SEQ ID NO: 26 (or a sequence at least around 90%, 95%, 99% or more identical to it, and / or having one, two, three or more substitutions, insertions, deletions, or modifications). In some embodiments, the antibody that specifically binds human TREM2 comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 35 (or a sequence at least about 90%, 95%, 99% or more identical to it, and / or having one, two, three or more substitutions, insertions, deletions, or modifications), and a light chain that njztznn / i ζπζ / ε / υιλι comprises the amino acid sequence of SEQ ID NO: 26 (or a sequence at least about 90%, 95%, 99% or more identical to it, and / or having one, two, three or more substitutions, insertions, deletions, or modifications). In some embodiments, the antibody that specifically binds human TREM2 comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 37 (or a sequence at least about 90%, 95%, 99% or more identical to it, and / or having one, two, three or more substitutions, insertions, deletions, or modifications), and a light chain comprising the amino acid sequence of SEQ ID NO: 26 (or a sequence at least around 90%, 95%, 99% or more identical to it, and / or having one, two, three or more substitutions, insertions, deletions, or modifications). In some embodiments, the antibody that specifically binds human TREM2 comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 39 (or a sequence at least about 90%, 95%, 99% or more identical to it, and / or having one, two, three or more substitutions, insertions, deletions, or modifications), and a light chain comprising the amino acid sequence of SEQ ID NO: 26 (or a sequence at least around 90%, 95%, 99% or more identical to it, and / or having one, two, three or more substitutions, insertions, deletions, or modifications). In some embodiments, the antibody that specifically binds human TREM2 comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 52 (or a sequence at least about 90%, 95%, 99% or more identical to it, and / or having one, two, three or more substitutions, insertions, deletions, or modifications), and a light chain comprising the amino acid sequence of SEQ ID NO: 63 (or a sequence at least around 90%, 95%, 99% or more identical to it, and / or having one, two, three or more substitutions, insertions, deletions, or modifications). In some embodiments, the antibody that specifically binds human TREM2 comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 66 (or a sequence at least about 90%, 95%, 99% or more identical to it, and / or having one, two, three or more substitutions, insertions, deletions, or modifications), and a light chain comprising the amino acid sequence of SEQ ID NO: 63 (or a sequence at least around 90%, 95%, 99% or more identical to it, and / or having one, two, three or more substitutions, insertions, deletions, or modifications). In some embodiments, the antibody that specifically binds human TREM2 comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 70 (or a sequence at least about 90%, 95%, 99% or more identical to it, and / or having one, two, three or more substitutions, insertions, deletions, or modifications), and a light chain that n / ztznn / i ζπζ / β / υιλι comprises the amino acid sequence of SEQ ID NO : 63 (or a sequence at least about 90%, 95%, 99% or more identical to it, and / or having one, two, three or more substitutions, insertions, deletions, or modifications). In some embodiments, the antibody that specifically binds human TREM2 comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 72 (or a sequence at least about 90%, 95%, 99% or more identical to it, and / or having one, two, three or more substitutions, insertions, deletions, or modifications), and a light chain comprising the amino acid sequence of SEQ ID NO: 63 (or a sequence at least around 90%, 95%, 99% or more identical to it, and / or having one, two, three or more substitutions, insertions, deletions, or modifications). In some embodiments, the antibody that specifically binds human TREM2 comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 74 (or a sequence at least about 90%, 95%, 99% or more identical to it, and / or having one, two, three or more substitutions, insertions, deletions, or modifications), and a light chain comprising the amino acid sequence of SEQ ID NO: 63 (or a sequence at least around 90%, 95%, 99% or more identical to it, and / or having one, two, three or more substitutions, insertions, deletions, or modifications). In some embodiments, the antibody that specifically binds human TREM2 comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 76 (or a sequence at least about 90%, 95%, 99% or more identical to it, and / or having one, two, three or more substitutions, insertions, deletions, or modifications), and a light chain comprising the amino acid sequence of SEQ ID NO: 63 (or a sequence at least around 90%, 95%, 99% or more identical to it, and / or having one, two, three or more substitutions, insertions, deletions, or modifications). In some embodiments, the present invention provides an antibody or antigen-binding fragment thereof, which binds to the IgSF domain of the TREM2 protein with a dissociation constant (KD) of less than 200 pM, eg, one KD of less. less than 150 pM, less than 120 pM, less than 100 pM, less than 90 pM, less than 70 pM, less than 50 pM, less than 40 pM, less than 30 pM, less than 20 pM, or less than 10 pM, for example, measured by surface plasmon resonance (SPR). In some preferred embodiments, the antibodies or their antigen-binding fragments provided in this application bind to the IgSF domain of the TREM2 protein with a dissociation constant (KD) of less than 50 pM. In some preferred embodiments, the antibodies or their antigen-binding fragments provided in this application bind to the IgSF domain of the TREM2 protein with a dissociation constant (KD) of less than 5 pM. njztznn / i ζπζ / β / υιλι Once a desired epitope on an antigen is determined, it is possible to generate antibodies to that epitope, for example, using the techniques described in the present invention. Alternatively, during the discovery process, antibody generation and characterization can elucidate information about desirable epitopes. From this information, it is then possible to competitively select antibodies to bind to the same epitope. One approach to accomplish this is to perform cross-competition studies to find antibodies that competitively bind to each other, eg, antibodies compete to bind antigen. In International Patent Application No. WO 2003 / 48731 a high throughput process for pooling antibodies on the basis of their cross competition is described. An epitope can comprise those residues to which the antibody binds. In general, antibodies specific for a particular target antigen will preferentially recognize an epitope on the target antigen in a complex mixture of proteins and / or macromolecules. Regions of a given polypeptide that include an epitope can be identified using any number of epitope mapping techniques, well known in the art. See, for example, Epitope Mapping Protocols in Methods in Molecular Biology, Vol. 66 (Glenn E. Morris, Ed., 1996, Humana Press, Totowa, N.J.). For example, linear epitopes can be determined, for example, by concurrently synthesizing large numbers of peptides on solid supports, the peptides corresponding to portions of the protein molecule, and reacting the peptides with antibodies while the peptides are still bound to the protein. the supports. Such techniques are known in the art and are described in, for example, US Patent No. 4,708,871; Geysen et al., (1984), Proc. nati. Acad. Sci. USA 8: 3998-4002; Geysen et al, (1985) Proc. nati. Acad. Sci. USA 82: 78-182; Geysen et al., (1986) Mol. Immunol 23: 709-715. Similarly, conformational epitopes are readily identified by determining the spatial conformation of amino acids, eg, by X-ray crystallography and two-dimensional nuclear magnetic resonance. See, eg, Epitope Mapping Protocols, supra. Antigenic regions of proteins can also be identified using standard antigenicity and hydropathy plots, such as those calculated using, for example, the Omiga version 1.0 software available from the Oxford Molecular Group. This computer program employs the Hopp / Woods method, Hopp et al., (1981) Proc. nati. Acad. Sci USA 78: 3824-3828, to determine antigenicity profiles, and the Kyte-Doolittle technique, Kyte et al, (1982) J. Mol. BioL 157: 105-132, for charts of hydropathy. In some embodiments, an anti-TREM2 antibody specifically binds to an epitope on the IgSF domain of human TREM2. For example, an anti-TREM2 antibody can specifically bind to an epitope within amino acid residues 19 to 132 of any of SEQ ID NROs: 1, 2, or 3. n / ztznn / i ζπζ / β / υιλι The antibody molecule can be a polyclonal or monoclonal antibody. A monoclonal antibody can be made by hybridoma technology or by other methods, such as phage display or combination methods. Phage display and combination methods for generating antibodies are known in the art (as described in, for example, Ladner et al. US Patent No. 5,223,409; Kang et al., International Publication No. WO 92 / 18619 Dower et al International Publication No WO 91 / 17271 Winter et al International Publication WO 92 / 20791 Markland et al International Publication No WO 92 / 15679 Breitling et al International Publication WO 93 / 01288 McCafferty et al International Publication No WO 92 / 01047 Garrard et al International Publication No WO 92 / 09690 Ladner et al International Publication No WO 90 / 02809 Fuchs et al (1991) Bio / Technology 9:1370-1372 Hay et al (1992) Hum Antibod Hybridomas 3:81-85 Huse et al (1989) Science 246:1275-1281 Griffths et al (1993) EMBO J 12:725 -734, Hawkins et al (1992) J Mol Biol 226:889-896, Clackson et al (1991) Nature 352:624-628, Gram et al (1992) PNAS 89:3576-3580, Garrad et al (1991) Bio / Technology 9:1373-1377; Hoogenboom et al. (1991) Nuc Acid Res 19:41334137; and Barbas et al (1991) PNAS 88:7978-7982). In one embodiment, the antibody is a human antibody (eg, an antibody produced in a transgenic mouse that has been genetically engineered to produce an antibody from a human immunoglobulin sequence), or a non-human antibody, eg , an antibody from a rodent (mouse or rat), goat, primate (eg, monkey), or camel Chimeric and / or humanized antibodies can be designed to minimize a human patient's immune response to antibodies produced in non-human subjects or derived from non-human antibody gene expression. Chimeric antibodies comprise a non-human animal antibody variable region and a human antibody constant region. Such antibodies retain the epitope binding specificity of the original monoclonal antibody, but may be less immunogenic when administered to humans and are therefore more likely to be tolerated by the patient. For example, one or all (eg, one, two, or three) of the light chain variable regions and / or one or all (eg, one, two, or three) of the heavy chain variable regions of a mouse antibody (eg, a mouse monoclonal antibody) can each bind to a human constant region, such as, without limitation, a human lgG1 constant region. Chimeric monoclonal antibodies can be produced by recombinant DNA techniques known in the art. For example, a gene encoding the constant region of a non-human antibody molecule can be replaced with a gene encoding a human constant region (see Robinson et al, PCT Patent Application PCT / US86 / 02269; Akira, et al, Application European Patent Application 184,187; or Taniguchi, M., European Patent Application 171,496). In addition, other suitable njztznn / i ζπζ / β / υιλι techniques that can be used to generate chimeric antibodies are described, for example, in US Patent Numbers 4,816,567; 4,978,775; 4,975,369; and 4,816,397. A chimeric antibody can be further humanized by replacing portions of the variable region that do not participate in antigen binding with equivalent portions of the human variable regions. Humanized antibodies comprise one or more human framework regions in the variable region together with non-human (eg, mouse, rat, or hamster) complementarity determining regions (CDRs) of the heavy and / or light chain. In some embodiments, a humanized antibody comprises sequences that are fully human, except for the CDR regions. Humanized antibodies are typically less immunogenic for humans, relative to non-humanized antibodies, and therefore offer therapeutic benefits in certain situations. Humanized TREM2 antibodies can be generated using methods known in the art. See, for example, Hwang et al, Methods 36:35, 2005; Queen et al., Proc. nati. Acad. Sci. U.S.A. 86: 10029-10033, 1989; Jones et al, Nature 321: 522-25, 1986; Riechmann et al, Nature 332: 323-27, 1988; Verhoeyen et al, Science 239: 1534-36, 1988; Orlandi et al, Proc. nati. Acad. Sci.U.S.A. 86:3833-3837, 1989; United States Patents Nos. 5,225,539; 5,530,101; 5,585,089; 5,693,761; 5,693,762; and 6,180,370; and WO 90 / 07861. Human TREM2 antibodies can be generated using methods that are known in the art; for example, humanization technology used to convert non-human antibodies into engineered human antibodies. United States Patent Publication No. 20050008625 describes an in vivo method of replacing a non-human antibody variable region with a human variable region in an antibody while maintaining the same binding or providing better binding characteristics relative to that of the antibody. non-human. The method relies on the guided epitope replacement of variable regions of a non-human reference antibody with a fully human antibody. The resulting human antibody is generally structurally unrelated to the reference non-human antibody, but binds to the same epitope on the same antigen as the reference antibody. Briefly, the serial epitope-guided complementarity replacement approach is enabled by creating competition in cells between a competitor and a library of various hybrids of the reference antibody (test antibodies), for binding to limiting amounts of antigen in the presence of a reporter system that responds to the binding of the test antibody to the antigen. The competitor can be the reference antibody or derived from it, such as a single chain Fv fragment. The competitor can also be a natural or artificial ligand of the antigen that binds to the same epitope as the reference antibody. The only requirements of the competitor are that it bind to the same epitope as the reference antibody, and that it compete with the reference antibody for antigen binding. The test antibodies have one antigen-binding V region in common with the non-human reference antibody, and the other V region n / ztznn / i ζπζ / ε / υιλι selected randomly from a diverse source such as a repertoire library of human antibodies. The common V region of the reference antibody serves as a guide, so as to place the test antibodies at the same epitope on the antigen and in the same orientation, so that selection is biased toward the highest fidelity of antigen binding to the antibody. reference. Many types of reporter systems can be used to detect the desired interactions between test antibodies and antigen. For example, complementary reporter fragments may be bound to antigen and test antibody, respectively, such that reporter activation by fragment complementation only occurs when test antibody binds antigen. When test antibody- and antigen-reporter fragment fusions are coexpressed with a competitor, reporter activation depends on the ability of the test antibody to compete with the competitor, which is proportional to the affinity of the test antibody for the competitor. antigen. Other reporter systems that can be used include a reactivation auto-inhibited reporter (RAIR) system reactivator, as described in US Patent Application No. 10 / 208,730 (Publication No. 10 / 076,845 (Publication No. 20030157579). With the serial epitope-guided complementarity replacement system, selection is performed to identify cells that express a single test antibody along with competitor, antigen, and reporter components. In these cells, each test antibody competes one-on-one with the competitor for binding to a limiting amount of antigen. The activity of the reporter is proportional to the amount of antigen bound to the test antibody, which in turn is proportional to the affinity of the test antibody for the antigen and the stability of the test antibody. Test antibodies are initially selected based on their activity relative to that of the reference antibody when expressed as the test antibody. The result of the first round of selection is a pool of hybrid antibodies, each of which is composed of the same non-human V region from the reference antibody and a human V region from the library, and each of which binds to the same epitope on the antigen as the reference antibody. One or more of the chimeric antibodies selected in the first round will have an affinity for the antigen comparable to or greater than that of the reference antibody. In the second stage of V region replacement, the human V regions selected in the first stage are used as a guide for the selection of human replacements for the remaining non-human reference antibody region V with a diverse library of cognate human V regions. . Hybrid antibodies selected in the first round can also be used as competitors for the second round of selection. The result of the second round of selection is a pool of fully human antibodies that differ structurally from the reference antibody, but compete with the reference antibody to bind to the same antigen. Some of the selected human njztznn / i ζπζ / β / υιλι antibodies bind to the same epitope on the same antigen as the reference antibody. Among these selected human antibodies, one or more binds to the same epitope with an affinity that is comparable to or greater than that of the reference antibody. In some embodiments, the present invention provides an antibody or antigen-binding fragment thereof that binds to human TREM2 protein and facilitates TREM2-dependent physiological activities, for example, enhancing phagocytosis (eg, in macrophages hM2A, or in human iPS-derived microglia-like cells, or in microglia / macrophages in the brain), enhance chemotaxis in human iPS-derived microglia-like cells, increase NFAT-driven reporter gene activity in a line human monocyte cell, or increase Syk phosphorylation in hM2A macrophages. This facilitation and / or improvement can be, for example, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least least 70%, at least 80% or at least 90%. Designed and modified antibodies. An antibody of the invention can be prepared using an antibody having one or more of the VH and / or VL sequences described in Table 1 as a starting material, to design a modified antibody, wherein said modified antibody may have altered antibody properties. of departure. An antibody can be designed by modifying one or more residues within one or both of the variable regions (ie, VH and / or VL), for example, within one or more CDR regions and / or within one or more framework regions. Additionally or alternatively, an antibody can be designed by modifying residues within the constant regions, for example, to alter the effector functions of the antibody. One type of variable region engineering that can be performed is CDR grafting. Antibodies interact with target antigens predominantly through amino acid residues found in the six heavy and light chain complementarity determining regions (CDRs). For this reason, the amino acid sequences within the CDRs are more diverse between individual antibodies than the sequences outside the CDRs. Because CDR sequences are responsible for most antibody-antigen interactions, it is possible to express recombinant antibodies that mimic the properties of specific natural antibodies by constructing expression vectors that include CDR sequences of the specific natural antibody grafted onto them. framework sequences of a different antibody with different properties (see, for example, Riechmann, L. et al., 1998 Nature 332: 323-327; Jones, P. et al., 1986 Nature 321: 522-525; Queen, C. et al., 1989 Proc. Nati. Acad., USA, 86: 10029-10033; US Patent No. 5,225,539 issued to Winter, and US Patent Nos. 5,530,101; 5,585 089, 5,693,762 and 6,180,370 issued to Queen et al.). Such framework sequences can be obtained from public DNA databases or published references that include germline antibody gene sequences or rearranged antibody sequences. For example, germline DNA sequences for human heavy and light chain variable region genes can be found in the VBase Human Germline Sequence Database (available on the Internet at www.mrc-cpe.cam.ac .uk / vbase), as well as Kabat, E. A., et al., 1991 Sequences of Proteins of Immunological Interest, Fifth Edition, US Department of Health and Human Services, NIH Publication No. 913242; Tomlinson, I.M., et al., 1992 J. fol. Biol. 227: 776-798; and Cox, J.P.L. et al., 1994 Eur. J Immunol. 24:827-836; the contents of which are expressly incorporated herein by reference. For example, germline DNA sequences for human heavy and light chain variable region genes and rearranged antibody sequences can be found in the IMGT database (available on the Internet at www.imgt.org; see Lefranc, Μ , P, et al., 1999 Nucleic Acids Res. 27: 209-212, the contents of which are expressly incorporated herein by reference). An example of framework sequences for use in the antibodies and their antigen-binding fragments of the invention are those that are structurally similar to the framework sequences used by selected antibodies and their antigen-binding fragments of the invention, for example, consensus sequences and / or framework sequences used by monoclonal antibodies of the invention. The VH CDR1, 2 and 3 sequences and the VL CDR1, 2 and 3 sequences can be grafted into framework regions having the identical sequence to that found in the germline immunoglobulin gene from which the framework sequence is derived, or CDR sequences can be grafted into framework regions that contain one or more mutations compared to germline sequences. For example, it has been found that, in certain instances, it is beneficial to mutate residues within framework regions to maintain or improve the antigen-binding ability of the antibody (see, for example, United States Patent Numbers 5,530. 101; 5,585,089; 5,693,762 and 6,180,370, issued to Queen et al). Another type of variable region modification is to mutate amino acid residues within the VH and / or VL CDR1, CDR2 and / or CDR3 regions of the VH and / or VL to thereby improve one or more binding properties (e.g., affinity ) of the antibody of interest, known as affinity maturation. Site-directed mutagenesis or PCR-mediated mutagenesis can be performed to introduce the mutations, and the effect on antibody binding, or other functional property of interest, can be assessed in in vitro or in vivo assays as described in this document and is provided in the Examples. Conservative modifications can be introduced (as discussed above). Mutations can be amino acid substitutions, additions, or deletions. Furthermore, typically no more than one, two, three, four, or five residues within a CDR region are altered. n / ztznn / i ζπζ / β / υιλι A wide variety of antibody / immunoglobulin scaffolds or frameworks can be employed, as long as the resulting polypeptide includes at least one binding region that specifically binds to TREM2. Said scaffolds or frameworks include the 5 major idiotypes of human immunoglobulins, their antigen-binding fragments, and include immunoglobulins from other animal species, preferably having humanized characteristics. Single heavy chain antibodies such as those identified in camelids are of particular interest in this regard. New frameworks, scaffolds, and fragments continue to be discovered and developed by those skilled in the art. In one aspect, the invention relates to a method of generating non-immunoglobulin-supported antibodies, using CDR-graftable non-immunoglobulin scaffolds of the invention. Known or future non-immunoglobulin scaffolds and frameworks may be employed, as long as they comprise a specific binding region for the target TREM2 protein. Known non-immunoglobulin frameworks or scaffolds include, but are not limited to, fibronectin (Compound Therapeutics, Inc., Waltham, Massachusetts), ankyrin (Molecular Partners AG, Zurich, Switzerland), domain antibodies (Domantis, Ltd., Cambridge, Mass., and Ablynx nv, Zwijnaarde, Belgium), lipocalin (Pieris Proteolab AG, Freising, Germany), small modular immunopharmaceuticals (Trubion Pharmaceuticals Inc., Seattle, Washington), maxibodies (Avidia, Inc., Mountain View, Calif.), Protein A (Affibody AG, Sweden) and afilin (gamma crystalline or ubiquitin) (Scil Proteins GmbH, Halle, Germany). Fibronectin scaffolds are supported by the fibronectin type III domain (eg, the tenth module of fibronectin type III (domain 10 Fn3)). The fibronectin type III domain has 7 or 8 beta strands that are distributed between two beta sheets, which pack together to form the core of the protein, and also contain loops (analogous to CDRs) that connect the beta strands together. and are exposed to solvent. There are at least three of these loops at each edge of the beta sheet sandwich, where the edge is the protein boundary perpendicular to the direction of the beta strands (see US Patent No. 6,818,418). These fibronectin-based scaffolds are not an immunoglobulin, although the overall fold is closely related to that of the smallest functional antibody fragment, the heavy chain variable region, which comprises the entire antigen recognition unit in camel IgG and calls. Because of this structure, the non-immunoglobulin antibody mimics antigen-binding properties that are similar in nature and affinity to those of antibodies. These scaffolds can be used in an in vitro loop shuffling and randomization approach that is similar to the in vivo antibody affinity maturation process. These fibronectin-based molecules can be used as scaffolds where the loop regions of the molecule can be replaced with CDRs of the invention using standard cloning techniques. Camelid antibodies. njztznn / i ζπζ / β / υιλι Antibody proteins obtained from members of the camel and dromedary family (Camelus bactrianus and Camelus dromaderius), which include members of the Americas such as llama species (Lama paceos, Lama glama and Lama vicugna), have been characterized with respect to the size, structural complexity and antigenicity for human subjects. Certain naturally occurring IgG antibodies from this family of mammals lack light chains and are therefore structurally distinct from the typical four-chain quaternary structure, which has two heavy chains and two light chains, for antibodies from other animals. . See PCT / EP93 / 02214 (WO 94 / 04678 published March 3, 1994). A region of the camelid antibody that is the small unique variable domain identified as VHH can be engineered to produce a small protein that has high affinity for a target, resulting in a low molecular weight antibody-derived protein known as a "camelid nanobody". ”. See US Patent No. 5,759,808, issued June 2, 1998; see also Stijlemans, B. et al, 2004, J Biol Chem 279:1256-1261; Dumoulin, M. et al, 2003 Nature 424: 783-788; Pleschberger, M. et al. 2003 Bioconjugate Chem 14: 440-448; Cortez-Retamozo, V. et al. 2002 Int J Cancer 89: 456-62; and Lauwereys, M. et al, 1998 EMBO J 17: 3512-3520. Engineered libraries of camelid antibodies and antibody fragments are commercially available, for example, from Ablynx, Ghent, Belgium. As with other antibodies and their antigen-binding fragments of non-human origin, an amino acid sequence of a camelid antibody can be recombinantly altered to obtain a sequence that more closely resembles a human sequence; that is, the nanobody can be humanized. Therefore, the naturally low antigenicity of camelid antibodies to humans can be further reduced. The camelid nanobody has a molecular weight of about one tenth that of a human IgG molecule, and the protein has a physical diameter of only a few nanometers. One consequence of the small size is the ability of camelid nanobodies to bind to antigenic sites that are functionally invisible to larger antibody proteins, i.e. camelid nanobodies are useful as reagents that detect otherwise cryptic antigens using classical immunological techniques, and as possible therapeutic agents. Thus, another consequence of the small size is that a camelid nanobody may inhibit as a result of binding to a specific site in a narrow groove or cleft of a target protein, and thus may serve in a capacity resembling more to the function of a classic low molecular weight drug than that of a classic antibody. The low molecular weight and compact size also make camelid nanobodies extremely thermostable, stable at extreme pH and proteolytic digestion, and poorly antigenic. Another consequence is that camelid nanobodies easily move from the circulatory system to tissues, and even cross the blood-brain barrier and can treat n / ztznn / i ζπζ / ε / υιλι disorders that affect nervous tissue. Nanobodies may further facilitate the transport of drugs across the blood-brain barrier. See US Patent Application 20040161738 published August 19, 2004. These features combined with low human antigenicity indicate great therapeutic potential. Furthermore, these molecules can be fully expressed in prokaryotic cells such as E. coli, and are expressed as fusion proteins with bacteriophage and are functional. Accordingly, a feature of the present invention is a camelid antibody or nanobody that has high affinity for TREM2. In one embodiment herein, the camelid antibody or nanobody occurs naturally in the camelid animal, that is, it is produced by the camelid after immunization with TREM2 or one of its peptide fragments, using techniques described herein. document for other antibodies. Alternatively, the TREM2-binding camelid nanobody is engineered, i.e., produced by selection, for example, from a phage library displaying appropriately mutagenized camelid nanobody proteins using targeting TREM2 panning procedures, as described in the examples in this document. Engineered nanobodies can be further adapted by genetic engineering to have a half-life in a recipient subject of 45 minutes to two weeks. In a specific embodiment, the camelid antibody or nanobody is obtained by grafting the CDR sequences of the heavy or light chain of the human antibodies of the invention onto single domain antibody or nanobody framework sequences, as described, for example , in document PCT / EP93 / 02214. Bispecific molecules and multivalent antibodies. In another aspect, the present invention features bispecific or multispecific molecules comprising an antibody binding to TREM2, or a fragment thereof, of the invention. An antibody of the invention, or its antigen-binding regions, can be derived from or linked to another functional molecule, eg, another peptide or protein (eg, another antibody or ligand for a receptor) to generate a bispecific binding molecule. to at least two different binding sites or target molecules. In fact, the antibody of the invention can be derived from or linked to more than one additional functional molecule, to generate multispecific molecules that bind to more than two different binding sites and / or target molecules; such multispecific molecules are also intended to be encompassed by the term bispecific molecule as used herein. To create a bispecific molecule of the invention, an antibody of the invention may be operatively linked (eg, by chemical coupling, gene fusion, non-covalent association, or otherwise) to one or more additional binding molecules, such as binding antibody, antibody fragment, peptide or mimetic, such that a bispecific molecule results. n / ztznn / i ζπζ / β / υιλι Accordingly, the present invention includes bispecific molecules comprising at least a first binding specificity for TREM2 and a second binding specificity for a second target epitope. For example, the second target epitope is another TREM2 epitope different from the first target epitope. Furthermore, for the invention in which the bispecific molecule is multispecific, the molecule may further include a third binding specificity, in addition to the first and second target epitopes. In one embodiment, the bispecific molecules of the invention comprise as binding specificity at least one antibody, or an antibody fragment thereof, including, for example, a Fab, Fab', F(ab')2, Fv or single-stranded Fv. The antibody can also be a heavy or light chain dimer, or any of their minimal fragments such as an Fv or a single chain construct as described in Ladner et al. United States Patent No. 4,946,778. Diabodies are bispecific bivalent molecules in which the VH and VL domains are expressed on a single polypeptide chain, connected by a linker that is too short to allow pairing between the two domains on the same chain. The VH and VL domains pair with complementary domains from another strand, so as to create two antigen-binding sites (see, for example, Holliger et aL, 1993 Proc. Nati. Acad. Sci. USA 90:6444-6448; Poijak et al., 1994 Structure 2:1121-1123). Diabodies can be produced by expressing two polypeptide chains either in the structure HAV-LBV and HBV-VLA (VH-VL configuration), or VLA-HBV and LBV-HAV (VL-VH configuration) within the same cell. Most of them can be expressed in soluble form in bacteria. Single-chain diabodies (scDb) are produced by connecting the two diabody-forming polypeptide chains with a linker of about 15 amino acid residues (see Holliger and Winter, 1997 Cancer Immunol. Immunother., 45 (3-4): 128-30 Wu et al, 1996 Immunotechnology, 2(1):21-36). scDb can be expressed in bacteria in an active and soluble monomeric form (see Holliger and Winter, 1997 Cancer Immunol. Immunother., 45(34):128-30; Wu et aL, 1996 Immunotechnology, 2(1):21-36; Pluckthun and Pack, 1997 Immunotechnology, 3(2):83-105, Ridgway et al, 1996 Protein Eng., 9(7):617-21). A diabody can be fused with Fe to generate a didiabody (see Lu et al., 2004 J. Biol. Chem., 279(4):2856-65). Other antibodies that can be used in the bispecific molecules of the invention are murine, chimeric, and humanized monoclonal antibodies. The bispecific molecules of the present invention can be prepared by conjugating the binding specificities of constituents, using methods known in the art. For example, each binding specificity of the bispecific molecule can be generated separately, and these can then be conjugated to each other. When the binding specificities are proteins or peptides, a variety of coupling or crosslinking agents can be used for covalent conjugation. n / ztznn / i ζπζ / ε / υιλι examples of crosslinking agents include protein A, carbodiimide, N-succinimidyl-5-acetylthioacetate (SATA), 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB), or -phenylendimaleimide (oPDM), Nsuccin¡m¡d¡l-3-(2-pyr¡d¡ld¡o) propionate (SPDP) and sulfosuccinimidyl 4-(N-maleimidomethyl)c¡clohaxane1-carboxylate ( sulfo-SMCC) (see, for example, Karpovsky et al., 1984 J. Exp. Med. 160:1686; Liu, MA et al., 1985 Proc. Nati. Acad. Sci. USA 82: 8648). Other methods include those described in Paulus, 1985 Behring Ins. Glove. No. 78, 118-132; Brennan et al., 1985 Science 229: 81-83), and Glennie et al., 1987 J. Immunol. 139: 2367-2375). Conjugating agents are SATA and sulfo-SMCC, both available from Pierce Chemical Co. (Rockford, IL). When the binding specificities are antibodies, they can be conjugated by sulfhydryl linkage of the C-terminus hinge regions of the two heavy chains. In a particular embodiment, the hinge region is modified to contain an odd number of sulfhydryl residues, eg, one, prior to conjugation. Alternatively, both binding specificities can be encoded on the same vector and expressed and assembled in the same host cell. This method is particularly useful when the bispecific molecule is a mAb X mAb, mAb X Fab, Fab X F(ab')2, or X Fab ligand fusion protein. A bispecific molecule of the invention may be a single-chain molecule comprising a single-chain antibody and a binding determinant, or a single-chain bispecific molecule comprising two binding determinants. Bispecific molecules can comprise at least two single-stranded molecules. Methods for preparing bispecific molecules are described, for example, in US Patent Nos. 5,260,203; United States Patent No. 5,455,030; US Patent No. 4,881,175; United States Patent No. 5,132,405; US Patent No. 5,091,513; United States Patent No. 5,476,786; US Patent No. 5,013,653; United States Patent No. 5,258,498; and US Patent No. 5,482,858. Binding of bispecific molecules to their specific targets can be confirmed by, for example, enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), FACS analysis, bioassay (eg, growth inhibition), or Western blot assay. Each of these assays generally detects the presence of protein-antibody complexes of particular interest by using a labeled reagent (eg, an antibody) specific for the complex of interest. In another aspect, the present invention provides multivalent compounds comprising at least two identical or different antigen-binding moieties of the antibodies and their antigen-binding fragments of the invention that bind to TREM2. The antigen-binding moieties may be linked together by protein fusion or covalent or non-covalent attachment. Alternatively, binding methods have been described for bispecific molecules. Tetravalent compounds can be obtained, for example, by cross-linking antibodies and their antigen-binding fragments of the invention with an antibody or antigen-binding fragment that binds to the regions. constants of the antibodies and their antigen-binding fragments of the invention, eg the Fe or hinge region. The trimerization domain is described, for example, in EP 1 012 280B1. Pentamerization modules are described, for example, in PCT / EP97 / 05897. In some embodiments, the TREM2 binding molecule is a bispecific antibody that binds both TREM2 and DAP12. In some embodiments, the TREM2 binding molecule is a bispecific antibody that recognizes a first antigen and a second antigen. In some embodiments, the first antigen is human TREM2 or one of its natural variants. In some embodiments, the second antigen is human DAP12 or one of its natural variants. In some embodiments, the second antigen is human DAP10 or a Siglec (sialic acid-binding immunoglobulin-like lectin). In some embodiments, the second antigen is a disease-causing protein selected from amyloid beta or its fragments, Tau, IAPP, alpha-synuclein, TDP-43, FUS protein, prion protein, PrPSc, huntingtin, calcitonin, superoxide dismutase, ataxin, Lewy body, atrial natriuretic factor, islet amyloid polypeptide, insulin, apolipoprotein Al, serum amyloid A, medin, prolactin, transthyretin, lysozyme, beta 2 microglobulin, gelsolin, keratoepithelin, cystatin, immunoglobulin AL light chain, protein S -IBM, Non-ATG Translational Products Associated Repeat (RAN), DiPeptide Repeat Peptides (DPR), Glycine-Alanine (GA) Repeat Peptides, Glycine-Proline (GP) Repeat Peptides, Glycine Repeat Peptides -arginine (GR), proline-alanine (PA) repeat peptides and proline-arginine (PR) repeat peptides. In some embodiments, the second antigen is a blood-brain barrier targeting protein selected from transferrin receptor, insulin receptor, insulin-like growth factor receptor, LRP-1, and LRP1; or ligands and / or proteins expressed in immune cells, wherein the ligands and / or proteins are selected from the group consisting of: CD40, 0X40, ICOS, CD28, CD137 / 4-1 BB, CD27, GITR, PDL1, CTLA4 , PD-L2, PD-1, B7-H3, B7-H4, HVEM, BTLA, KIR, GAL9, TIM3, A2AR, LAG, and phosphatidylserine. Alternatively, the second antigen can be a protein expressed on one or more tumor cells. Antibodies with extended half-life. The present invention provides antibodies that specifically bind to TREM2 and have an extended half-life in vivo. Many factors can affect the half-life of a protein in vivo. For example, renal filtration, metabolism in the liver, degradation by proteolytic enzymes (proteases), and immunogenic responses (for example, protein neutralization by antibodies and uptake by njztznn / i ζπζ / β / υιλι macrophages and dendritic cells) . A variety of strategies can be used to extend the half-life of the antibodies and their antigen-binding fragments of the present invention. For example, by chemical linkage to polyethylene glycol (PEG), reCODE PEG, antibody scaffolds, polysalic acid (PSA), hydroxyethyl starch (HES), albumin-binding ligands, and carbohydrate protectants; by genetic fusion to proteins that bind to serum proteins, such as albumin, IgG, FcRn, and transferrin; by coupling (genetic or chemical) to other binding moieties that bind to serum proteins, such as nanobodies, Fabs, DARPin, avimers, afibodies, and anticalins; by genetic fusion to rPEG, albumin, albumin domain, albumin and Fe binding proteins; or by incorporation into nanocarriers, slow-release formulations, or medical devices In order to prolong the serum circulation of antibodies in vivo, inert polymer molecules such as high molecular weight PEG can be attached to the antibodies or a fragment thereof with or without a multifunctional linker, or through specific conjugation of PEG site at the N or C terminus of antibodies, or via epsilon-amino groups present on lysine residues. To pegylate an antibody, the antibody, antigen-binding fragment thereof, is typically reacted with polyethylene glycol (PEG), such as a reactive ester or aldehyde derivative of PEG, under conditions in which one or more PEG groups become bind to the antibody or antibody fragment. Pegylation can be carried out by an acylation reaction or an alkylation reaction with a reactive PEG molecule (or an analogous reactive water-soluble polymer). As used herein, the term "polyethylene glycol" is intended to encompass any of the forms of PEG that have been used to derive other proteins, such as mono(C1-C10)alkoxyα- or aryloxypolyethylene glycol or polyethyleneglycol-maleimide. In one embodiment, the antibody to be pegylated is an aglycosylated antibody. Linear or branched polymer derivatization that produces minimal loss of biological activity will be used. The degree of conjugation can be closely monitored by SDS-PAGE and mass spectrometry to ensure proper conjugation of the PEG molecules with the antibodies. Unreacted PEG can be separated from the antibody-PEG conjugates by size exclusion chromatography or ion exchange chromatography. PEG-derived antibodies can be tested for binding activity as well as efficacy in vivo using methods well known to those skilled in the art, eg, by immunoassays described herein. Methods for pegylated proteins are known in the art and can be applied to the antibodies and their antigen-binding fragments of the invention. See, for example, EP 0 154 316 to Nishimura et al, and EP 0 401 384 to Ishikawa et al. Other modified pegylation technologies include reconstituting orthogonal chemically targeted engineering (ReCODE PEG) technology, which incorporates chemically specified side chains into biosynthetic proteins via a reconstituted system including tRNA synthase and tRNA. This technology allows the incorporation of more than 30 new amino acids into njztznn / i ζπζ / β / υιλι biosynthetic proteins in E. coli, yeast and mammalian cells. The tRNA incorporates a regulatory amino acid anywhere an amber codon is placed, converting the amber from a stop codon to one that signals incorporation of the chemically specified amino acid. Recombinant pegylation (rPEG) technology can also be used for extension of serum half-life. This technology involves genetically fusing a 300-600 amino acid unstructured protein tail with an existing pharmaceutical protein. Since the apparent molecular weight of such an unstructured protein chain is about 15 times greater than its actual molecular weight, the serum half-life of the protein is greatly increased. Unlike traditional PEGylation, which requires chemical conjugation and repurification, the manufacturing process is greatly simplified, and the product is homogeneous. Polysialicion is another technology that uses naturally occurring polymeric polysialic acid (PSA) to extend the active life and improve the stability of therapeutic peptides and proteins. PSA is a polymer of sialic acid (a sugar). When used for drug delivery of therapeutic peptides and proteins, polysialic acid provides a protective microenvironment upon conjugation. This increases the active life of the therapeutic protein in the circulation, and prevents it from being recognized by the immune system. The PSA polymer is found naturally in the human body. It was adopted by certain bacteria that evolved over millions of years to cover their walls. These naturally polysialylated bacteria were able, by virtue of molecular mimicry, to thwart the body's defense system. PSA, nature's latest stealth technology, can easily be produced from such bacteria in large numbers and with predetermined physical characteristics. Bacterial PSA is completely non-immunogenic, even when protein-coupled, since it is chemically identical to PSA in the human body. Other technology includes the use of hydroxyethyl starch (HES) derivatives linked to antibodies. HES is a modified natural polymer derived from waxy maize starch and can be metabolized by enzymes in the body. HES solutions are generally administered to replace deficient blood volume and to improve the rheological properties of blood. Hesylation of an antibody allows prolongation of the circulating half-life by increasing the stability of the molecule, as well as reducing renal clearance, resulting in increased biologic activity. By varying different parameters, such as the HES molecular weight, a wide range of HES-antibody conjugates can be customized. Antibodies that have an increased half-life in vivo can also be generated by introducing one or more amino acid modifications (i.e., substitutions, insertions, or deletions) into an IgG constant domain, or an FcRn-binding fragment thereof (preferably an Fe or a hinge Fe domain fragment). See, for example, International Publication No. WO 98 / 23289; International Publication No. WO 97 / 34631; and U.S. Pat. No. 6,277,375. n / ztznn / i ζπζ / β / υιλι In addition, antibodies can be conjugated to albumin to make the antibody or antibody fragment more stable in vivo or have a longer half-life in vivo. The techniques are well known in the art; see, for example, International Publications Nos. WO 93 / 15199, WO 93 / 15200 and WO 01 / 77137; and European Patent No. EP 413,622. Strategies to increase half-life are especially useful in nanobodies, fibronectin-based binders, and other antibodies or proteins for which increased in vivo half-life is desired. Antibody conjugates. The present invention provides antibodies or antigen-binding fragments thereof that specifically bind to the IgSF domain of human TREM2 recombinantly fused or chemically conjugated (including both covalent and non-covalent conjugations) to a heterologous protein or polypeptide (or fragment thereof). binding to antigen, preferably to a polypeptide of at least 10, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, per at least 90 or at least 100 amino acids) to generate fusion proteins. In particular, the invention provides fusion proteins comprising an antigen-binding fragment of an antibody described herein (for example, a Fab fragment, Fd fragment, Fv fragment, F(ab)2 fragment, a VH domain, a VH CDR, a VL domain or a VL CDR and a heterologous protein, polypeptide or peptide Methods for fusing or conjugating proteins, polypeptides or peptides to an antibody or antibody fragment are known in the art See, for example , United States Patent Nos. 5,336,603, 5,622,929, 5,359,046, 5,349,053, 5,447,851, and 5,112,946; European Patent Nos. EP 307,434 and EP 367,166; International Publications Nos. WO 96 / 04388 and WO 91 / 06570, Ashkenazi et al., 1991, Proc. Nati. Acad. Sci. USA 88: 10535-10539, Zheng et al., 1995, J. Immunol. 154:5590-5600, and Vil et al., 1992, Proc. Nati. Acad. Sci. USA 89:11337-11341. Additional fusion proteins can be generated through the techniques of gene shuffling, motif shuffling, exon shuffling, and / or codon shuffling (collectively referred to as DNA shuffling). DNA shuffling can be used to alter the activities of antibodies and antigen-binding fragments thereof of the invention (eg, antibodies and antigen-binding fragments thereof with higher affinities and lower dissociation rates). See, generally, US Pat. Nos. 5,605,793, 5,811,238, 5,830,721, 5,834,252 and 5,837,458; Patten et al., 1997, Curr. Opinion BiotechnoL 8: 724-33; Harayama, 1998, Trends Biotechnol. 16(2):76-82; Hansson, et al, 1999, J. Mol. Biol. 287: 265-76; and Lorenzo and Blasco, 1998, Biotechniques 24(2): SOSSIS (each of these patents and publications are incorporated herein by reference in their entirety). Antibodies and their antigen-binding fragments, or encoded antibodies and their antigen-binding fragments, can be altered when subjected to random PCR mutagenesis prone to n / ztznn / i ζπζ / ε / υιλι errors, random nucleotide insertion, or other methods before recombination. A polynucleotide encoding one of its antibody antigen-binding fragments that specifically binds to the TREM2 IgSF region can be recombined with one or more components, motifs, sections, parts, domains, fragments, etc. of one or more heterologous molecules. In addition, the antibodies and antigen-binding fragments thereof can be fused to marker sequences, such as a peptide, to facilitate purification. In one embodiment, the marker amino acid sequence is a hexahistidine peptide, such as the tag provided in a pQE vector (QIAGEN, Inc., 9259 Eton Avenue, Chatsworth, California, 91311), among others many of the which are commercially available. As described in Gentz ​​et al., 1989, Proc. nati. Acad. Sci. USA 86: 821-824, for example, hexahistidine provides convenient purification of the fusion protein. Other useful peptide tags for purification include, among others, the hemagglutinin (HA) tag, which corresponds to an epitope derived from the influenza hemagglutinin protein (Wilson et al., 1984, Cell 37:767), and the FLAG tag (Hopp et al., Bio / Technology 6 (1988): 1204-1210). In one embodiment, the antibodies and their antigen-binding fragments of the present invention are conjugated to a detectable or diagnostic agent. Such antibodies may be useful in monitoring or predicting the onset, development, progression, and / or severity of a disease or disorder as part of a clinical evaluation procedure, such as determining the efficacy of a particular therapy. Said diagnosis and detection may be accomplished by coupling the antibody to detectable substances including, without limitation, various enzymes, such as, without limitation, horseradish peroxidase, alkaline phosphatase, beta-galactosidase, or acetylcholinesterase; prosthetic groups, such as, without limitation, streptavidin / biotin and avidin / biotin; fluorescent materials, such as, without limitation, umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride, or phycoerythrin; luminescent materials, such as, without limitation, luminol; bioluminescent materials, such as, without limitation, luciferase, luciferin, and aequorin; radioactive materials such as, but not limited to, iodine (1311, 1251, 1231, and 1211), carbon (14C), sulfur (35S), tritium (3H), indium (115ln, 113ln, 112ln, and 111ln), technetium (99Tc) , stem (201 Ti), gallium (68Ga, 67Ga), palladium (103Pd), molybdenum (99Mo), xenon (133Xe), fluorine (18F), 153Sm, 177Lu, 159Gd, 149Pm, 140La, 175Yb, 166Ho, 90Y , 47Sc, 186Re, 188Re, 142Pr, 105Rh, 97Ru, 68Ge, 57Co, 65Zn, 85Sr, 32P, 153Gd, 169Yb, 51Cr, 54Mn, 75Se, 113Sn and 117Tin; and positron-emitting metals using various non-radioactive paramagnetic metal ion and positron emission tomography scans. In addition, an antibody or antigen-binding fragment thereof can be conjugated to a therapeutic moiety or drug moiety. Therapeutic moieties or drug moieties are not to be construed as being limited to classical chemical therapeutic agents. For example, the moiety of the drug may nyztznn / i ζπζ / ε / υιλι be a protein, peptide, or polypeptide possessing a desired biological activity. Such proteins may include, for example, a toxin such as abrin, ricin A, pseudomonas exotoxin, cholera toxin, or diphtheria toxin; a protein such as tumor necrosis factor, alpha-interferon, beta-interferon, nerve growth factor, platelet-derived growth factor, tissue plasminogen activator, an apoptotic agent, an antiangiogenic agent; or a biological response modifier such as, for example, a lymphokine. In addition, an antibody can be conjugated to therapeutic moieties such as a radioactive metal ion, such as alpha emitters such as 213Bi or macrocyclic chelators useful for conjugating radiometal ions, including, but not limited to, 131 In, 131LU, 131Y, 131Ho, 131Sm, to polypeptides. In one embodiment, the macrocyclic chelator is 1,4,7,10-tetraazacyclododecane-N,N',N,N'tetraacetic acid (DOTA), which can be attached to the antibody via a linker molecule. Such linker molecules are commonly known in the art and are described in Denardo et al., 1998, Clin Cancer Res. 4(10): 2483-90; Peterson et al., 1999, Bioconjug. Chem 10(4): 553-7; and Zimmerman et al., 1999, Nuci. Med. Biol. 26(8): 943-50, each, incorporated by reference in their entirety. Techniques for conjugating therapeutic moieties with antibodies are well known, see, for example, Amon et al., Monoclonal Antibodies For Immunotargeting Of Drugs In Cancer Therapy, in Monoclonal Antibodies And Cancer Therapy, Reisfeld et al. (eds.), p. 243-56 (Alan R. Liss, Inc. 1985); Hellstrom et al., Antibodies For Drug Delivery, in Controlled Drug Delivery (2ndEd.), Robinson et al. (eds.), p. 623-53 (Marcel Dekker, Inc. 1987); Thorpe, Antibody Carriers Of Cytotoxic Agents In Cancer Therapy: A Review, in Monoclonal Antibodies 84: Biological And Clinical Applications, Finchera et al. (eds.), p. 475-506 (1985); Analysis, Results, And Future Prospective Of The Therapeutic Use Of Radiolabeled Antibody In Cancer Therapy, in Monoclonal Antibodies For Cancer Detection And Therapy, Baldwin et al. (eds.), p. 303-16 (Academic Press 1985), and Thorpe et al., 1982, ImmunoL Rev. 62:119-58. Antibodies can also be attached to solid supports, which are particularly useful for immunoassays or purification of the target antigen. Such solid supports include, among others, glass, cellulose, polyacrylamide, nylon, polystyrene, polyvinyl chloride, or polypropylene. Nucleic acids encoding antibodies. Also provided herein are nucleic acids encoding an antibody or antigen-binding fragment herein described. Such nucleic acids may encode polypeptides comprising segments or domains of the hTREM2 antibodies or antigen-binding fragments thereof described herein. Said nucleic acids or polynucleotides may encode at least one CDR region and usually all three CDR regions of the heavy or light chain of the hTREM2 antibodies described herein. Such nucleic acids or polynucleotides may also encode all or substantially all of the heavy chain and / or light chain variable region sequence of the hTREM2 antibodies described herein. Said nucleic acids or njztznn / i ζπζ / β / υιλι polynucleotides can also encode both a variable region and a constant region of the antibody. Due to the degeneracy of the genetic code, a variety of nucleic acid sequences will encode each of the immunoglobulin amino acid sequences. For example, the invention features first and second nucleic acids encoding heavy and light chain variable regions, respectively, of an hTREM2 antibody or an antigen-binding fragment thereof selected from one or more of the antibodies described herein. The nucleic acid may comprise a nucleotide sequence as set forth in Table 1, or a sequence substantially identical thereto (for example, a sequence having at least about 85%, 90%, 95%, or 99% identity). of sequence to it, or differing by no more than 3, 6, 15, 30, or 45 nucleotides from the sequences shown in Table 1). The nucleic acid may comprise more than one nucleotide sequence as set out in Table 1 (for example, a light chain variable domain sequence and a heavy chain variable domain sequence, or for example, a light chain sequence or a heavy chain sequence), or a sequence substantially identical to it (for example, a sequence that has at least about 85%, 90%, 95%, or 99% sequence identity to it, or that differs at no more than 3, 6, 15, 30, or 45 nucleotides from the sequences shown in Table 1). In certain embodiments, the nucleic acid may comprise a nucleotide sequence encoding at least one, two, or three CDRs or hypervariable loops of a heavy chain variable region having an amino acid sequence as set forth in Table 1, or a sequence substantially homologous to it (for example, a sequence that has at least about 85%, 90%, 95%, or 99% sequence identity to it, and / or that has one or more substitutions, for example , conserved substitutions). In other embodiments, the nucleic acid may comprise a nucleotide sequence encoding at least one, two, or three CDRs or hypervariable loops of a light chain variable region having an amino acid sequence as set forth in Table 1, or a sequence substantially homologous to it (for example, a sequence that has at least about 85%, 90%, 95%, or 99% sequence identity to it, and / or has one or more substitutions, for example , conserved substitutions). In yet another embodiment, the nucleic acid may comprise a nucleotide sequence encoding at least one, two, three, four, five, or six CDRs or hypervariable loops of heavy and light chain variable regions having an amino acid sequence as set forth in Table 1, or a sequence substantially homologous to it (for example, a sequence that has at least about 85%, 90%, 95%, or 99% sequence identity to it, and / or that has one or more substitutions, eg, conserved substitutions). In certain embodiments, the nucleic acid may comprise a nucleotide sequence encoding at least one, two, or three CDRs or hypervariable loops of a n / 7bnn / i ζπζ / ε / υιλι heavy chain variable region having the sequence of nucleotides as set forth in Table 1, a sequence substantially homologous to it (eg, a sequence having at least about 85%, 90%, 95%, or 99% sequence identity to it). In another embodiment, the nucleic acid may comprise a nucleotide sequence encoding at least one, two, or three CDRs or hypervariable loops of a light chain variable region having the nucleotide sequence as set forth in Table 1. , or a sequence substantially homologous thereto (eg, a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto). In yet another embodiment, the nucleic acid may comprise a nucleotide sequence encoding at least one, two, three, four, five, or six CDRs or hypervariable loops of heavy and light chain variable regions having the nucleotide sequence as set forth in Table 1, or a sequence substantially homologous thereto (eg, a sequence having at least about 85%, 90%, 95%, or 99% sequence identity thereto). Polynucleotide sequences can be produced by de novo synthesis (eg, solid phase DNA synthesis) or by PCR mutagenesis of an existing sequence encoding an hTREM2 antibody or antigen-binding fragment thereof. Direct chemical synthesis of nucleic acids can be accomplished by methods known in the art, such as the phosphotriester method of Narang et al., 1979, Meth. Enzymol 68:90; The phosphodiester method of Brown et al, Meth. Enzymol 68: 109, 1979; the diethylphosphoramidite method of Beaucage et al, Tetra. Lett., 22: 1859, 1981; and the solid support method of US Patent No. 4,458,066. Introduction of mutations into a polynucleotide sequence by PCR can be performed as described in, for example, PCR Technology: Principles and Applications for DNA Amplification, H. A. Erlich (Ed.), Freeman Press, NY, N.Y., 1992; PCR Protocols: A Guide to Methods and Applications, Innis et al. (Ed.), Academic Press, San Diego, Calif., 1990; Mattila et al., Nucleic Acids Res. 19:967, 1991; and Eckert et al., PCR Methods and Applications 1:17, 1991. Also provided herein are vectors (eg, expression vectors) comprising a polynucleotide encoding a polypeptide comprising a segment or domain of the hTREM2 antibodies or antigen-binding fragments thereof described herein. Such vectors can be used to express and / or produce, or affect the expression of, an hTREM2 antibody or antigen-binding fragments (eg, as described herein), eg, in cells ex vivo or in cells in vivo. eg in a tissue or tissues of interest in an organism. Various expression vectors can be used to express the polynucleotides encoding the hTREM2 antibodies or junction fragments thereof. Both viral and non-viral expression vectors can be used to produce the antibodies or fragments thereof in a cell, eg, a mammalian cell. Non-viral n / ztznn / i ζπζ / β / υιλι vectors and systems include plasmids, episomal vectors, typically with an expression cassette to express a protein or RNA, and human artificial chromosomes (see, for example, Harrington et al., Nat Genet. 15: 345, 1997). Such non-viral vectors can be delivered to a cell of interest using methods of transfection or transduction known in the art, eg, using lipids (eg, lipofectamine), electroporation, mechanical distortion of the cell membrane, and the like. The term "expression vector" refers to a carrier nucleic acid molecule into which a desired coding sequence can be inserted for introduction into a cell where it can be expressed. The vector can be a DNA vector, RNA vector, plasmid, cosmid or viral vector, or artificial chromosomes (see, for example, Harrington et al., Nat Genet 15: 345, 1997). For example, non-viral vectors useful for expression of hTREM2 antibodies or their antigen-binding fragments in mammalian (eg, human) cells include pThioHis A, B, and C, pcDNA3.1 / His, pEBVHis A , B and C (Invitrogen, San Diego, California), MPSV vectors, and many other vectors known in the art to express proteins. For example, one class of vectors uses DNA elements that are derived from animal viruses such as bovine papilloma virus, polyoma virus, adenovirus, vaccinia virus, baculovirus, retrovirus (Rous sarcoma virus, MMTV, or MOMLV) or SV40 virus. Another class of vectors uses RNA elements derived from RNA viruses such as Semliki Forest virus, Eastern equine encephalitis virus, and flaviviruses. Useful viral vectors include vectors based on any of the following viruses: retrovirus (eg, lentivirus), adenovirus lentivirus, adeno-associated virus, herpes virus (eg, herpes simplex virus (HSV)), vectors SV40-based, papillomavirus, Epstein Barr HBP virus, vaccinia virus, Sinbis virus, influenza virus, reovirus, Newcastle disease virus (NDV), measles virus, vesicular stomatitis virus ( VSV), parvovirus, poliovirus, poxvirus, Seneca Valley virus, coxsackievirus, enterovirus, myxoma virus, maraba virus, or Semliki Forest virus (SFV). See, Brent et al, supra; Smith, Ann. Rev. Microbiol. 49:807, 1995; and Rosenfeld et al, Cell 68:143, 1992. In some embodiments, the vector is a retroviral vector. In some embodiments, the vector is a lentiviral vector. Retrovirus-derived vectors such as the lentivirus are suitable tools to achieve long-term gene transfer, as they allow long-term stable integration of a transgene and its propagation in progeny cells. Lentiviral vectors have the added advantage over vectors derived from oncoretroviruses, such as murine leukemia viruses, in that they can transduce non-proliferating cells, such as hepatocytes. They also have the added advantage of low immunogenicity. A retroviral vector can also be, for example, a gammarretroviral vector. A gammarretroviral vector can include, for example, a promoter, a packaging signal (ψ), a primer binding site (PBS), one or more (eg, two) long terminal repeats (LTRs) and a transgene of interest, eg, a gene encoding a CAR. A gammarretroviral vector may n / ztznn / i ζπζ / β / υιλι lack viral structural genes such as gag, pol and env. Examples of gamma retroviral vectors include murine leukemia virus (MLV), spleen focus formation virus (SFFV) and myeloproliferative sarcoma virus (MPSV), and vectors derived therefrom. Other gammaretroviral vectors are described, for example, in Tobias Maetzig et al., "Gammaretroviral Vectors: Biology, Technology and Application" Viruses. 2011 Jun; 3(6): 677-713. In some embodiments, the vector is an adeno-associated virus (AAV) vector, eg, a recombinant AAV (rAAV) vector. AAV is an abbreviation for adeno-associated virus, and can be used to refer to the virus itself or its derivatives. The term covers all subtypes and both natural and recombinant forms, except where otherwise required. The abbreviation rAAV refers to recombinant adeno-associated virus, also called recombinant AAV vector (or rAAV vector). The term AAV includes, for example, AAV type 1 (AAV1), AAV type 2 (AAV2), AAV type 3 (AAV3), AAV type 4 (AAV4), AAV type 5 (AAV5), AAV type 6 (AAV6), AAV type 7 (AAV7), AAV type 8 (AAV8), AAV type 9 (AAV9), AAV type 10 (AAV10, which includes AAVrhl 0), AAV type 12 (AAV12), Avian AAV, Bovine AAV, Canine AAV, AAV equine, primate AAV, non-primate AAV, and ovine AAV. "Primate AAV" refers to AAV that infects primates, "non-primate AAV" refers to AAV that infects non-primate mammals, "bovine AAV" refers to AAV that infects bovine mammals, etc. The genomic sequences of various AAV serotypes, as well as the sequences of native inverted terminal repeats (ITRs), Rep proteins, and capsid subunits are known in the art. Such sequences can be found in the literature or in public databases such as GenBank. See, for example, GenBank Access Nos. NC-002077 (AAV1), AF063497 (AAV1), NC001401 (AAV2), AF043303 (AAV2), NC-001729 (AAV3), NC-001829 (AAV4), U89790 (AAV4), NC006152 (AAV5), AF513851 (AAV7) , AF513852 (AAV8) and NC-006261 (AAV8); or in publications such as WO 2005033321 (AAV1-9), the contents of which are incorporated by reference herein. See also, for example, Srivistava et al. (1983) J. Virology 45:555; Chiorini et al. (1998) J. Virology 71 :6823; Chiorini et al. (1999) J. Virology 73:1309; Bantel-Schaal et al. (1999) J. Virology 73:939; Xiao et al. (1999) J. Virology 73:3994; Muramatsu et al. (1996) Virology 221 :208; Shade et al, (1986) J. Virol. 58:921; Gao et al. (2002) Proc. Nat. Acad. Sci. USA 99: 11854; Morís et al. (2004) Virology 33:375383; International Patent Publications WO 00 / 28061, WO 99 / 61601, WO 98 / 11244; and US Patent No. 6,156,303. An rAAV vector as used herein refers to an AAV vector comprising a polynucleotide sequence of non-AAV origin (i.e., a polynucleotide heterologous to AAV), typically a sequence of interest for genetic transformation of a cell. In some embodiments, the heterologous polynucleotide may be flanked by at least one, and sometimes two, AAV inverted terminal repeat (ITR) sequences. The term rAAV vector encompasses n / ztznn / i ζπζ / β / υιλι both rAAV vector particles and rAAV vector plasmids. An rAAV vector can be single-stranded (ssAAV) or self-complementary (scAAV). An AAV virus or AAV viral particle or rAAV vector particle refers to a viral particle composed of at least one AAV capsid protein (typically all capsid proteins, or derived from one or more AAV capsid proteins). wild-type) and an rAAV encapsulated polynucleotide vector. If the particle comprises a heterologous polynucleotide (ie, a polynucleotide that is not a wild-type AAV genome, such as a transgene for delivery to a mammalian cell), it is typically referred to as a rAAV vector particle or simply a rAAV vector. . Therefore, the production of rAAV particles necessarily includes the production of rAAV vectors, since such a vector is contained within a rAAV particle. In some embodiments, the vector may be a recombinant DNA molecule comprising a nucleic acid encoding an hTREM2 antibody or an antigen-binding fragment thereof, for example as described herein. Recombinant as used herein means that the vector, polynucleotide, polypeptide, or cell is the product of various combinations of cloning, restriction, or ligation steps (for example, related to a polynucleotide or polypeptide encompassed therein), and / or other procedures that result in a construction that is distinct from a product found in nature. A recombinant virus or vector is a viral particle that comprises a recombinant polynucleotide. The terms respectively include replicates of the original polynucleotide construct and progeny of the original virus construct. The recombinant vector typically includes one or more regulatory sequences operatively linked to the nucleic acid sequence to be expressed. The term "regulatory sequence" includes promoters, enhancers, and other expression control elements (eg, polyadenylation signals). Regulatory sequences include those that direct constitutive expression of a nucleotide sequence, as well as tissue-specific regulatory and / or inducible sequences. Expression vectors may also include elements designed to optimize stability and translatability of messenger RNA in host cells, and / or drug selection markers to establish permanent stable cell clones expressing an hTREM2 antibody or a binding fragment thereof. antigen, eg, as described herein. Expression vector design may depend on factors such as the choice of host cell to be transformed, the expression level of the desired protein, and the like. General methods for generating such recombinant expression vectors can be found in Sambrook and Russell eds. (2001) Molecular Cloning: A Laboratory Manual, 3rd edition; the Ausubel et al. eds. (2007 updated to 2010), Current Protocols in Molecular Biology, among others known in the art. n / ztznn / i ζπζ / ε / υιλι A specific start signal may also be required for efficient translation of coding sequences. These signals include the ATG initiation codon or adjacent sequences. Exogenous translational control signals, including the ATG initiation codon, may need to be provided. One skilled in the art would be able to determine this and provide the necessary signals. It is well known that the initiation codon must be in frame with the reading frame of the desired coding sequence to ensure translation of the entire insert. The exogenous translation control signals and initiation codons can be natural or synthetic. Expression efficiency can be improved by including appropriate transcription enhancer elements. The expression may employ any appropriate host cell known in the art, eg, mammalian host cells, bacterial host cells, yeast host cells, insect host cells, etc. Both prokaryotic and eukaryotic expression systems are widely available. In some embodiments, the expression system is a mammalian cell expression, such as a CHO cell expression system. In some embodiments, a nucleic acid may be codon optimized to facilitate expression in a desired host cell. It will be important to employ a promoter and / or enhancer that effectively drives the expression of the DNA segment in the cell type, organelle, and organism chosen for expression. The use of promoters, enhancers, and combinations of cell types for protein expression is generally known to those skilled in the art of molecular biology, for example, see Sambrook et al. (2001) Most transcribed eukaryotic RNA molecules will undergo RNA splicing to remove introns from the primary transcripts. Vectors containing eukaryotic genomic sequences may require donor and / or acceptor splice sites to ensure proper processing of transcription for protein expression (see Chandler et al., 1997, Proc. Nati. Acad. Sci. USA, 94(8):3596-601). Vectors or constructs of the present disclosure will generally comprise at least one termination signal. A termination signal or terminator is made up of the DNA sequences involved in the specific termination of an RNA transcription by an RNA polymerase. Therefore, in certain embodiments, a termination signal is contemplated that terminates the production of an RNA transcript. An in vivo terminator may be necessary to achieve desirable message levels. In eukaryotic systems, the terminator region may also comprise specific DNA sequences that allow site-specific cleavage of new transcription to expose a polyadenylation site. This signals a specialized endogenous polymerase to add a stretch of about 200 A residues (poly A) to the 3' end of the transcript. RNA molecules modified with this polyA tail appear to be more stable and translate n / ztznn / i ζπζ / β / υιλι more efficiently. Therefore, in other embodiments involving eukaryotes, it is preferred that the terminator comprise a signal for RNA cleavage, and it is more preferred that the terminator signal promote polyadenylation of the message. Terminator and / or polyadenylation site elements may serve to enhance message levels and / or minimize readthrough from the cassette to other sequences. Terminators contemplated for use in the disclosure include any known transcription terminator described herein or known to one of ordinary skill in the art, including, without limitation, for example, gene termination sequences, such as the terminator of bovine growth hormone or viral termination sequences, such as the SV40 terminator. In certain embodiments, the termination signal may be a lack of transcriptional or translatable sequence, such as due to sequence truncation. In expression, particularly eukaryotic expression, a polyadenylation signal will typically be included to effect proper polyadenylation of transcription. The nature of the polyadenylation signal is not believed to be crucial to the successful practice of the disclosure, and / or any such sequence may be employed. Preferred embodiments include the SV40 polyadenylation signal and / or the bovine growth hormone polyadenylation signal, suitable and / or known to work well in various target cells. Polyadenylation may increase transcriptional stability or may facilitate cytoplasmic transport. To propagate a vector in a host cell, it may contain one or more origin of replication sites (often referred to as an ori), which is a specific nucleic acid sequence at which replication begins. Alternatively, an Autonomous Replication Sequence (ARS) may be employed if the host cell is yeast. In certain embodiments of the disclosure, cells containing a nucleic acid construct of the present disclosure can be identified in vitro or in vivo, including a marker in the expression vector. Such markers will confer an identifiable change to the cell, so as to allow easy identification of cells containing the expression vector. Generally, a selectable marker is one that confers a property that allows selection. A positive selectable marker is one in which the presence of the marker allows its selection, while a negative selectable marker is one in which its presence prevents its selection. An example of a positive selectable marker is a drug resistance marker. In general, the inclusion of a drug selection marker aids in the cloning and identification of transformants; for example, genes that confer resistance to neomycin, puromycin, hygromycin, DHFR, GPT, zeocin, and histidinol are useful selectable markers. In addition to markers that confer a phenotype that allows discrimination of transformants based on implementation conditions, other types of markers are also contemplated, including n / ztznn / i ζπζ / β / υιλι screening markers, such as GFP, whose base is the colorimetric analysis. Alternatively, detectable enzymes such as herpes simplex virus thymidine kinase (HSV-tk) or chloramphenicol acetyltransferase (CAT) may be used. One skilled in the art would also know how to employ immunological markers, possibly in conjunction with FACS analysis. The marker used is not believed to be important, as long as it is capable of co-expressing with the nucleic acid encoding a gene product. Additional examples of critical and selectable markers are known to those skilled in the art. The choice of expression vector depends on the anticipated cells in which one or more components of the vector are to be expressed. Vectors typically contain one or more regulatory sequences, such as a promoter and other regulatory sequence (eg, enhancers) that are operably linked to polynucleotides encoding an hTREM2 antibody or antigen-binding fragment thereof. A promoter is a control sequence which is a region of a nucleic acid sequence where the initiation and rate of transcription is controlled. It may contain genetic elements to which proteins and regulatory molecules, such as RNA polymerase and other transcription factors, can bind. The phrases operatively positioned, operably linked, given control, and given transcriptional control mean that a promoter is in a correct functional location or orientation relative to a nucleic acid sequence to control transcriptional initiation and / or expression of that sequence. A promoter may or may not be used in conjunction with an enhancer, which refers to a cis-acting regulatory sequence involved in transcriptional activation of a nucleic acid sequence. A promoter may be naturally associated with a gene or sequence, as may be obtained by isolating 5' non-coding sequences located upstream of the coding segment and / or exon. Said promoter can be referred to as endogenous. Similarly, an enhancer can be one naturally associated with a nucleic acid sequence, located downstream or upstream of said sequence. Alternatively, certain advantages will be obtained by placing the encoding nucleic acid segment under the control of a recombinant or heterologous promoter, which refers to a promoter that is not normally associated with a nucleic acid sequence in its natural environment. A recombinant or heterologous enhancer also refers to an enhancer that is not normally associated with a nucleic acid sequence in its natural environment. Such promoters or enhancers may include promoters or enhancers from other genes, and promoters or enhancers isolated from any other prokaryotic, viral or eukaryotic cell, and non-naturally occurring / non-natural promoters or enhancers, i.e. containing different elements from different regions. transcription regulators, and / or mutations that alter expression. In addition to producing nucleic acid sequences of n / ztznn / i ζπζ / β / υιλι promoters and enhancers synthetically, the sequences can be produced using recombinant cloning and / or nucleic acid amplification technology, eg, PCR, in conjunction with the compositions described in this document (see US 4683202, US 5928906). In addition, it is contemplated that control sequences that direct the transcription and / or expression of sequences within non-nuclear organelles such as mitochondria, chloroplasts, and the like, may also be employed. The promoters employed may be constitutive, inducible, synthetic, tissue- or cell-specific, and / or useful under the appropriate conditions to drive high-level expression of the introduced DNA segment, as is advantageous in large-scale production of proteins and / or recombinant peptides. In addition, other regulatory elements may also be incorporated to enhance the expression of a nucleic acid encoding an antibody that binds to human TREM2 (i.e., hTREM2) protein, eg, enhancers, ribosome binding site, termination sequences. transcription and the like. In some embodiments, a constitutive promoter is employed to provide constant expression of an hTREM2 antibody or an antigen-binding fragment thereof. Examples of a constitutive promoter include, without limitation, the cytomegalovirus (CMV) immediate early promoter, the simian virus 40 (SV40) early promoter, the mouse mammary tumor virus (MMTV) promoter, the terminal repeat promoter long human immunodeficiency virus (HIV) (LTR) promoter, MoMuLV promoter, an avian leukemia virus promoter, an Epstein-Barr virus immediate early promoter, a Rous sarcoma virus promoter, as well as gene promoters such as, inter alia, the actin promoter, the myosin promoter, the elongation factor-1α promoter, the hemoglobin promoter and the creatine kinase promoter. In one embodiment, an inducible promoter is used to prevent expression of inserted sequences except under inducing conditions. The use of an inducible promoter provides a molecular switch or switch capable of turning on expression of the polynucleotide sequence that is operably linked when such expression is desired, or turning off expression, when expression is not desired. Examples of inducible promoters include, without limitation, a metallothionein promoter. Inducible promoters include, without limitation, for example, an arabinose promoter, lacZ promoter, tetracycline promoter, metallothionein promoter, glucocorticoid promoter, progesterone promoter, or heat shock promoter. In addition to promoters, other regulatory elements may also be required or desired for efficient expression of an hTREM2 antibody or antigen-binding fragment thereof. These elements include an ATG initiation codon and an adjacent ribosome binding site or other sequences. Furthermore, the efficiency of expression can be improved by including enhancers appropriate for the cell system in use (see, for example, Scharf et al., Results Probl. Cell Differ. n / ztznn / i ζπζ / β / υιλι 20:125, 1994; and Bittner et al., Meth. Enzymol., 153: 516, 1987). For example, the SV40 enhancer or the CMV enhancer can be used to increase expression in mammalian host cells. In some embodiments, a tissue- or cell-specific promoter is employed to provide expression of an hTREM2 antibody or antigen-binding fragment thereof only in specific tissues or cells. The identity of tissue- or cell-specific promoters or elements, as well as assays to characterize their activities, are well known to those skilled in the art. Examples include the human LIMK2 gene (Nomoto et al. 1999, Gene, 236(2):259-271), the somatostatin 2 receptor gene (Kraus et al., 1998, PEES Lett., 428(3): 165-170), murine epididymal retinoic acid binding gene (Lareyre et al, 1999, J. BioL Chem., 274 (12): 8282-8290), human CD4 (Zhao-Emonet et al, 1998, Biochirn. Biophys Acta, 1442 (2-3): 109-119), mouse collagen alpha2 (XI) (Tsumaki, et al., 1998, J. BioL Chem., 273 (36): 22861-22864), receptor gene dopamine D1A (Lee , et al., 1997, J. Auton. Nerv. Syst., 74 (2-3): 86-90), insulin-like growth factor II (Wu et al., 1997, Biochem. Biophys Res. Commun., 233(1):221-226), human platelet endothelial cell adhesion molecule-1 (Almendro et al, 1996, J. Immunol., 157(12):5411-5421), promoter of muscle creatine kinase (MCK) ( Wang et al, Gene Ther. 2008 Nov;15(22):1489-99). In some embodiments, a synthetic promoter is used to provide expression of an hTREM2 antibody or an antigen-binding fragment thereof. Synthetic promoters can greatly exceed the transcriptional power of natural promoters. For example, one can select for synthetic promoters that are not turned off or reduced in activity by endogenous cellular machinery or factors. Other elements, including enhancer and trans-acting factor binding sites, can be inserted into the synthetic promoter to improve transcriptional efficiency. Synthetic promoters can be rationally designed and chemically synthesized to combine the best features of synthetic and biological promoters. The synthetic oligos are annealed and ligated through various processes to generate the full length chemically synthesized promoter. Synthetic promoters can be inducible or cell-type specific promoters. In a preferred embodiment, the vector is an adeno-associated (AAV) vector. In embodiments, the AAV vector comprises a polynucleotide encoding an hTREM2 antibody or an antigen-binding fragment thereof, eg, as described herein. In typical embodiments, the AAV vector comprises a polynucleotide encoding an hTREM2 antibody or a binding fragment thereof that is flanked on one or both sides by an inverted terminal repeat (ITR) sequence. The polynucleotide may further comprise one or more additional elements such as, for example, a promoter, an enhancer, one or more intron sequences, a poly(A) sequence, and combinations thereof. In some embodiments, the vector comprises an AAV polynucleotide vector plasmid comprising the njztznn / i ζπζ / β / υιλι polynucleotide encoding an hTREM2 antibody or an antigen-binding fragment thereof, for example, as described herein, encapsulated in an AAV capsid. In some embodiments, the vector comprises the polynucleotide encoding an hTREM2 antibody or an antigen-binding fragment thereof, eg, as described herein, operatively linked to at least one target cell-compatible regulatory sequence. eg a promoter. In some embodiments, the ITRs in the AAV vector are derived from the same AAV serotype. In some embodiments, the ITRs in the AAV vector are derived from different AAV serotypes. In some embodiments, the ITRs on the AAV particle are the same. In embodiments, the ITRs on the AAV particle are different. In some embodiments, the ITRs in the AAV vector are derived from the same AAV serotype as the AAV capsid. In embodiments, the ITRs in the AAV vector are derived from a different serotype than the AAV capsid. In one embodiment, the ITRs are derived from AAV2 and the AAV capsid is derived from a serotype other than AAV2, eg, AAV9. Expression vectors can also provide a secretion signal sequence position to form a fusion protein with polypeptides encoded by inserted hTREM2 antibody sequences or their antigen-binding fragment. More often, the inserted sequences of an hTREM2 antibody or an antigen-binding fragment thereof are ligated to a signal sequence prior to their inclusion in the vector. Vectors that will be used to receive sequences encoding the heavy and light chain variable domains of the hTREM2 antibody sometimes also encode constant regions or parts thereof. Such vectors allow expression of the variable regions as fusion proteins with the constant regions, leading to the production of intact antibodies and antigen-binding fragments thereof. Typically, such constant regions are human. Generation of an expression vector can use a vector that includes a multiple cloning site (MCS), which is a region of nucleic acid that contains multiple restriction enzyme sites, any one of which can used in conjunction with standard recombinant technology to digest the vector. See Carbonelli et al., 1999, Levenson et al., 1998, and Cocea, 1997. Restriction enzyme digestion refers to the catalytic cleavage of a nucleic acid molecule with an enzyme that functions only at specific locations in a nucleic acid molecule. nucleic. Many of these restriction enzymes are commercially available. The use of such enzymes is well understood by those skilled in the art. Often, a vector is linearized or cleaved using a restriction enzyme that cuts within the MCS to allow foreign sequences to be ligated into the vector. Ligation refers to the process of forming phosphodiester bonds between two nucleic acid fragments, which may or may not be contiguous with each other. Techniques involving restriction enzymes and ligation reactions are well known to those skilled in the art of recombinant technology. Methods for introducing expression vectors containing the polynucleotide sequences of interest vary according to the type of host cell. For example, calcium chloride transfection is commonly used for prokaryotic cells, while calcium phosphate treatment or electroporation can be used for other cell hosts (see generally Sambrook et al, Supra). Other methods include, for example, electroporation, calcium phosphate treatment, liposome-mediated transformation, injection and microinjection, ballistic / gene gun methods, virosomes, immunoliposomes, polycation-nucleic acid conjugates, naked DNA, artificial virions, fusion to herpes virus VP22 structural protein, agent-enhanced DNA uptake, ex vivo transduction, protoplast fusion, retroviral transduction, viral transfection, lipid-based transfection, or other conventional techniques. In the case of protoplast fusion, cells are grown in media and screened for appropriate activity. For long-term, high-yield production of recombinant proteins, stable expression will often be desired. For example, cell lines that stably express polypeptides can be prepared using expression vectors that contain viral origins of replication or endogenous expression elements and a selectable marker gene. After vector introduction, cells can be allowed to grow for 1-2 days in enriched medium before switching to selective medium. The purpose of the selectable marker is to confer resistance to selection, and its presence allows the growth of cells that successfully express the introduced sequences in selective media. Resistant and stably transfected cells can be proliferated using tissue culture techniques appropriate for the cell type. Methods and conditions for culturing the resulting transfected cells and for recovering the antibody produced are known to those skilled in the art, and can be varied or optimized according to the specific expression vector and mammalian host cell employed, based on the present disclosure. . Also provided herein are cells that include any of the expression vectors described herein. In some embodiments, the disclosure features a host cell that includes a nucleic acid molecule described herein. Said cells can be a host cell or a therapeutic cell. The terms host cell and recombinant host cell are used interchangeably herein, and refer not only to the particular subject cell but to the progeny or potential progeny of said cell. Since certain modifications may occur in subsequent generations due to mutations or environmental influences, such progeny may, in fact, not be identical to the parental cell, but is still included within the scope of the term as used herein. n / ztznn / i ζπζ / β / υιλι In one embodiment, host cells are genetically engineered to comprise nucleic acids encoding the hTREM2 antibody or an antigen-binding fragment thereof. In one embodiment, host cells are engineered using an expression cassette. The phrase "expression cassette" refers to nucleotide sequences, which can affect the expression of a gene in hosts compatible with such sequences. Such cassettes may include a promoter, an open reading frame with or without introns, and a termination signal. Additional factors necessary or useful to effect expression may also be used, such as, for example, an inducible promoter. The host cells for harboring and expressing the hTREM2 antibody chains or an antigen-binding fragment thereof may be, among others, a eukaryotic cell or a prokaryotic cell, such as a bacterial cell, an insect cell, or a human cell. E. cali is a useful procahotic host for cloning and expressing the polynucleotides of the present invention. Other suitable microbial hosts for use include bacilli, such as Bacillus subtilis, and other enterobacteria, such as Salmonella, Serratia, and various Pseudomonas species. In these prokaryotic hosts, expression vectors can also be made, which typically contain expression control sequences compatible with the host cell (eg, an origin of replication). In addition, any variety of known promoters will be present, such as the lactose promoter system, a tryptophan (trp) promoter system, a beta-lactamase promoter system, or a lambda phage promoter system. Promoters typically control expression, optionally with an operator sequence, and have ribosome binding site sequences and the like, to initiate and complete transcription and translation. Other microbes, such as yeast, may also be used to express the hTREM2 antibodies or antigen-binding fragments thereof of the invention. Insect cells can also be used in combination with baculovirus vectors. Suitable insect cells include, without limitation, Sf9 cells. In one embodiment, mammalian host cells are used to express and produce the hTREM2 antibodies or antigen-binding fragments thereof of the present invention. For example, they may be a hibhdoma cell line that expresses endogenous immunoglobulin genes (for example, the myeloma hybridoma cell 1 D6.C9) or a mammalian cell line that harbors an exogenous expression vector (for example, the cell myeloma SP2 / 0). These include any mortal normal animal or human cell, or immortal normal or abnormal. For example, several suitable host cell lines capable of secreting intact immunoglobulins have been developed, including CHO cell lines, various Cos cell lines, HeLa cells, myeloma cell lines, transformed B cells, and hybridomas. The use of mammalian tissue cell culture to express polypeptides is generally discussed in, for example, Winnacker, From Genes to Clones, VCH Publishers, NY, NY, 1987. Expression vectors for mammalian host cells n / ztznn / i ζπζ / β / υιλι may include expression control sequences, such as an origin of replication, a promoter, and an enhancer (see, for example, Queen, et al., Immunol. Rev. 89:49-68, 1986), and necessary processing information sites, such as ribosome binding sites, RNA splice sites, polyadenylation sites, and transcriptional terminator sequences. These expression vectors generally contain promoters derived from mammalian genes or from mammalian viruses. Suitable promoters may be constitutive, cell type specific, stage specific, and / or modulatable or regulatable. Useful promoters include, without limitation, the metallothionein promoter, the constitutive adenovirus major late promoter, the dexamethasone-inducible MMTV promoter, the SV40 promoter, the MRP pol III promoter, the MPSV constitutive promoter, the CMV promoter inducible by tetracycline (such as the immediate early human CMV promoter), the CMV constitutive promoter, and promoter-enhancer combinations known in the art. A host cell can be used to produce or express an antibody that binds to the human TREM2 protein (ie, hTREM2). Accordingly, the disclosure also presents methods for producing an hTREM2 antibody or an antigen-binding fragment thereof using a host cell. In one embodiment, the method includes culturing the host cell (into which a recombinant expression vector encoding the antibody has been introduced) in a suitable medium such that the hTREM2 antibody or antigen-binding fragment is produced. of the same. In another embodiment, the method further includes isolating the antibody from the host cell or medium. Suitable eukaryotic cells include, without limitation, Vero cells, HeLa cells, COS cells, CHO cells, HEK293 cells, BHK cells, and MDCKII cells. Methods for introducing expression vectors containing the polynucleotide sequences of interest vary according to the type of host cell. For example, calcium chloride transfection is commonly used for prokaryotic cells, while calcium phosphate treatment or electroporation can be used for other cell hosts. (See generally Sambrook, et al., supra). Other methods include, for example, electroporation, calcium phosphate treatment, liposome-mediated transformation, injection and microinjection, ballistic methods, virosomes, immunoliposomes, polycation:nucleic acid conjugates, naked DNA, artificial virions, protein fusion. herpes virus VP22 (Elliot and O'Hare, Cell 88: 223, 1997), agent-enhanced DNA uptake and ex vivo transduction. For long-term, high-yield production of recombinant proteins, stable expression will often be desired. For example, cell lines that stably express hTREM2 antibody chains or antigen-binding fragments can be prepared using expression vectors of the invention that contain viral origins of replication or endogenous expression elements and a selectable marker gene. After vector introduction, cells can be allowed to grow for 1-2 days in enriched medium before switching to selective medium. The purpose of the selectable marker is to confer resistance to njztznn / i ζπζ / β / υιλι selection, and its presence allows growth of cells that successfully express the introduced sequences in selective media. Resistant and stably transfected cells can be proliterated using tissue culture techniques appropriate for the cell type. regulatory sequence A person skilled in the art can recognize that expression of one or more vector components in a target cell may require a regulatory sequence. In one embodiment, the AAV vector plasmid comprises a regulatory sequence effective for expression of an hTREM2 antibody or an antigen-binding fragment thereof, eg, as described herein. In one embodiment, the AAV vector plasmid comprises an efficient regulatory sequence to direct expression in the targeted cell. In one embodiment, the AAV vector plasmid comprises a regulatory sequence such as, without limitation, promoters. As a non-limiting example, the promoter can be (1) CMV promoter, (2) CBA promoter, (3) FRDA or FXN promoter, (4) UBC promoter, (5) GUSB promoter, (6) NSE promoter, (7) synapsin promoter, (8) MeCP2 promoter, (9) GFAP promoter, (10) Hl promoter, (11) U6 promoter, (12) NFL promoter, (13) NFH promoter, (14) SCN8A promoter, or (15) PGK promoter. Promoters. One of skill in the art can recognize that expression of an hTREM2 antibody or antigen-binding fragment thereof, for example, as described herein, in a target cell may require a specific promoter including, without limitation, a promoter which is species specific, inducible, tissue specific or cell cycle specific (Parr et al., Nat. Med.3: 1145-9 (1997); the contents of which are incorporated herein by reference in their entirety) . In one embodiment, the AAV vector plasmid comprises an efficient promoter for expression of the hTREM2 antibody or an antigen-binding fragment thereof, eg, as described herein. In one embodiment, the AAV vector plasmid comprises an efficient promoter to drive expression in the targeted cell. In one embodiment, the promoter provides for expression of an hTREM2 antibody or antigen-binding fragment thereof, eg, as described herein, for a period of time in specific tissues such as, but not limited to , tissues of the nervous system. Expression of the hTREM2 antibody or an antigen-binding fragment thereof, for example, as described herein, can be over a period of 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours , 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 8 days, 9 days, 10 days, 11 days, 12 days, n / 7bnn / i ζπζ / β / υιλι days, 2 weeks, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 3 weeks, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days , 31 days, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, 11 years, 12 years, 13 years, 14 years, 15 years, 16 years, 17 years, 18 years, 19 years, 20 years, 21 years, 22 years, 23 years, 24 years, 25 years, 26 years, 27 years , 28 years, 29 years, 30 years, 31 years, 32 years, 33 years, 34 years, 35 years, 36 years, 37 years, 38 years, 39 years, 40 years, 41 years, 42 years, 43 years, 44 years, 45 years, 46 years, 47 years, 48 ​​years, 49 years, 50 years, 55 years, 60 years, 65 years, or more than 65 years. Expression of the hTREM2 antibody or one of its antigen-binding fragments, for example, as described herein, can be for 1-5 hours, 1-12 hours, 1-2 days, 1-5 days, 1- 2 weeks, 1-3 weeks, 1-4 weeks, 1-2 months, 1-4 months, 1-6 months, 2-6 months, 3-6 months, 3-9 months, 48 ​​months, 6-12 months , 1-2 years, 1-5 years, 2-5 years, 3-6 years, 3-8 years, 4-8 years or 5-10 years or 10-15 years, or 15-20 years, or 20- 25 years, or 25-30 years, or 30-35 years, or 35-40 years, or 40-45 years, or 45-50 years, or 50-55 years, or 55-60 years, or 60-65 years . In one embodiment, the AAV vector plasmid comprises a region located about 5 kb upstream of the first exon of the encoded hTREM2 antibody or an antigen-binding fragment thereof, eg, as described herein; more specifically, there is a region of 17 p. b. located approximately 4.9 kb upstream of the first exon of the Frataxin gene encoded to allow expression with the FRDA promoter (see, for example, Puspasañ et al, Long Range Regulation of Human FXN Gene Expression, PLOS ONE, 2011 ; the contents of which are incorporated herein by reference in its entirety). In one embodiment, the promoter is less than 1 kb. The promoter can have a length of 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800 or more than 800. The promoter can have a length of 200-300, 200-400, 200-500, 200-600, 200-700, 200-800, 300-400, 300-500, 300-600, 300-700, 300-800, 400-500, 400-600, 400-700, 400-800, 500-600, 500- 700, 500-800, 600-700, 600-800 or 700-800. In one embodiment, the promoter can be a combination of two or more components, regions, or sequences of the same or different promoters such as, without limitation, CMV and CBA. Each component can be 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 381,382, 383, 384 in length , 385, 386, 387, 388, 389, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580 , 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800 or more n / ztznn / i ζπζ / β / υ 100 of 800. Each component can have a length of 200-300, 200-400, 200-500, 200-600, 200-700, 200-800, 300-400, 300-500, 300-600, 300-700, 300 -800, 400-500, 400-600, 400-700, 400-800, 500-600, 500-700, 500-800, 600-700, 600-800 or 700-800. In one embodiment, the promoter is a combination of a CMV enhancer sequence, eg, an immediate / early CMV enhancer sequence (eg, a 382 nucleotide CMV enhancer sequence) and a beta-actin promoter sequence. chicken (CBA) (eg, 260 nucleotide CBA promoter sequence). In one embodiment, the promoter is a combination of a 280 nucleotide fragment of a CMV enhancer sequence and a 266 nucleotide fragment of a chicken beta-actin (CBA) promoter sequence. In some embodiments, the CMV enhancer sequence comprises, for example, consists of: cgttacat aacttacggt aaatggcccg cctggctgac cgcccaacga cccccgccca ttgacgtcaa taatgacgta tgttcccata gtaacgccaa tagggacttt ccattgacgt caatgggtgg agtatttacg gtaaactgcc cacttggcag tacatcaagt gtatcatatg ccaagtacgc ccccta ttga cgtcaatgac ggtaaatggc ccgcctggca ttatgcccag tacatgacct tatgggactt tcctacttgg cagtacatct ac (SEQ ID NO: 134) In some embodiments, the CBA promoter sequence comprises, for example, consists of: cc acgttctgct tcactctccc catctccccc ccctccccac ccccaatttt gtattattt attttttaat tatttgtgc agcgatgggg gcgggggggg ggggggggcg cgcgccaggc ggggcggggc ggggcgaggg gcggggcggg gcgaggcgga gaggtgcggc ggcagccaat cagagc ggcg cgctccgaaa gtttcctttt atggcgaggc ggcggcggcg gcggccctat aaaaagcgaa gcgcgcggcg ggcg (SEQ ID NO: 135) In one embodiment, the AAV vector comprises the chicken CMV enhancer / beta actin hybrid promoter comprising, for example, consisting of the sequence: cgttacat aacttacggt aaatggcccg cctggctgac cgcccaacga cccccgccca ttgacgtcaa taatgacgta tgttcccata gtaacgccaa tagggacttt ccattgacgt caatgggtgg agtatttacg gtaaactgcc cacttggcag tacatcaagt gtatcatatg ccaagtacgc ccccta ttga cgtcaatgac ggtaaatggc ccgcctggca ttatgcccag tacatgacct tatgggactt tcctacttgg cagtacatct actcgaggcc acgttctgct tcactctccc catctccccc ccctccccac ccccaatttt gtatttattt attttttaat tatttgtgc agcgatgggg gcgggggggg gggggg ggcg cgcgccaggc ggggcggggc ggggcgaggg gcggggcggg gcgaggcgga gaggtgcggc ggcagccaat cagagcggcg cgctccgaaa gtttcctttt atggcgaggc ggcggcggcg gcggccctat aaaaagcgaa gcgcgcggcg ggcg (SEQ ID NO: 136) In one embodiment, the AAV vector plasmid comprises a ubiquitous promoter. Non-limiting examples of ubiquitous promoters include CMV, CBA (including CAG derivatives, CBh, etc.), EF njztznn / i znz / R / v 101 1a, PGK, UBC, GUSB (hGBp) and UCOE (HNRPA2B1-CBX3 promoter). In one embodiment, any of the promoters taught by Yu, Soderblom, Gil, Husain, Passini, Xu, Drews, or Raymond can be used in the present inventions. Yu et al. (Molecular Pain 2011, 7:63; the contents of which are incorporated herein by reference in their entirety) evaluated eGFP expression under the CAG, EF-1a, PGK, and UBC promoters in rat DRG cells and primary DRG cells using lentiviral vectors. , and found that UBC showed weaker expression than the other 3 promoters, and only 10-12% glial expression was observed for all promoters. Soderblom et al. (E. Neuro 2015; the contents of which are incorporated herein by reference in their entirety) evaluated eGFP expression in AAV8 with CMV and UBC promoters and AAV2 with CMV promoter after injection into the motor cortex. Intranasal administration of a plasmid containing a UBC or EF-1 a promoter showed sustained airway expression greater than expression with the CMV promoter (see, for example, Gil et al., Gene Therapy 2001, Vol. 8 , 1539-1546; the contents of which are incorporated herein by reference in their entirety). Husain et al. (Gene Therapy 2009; the contents of which are incorporated herein by reference in their entirety) evaluated a ΗβΗ construct with an hGUSB promoter, an HSV-1LAT promoter, and an NSE promoter, and found that the ΗβΗ construct showed weaker expression than NSE in the mouse brain. Passini and Wolfe (J. Viral. 2001,1238212392, the contents of which are incorporated herein by reference in their entirety) evaluated the long-term effects of the ΗβΗ vector after intraventricular injection in neonatal mice and found that expression was maintained for at least less 1 year. Low expression in all brain regions was found by Xu et al. (Gene Therapy 2001,8, 1323-1332; contents of which are incorporated herein by reference in their entirety) when NF-L and NF-H promoters were used compared to CMV-lacZ, CMV-luc, EF, GFAP, hENK, nAChR, PPE, PPE + wpre, NSE (0.3 kb), NSE (1.8 kb) and NSE (1.8 kb + wpre). Xu et al. found that promoter activity in descending order was NSE (1.8 kb), EF, NSE (0.3 kb), GFAP, CMV, hENK, PPE, NFL, and NFH. NFL is a 650 nucleotide promoter, and NFH is a 920 nucleotide promoter, which are absent in the liver, but NFH is abundant in proprioceptive sensory neurons, brain, and spinal cord, and NFH is present in the heart. SCN8A is a 470 nucleotide promoter that is expressed throughout the DRG, spinal cord, and brain, with particularly high expression seen in hippocampal neurons and cerebellar Purkinje cells, cortex, thalamus, and hypothalamus (see, for example , Drews et al., Identification of evolutionary conserved, functional noncoding elements in the promoter region of the sodium channel gene SCN8A, Mamm Genome (2007) 18:723-731, and Raymond et al., Expression of Alternatively Spliced ​​Sodium Channel a-subunit genes, Journal of Biological Chemistry (2004) 279(44) 46234-4624; the contents of each of which are incorporated herein by reference in their entirety). n / ztznn / i ζπζ / β / υιλι 102 In one embodiment, the AAV vector plasmid comprises a promoter that is not cell-specific. In one embodiment, the promoter is a weak promoter (ranked according to its affinity and the affinity of other promoters for RNA polymerase and / or sigma factor) for sustained expression of an hTREM2 antibody or an antigen-binding fragment of hTREM2. same, for example, as described herein, in neural tissues. In one embodiment, the promoter is a weak promoter for sustained expression of Frataxin in nervous system tissue such as, without limitation, neuronal tissue and glial tissue. In one embodiment, the AAV vector plasmid comprises a Friedreich Ataxia (FRDA) promoter. In one embodiment, the AAV vector plasmid comprises a ubiquitin c (UBC) promoter. The UBC promoter may be 300-350 nucleotides in size. As a non-limiting example, the UBC promoter is 332 nucleotides. In one embodiment, the AAV vector plasmid comprises a β-glucuronidase (GUSB) promoter. The GUSB promoter can be 350-400 nucleotides in size. As a non-limiting example, the GUSB promoter is 378 nucleotides. As a non-limiting example, the AAV vector plasmid may be 5'-promoter-CMV / globin intron-hFXN-RBG-3', where the AAV vector plasmid may be self-complementary, and the capsid may be serotype DJ. In one embodiment, the AAV vector plasmid comprises a neurofilament promoter (NFL). The NFL promoter can be 600-700 nucleotides in size. As a non-limiting example, the NFL promoter is 650 nucleotides. As a non-limiting example, the AAV vector plasmid may be 5'-promoter-CMV / globin intron-hFXN-RBG-3, where the AAV vector plasmid may be self-complementary, and the capsid may be serotype DJ. In one embodiment, the AAV vector plasmid comprises a neurofilament heavy (NFH) promoter. The NFH promoter can be 900-950 nucleotides in size. As a non-limiting example, the NFH promoter is 920 nucleotides. As a non-limiting example, the AAV vector plasmid may be 5'-promoter-CMV / globin intron-hFXN-RBG-3', where the AAV vector plasmid may be self-complementary, and the capsid may be serotype DJ. In one embodiment, the AAV vector plasmid comprises an SCN8A promoter. The SCN8A promoter can be 450-500 nucleotides in size. As a non-limiting example, the SCN8A promoter is 470 nucleotides. As a non-limiting example, the AAV vector plasmid may be d'promoter-CMV / globin intron-hFXN-RBG-3, where the AAV vector plasmid may be self-complementary, and the capsid may be serotype DJ. In one embodiment, the AAV vector plasmid comprises a frataxin (FXN) promoter. In one embodiment, the AAV vector plasmid comprises a phosphoglycerate kinase 1 (PGK) promoter. n / ztznn / i ζπζ / β / υιλι 103 In one embodiment, the AAV vector plasmid comprises a chicken β-actin (CBA) promoter. In one embodiment, the AAV vector plasmid comprises an immediate early cytomegalovirus (CMV) promoter. In one embodiment, the AAV vector plasmid comprises an H1 promoter. In one embodiment, the AAV vector plasmid comprises a U6 promoter. In one embodiment, the AAV vector plasmid comprises a skeletal muscle or liver promoter. Non-limiting examples of liver promoters include hAAT and TBG. Non-limiting examples of skeletal muscle promoters include Desmin, MCK, and C5-12. In one embodiment, the AAV vector plasmid comprises a designed promoter, eg, a promoter derived from, but not identical to, a promoter described herein. Enhancer element. In one embodiment, the AAV vector plasmid may comprise at least one enhancer and / or expression element. The enhancer or expression element can be used in combination with a regulatory sequence (eg, a promoter). In one embodiment, the AAV vector plasmid comprises a transgenic enhancer, promoter, and / or 5'UTR intron. The transgenic enhancer, also referred to herein as an enhancer, can be, without limitation, a CMV enhancer (or a fragment thereof, eg, as described herein). The promoter can be, among others, a CMV, CBA, UBC, GUSB, NSE, Synapsin, MeCP2 and GFAP promoter. The 5'UTR / intron can be, among others, SV40 and CBA-MVM. In one embodiment, the AAV vector comprises an intron, optionally disposed between a promoter element and the polynucleotide encoding the hTREM2 antibody or the antigen-binding fragment thereof (eg, as described herein). Without being limited by theory, the inclusion of a 5' intron has been shown to improve the level and steady state of the mRNA encoding the hTREM2 antibody or the antigen-binding fragment thereof (eg, as described herein). document). In embodiments, the enhancer is a 5' intron derived from SV40. In one embodiment, the SV40 intron comprises, for example, consists of the sequence: gtaagtt tagtcttttt gtcttttatt tcaggtcccg gatccggtgg tggtgcaaat caaagaactg ctcctcagtg gatgttgcct ttacttctag (SEQ ID NO: 137) In one embodiment, the AAV vector (eg, AAV vector) plasmid comprises a combination of enhancer, promoter, and / or intron, such as, without limitation, (1) CMV enhancer, CMV promoter, intron SV40 5'UTR (eg, as described here); (2) CMV enhancer, CBA promoter, SV40 intron 5'UTR (eg, as described herein); (3) CMV enhancer, CBA promoter, CBA-MVM intron 5'UTR (eg, as described herein). transgenic enhancer. n / ztznn / i ζπζ / β / υιλι 104 In one embodiment, the AAV vector plasmid comprises at least one transgene enhancer element that can enhance transgene target specificity and expression (see, for example, Powell et al. Viral Expression Cassette Elements to Enhance Transgene Target Specificity and Expression in Gene Therapy, 2015; the contents of which are incorporated herein by reference in their entirety). Non-limiting examples of transgenic enhancer elements for enhancing transgenic target specificity and expression include promoters, endogenous miRNAs, post-transcriptional regulatory elements (PREs), polyadenylation (Poly A) signal sequences and upstream enhancers (USE), CMV enhancers and introns. In one embodiment, the AAV vector plasmid comprises at least one transgenic enhancer element that is a CMV enhancer. In one embodiment, the AAV vector plasmid comprises at least one transgenic enhancer element that is a promoter. In one embodiment, the AAV vector plasmid comprises at least one transgenic enhancer element which is an intron. In one embodiment, the AAV vector plasmid comprises at least one transgenic enhancer element that is endogenous miRNA. In one embodiment, the AAV vector plasmid comprises at least one transgenic enhancer element which is post-transcriptional regulatory elements (PREs). In one embodiment, the AAV vector plasmid comprises at least one transgenic enhancer element that is polyadenylation (Poly A) signal sequences. In embodiments, the AAV vector plasmid of the AAV vector comprises a growth hormone poly A signal. In one embodiment, the growth hormone poly A signal is derived from the bovine growth hormone (BGH) poly A signal. An example of a BGH poly A signal sequence is: ctagagct cgctgatcag cctcgactgt gccttctagt tgccagccat ctgttgtttg cccctccccc gtgcccttcct tgaccctgga aggtgccact cccactgtcc tttcctaata aaatgaggaa attgcatcgc attgtctgag taggtgtcat tctattctgg ggggtggggt ggggcaggac ag caaggggg aggattggga agacaatagc aggcatgctg ggga (SEQ ID NO: 138) In embodiments, the AAV vector plasmid comprises the poly A signal (eg, the BGH poly A signal) downstream (eg, 3'a) of the polynucleotide encoding the hTREM2 antibody or an antigen-binding fragment. thereof, for example, as described here. In one embodiment, the AAV vector plasmid comprises at least one transgenic enhancer element that is upstream enhancers (USE). Tissue-specific expression. n / ztznn / i ζπζ / β / υιλι 105 In one embodiment, the vector genome may comprise a tissue-specific expression element for promoting expression of the hTREM2 antibody or an antigen-binding fragment thereof, eg, as described herein, in tissues and / or cells. . As a non-limiting example, promoters can be tissue-specific expression elements including, without limitation, human elongation factor la subunit (EF-1a), immediate-early cytomegalovirus (CMV), chicken β-actin (CBA), and its CAG derivative, β-glucuronidase (GUSB) and ubiquitin C (UBC). In one embodiment, the vector genome may comprise tissue-specific expression elements that can be used to restrict expression to certain cell types such as, without limitation, nervous system promoters that can be used to restrict expression to neurons, astrocytes or oligodendrocytes. In one embodiment, the vector genome may comprise tissue-specific expression elements for neurons such as, without limitation, neuron-specific enolase (NSE), platelet-derived growth factor (PDGF, platelet-derived growth factor B chain (PDGF-β), synapsin (Syn), methyl-CpG binding protein 2 (MeCP2), Ca<2+>-dependent protein kinase II / calmodulin (CaMKII), metabotropic glutamate receptor 2 (mGluR2), NFL, NFH, ηβ2, PPE, Enk, and EAAT2 promoters. In one embodiment, the vector genome may comprise tissue-specific expression elements for astrocytes such as, without limitation, glial fibrillary acidic protein (GFAP) and EAAT2 promoters. In one embodiment, the vector genome may comprise tissue-specific expression elements for oligodendrocytes such as, without limitation, the myelin basic protein (MBP) promoter. introns. In one embodiment, the AAV vector plasmid comprises at least one element to enhance transgene expression such as one or more introns or portions thereof. In one embodiment, the payload construct comprises at least one element for enhancing transgene expression such as one or more introns or portions thereof. Non-limiting examples of introns include MVM (67-97 bp), FIX truncated intron 1 (300 bp), immunoglobulin heavy chain splice acceptor / p-globin SD (250 bp), adenovirus splice donor / immunoglobin splice acceptor (500 bp), SV40 late splice donor / (19S / 16S) splice acceptor (180 bp) and hybrid adenovirus splice donor / IgG splice acceptor (230 bp). In one embodiment, the intron or intron portion may be 100-500 nucleotides in length. The intron can have a length of 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 171 n / ztznn / i ζπζ / β / υιλι 106, 172, 173, 174, 175, 176, 177, 178, 179, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490 or 500. The intron can have a length between 80-100, 80-120, 80 -140, 80-160, 80-180, 80-200, 80250, 80-300, 80-350, 80-400, 80-450, 80-500, 200-300, 200-400, 200-500, 300 -400, 300-500, or 400-500. In one embodiment, the AAV vector comprises an intron, optionally disposed between a promoter element and the polynucleotide encoding the hTREM2 antibody or an antigen-binding fragment thereof (eg, as described herein). Without being limited by theory, the inclusion of a 5' intron has been shown to improve the level and steady state of the mRNA encoding the hTREM2 antibody or the antigen-binding fragment thereof (eg, as described herein). document). In embodiments, the enhancer is a 5' intron derived from SV40. In one embodiment, the SV40 intron comprises, for example, consists of the sequence: gtaagtt tagtcttttt gtcttttatt tcaggtcccg gatccggtgg tggtgcaaat caaagaactg ctcctcagtg gatgttgcct ttacttctag (SEQ ID NO: 137) In one embodiment, the AAV vector plasmid of the AAV vector comprises (1) a CMV enhancer (eg SEQ ID NO: 134), (2) a CBA promoter (eg SEQ ID NO: 135) , (3) an SV40 intron (eg, SEQ ID NO: 137), (4) a polynucleotide encoding an hTREM2 antibody or an antigen-binding fragment thereof (eg, as described herein), and (5) ) a BGH poly A signal (eg, SEQ ID NO: 138). In one embodiment, elements (1) to (5) are arranged on the AAV vector plasmid 5' to 3'. In embodiments, elements (1) to (5) are arranged in an AAV vector plasmid that further comprises ITRs (eg, a 5' ITR and a 3' ITR). In embodiments, the ITRs are derived from AAV2 ITRs. In one embodiment, the AAV vector plasmid is a self-complementing AAV vector plasmid. Autocomplementary or the abbreviation refers to autocomplementaho. Self-complementary AAV or scAAV refers to a construct in which a coding region carried by a recombinant AAV nucleic acid sequence has been designed to form an intramolecular double-stranded DNA pattern. Without being bound by theory, upon infection, rather than waiting for cell-mediated synthesis of the second strand, the two complementary halves of scAAV will associate to form a double-stranded DNA (dsDNA) unit that is ready for synthesis. immediate replication and transcription. See, for example, D. M. McCarty et al., Self-complementary recombinant adeno-associated virus (scAAV) vectors promote efficient transduction independently of DNA synthesis, Gene Therapy, (Ag. 2001), Vol 8, No. 16, pp. 1248-1254 (incorporated by reference in their entirety). Self-complementary AAVs are described, for example, in US Patent Numbers 6,596,535; 7,125,717; and 7,456,683, each of which incorporates n / ztznn / i ζπζ / β / υιλι 107 here for reference in its entirety. For example, the 5' ITR can be mutated, eg by deleting the terminal resolution site to allow hairpin formation of the genome. Capsids and capsid serotypes. In some embodiments, the AAV particles of the present invention may be packaged in a capsid structure or may be capsid-free. Such donor and / or acceptor sequences from capsid-free viral vectors, such as AAV, are described, for example, in US publication 2014 / 0107186, the contents of which are incorporated by reference in their entirety. In some embodiments, the AAV particles produced in accordance with the present invention may comprise hybrid serotypes with enhanced transduction for specific cell types of interest in the central nervous system, prolonged transgene expression, and / or safety profile. Hybrid serotypes can be generated by transcapsidation, adsorption of bispecific antibodies to the capsid surface, mosaic capsid, and chimeric capsid, and / or other modifications of the capsid protein. In some embodiments, the AAV particles of the present invention may be further modified for a specific therapeutic application by rational mutagenesis of capsid proteins (see, for example, Pulicherla et al, Mol Ther, 201 1,19: 1070- 1078), incorporation of peptide ligands into the capsid, for example, a peptide derived from an NMDA receptor agonist for enhanced retrograde transport (Xu et aL, Virology, 2005, 341: 203-214), and directed evolution to produce new AAV variants, eg, for increased CNS transduction. In some embodiments, the AAV particles produced in accordance with the present invention may comprise different capsid proteins, either naturally occurring and / or recombinant, including, but not limited to, capsid serotypes AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV 8, AAV9, AAV 10, and AAV11, AAV 12, AAVrh8, AAVrhIO, AAV-DJ, and AAV-DJ / 8, or their variants (eg, AAV3A and AAV3B). Nucleic acid sequences encoding one or more AAV capsid proteins useful in the present invention are described in International Publication Number WO 2015191508, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the AAV particles of the present invention may comprise or be derived from any natural or recombinant AAV serotype. In accordance with the present invention, the AAV particles may utilize or be based on a serotype selected from any of the following AAV1, AAV2, AAV2G9, AAV3, AAV3a, AAV3b, AAV3-3, AAV4, AAV4-4, AAV5, AAV6, AAV6.1, AAV6.2, AAV6.1.2, AAV7, AAV7.2, AAV8, AAV9, AAV9.11, AAV9.13, AAV9.16, AAV9.24, AAV9.45, AAV9.47, AAV9. 61, AAV9.68, AAV9.84, AAV9.9, AAV10, AAV11, AAV 12, AAV16.3, AAV24.1, AAV27.3, AAV42.12, AAV42-lb, AAV42-2, AAV42-3a, AAV42 -3b, AAV42-4, AAV42-5a, AAV42-5b, AAV42-6b, AAV42-8, AAV42-10, AAV42-11, AAV42-12, AAV42-13, AAV42-15, AAV42nyztznn / i ζπζ / β / υιλι 108 aa, AAV43-1, AAV43-12, AAV43-20, AAV43-21, AAV43-23, AAV43-25, AAV43-5, AAV44.1, AAV44.2, AAV44.5, AAV223.1, AAV223.2 , AAV223.4, AAV223.5, AAV223.6, AAV223.7, AAVI-7 / rh.48, AAVI-8 / rh.49, AAV2-15 / rh.62, AAV2-3 / rh.61, AAV2 -4 / rh.50, AAV2-5 / rh.51, AAV3.1 / hu.6, AAV3.1 / hu.9, AAV3-9 / rh.52, AAV3-I l / rh.53, AAV4- 8 / r 11.64, AAV4-9 / rh.54, AAV4-19 / rh.55, AAV53 / rh.57, AAV5-22 / rh.58, AAV7.3 / hu.7, AAV16.8 / hu.1O , AAV16.12 / hu.11, AAV29.3 / bb.1, AAV29.5 / bb.2, AAV106.1 / hu.37, AAV114.3 / hu.40, AAV127.2 / hu.41, AAV127 .5 / hu.42, AAV128.3 / hu.44, AAV130.4 / hu.48, AAV145.1 / hu.53, AAV145.5 / hu.54, AAV145.6 / hu.55, AAV161.1O / hu.6O, AAV161.6 / hu.61, AAV33.12 / hu.17, AAV33.4 / hu.15, AAV33.8 / hu.16, AAV52 / hu.19, AAV52.1 / hu.2O , AAV58.2 / hu.25, AAV A3.3, AAV A3.4, AAV A3.5, AAV A3.7, AAVC1, AAVC2, AAVC5, AAV-DJ, AAVDJ8, AAVF3, AAVF5, AAVH2, AAVrh.72 , AAVhu.8, AAVrh.68, AAVrh.70, AAVpi.1, AAVp¡.3, AAVp¡.2, AAVrh.60, AAVrh.44, AAVrh.65, AAVrh.55, AAVrh.47, AAVrh.69 , AAVrh.45, AAVrh.59, AAVhu.12, AAVH6, AAVLK03, AAVH-1 / hu.1, AAVH-5 / hu.3, AAVLG-10 / rh.40, AAVLG-4 / rh.38, AAVLG - 9 / hu.39, AAVN721-8 / rh.43, AAVCh.5, AAVCh.5RI, AAVcy.2, AAVcy.3, AAVcy.4, AAVcy.5, AAVCy.5RI, AAVCy.5R2, AAVCy.5R3 , AAVCy.5R4, AAVcy.6, AAVhu.1, AAVhu.2, AAVhu.3, AAVhu.4, AAVhu.5, AAVhu.6, AAVhu.7, AAVhu.9, AAVhu.10, AAVhu.11, AAVhu .13, AAVhu.15, AAVhu.16, AAVhu.17, AAVhu.18, AAVhu.20, AAVhu.21, AAVhu.22, AAVhu.23.2, AAVhu.24, AAVhu.25, AAVhu.27, AAVhu.28 , AAVhu.29, AAVhu.29R, AAVhu.31, AAVhu.32, AAVhu.34, AAVhu.35, AAVhu.37, AAVhu.39, AAVhu.40, AAVhu.41, AAVhu.42, AAVhu.43, AAVhu .44, AAVhu.44RI, AAVhu.44R2, AAVhu.44R3, AAVhu.45, AAVhu.46, AAVhu.47, AAVhu.48, AAVhu.48RI, AAVhu.48R2, AAVhu.48R3, AAVhu.49, AAVhu.51 , AAVhu.52, AAVhu.54, AAVhu.55, AAVhu.56, AAVhu.57, AAVhu.58, AAVhu.60, AAVhu.61, AAVhu.63, AAVhu.64, AAVhu.66, AAVhu.67, AAVhu .14 / 9, AAVhu.t 19, AAVrh.2, AAVrh.2R, AAVrh.8, AAVrh.SR, AAVrh.10, AAVrh.12, AAVrh.13, AAVrh.13R, AAVrh.14, AAVrh.17, AAVrh.18, AAVrh.19, AAVrh.20, AAVrh.21, AAVrh.22, AAVrh.23, AAVrh.24, AAVrh.25, AAVrh.31, AAVrh.32, AAVrh.33, AAVrh.34, AAVrh. 35, AAVrh.36, AAVrh.37, AAVrh.37R2, AAVrh.38, AAVrh.39, AAVrh.40, AAVrh.46, AAVrh.48, AAVrh.48.1, AAVrh.48.1.2, AAVrh.48.2, AAVrh. 49, AAVrh.51, AAVrh.52, AAVrh.53, AAVrh.54, AAVrh.56, AAVrh.57, AAVrh.58, AAVrh.61, AAVrh.64, AAVrh.64RI, AAVrh.64R2, AAVrh.67, AAVrh.73, AAVrh.74, AAVrh8R, AAVrh8R A586R mutant, AAVrh8R R533A mutant, AAAV, BAAV, Caprine AAV, Bovine AAV, AAVhE1.1, AAVhEr1.5, AAVhER1.14, AAVhEr1.8, AAVhE r1.16, AAVhEr1. 18, AAVhEr1.35, AAVhEr1.7, AAVhEr1.36, AAVhEr2.29, AAVhEr2.4, AAVhEr2.16, AAVhEr2.30, AAVhEr2.31, AAVhEr2.36, AAVhER1.23, AAVhEr3.1, A AV2.5T , AAVPAEC, AAV-LK01, AAV-LK02, AAV-LK03, AAV-LK04, AAV-LK05, AAV-LK06, AAV-LK07, AAVLK08, AAV-LK09, AAV-LK10, AAV-LK11, AAV-LK12, AAV- LK13, AAV-LK14, AAV-LK15, AAVLK16, AAV-LK17, AAV-LK18, AAV-LK19, AAV-PAEC2, AAV-PAEC4, AAV-PAEC6, AAV-PAEC7, AAV-PAEC8, AAV-PAEC11, AAV- PAEC 12, AAV-2-pre-mRNA-IOI, AAV-8h, AAV-8b, AAV-h, AAV-b, AAV SM 10-2, AAV Shuffled 100-1, AAV Shuffled 100-3, AAV Shuffled 100 -7, AAV n / ztznn / i znz / E / v 109 Shuffled 10-2, AAV Shuffled 10-6, AAV Shuffled 10-8, AAV Shuffled 100-2, AAV SM 10-1, AAV SM 10-8, AAV SM 100-3, AAV SM 100-10, BNP61 AAV, BNP62 AAV, BNP63 AAV, AAVrh.50, AAVrh.43, AAVrh.62, AAVrh.48, AAVhu.19, AAVhu. I, AAVhu.53, AAV4-8 / rh.64, AAVLG-9 / hu.39, AAV54.5 / hu.23, AAV54.2 / hu.22, AAV54.7 / hu.24, AAV54.1 / hu.21, AAV54.4R / hu.27, AAV46.2 / hu.28, AAV46.6 / hu.29, AAV128.1 / hu.43, AAV genuine type (ttAAV), UPEN AAV 10 and / or serotypes Japanese AAV 10, its variants. As a non-limiting example, the recombinant AAV virus capsid is AAV2. As a non-limiting example, the recombinant AAV virus capsid is AAVrhIO. As a non-limiting example, the recombinant AAV virus capsid is AAV9 (hul4). As a non-limiting example, the recombinant AAV virus capsid is AAV-DJ. As a non-limiting example, the recombinant AAV virus capsid is AAV9.47. As a non-limiting example, the recombinant AAV virus capsid is AAV-DJ8. In some embodiments, the AAV particles of the present invention may comprise or be derived from an AAV serotype that may be, or have, a sequence as described in United States Publication No. US 20030138772, the contents of which are incorporated herein by reference in their entirety, such as, without limitation, AAV1 (SEQ ID NO: 6 and 64 of US 20030138772), AAV2 (SEQ ID NO: 7 and 70 of US20030138772), AAV3 (SEQ ID NO: 8 and 71 of US20030138772), AAV4 (SEQ ID NO: 63 of US20030138772), AAV5 (SEQ ID NO: 114 of US20030138772), AAV6 (SEQ ID NO: 65 of US20030138772), AAV7 (SEQ ID NO: 1-3 of US2003013877 2), AAV 8 (SEQ ID NO: 4 and 95 of US20030138772), AAV9 (SEQ ID NO: 5 and 100 of US20030138772), AAV10 (SEQ ID NO: 117 of US20030138772), AAV11 (SEQ ID NO: 118 of US20030138772), AA V 12 (SEQ ID NO: 119 of US20030138772), AAVrhIO (amino acids 1 to 738 of SEQ ID NO: 81 of US20030138772), AAV16.3 (US20030138772 SEQ ID NO: 10), AAV29.3 / bb. I (US20030138772 SEQ ID NO: 11), AAV29.4 (US20030138772 SEQ ID NO: 12), AAV29.5 / bb.2 (US20030138772 SEQ ID NO: 13), AAV1.3 (US20030138772 SEQ ID NO: 14), AAV13.3 (US20030138772 SEQ ID NO: 15), AAV24.1 (US20030138772 SEQ ID NO: 16), AAV27.3 (US20030138772 SEQ ID NO: 17), AAV7.2 (US20030138772 SEQ ID NO: 18), AAVC1 ( US20030138772 SEQ ID NO: 19), AAVC3 (US20030138772 SEQ ID NO: 20), AAVC5 (US20030138772 SEQ ID NO: 21), AAVF1 (US20030138772 SEQ ID NO: 22), AAVF3 (US20030138772 SEQ ID NO: 23), AAVF5 ( US20030138772 SEQ ID NO: 24), AAVH6 (US20030138772 SEQ ID NO: 25), AAVH2 (US20030138772 SEQ ID NO: 26), AAV42-8 (US20030138772 SEQ ID NO: 27), AAV42-15 (US20030138 772 SEQ ID NO: 28 ), AAV42-5B (US20030138772 SEQ ID NO: 29), AAV42-LB (US20030138772 SEQ ID NO: 30), AAV42-13 (US20030138772 SEQ ID NO: 31), AAV42-3A (US20030138772 SEQ ID NO: 32), 32) AAV42-4 (US20030138772 SEQ ID NO: 33), AAV42-5a (US20030138772 SEQ ID NO: 34), AAV42-10 (US20030138772 SEQ ID NO: 35), AAV42-3b (US20030138772 SEQ ID NO: 36), AAV 42- 11 (US20030138772 SEQ ID NO: 37), AAV42-6b njztznn / i ζπζ / ε / υιλι 110 (US20030138772 SEQ ID NO: 38), AAV43-1 (US20030138772 SEQ ID NO: 39), AAV43-5 (US20030138772 SEQ ID NO: 40), AAV43-12 (US20030138772 SEQ ID NO: 41), AAV43-20 ( US20030138772 SEQ ID NO: 42), AAV43-21 (US20030138772 SEQ ID NO: 43), AAV43-23 (US20030138772 SEQ ID NO: 44), AAV43-25 (US20030138772 SEQ ID NO: 45), AAV44.1 (US20 030138772 SEQ ID NO: 46), AAV44.5 (US20030138772 SEQ ID NO: 47), AAV223.1 (US20030138772 SEQ ID NO: 48), AAV223.2 (US20030138772 SEQ ID NO: 49), AAV223.4 (US20030138772 SEQ ID NO : 50), AAV223.5 (US20030138772 SEQ ID NO: 51), AAV223.6 (US20030138772 SEQ ID NO: 52), AAV223.7 (US20030138772 SEQ ID NO: 53), AAV A3.4 (US20030138772 SEQ ID NO: 54), AAV A3.5 (US20030138772 SEQ ID NO: 55), AAV A3.7 (US20030138772 SEQ ID NO: 56), AAV A3.3 (US20030138772 SEQ ID NO: 57), AAV42.12 (US20030138772 SEQ ID NO : 58), AAV44.2 (US20030138772 SEQ ID NO: 59), AAV42-2 (US20030138772 SEQ ID NO: 9), or their variants. In some embodiments, the AAV particles of the present invention may comprise or be derived from an AAV serotype that may be or have a sequence as described in United States Publication No. US 20150159173, the contents of which are incorporated into the present application by reference in its entirety, such as, without limitation, AAV2 (SEQ ID NO: 7 and 23 of US20150159173), rh20 (SEQ ID NO: 1 of US20150159173), rh32 / 33 (SEQ ID NO: 2 of US20150159173 ), rh39 (SEQ ID NO: 3, 20 and 36 of US20150159173), rh46 (SEQ ID NO: 4 and 22 of US20150159173), rh73 (SEQ ID NO: 5 of US20150159173), rh74 (SEQ ID NO: 6 of US20150159173 ), AAV6.1 (SEQ ID NO: 29 of US20150159173), rh.8 (SEQ ID NO: 41 of US20150159173), rh.48.1 (SEQ ID NO: 44 of US20150159173), hu.44 (SEQ ID NO: 45 of US20150159173), hu.29 (SEQ ID NO: 42 of US20150159173), hu.48 (SEQ ID NO: 38 of US20150159173), rh54 (SEQ ID NO: 49 of US20150159173), AAV2 (SEQ ID NO: 7 of US20150159173 ), cy.5 (SEQ ID NO: 8 and 24 of US20150159173), rh.10 (SEQ ID NO: 9 and 25 of US20150159173), rh.13 (SEQ ID NO: 10 and 26 of US20150159173), AAV1 (SEQ ID NO: 11 and 27 of US20150159173), AAV3 (SEQ ID NO: 12 and 28 of US20150159173), AAV6 (SEQ ID NO: 13 and 29 of US20150159173), AAV7 (SEQ ID NO: 14 and 30 of US20150159173), AAV 8 (SEQ ID NO: 15 and 31 of US20150159173), hu.13 (SEQ ID NO: 16 and 32 of US20150159173), hu.26 (SEQ ID NO: 17 and 33 of US20150159173), hu.37 (SEQ ID NO: 18 and 34 of US20150159173), hu.53 (SEQ ID NO: 19 and 35 of US20150159173), rh.43 (SEQ ID NO: 21 and 37 of US20150159173), rh2 (SEQ ID NO: 39 of US20150159173), rh.37 (SEQ ID NO: 40 of US20150159173), rh.64 (SEQ ID NO: 43 of US20150159173), rh.48 (SEQ ID NO: 44 of US20150159173), ch.5 (SEQ ID NO: 46 of US20150159173), rh.67 (SEQ ID NO: 47 of US20150159173), rh.58 (SEQ ID NO: 48 of US20150159173), or its variants, including, without limitation, Cy5RI, Cy5R2, Cy5R3, Cy5R4, rh.13R, rh.37R2, rh.2R, rh.8R, rh.48.1, rh.48.2, rh.48.1.2, n / ztznn / i ζπζ / ε / υιλι 111 hu.44RI, hu.44R2, hu.44R3, hu.29R, ch.5R1, rh64R1, rh64R2, AAV6.2, AAV6.1, AAV6.12, hu.48RI, hu.48R2, and hu.48R3. In some embodiments, the AAV particles of the present invention may comprise or be derived from an AAV serotype that may be or have a sequence as described in United States Patent No. US 7198951, the contents of which are incorporated into this application by reference in its entirety, such as, without limitation, AAV9 (US 7198951 SEQ ID NO: 1-3), AAV2 (US 7198951 SEQ ID NO: 4), AAV1 (US 7198951 SEQ ID NO: 5 7198951), AAV3 (SEQ ID NO: 6 of US 7198951), and AAV 8 (SEQ ID NO: 7 of US7198951). In some embodiments, the AAV vectors comprise or are derived from an AAV serotype that may be or have a mutation in the AAV9 sequence as described by N Pulicherla et al. (Molecular Therapy 19(6): 1070-1078 (2011), incorporated herein by reference in their entirety), such as, without limitation, AAV9.9, AAV9.11, AAV9.13, AAV9.16, AAV9.24, AAV9.45, AAV9.47, AAV9.61, AAV9.68, AAV9.84. In some embodiments, the AAV capsid comprises one or more sequences designed to deliver the vector across the blood-brain barrier (see, for example, B. E. Deverman et al, Nature Biotech, VoL 34, No. 2, p 204 - 211 (published online February 1, 2016), and Caltech press release, A. Wetherston, www.neurologycenfrd.com / 2016 / 02 / 10 / successfd / brain-barrier, see also WO 2016 / 0492301 and US 8,734,809 (the contents of each of these are incorporated by reference in their entirety). In some embodiments, the AVV particles of the present invention may comprise or be derived from an AVV serotype that may be or have a sequence as described in United States Patent No. US 6,156,303, the contents of which are incorporated herein. present application by reference in their entirety, such as, without limitation, AAV3B (SEQ ID NO: 1 and 10 of US 6156303), AAV6 (SEQ ID NO: 2, 7 and 11 of US 6156303), AAV2 (SEQ ID NO: 3 and 8 of US 6156303), AAV3A (SEQ ID NO: 4 and 9, of US 6156303), or their derivatives. In some embodiments, the AVV particles of the present invention may comprise or be derived from AVV serotype which may be or have a sequence as described in United States Publication No. US20140359799, the contents of which are incorporated herein. application by reference in its entirety, such as, without limitation, AAV 8 (SEQ ID NO: 1 of US20140359799), AAVDJ (SEQ ID NO: 2 and 3 of US20140359799), or variants thereof. In some embodiments, the AAV particle may comprise a capsid of a serotype such as, without limitation, AAVDJ or one of its variants, such as AAVDJ8 (or AAV-DJ8), as described by Grimm et al. (Journal of Virology 82(12): 5887-5911 (2008), incorporated herein by reference in its entirety). The AAVDJ8 amino acid sequence may comprise two or more mutations to delete the heparin-binding domain (HBD). As a non-limiting example, the AAV-DJ sequence described as SEQ ID NO: 1 in US Patent No. 7,588,772, n / ztznn / i ζπζ / β / υιλι 112, the contents of which are incorporated herein by reference in their entirety, may comprise two mutations: (1) R587Q where arginine (R; Arg) at amino acid 587 is changed to glutamine (Q; Gln) and (2) R590T where arginine ( R; Arg) at amino acid 590 is changed to threonine (T; Thr). As another non-limiting example, it can comprise three mutations: (1) K406R where lysine (K; Lys) at amino acid 406 is changed to arginine (R; Arg), (2) R587Q where arginine (R; Arg) at amino acid 587 is changed to glutamine (Q; Gln) and (3) R590T where arginine (R; Arg) at amino acid 590 is changed to threonine (T; Thr). In some embodiments, the AAV particles of the present invention may comprise or be derived from an AAV serotype that may be, or have, an AAV4 sequence as described in International Publication No. WO 1998011244, the contents of which are incorporated herein by reference in its entirety, such as, without limitation, AAV4 (SEQ ID NO: 1-20 of WO 1998011244). In some embodiments, the AAV particles of the present invention may comprise or be derived from an AAV serotype that may be, or have, a mutation in the AAV2 sequence to generate AAV2G9 as described in International Publication Number WO2014144229. and incorporated herein by reference in its entirety. In some embodiments, the AAV particles of the present invention may comprise or be derived from an AAV serotype that may be, or have, a sequence as described in International Publication Number WO2005033321, the contents of which are incorporated herein by reference into in their entirety, such as, without limitation, AAV3-3 (SEQ ID NO: 217 of WO2005033321), AAV1 (SEQ ID NO: 219 and 202 of WO2005033321), AAV106.1 / hu.37 (SEQ ID No: 10 of WO2005033321), AAV114.3 / hu.4O (SEQ ID No: 11 of WO2005033321), AAV127.2 / hu.41 (SEQ ID NO: 6 and 8 of WO2005033321), AAV128.3 / hu.44 (SEQ ID No : 81 of WO2005033321), AAV130.4 / hu.48 (SEQ ID NO: 78 of WO2005033321), AAV145.1 / hu.53 (SEQ ID No: 176 and 177 of WO2005033321), AAV145.6 / hu.56 ( SEQ ID NO: 168 and 192 of WO2005033321), AAV16.12 / hu.11 (SEQ ID NO: 153 and 57 of WO2005033321), AAV16.8 / hu.10 (SEQ ID NO: 156 and 56 of WO2005033321), AAV161 .10 / hu.60 (SEQ ID No: 170 of WO2005033321), AAV161.6 / hu.61 (SEQ ID No: 174 of WO2005033321), AAV1-7 / rh.48 (SEQ ID NO: 32 of WO2005033321), AAVI -8 / rh.49 (SEQ ID NOs: 103 and 25 of WO2005033321), AAV2 (SEQ ID NO: 211 and 221 of WO2005033321), AAV2-15 / rh.62 (SEQ ID No: 33 and 114 of WO2005033321), AAV2-3 / rh.61 (SEQ ID NO: 21 of WO2005033321), AAV2-4 / rh.5O (SEQ ID No: 23 and 108 of WO2005033321), AAV2-5 / rh.51 (SEQ ID NO: 104 and 22 of WO2005033321), AAV3.1 / hu.6 (SEQ ID NO: 5 and 84 of WO2005033321), AAV3.1 / hu.9 (SEQ ID NO: 155 and 58 of WO2005033321), AAV3-I l / rh. 53 (SEQ ID NO: 186 and 176 of WO2005033321), AAV3-3 (SEQ ID NO: 200 of WO2005033321), AAV33.12 / hu.17 (SEQ ID NO: 4 of WO2005033321), AAV33.4 / hu.15 (SEQ ID No: 50 of WO2005033321), AAV33.8 / hu.16 (SEQ ID No: 51 of WO2005033321), AAV3-9 / rh.52 (SEQ ID NO: 96 and 18 of WO2005033321), AAV4-19 / rh.55 (SEQ ID NO: 117 of WO2005033321), AAV4-4 (SEQ n / ztznn / i ζπζ / ε / υιλι 113 ID NO: 201 and 218 of WO2005033321), AAV4-9 / rh.54 (SEQ ID NO: 116 of WO2005033321), AAV5 (SEQ ID NO: 199 and 216 of WO2005033321), AAV52.1 / hu.2O (SEQ ID NO: 63 of WO2005033321), AAV52 / hu. I9 (SEQ ID NO: 133 of WO2005033321), AAV5-22 / rh.58 (SEQ ID No: 27 of WO2005033321), AAV5-3 / rh.57 (SEQ ID NO: 105 of WO2005033321), AAV5-3 / rh .57 (SEQ ID No: 26 of WO2005033321), AAV58.2 / hu.25 (SEQ ID No: 49 of WO2005033321), AAV6 (SEQ ID NO: 20...

Claims

1. An antibody or its antigen-binding fragment that binds to the immunoglobulin superfamily (IgSF) domain of human myeloid cell expression activation protein 2 (hTREM2) and stabilizes the TREM2 protein (e.g., SEQ ID NO: 1,2 or 3).

2. The antibody or its antigen-binding fragment of claim 1, wherein the antibody or its antigen-binding fragment binds to one or more residues selected from a group consisting of D39, S40, M41, K42, W44, G45, R46, R47, H67, N68, L69, W70, L71, L72, F74, L75, R77, D87, T88, L89 and G90 of hTREM2.

3. The antibody or its antigen-binding fragment of claim 1, wherein the antibody or its antigen-binding fragment binds to one or more residues selected from a group consisting of D39, S40, M41, K42, W44, G45, R46 and R47, one or more residues selected from a group consisting of H67, N68, L69, W70, L71, L72, F74, L75 and R77, and one or more residues selected from a group consisting of D87, T88, L89 and G90 of hTREM2.

4. The antibody or its antigen-binding fragment of claim 1, wherein the antibody or its antigen-binding fragment binds to five or more residues selected from a group consisting of D39, S40, M41, K42, W44, G45, R46 and R47, four or more residues selected from a group consisting of H67, N68, L69, W70, L71, L72, F74, L75 and R77, and three or more residues selected from a group consisting of D87, T88, L89 and G90 of hTREM2.

5. The antibody or its antigen-binding fragment of claim 1, wherein the antibody or its antigen-binding fragment binds to seven or more residues selected from a group consisting of D39, S40, M41, K42, W44, G45, R46 and R47, four or more residues selected from a group consisting of H67, N68, L69, W70, L71, L72, F74, L75 and R77, and three or more residues selected from a group consisting of D87, T88, L89 and G90 of hTREM2.

6. The antibody or its antigen-binding fragment of claim 1, wherein the antibody or its antigen-binding fragment binds to five or more residues selected from a group consisting of D39, S40, M41, K42, W44, G45, R46 and R47, all residues H67, N68, L69, W70, L71, L72, F74, L75 and R77, and three or more residues selected from a group consisting of D87, T88, L89 and G90 of hTREM2.

7. The antibody or its antigen-binding fragment of claim 1, wherein the antibody or its antigen-binding fragment binds to one or more residues selected from a group consisting of S40, M41, W44, G45, W70, L71, L72, F74, T88 and L89 of hTREM2.

8. The antibody or its antigen-binding fragment of claim 1, wherein the antibody or its antigen-binding fragment binds to two or more residues selected from a group consisting of S40, M41, W44, G45, W70, L71, L72, F74, T88, and L89 of hTREM2. n / ztznn / i ζπζ / β / υιλι 233 9. The antibody or its antigen-binding fragment of claim 1, wherein the antibody or its antigen-binding fragment binds to three or more residues selected from a group consisting of S40, M41, W44, G45, W70, L71, L72, F74, T88 and L89 of hTREM2.

10. The antibody or its antigen-binding fragment of claim 1, wherein the antibody or its antigen-binding fragment binds to four or more residues selected from a group consisting of S40, M41, W44, G45, W70, L71, L72, F74, T88 and L89 of hTREM2.

11. The antibody or its antigen-binding fragment of claim 1, wherein the antibody or its antigen-binding fragment binds to five or more residues selected from a group consisting of S40, M41, W44, G45, W70, L71, L72, F74, T88 and L89 of hTREM2.

12. The antibody or its antigen-binding fragment of claim 1, wherein the antibody or its antigen-binding fragment binds to six or more residues selected from a group consisting of S40, M41, W44, G45, W70, L71, L72, F74, T88 and L89 of hTREM2.

13. The antibody or its antigen-binding fragment of claim 1, wherein the antibody or its antigen-binding fragment binds to seven or more residues selected from a group consisting of S40, M41, W44, G45, W70, L71, L72, F74, T88 and L89 of hTREM2.

14. The antibody or its antigen-binding fragment of claim 1, wherein the antibody or its antigen-binding fragment binds to eight or more residues selected from a group consisting of S40, M41, W44, G45, W70, L71, L72, F74, T88 and L89 of hTREM2.

15. The antibody or its antigen-binding fragment of claim 1, wherein the antibody or its antigen-binding fragment binds to nine or more residues selected from a group consisting of S40, M41, W44, G45, W70, L71, L72, F74, T88 and L89 of hTREM2.

16. The antibody or its antigen-binding fragment of claim 1, wherein the antibody or its antigen-binding fragment binds to all residues S40, M41, W44, G45, W70, L71, L72, F74, T88 and L89 of hTREM2.

17. The antibody or its antigen-binding fragment of any of claims 7 to 16, wherein the antibody or its antigen-binding fragment binds to one or more residues selected from a group consisting of D39, K42, R46 and G90 of hTREM2.

18. The antibody or its antigen-binding fragment of any of claims 7 to 16, wherein the antibody or its antigen-binding fragment binds to two or more residues selected from a group consisting of D39, K42, R46 and G90 of hTREM2.

19. The antibody or its antigen-binding fragment of any of claims 7 to 16, wherein the antibody or its antigen-binding fragment binds to three or more residues selected from a group consisting of D39, K42, R46, and G90 of hTREM2. n / 7bnn / i ζπζ / β / υιλι 234 20. The antibody or its antigen-binding fragment of any of claims 7 to 15, wherein the antibody or its antigen-binding fragment binds to all residues D39, K42, R46 and G90 of hTREM2.

21. The antibody or its antigen-binding fragment of claim 1, wherein the antibody or its antigen-binding fragment binds to all residues S40, M41, W44, G45, W70, L71, L72, F74, T88, L89, D39, K42, R46 and G90 of hTREM2.

22. The antibody or its antigen-binding fragment of any of claims 7 to 16, wherein the antibody or its antigen-binding fragment binds to one or more residues selected from a group consisting of R47, H67, N68, L69, L75, R77 and D87 of hTREM2.

23. The antibody or its antigen-binding fragment of any of claims 7 to 16, wherein the antibody or its antigen-binding fragment binds to two or more residues selected from a group consisting of R47, H67, N68, L69, L75, R77 and D87 of hTREM2.

24. The antibody or its antigen-binding fragment of any of claims 7 to 16, wherein the antibody or its antigen-binding fragment binds to three or more residues selected from a group consisting of R47, H67, N68, L69, L75, R77 and D87 of hTREM2.

25. The antibody or its antigen-binding fragment of any of claims 7 to 16, wherein the antibody or its antigen-binding fragment binds to four or more residues selected from a group consisting of R47, H67, N68, L69, L75, R77 and D87 of hTREM2.

26. The antibody or its antigen-binding fragment of any of claims 7 to 16, wherein the antibody or its antigen-binding fragment binds to five or more residues selected from a group consisting of R47, H67, N68, L69, L75, R77 and D87 of hTREM2.

27. The antibody or its antigen-binding fragment of any of claims 7 to 15, wherein the antibody or its antigen-binding fragment binds to six or more residues selected from a group consisting of R47, H67, N68, L69, L75, R77 and D87 of hTREM2.

28. The antibody or its antigen-binding fragment of claim 1, wherein the antibody or its antigen-binding fragment binds to all residues S40, M41, W44, G45, W70, L71, L72, F74, T88, L89, R47, H67, N68, L69, L75, R77 and D87 of hTREM2.

29. The antibody or its antigen-binding fragment of any of claims 1 to 28, wherein the antibody or its antigen-binding fragment activates hTREM2.

30. The antibody or its antigen-binding fragment of any of claims 1 to 29, wherein the antibody or its antigen-binding fragment facilitates one or more hTREM2-dependent physiological activities in a cell expressing TREM2.

31. The antibody or its antigen-binding fragment of any of claims 1 to 30, wherein the antibody or its antigen-binding fragment: a) enhances phagocytosis, for example, in a cell expressing hTREM2, for example, wherein the cell expressing TREM2 is an hM2A macrophage or a human iPS-derived microglia-like cell; b) enhances chemotaxis, for example, in a cell expressing hTREM2, for example, wherein the cell expressing TREM2 is an hM2a ​​macrophage or a human iPS-derived microglia-like cell; c) enhances NFAT-directed reporter gene activity in a human monocytic cell line; d) increases Syk phosphorylation, for example, in a cell expressing hTREM2, for example, where the cell expressing TREM2 is an hM2A macrophage; or e) increases any combination of two or more of a) ad).

32. The antibody or its antigen-binding fragment of any of claims 1 to 31, wherein the antibody or its antigen-binding fragment binds to hTREM2, for example, on the surface of a cell, with a mean maximum effective concentration (EC50) of 1 nM or less, for example, as measured by FACS assay on hM2a ​​macrophages.

33. The antibody or its antigen-binding fragment of any of claims 1 to 32, wherein the antibody or its antigen-binding fragment binds to hTREM2, for example, on the surface of a cell, with a mean maximum effective concentration (EC50) of 0.59 nM or less, for example, as measured by FACS assay on hM2a ​​macrophages.

34. The antibody or its antigen-binding fragment of any of claims 1 to 33, wherein the antibody or its antigen-binding fragment binds to hTREM2 with a dissociation constant (KD) of 150 pM or less, for example, as measured by surface plasmon resonance (SPR).

35. The antibody or its antigen-binding fragment of any of claims 1 to 34, wherein the antibody or its antigen-binding fragment binds to hTREM2 with a dissociation constant (KD) of 50 pM or less, e.g., as measured by surface plasmon resonance (SPR).

36. The antibody or its antigen-binding fragment of any of claims 1 to 35, wherein the antibody or its antigen-binding fragment stabilizes the hTREM2 protein on a cell surface of a cell expressing hTREM2.

37. The antibody or its antigen-binding fragment of claim 36, wherein the cell expressing hTREM2 is a macrophage, for example, an M2a macrophage, dendritic cell, osteoclast, microglia, mast cell, monocyte, lung epithelial cell, Langerhans cell of the skin, Kupffer cell, neutrophil, or hepatocellular carcinoma cell. 236 38. The antibody or its antigen-binding fragment of any of claims 1 to 37, wherein the antibody or its antigen-binding fragment reduces the ectodomain shedding of the hTREM2 protein at a concentration of 100 nM or lower in hM2A macrophages.

39. The antibody or its antigen-binding fragment of any of claims 1 to 38, wherein the cell surface expression TREM2 is 3 times greater or more.

40. The antibody or its antigen-binding fragment of any of claims 1 to 39, wherein the IgSF domain of hTREM2 comprises amino acid residues 19 to 132 of any of SEQIDNOs 1, 2 and 3.

41. The antibody or its antigen-binding fragment of any of claims 1 to 40, wherein said antibody or its antigen-binding fragment comprises: a) a variable heavy chain region CDR1 comprising, for example, SEQ ID NO: 41 or SEQ ID NO: 44 or SEQ ID NO: 45 or SEQ ID NO: 47; a variable heavy chain region CDR2 comprising, for example, SEQ ID NO: 42 or SEQ ID NO: 46, or SEQ ID NO: 48; a variable heavy chain region CDR3 comprising, for example, SEQ ID NO: 43 or SEQ ID NO: 49; a variable light chain region CDR1 comprising, for example, SEQ ID NO: 54 or SEQ ID NO: 57 or SEQ ID NO: 60; a CDR2 light chain variable region comprising, for example, SEQ ID NO: 55 or SEQ ID NO: 58; and a CDR3 light chain variable region comprising, for example, SEQ ID NO: 56 or SEQ ID NOs: 59;(b) a variable heavy chain region CDR1 comprising, for example, SEQ ID NO: 4 or SEQ ID NO: 7 or SEQ ID NO: 8 or SEQ ID NO: 10; a variable heavy chain region CDR2 comprising, for example, SEQ ID NO: 5 or SEQ ID NO: 9 or SEQ ID NO: 11; a variable heavy chain region CDR3 comprising, for example, SEQ ID NO: 6 or SEQ ID NO: 12; a variable light chain region CDR1 comprising, for example, SEQ ID NO: 17 or SEQ ID NO: 20 or SEQ ID NO: 23; a variable light chain region CDR2 comprising, for example, SEQ ID NO: 18 or SEQ ID NO: 21; and a variable light chain region CDR3 comprising, for example, SEQ ID NO: 19 or SEQ ID NO: 22; c) a variable heavy chain region CDR1 comprising, for example, SEQ ID NO: 4 or SEQ ID NO: 7 or SEQ ID NO: 8 or SEQ ID NO: 10;a CDR2 heavy chain variable region comprising, for example, SEQ ID NO: 5 or SEQ ID NO: 9 or SEQ ID NO: 11; a CDR3 heavy chain variable region comprising, for example, SEQ ID NO: 6 or SEQ ID NO: 12; a CDR1 light chain variable region comprising, for example, SEQ ID NO: 17 or SEQ ID NO: 20 or SEQ ID NO: 23; a CDR2 light chain variable region comprising, for example, SEQ ID NO: 18 or SEQ ID NO: 21; and a CDR3 light chain variable region comprising, for example, SEQ ID NO: 78 or SEQ ID NO: 79; (od) a variable heavy chain region CDR1 comprising, for example, SEQ ID NO: 84 or SEQ ID NO: 87 or SEQ ID NO: 88 or SEQ ID NO: 90; a variable heavy chain region CDR2 comprising, for example, SEQ ID NO: 85 or SEQ ID NO: 89 or SEQ ID NO: 91;a CDR3 heavy chain variable region comprising, for example, SEQ ID NO: 86 or SEQ ID NO: 92; a CDR1 light chain variable region comprising, for example, SEQ ID NO: 97 or SEQ ID NO: 100 or SEQ ID NO: 103; a CDR2 light chain variable region comprising, for example, SEQ ID NO: 98 or SEQ ID NO: 101; and a CDR3 light chain variable region comprising, for example, SEQ ID NO: 99 or SEQ ID NO:

102.

42. An antibody or its antigen-binding fragment that binds to the IgSF domain of the hTREM2 protein, wherein said antibody or its antigen-binding fragment comprises: a) a CDR1 heavy chain variable region comprising, for example, SEQ ID NO: 41 or SEQ ID NO: 44 or SEQ ID NO: 45 or SEQ ID NO: 47; a CDR2 heavy chain variable region comprising, for example, SEQ ID NO: 42 or SEQ ID NO: 46, or SEQ ID NO: 48; a CDR3 heavy chain variable region comprising, for example, SEQ ID NO: 43 or SEQ ID NO: 49; a CDR1 light chain variable region comprising, for example, SEQ ID NO: 54 or SEQ ID NO: 57 or SEQ ID NO: 60; a CDR2 light chain variable region comprising, for example, SEQ ID NO: 55 or SEQ ID NO: 58; and a CDR3 light chain variable region comprising, for example, SEQ ID NO: 56 or SEQ ID NOs: 59;(b) a variable heavy chain region CDR1 comprising, for example, SEQ ID NO: 4 or SEQ ID NO: 7 or SEQ ID NO: 8 or SEQ ID NO: 10; a variable heavy chain region CDR2 comprising, for example, SEQ ID NO: 5 or SEQ ID NO: 9 or SEQ ID NO: 11; a variable heavy chain region CDR3 comprising, for example, SEQ ID NO: 6 or SEQ ID NO: 12; a variable light chain region CDR1 comprising, for example, SEQ ID NO: 17 or SEQ ID NO: 20 or SEQ ID NO: 23; a variable light chain region CDR2 comprising, for example, SEQ ID NO: 18 or SEQ ID NO: 21; and a variable light chain region CDR3 comprising, for example, SEQ ID NO: 19 or SEQ ID NO: 22; c) a variable heavy chain region CDR1 comprising, for example, SEQ ID NO: 4 or SEQ ID NO: 7 or SEQ ID NO: 8 or SEQ ID NO: 10;a CDR2 heavy chain variable region comprising, for example, SEQ ID NO: 5 or SEQ ID NO: 9 or SEQ ID NO: 11; a CDR3 heavy chain variable region comprising, for example, SEQ ID NO: 6 or SEQ ID NO: 12; a CDR1 light chain variable region comprising, for example, SEQ ID NO: 17 or SEQ ID NO: 20 or SEQ ID NO: 23; a CDR2 light chain variable region comprising, for example, SEQ ID NO: 18 or SEQ ID NO: 21; and a CDR3 light chain variable region comprising, for example, SEQ ID NO: 78 or SEQ ID NO: 79; (od) a variable heavy chain region CDR1 comprising, for example, SEQ ID NO: 84 or SEQ ID NO: 87 or SEQ ID NO: 88 or SEQ ID NO: 90; a variable heavy chain region CDR2 comprising, for example, SEQ ID NO: 85 or SEQ ID NO: 89 or SEQ ID NO: 91;a CDR3 heavy chain variable region comprising, for example, SEQ ID NO: 86 or SEQ ID NO: 92; a CDR1 light chain variable region comprising, for example, SEQ ID NO: 97 or SEQ ID NO: 100 or SEQ ID NO: 103; a CDR2 light chain variable region comprising, for example, SEQ ID NO: 98 or SEQ ID NO: 101; and a CDR3 light chain variable region comprising, for example, SEQ ID NO: 99 or SEQ ID NO:

102.

43. The antibody or its antigen-binding fragment of any of claims 1 to 42 wherein the antibody or its antigen-binding fragment comprises a) a VH polypeptide sequence having at least 95% sequence identity with respect to SEQ ID NO: 13 to SEQ ID NO: 50, and a VL polypeptide sequence having at least 95% sequence identity with respect to SEQ ID NO: 24 to SEQ ID NO: 61; b) a VH polypeptide sequence having at least 95% sequence identity with respect to SEQ ID NO: 13 to SEQ ID NO: 93, and a VL polypeptide sequence having at least 95% sequence identity with respect to SEQ ID NO: 80 to SEQ ID NO:

104.

44. The antibody or its antigen-binding fragment of any of claims 1 to 43 comprising: a) a CDR1 heavy chain variable region comprising, for example, SEQ ID NO: 7; a CDR2 heavy chain variable region comprising, for example, SEQ ID NO: 5; a CDR3 heavy chain variable region comprising, for example, SEQ ID NO: 6; a CDR1 light chain variable region comprising, for example, SEQ ID NO: 17; a CDR2 light chain variable region comprising, for example, SEQ ID NO: 18; and a CDR3 light chain variable region comprising, for example, SEQ ID NO: 19; b) a CDR1 heavy chain variable region comprising, for example, SEQ ID NO: 44; a variable region of heavy chain CDR2 comprising, for example, SEQ ID NO: 42;a CDR3 heavy chain variable region comprising, for example, SEQ ID NO: 43; a CDR1 light chain variable region comprising, for example, SEQ ID NO: 54; a CDR2 light chain variable region comprising, for example, SEQ ID NO: 55; and a CDR3 light chain variable region comprising, for example, SEQ ID NO: 56; c) a CDR1 heavy chain variable region comprising, for example, SEQ ID NO: 7; a CDR2 heavy chain variable region comprising, for example, SEQ ID NO: 5; a CDR3 heavy chain variable region comprising, for example, SEQ ID NO: 6; a variable light chain region CDR1 comprising, for example, SEQ ID NO: 17; a variable light chain region CDR2 comprising, for example, SEQ ID NO: 18;and a CDR3 light chain variable region comprising, for example, SEQ ID NO: 78; od) a CDR1 heavy chain variable region comprising, for example, SEQ ID NO: 87; a CDR2 heavy chain variable region comprising, for example, SEQ ID NO: 85; a CDR3 heavy chain variable region comprising, for example, SEQ ID NO: 86; a CDR1 light chain variable region comprising, for example, SEQ ID NO: 97; a CDR2 light chain variable region comprising, for example, SEQ ID NO: 98; and a CDR3 light chain variable region comprising, for example, SEQ ID NO:

99.

45. The antibody or its antigen-binding fragment of any of claims 1 to 43 comprising: a) a CDR1 heavy chain variable region of SEQ ID NO: 8; a CDR2 heavy chain variable region comprising, for example, SEQ ID NO: 9; a CDR3 heavy chain variable region comprising, for example, SEQ ID NO: 6; a CDR1 light chain variable region comprising, for example, SEQ ID NO: 20; a CDR2 light chain variable region comprising, for example, SEQ ID NO: 21; and a CDR3 light chain variable region comprising, for example, SEQ ID NO: 22; b) a CDR1 heavy chain variable region comprising, for example, SEQ ID NO: 45; a CDR2 heavy chain variable region comprising, for example, SEQ ID NO: 46; a variable region of heavy chain CDR3 comprising, for example, SEQ ID NO: 43;a variable light chain region CDR1 comprising, for example, SEQ ID NO: 57; a variable light chain region CDR2 comprising, for example, SEQ ID NO: 58; and a variable light chain region CDR3 comprising, for example, SEQ ID NO: 59; c) a variable heavy chain region CDR1 comprising, for example, SEQ ID NO: 8; a variable heavy chain region CDR2 comprising, for example, SEQ ID NO: 9; a variable heavy chain region CDR3 comprising, for example, SEQ ID NO: 6; a variable light chain region CDR1 comprising, for example, SEQ ID NO: 20; a CDR2 light chain variable region comprising, for example, SEQ ID NO: 21; and a CDR3 light chain variable region comprising, for example, SEQ ID NO: 79;(od) a heavy chain variable region CDR1 comprising, for example, SEQ ID NO: 88; a heavy chain variable region CDR2 comprising, for example, SEQ ID NO: 89; a heavy chain variable region CDR3 comprising, for example, SEQ ID NO: 86; a light chain variable region CDR1 comprising, for example, SEQ ID NO: 100; a light chain variable region CDR2 comprising, for example, SEQ ID NO: 101; and a light chain variable region CDR3 comprising, for example, SEQ ID NO:

102.

46. ​​The antibody or its antigen-binding fragment of any of claims 1 to 43 comprising: a) a CDR1 heavy chain variable region comprising, for example, SEQ ID NO: 10; a CDR2 heavy chain variable region comprising, for example, SEQ ID NO: 11; a CDR3 heavy chain variable region comprising, for example, SEQ ID NO: 12; a CDR1 light chain variable region comprising, for example, SEQ ID NO: 23; a CDR2 light chain variable region comprising, for example, SEQ ID NO: 21; and a CDR3 light chain variable region comprising, for example, SEQ ID NO: 19; b) a CDR1 heavy chain variable region comprising, for example, SEQ ID NO: 47; a variable region of heavy chain CDR2 comprising, for example, consisting of, SEQ ID NO: 48;a CDR3 heavy chain variable region comprising, for example, SEQ ID NO: 49; a CDR1 light chain variable region comprising, for example, SEQ ID NO: 60; a CDR2 light chain variable region comprising, for example, SEQ ID NO: 58; and a CDR3 light chain variable region comprising, for example, SEQ ID NO: 56; c) a CDR1 heavy chain variable region comprising, for example, SEQ ID NO: 10; a CDR2 heavy chain variable region comprising, for example, SEQ ID NO: 11; a CDR3 heavy chain variable region comprising, for example, SEQ ID NO: 12; a CDR1 light chain variable region comprising, for example, SEQ ID NO: 23; a variable region of CDR2 light chain comprising, for example, SEQ ID NO: 21;and a CDR3 light chain variable region comprising, for example, SEQ ID NO: 78; or njztznn / i ζπζ / ε / υιλι 241 d) a CDR1 heavy chain variable region comprising, for example, SEQ ID NO: 90; a CDR2 heavy chain variable region comprising, for example, SEQ ID NO: 91; a CDR3 heavy chain variable region comprising, for example, SEQ ID NO: 92; a CDR1 light chain variable region comprising, for example, SEQ ID NO: 103; a CDR2 light chain variable region comprising, for example, SEQ ID NO: 101; and a CDR3 light chain variable region comprising, for example, SEQ ID NO: 99.; 47. The antibody or its antigen-binding fragment of any of claims 1 to 43 comprising: a) a CDR1 heavy chain variable region comprising, for example, SEQ ID NO: 4; a CDR2 heavy chain variable region comprising, for example, SEQ ID NO: 5; a CDR3 heavy chain variable region comprising, for example, SEQ ID NO: 6; a CDR1 light chain variable region comprising, for example, SEQ ID NO: 17; a CDR2 light chain variable region comprising, for example, SEQ ID NO: 18; and a CDR3 light chain variable region comprising, for example, SEQ ID NO: 19; b) a CDR1 heavy chain variable region comprising, for example, SEQ ID NO: 41; a variable region of heavy chain CDR2 comprising, for example, SEQ ID NO: 42;a CDR3 heavy chain variable region comprising, for example, SEQ ID NO: 43; a CDR1 light chain variable region comprising, for example, SEQ ID NO: 54; a CDR2 light chain variable region comprising, for example, SEQ ID NO: 55; and a CDR3 light chain variable region comprising, for example, SEQ ID NO: 56; c) a CDR1 heavy chain variable region comprising, for example, SEQ ID NO: 4; a CDR2 heavy chain variable region comprising, for example, SEQ ID NO: 5; a CDR3 heavy chain variable region comprising, for example, SEQ ID NO: 6; a CDR1 light chain variable region comprising, for example, SEQ ID NO: 17; a variable region of CDR2 light chain comprising, for example, SEQ ID NO: 18;and a CDR3 light chain variable region comprising, for example, SEQ ID NO: 78; (od) a CDR1 heavy chain variable region comprising, for example, SEQ ID NO: 84; a CDR2 heavy chain variable region comprising, for example, SEQ ID NO: 85; a CDR3 heavy chain variable region comprising, for example, SEQ ID NO: 86; a CDR1 light chain variable region comprising, for example, SEQ ID NO: 97; a CDR2 light chain variable region comprising, for example, SEQ ID NO: 98; and a CDR3 light chain variable region comprising, for example, SEQ ID NO:

99.

48. The antibody or its antigen-binding fragment of any of claims 1-47, wherein the antibody or its antigen-binding fragment comprises: a) a VH comprising, for example, SEQ ID NO: 13 and a VL comprising, for example, SEQ ID NO: 24; b) a VH comprising, for example, SEQ ID NO: 50 and a VL comprising, for example, SEQ ID NO: 61; c) a VH comprising, for example, a sequence having at least 95% homology with respect to SEQ ID NO: 13 and a VL comprising, for example, a sequence having at least 95% homology with respect to SEQ ID NO: 24; (od) a VH comprising, for example, consisting of, a sequence having at least 95% homology with respect to SEQ ID NO: 50 and a VL comprising, for example, consisting of, a sequence having at least 95% homology with respect to SEQ ID NO: 61;(e) a VH comprising, for example, consisting of, a sequence that differs by at least 1, 2, 3, 4, 5, or 6 amino acids from SEQ ID NO: 13 and a VL comprising, for example, consisting of, a sequence that differs by at least 1, 2, 3, 4, 5, or 6 amino acids from SEQ ID NO: 24; (of) a VH comprising, for example, consisting of, a sequence that differs by at least 1, 2, 3, 4, 5, or 6 amino acids from SEQ ID NO: 50 and a VL comprising, for example, consisting of, a sequence that differs by at least 1, 2, 3, 4, 5, or 6 amino acids from SEQ ID NO: 61; g) a VH comprising, for example, SEQ ID NO: 13 and a VL comprising, for example, SEQ ID NO: 80; oh) a VH comprising, for example, SEQ ID NO: 93 and a VL comprising, for example, SEQ ID NO: 104;oi) a VH comprising, for example, consisting of, a sequence having at least 95% homology with respect to SEQ ID NO: 13 and a VL comprising, for example, consisting of, a sequence having at least 95% homology with respect to SEQ ID NO: 80; oj) a VH comprising, for example, consisting of, a sequence having at least 95% homology with respect to SEQ ID NO: 93 and a VL comprising, for example, consisting of, a sequence having at least 95% homology with respect to SEQ ID NO: 104; ok) a VH comprising, for example, that consists of, a sequence that differs by at least 1, 2, 3, 4, 5, or 6 amino acids with respect to SEQ ID NO: 13 and a VL comprising, for example, that n / ztznn / i ζπζ / β / υιλι 243 consists of, a sequence that differs by at least 1, 2, 3, 4, 5, or 6 amino acids with respect to SEQ ID NO: 80;or I) a VH comprising, for example, consisting of, a sequence that differs by at least 1, 2, 3, 4, 5, or 6 amino acids from SEQ ID NO: 93 and a VL comprising, for example, consisting of, a sequence that differs by at least 1, 2, 3, 4, 5, or 6 amino acids from SEQ ID NO: 104.; 49. The antibody or its antigen-binding fragment of any of claims 1-48, wherein the antibody or its antigen-binding fragment comprises: a) a heavy-chain amino acid sequence comprising, for example, SEQ ID NO: 15, SEQ ID NO: 29, SEQ ID NO: 33, SEQ ID NO: 35, SEQ ID NO: 37, or SEQ ID NO: 39, and a light-chain amino acid sequence comprising, for example, SEQ ID NO: 26; b) a heavy-chain amino acid sequence comprising, for example, SEQ ID NO: 52, SEQ ID NO: 66, SEQ ID NO: 70, SEQ ID NO: 72, SEQ ID NO: 74, or SEQ ID NO: 76, and a light-chain amino acid sequence comprising, for example, SEQ ID NO: 63;c) a heavy chain amino acid sequence having at least 95% sequence identity with respect to SEQ ID NO: 15, SEQ ID NO: 29, SEQ ID NO: 33, SEQ ID NO: 35, SEQ ID NO: 37, or SEQ ID NO: 39, and a light chain amino acid sequence having at least 95% sequence identity with respect to SEQ ID NO: 26; d) a heavy chain amino acid sequence having at least 95% sequence identity with respect to SEQ ID NO: 52, SEQ ID NO: 66, SEQ ID NO: 70, SEQ ID NO: 72, SEQ ID NO: 74, or SEQ ID NO: 76, and a light chain amino acid sequence having at least 95% sequence identity with respect to SEQ ID NO: 63; e) a heavy chain amino acid sequence comprising, for example, SEQ ID NO: 15, and a light chain amino acid sequence comprising, for example, SEQ ID NO: 82;f) a heavy chain amino acid sequence comprising, for example, SEQ ID NO: 95, and a light chain amino acid sequence comprising, for example, SEQ ID NO: 106; g) a heavy chain amino acid sequence having at least 95% sequence identity with respect to SEQ ID NO: 15, and a light chain amino acid sequence having at least 95% sequence identity with respect to SEQ ID NO: 82; h) a heavy chain amino acid sequence having at least 95% sequence identity with respect to SEQ ID NO: 95, and a light chain amino acid sequence having at least 95% sequence identity with respect to SEQ ID NO:

106.

50. An antibody or its antigen-binding fragment that binds to the human myeloid cell activation superfamily (IgSF) expression 2 (hTREM2) domain comprising: a) a heavy chain sequence comprising, for example, SEQ ID NO: 15 and a light chain sequence comprising, for example, SEQ ID NO: 26; b) a heavy chain sequence comprising, for example, SEQ ID NO: 29 and a light chain sequence comprising, for example, SEQ ID NO: 26; c) a heavy chain sequence comprising, for example, SEQ ID NO: 33 and a light chain sequence comprising, for example, SEQ ID NO: 26; d) a heavy chain sequence comprising, for example, SEQ ID NO: 35 and a light chain sequence comprising, for example, SEQ ID NO: 26;e) a heavy chain sequence comprising, for example, SEQ ID NO: 37 and a light chain sequence comprising, for example, SEQ ID NO: 26; f) a heavy chain sequence comprising, for example, SEQ ID NO: 39 and a light chain sequence comprising, for example, SEQ ID NO: 26; g) a heavy chain sequence comprising, for example, SEQ ID NO: 52 and a light chain sequence comprising, for example, SEQ ID NO: 63; h) a heavy chain sequence comprising, for example, SEQ ID NO: 66 and a light chain sequence comprising, for example, SEQ ID NO: 63; i) a heavy chain sequence comprising, for example, SEQ ID NO: 70 and a light chain sequence comprising, for example, SEQ ID NO: 63;(j) a heavy chain sequence comprising, for example, SEQ ID NO: 72 and a light chain sequence comprising, for example, SEQ ID NO: 63; (k) a heavy chain sequence comprising, for example, SEQ ID NO: 74 and a light chain sequence comprising, for example, SEQ ID NO: 63; (l) a heavy chain sequence comprising, for example, SEQ ID NO: 76 and a light chain sequence comprising, for example, SEQ ID NO: 63; (m) a heavy chain sequence comprising, for example, SEQ ID NO: 15 and a light chain sequence comprising, for example, SEQ ID NO: 82; on) a heavy chain sequence comprising, for example, SEQ ID NO: 95 and a light chain sequence comprising, for example, SEQ ID NO:

106. n / ztznn / i znz / E / v 245; 51. An antibody or its antigen-binding fragment that competes with any antibody or its antigen-binding fragment of any of claims 1-50 for hTREM2 protein binding.

52. An antibody or its antigen-binding fragment that binds to an epitope that overlaps with the epitope of any antibody or its antigen-binding fragment of any of claims 1-51.

53. The antibody or its antigen-binding fragment of any of claims 1-52, wherein the antibody has an isotype lgG1, lgG2, lgG3 or lgG4.

54. The antibody or its antigen-binding fragment of any of claims 1-52, wherein the antibody or its antigen-binding fragment comprises an Fe region selected from an Fe region of lgG1, an Fe region of lgG2, an Fe region of lgG4, or a hybrid lgG2 / lgG4 Fe region.

55. The antibody or its antigen-binding fragment of any of claims 1-49, or 51-54, wherein the antibody or its antigen-binding fragment comprises a modified Fe region having reduced antibody-dependent cell cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC) activity compared to the parental antibody.

56. The antibody or its antigen-binding fragment of any of claims 1-55, wherein the antibody or its antigen-binding fragment is a human or humanized antibody or fragment thereof.

57. The antibody or its antigen-binding fragment of any of claims 1-56, wherein the antibody or its antigen-binding fragment is conjugated to another residue.

58. The antibody according to any of claims 1-57, wherein said antibody is of the isotype lgG1.

59. The antibody according to any of claims 1-56, wherein said antibody is a human or humanized antibody.

60. The antigen-binding fragment of the antibody according to any of claims 1-57, wherein the antigen-binding fragment is selected from a Fab, F(abj2, Fv fragments, scFv, minibody or diabody.

61. The antibody or its antigen-binding fragment of any of claims 1-60, wherein said antibody or its antigen-binding fragment is monoclonal.

62. The antibody of any of claims 1-61, wherein the antibody is a multispecific antibody, for example, a bispecific antibody.

63. The antibody of claim 62, wherein the multispecific antibody, for example, the bispecific antibody, binds specifically to human hTREM2 and DAP12 (12 kDa DNAX activating protein). n / ztznn / i ζπζ / β / υιλι 246 64. The antibody according to any of claims 1-63, wherein said antibody has altered effector function through mutation of the Fe region.

65. A nucleic acid molecule or a set of nucleic acid molecules encoding any of the antibodies or their antigen-binding fragments according to any of claims 1 to 64.

66. The nucleic acid molecule according to claim 65, wherein the nucleic acid is DNA.

67. The nucleic acid molecule or set of nucleic acid molecules according to claim 65 or 66, comprising one or more of SEQ ID Nos: 14, 28, 51, 65, 16, 30, 34, 36, 38, 40, 53, 67, 71, 73, 75, 77, 25, 31, 62, 68, 27, 32, 64, 69, 13, 93, 15, 95, 80, 104, 82 or 106.

68. A vector comprising nucleic acid molecules according to any of claims 65-67.

69. The vector of claim 68, wherein the vector is a cloning vector or an expression vector.

70. A vector according to claim 68 or 69, wherein said vector comprises one or more of SEQ ID NOs: 14, 28, 51, 65, 16, 30, 34, 36, 38, 40, 53, 67, 71, 73, 75, 77, 25, 31, 62, 68, 27, 32, 64, 69, 13, 93, 15, 95, 80, 104, 82 or 106, or one of its fragments encoding at least one CDR region.

71. A vector according to any of claims 68-70, wherein the vector is capable of replicating in a prokaryotic cell and / or a eukaryotic cell.

72. A vector according to any of claims 68-71, wherein the vector is selected from a DNA vector, an RNA vector, a plasmid, a cosmid, or a viral vector.

73. A vector according to any of claims 68-72 further comprising a detectable and / or selectable marker.

74. A set of two expression vectors according to any of claims 68-73, wherein one vector encodes a) at least one VH domain comprising SEQ ID NO: 13 or 50, and the other vector encodes at least one VL domain comprising SEQ ID NO: 24 or 61; or d) at least one VH domain comprising SEQ ID NO: 13 or 93, and the other vector encodes at least one VL domain comprising SEQ ID NO: 80 or 104.

75. A vector according to any one of claims 68-74, wherein the vector is a viral vector, optionally, wherein the viral vectors are a lentivirus, an adenovirus, an adeno-associated virus (AAV), a herpes simplex virus (HSV), a parvovirus, a retrovirus, a vaccine virus, a Sinbis virus, an influenza virus, a reovirus, a Newcastle disease virus (NDV), a measles virus, a vesicular stomatitis virus (VSV), a poliovirus, a poxvirus, a Seneca Valley virus, a coxsackievirus, an enterovirus, a myxoma virus, or a maraba virus.

76. A vector according to claim 75, wherein the vector is an AAV vector.

77. A vector according to any of claims 68-76, wherein the vector further comprises a promoter.

78. A vector according to any of claims 68-77, wherein the vector comprises an AAV9 capsid and an AAV vector plasmid comprising (1) AAV2-derived ITRs, (2) a CMV enhancer (e.g., comprising SEQ ID NO: 134), (3) a CBA promoter (e.g., comprising SEQ ID NO: 135), (4) an SV40 intron (e.g., comprising SEQ ID NO: 137), (5) a polynucleotide encoding an hTREM2 antibody or its antigen-binding fragment (e.g., as described herein), and (6) a poly A BGH signal (e.g., comprising SEQ ID NO: 138).

79. The vector of claim 78, wherein elements (2) to (6) are arranged in the AAV vector plasmid from 5' to 3'.

80. The vector of claim 78 or 79, wherein any of the elements (2) to (6) are arranged in the AAV vector plasmid between the 5' ITR and the 3' ITR.

81. The vector of any of claims 78-80, wherein the AAV vector is a scAAV vector.

82. A vector according to any of claims 68-75, wherein the vector is a lentiviral vector.

83. A cell comprising the nucleic acid molecule or the set of nucleic acid molecules according to any of claims 64-66 or the vector of any of claims 68-82.

84. A method for producing an hTREM2 antibody or its antigen-binding fragment, wherein the method comprises: (i) culturing the cell of claim 83 and (ii) isolating the hTREM2 antibody or its antigen-binding fragment from the culture.

85. A pharmaceutical composition comprising the antibody or its antigen-binding fragment of any of claims 1-64, the nucleic acid molecule or the set of nucleic acid molecules of any of claims 65-67, the vector of any of claims 68-82, or the cell of claim 83, and a pharmaceutically acceptable carrier.

86. The antibody or its antigen-binding fragment of any of claims 1-64, the nucleic acid molecule or the assembly of nucleic acid molecules of any of claims 65-67, the vector of any of claims 68-82, the cell of claim 83, or the pharmaceutical composition of claim 85, for use as a medicament.

87. The antibody or its antigen-binding fragment of any of claims 1-64, the nucleic acid molecule or the assembly of nucleic acid molecules of any of claims 65-67, the vector of any of claims 68-82, the cell of claim 83, or the pharmaceutical composition of claim 85, for use in the treatment of a disease associated with loss of hTREM2 function.

88. Use of the antibody or its antigen-binding fragment of any of claims 1-64, the nucleic acid molecule or the assembly of nucleic acid molecules of any of claims 65-67, the vector of any of claims 68-82, the cell of claim 83, or the pharmaceutical composition of claim 85, for the manufacture of a medicament for the treatment of a disease associated with loss of hTREM2 function.

89. The antibody or its antigen-binding fragment, the nucleic acid molecule or the assembly of nucleic acid molecules, the vector, the cell, or the pharmaceutical composition of claim 87, or the use according to claim 88, wherein the disease is a neuroinflammatory or neurodegenerative disease, optionally, wherein the neuroinflammatory or neurodegenerative disease is Alzheimer's disease, frontotemporal dementia, Parkinson's disease, amyotrophic lateral sclerosis, Nasu-Hakola disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS), NMDA receptor antibody encephalitis, autism, cerebral lupus (NP-SLE), chemo-induced peripheral neuropathy (CIPN), postherpetic neuralgia, chronic inflammatory demyelinating polyneuropathy (CIDP), epilepsy, Guillain-Barré syndrome (GBS), inclusion body myositis, lysosomal storage diseases, sphingomyelinlipidosis (Niemann-Pick C),mucopolysaccharidosis II / IIIB, metachromatic leukodystrophy, multifocal motor neuropathy, myasthenia gravis, Neuro-Behcet disease, neuromyelitis optica (NMO), optic neuritis, polymyositis, dermatomyositis, Rasmussen's encephalitis, Rett syndrome, stroke, transverse myelitis, traumatic brain injury, spinal cord injury, viral encephalitis, or bacterial meningitis.

90. The antibody or its antigen-binding fragment, the nucleic acid molecule or the assembly of nucleic acid molecules, the vector, the cell or the pharmaceutical composition of claim 87, or the use according to claim 88, wherein the disease is Alzheimer's disease.

91. The antibody or its antigen-binding fragment, the nucleic acid molecule or the assembly of nucleic acid molecules, the vector, the cell or the pharmaceutical composition of claim 87, or the use according to claim 88, wherein the disease is Parkinson's disease.

92. The antibody or its antigen-binding fragment, the nucleic acid molecule or the assembly of nucleic acid molecules, the vector, the cell or the pharmaceutical composition of claim 87, or the use according to claim 88, wherein the disease is multiple sclerosis.

93. The antibody or its antigen-binding fragment, the nucleic acid molecule or the assembly of nucleic acid molecules, the vector, the cell, or the pharmaceutical composition of claim 87, or the use according to claim 88, wherein the disease is frontotemporal dementia. n / ztznn / i ζπζ / β / υιλι 249 94. The antibody or its antigen-binding fragment, nucleic acid molecule or assembly of nucleic acid molecules, vector, cell, or pharmaceutical composition of claim 87, or the use according to claim 88, wherein the antibody or its antigen-binding fragment, nucleic acid molecule or assembly of nucleic acid molecules, vector, cell, or pharmaceutical composition is administered to the subject via an oral, intravenous, intracranial, intrathecal, subcutaneous, or intranasal route.

95. The antibody or its antigen-binding fragment, nucleic acid molecule or assembly of nucleic acid molecules, vector, cell or pharmaceutical composition of claim 87, or the use according to claim 88, wherein the antibody or its antigen-binding fragment, nucleic acid molecule or assembly of nucleic acid molecules, vector, cell or pharmaceutical composition is administered to the subject in combination with at least one additional therapeutic procedure or agent.

96. The antibody or its antigen-binding fragment, nucleic acid molecule or assembly of nucleic acid molecules, vector, cell, or pharmaceutical composition of claim 87, or the use according to claim 88, wherein the antibody or its antigen-binding fragment, nucleic acid molecule or assembly of nucleic acid molecules, vector, cell, or pharmaceutical composition is administered to the subject in combination with at least one additional therapeutic agent, wherein said agent comprises one or more of BACE inhibitors, anti-Tau antibodies, Tau antisense oligonucleotides, anti-beta-amyloid antibodies, fingolimod, BG12 or dimethyl fumarate, beta interferon, or Tysabri.

97. A method of treating a disease associated with loss of hTREM2 function in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of the antibody or its antigen-binding fragment of any of claims 1-64, the nucleic acid molecule or the assembly of nucleic acid molecules of any of claims 65-67, the vector of any of claims 68-82, the cell of claim 83, or the pharmaceutical composition of claim 85.

98. The method of claim 97, wherein the method comprises: a) testing the cell surface hTREM2 level in a sample obtained from a subject; b) selecting a subject whose cell surface hTREM2 level is below a reference level, wherein the reference level is the cell surface hTREM2 level in a sample obtained from a healthy subject; and c) administering to the selected subject a therapeutically effective amount of the antibody or its antigen-binding fragment of any of claims 1 to 64, the nucleic acid molecule or the set of nucleic acid molecules of any of claims 65-67, the vector of any of claims 68-82, the cell of claim 83, or the pharmaceutical composition of claim 85.

99. The method of claim 98, wherein the sample comprises cerebrospinal fluid.

100. The method of claim 98 or 99, wherein the level of TREM2 on the cell surface in said sample is determined by an assay selected from flow cytometry, immunohistochemistry, Western blot, immunofluorescence assay, radioimmunoassay (RIA), enzyme-linked immunosorbent assay (ELISA), homogeneous time-resolution fluorescence (HTRF), or positron emission tomography (PET).

101. The method of any one of claims 97-100, wherein the disease associated with the loss of TREM2 function is a neuroinflammatory or neurodegenerative disease, optionally wherein the neuroinflammatory or neurodegenerative disease is Alzheimer's disease, frontotemporal dementia, Parkinson's disease, amyotrophic lateral sclerosis, Nasu-Hakola disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS), NMDA receptor antibody encephalitis, autism, cerebral lupus (NP-SLE), chemoinduced peripheral neuropathy (CIPN), postherpetic neuralgia, chronic inflammatory demyelinating polyneuropathy (CIDP), epilepsy, Guillain-Barré syndrome (GBS), inclusion body myositis, lysosomal storage diseases, sphingomyelinlipidosis (Niemann-Pick C), mucopolysaccharidotase II / IIIB, metachromatic leukodystrophy, multifocal motor neuropathy, myasthenia gravis, Neuro-Behcet disease, neuromyelitis optica (NMO),Optic neuritis, polymyositis, dermatomyositis, Rasmussen's encephalitis, Rett syndrome, stroke, transverse myelitis, traumatic brain injury, spinal cord injury, viral encephalitis, or bacterial meningitis.

102. The method of any of claims 97-101, wherein the disease is Alzheimer's disease.

103. The method of any of claims 97-101, wherein the disease is Parkinson's disease.

104. The method of any of claims 97-101, wherein the disease is multiple sclerosis.

105. The method of any of claims 97-101, wherein the disease is frontotemporal dementia.

106. The method of any of claims 97-105, wherein said antibody or its antigen-binding fragment, nucleic acid molecule or assembly of nucleic acid molecules, vector, cell, or pharmaceutical composition is administered to the subject via an oral, intravenous, intracranial, intrathecal, subcutaneous, or intranasal route. n / ztznn / i ζπζ / β / υιλι 251 107. A method for stabilizing the hTREM2 protein in a subject, wherein the method comprises administering to the subject the antibody or its antigen-binding fragment of any of claims 1-64, the nucleic acid molecule or the set of nucleic acid molecules of any of claims 65-67, the vector of any of claims 68-82, the cell of claim 83, or the pharmaceutical composition of claim 85, in an amount effective to stabilize hTREM2.

108. The method of any of claims 97-107, wherein the method further comprises administering at least one additional therapeutic agent to the subject, or performing at least one additional therapeutic procedure.

109. The method of claim 108, wherein said additional therapeutic agent comprises one or more of BACE inhibitors, anti-Tau antibodies, Tau antisense oligonucleotides, anti-beta-amyloid antibodies, fingolimod, BG12 or dimethyl fumarate, beta interferon or Tysabri.

110. The method of claim 108 or 109, wherein the antibody or its antigen-binding fragment of any of claims 1-64, the nucleic acid molecule or the assembly of nucleic acid molecules of any of claims 65-67, the vector of any of claims 68-82, the cell of claim 83, or the pharmaceutical composition of claim 85 are administered concurrently with, or before or after, the additional therapeutic agent.

111. The method of any of claims 97-100, wherein the administration of the antibody or its antigen-binding fragment, the nucleic acid molecule or the assembly of nucleic acid molecules, the vector, the cell, or the pharmaceutical composition has one or more of the following effects: a) increased TREM2-dependent cellular activities such as phagocytosis and chemotaxis, b) activation of TREM2-dependent gene transcription, c) increased TREM2-dependent intracellular signaling pathways through Syk phosphorylation, d) increased clearance of cellular debris. 252 ABSTRACT The present invention provides antibodies that bind to and stabilize the Human Activating Receptor Expressed in Myeloid Cells 2 (TREM2) protein, and methods for using these antibodies.