Methods of treatment using Anti-TREM2 antibodies

Abstract

Methods, treatment regimens, uses, kits and therapies for treating neurological and neurodegenerative disorders, by administering anti-TREM2 antibodies, are disclosed.

Description

[0001] Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)

[0002] METHODS OF TREATMENT USING ANTI-TREM2 ANTIBODIES

[0003] CROSS REFERENCE TO RELATED APPLICATIONS

[0004] This application claims the benefit of U.S. Provisional Application No. 63 / 697,131, filed on September 20, 2024, the contents of which are incorporated by reference in their entirety.

[0005] TECHNICAL FIELD

[0006] The disclosure relates to methods, treatment regimens, uses, kits and therapies for treating neurological disorders or diseases, in particular for treating Alzheimer’s disease (AD), especially in a patient in need thereof, comprising administering an anti-TREM2 antibody, in particular VHB937, and related disclosure embodiments as mentioned herein.

[0007] REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0008] The contents of the electronic sequence listing PAT059764-US-PSP_SQL ST.26; Size: 128 Kbytes; and Date of Creation: 09 September 2024 are herein incorporated by reference in their entirety.

[0009] BACKGROUND OF THE DISCLOSURE

[0010] Alzheimer’s disease (AD) is the most common cause of dementia. There are about 50 million people around the globe living with dementia, with the number increasing to as high as 416 million when taking into account the preclinical and prodromal forms of AD (Gustavsson et al 2023). The clinical onset of AD is typically characterized by episodic memory impairment, followed by various combinations of attention-executive, language, and visuospatial impairments, reflecting the spread of AD pathology from the medial temporal lobes to neocortical areas of the brain (Weintraub et al 2012). The progressive cognitive decline slowly impacts the individual's ability to independently carry out activities of daily living (ADLs), such as eating, dressing and cooking, marking the shift from mild cognitive impairment (MCI) to dementia stages of the disease (Petersen 2004).

[0011] According to the ‘amyloid cascade hypothesis’, the deposition of A is the initiating event in the pathogenesis of AD, followed by the deposition of hyperphosphorylated tau (p-tau), Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) neurodegeneration, cognitive decline, and ultimately dementia (Hardy, Selkoe 2002; Hampel et al 2021). Currently approved ‘symptomatic treatments’ for AD are generally well- tolerated and can improve symptoms but do not prevent or slow down the neurodegenerative process and the disease course in patients with AD. The approved anti-amyloid monoclonal antibodies have safety risks (in particular amyloid-related imaging abnormalities (ARIA)), treatment effects are modest, and recent studies have shown that less than 10% of patients with early AD would be eligible for treatment with the anti-amyloid antibodies approved so far (Pittock et al 2023). Accordingly, an unmet need for therapies in AD that slow, halt, reverse or prevent the disease still remains. The focus of further development efforts in AD has been on drugs that target the underlying pathophysiology of AD, in order to affect the course of the disease.

[0012] Neuroinflammation plays a key role in AD as in several neurodegenerative disorders (Rodriguez, Mahy 2016). Chronic microglial activation and proliferation in the central nervous system (CNS) is an important factor in neuroinflammation which contributes to the pathophysiology of AD. With sustained activation in neurodegenerative disease, microglia can become neurotoxic and pro-inflammatory (Paolicelli et al 2022). The triggering receptor expressed on myeloid cells 2 (TREM2), a member of TREM immunoglobulin superfamily, plays a critical role in microglial physiology. TREM2 is a transmembrane protein expressed in microglia and certain tissue macrophages, pre-osteoclasts and dendritic cells in the periphery (Bouchon et al 2001, Sessa et al 2004, Lue et al 2005). Normally at low levels in homeostatic microglial cells, upon CNS injury TREM2 is upregulated and activated, to promote disease- associated microglia (DAM) as part of a physiological, neuroprotective response aimed at restoration of homeostasis (Keren-Shaul et al 2017). Chronic activation of TREM2 might therefore reduce the appearance of pro-inflammatory microglia and support microglial survival, chemotaxis, phagocytosis (e.g., of amyloid), improve metabolic fitness and skew microglia towards a neuroprotective and anti-inflammatory phenotype (Yeh et al 2017, Song, Colonna 2018).

[0013] Accordingly, there is a need in the art for novel methods of treating Alzheimer’s disease and other neurological and neurodegenerative diseases through activation of the microglial activity, for example, using antibodies that target TREM2.

[0014] All references cited herein, including patents, patent applications and publications, are hereby incorporated byreference in their entirety. Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)

[0015] SUMMARY OF THE INVENTION

[0016] The present disclosure is generally directed to methods of using antibodies, e.g., monoclonal, chimeric, humanized antibodies, antigen-binding fragments, etc., that specifically bind human TREM2 as well as compositions that include said antibodies.

[0017] In one aspect provided herein is a method of treating or slowing the progression of a disease or a disorder comprising administering an anti-TREM2 antibody. In particular, it has been surprisingly found that anti-TREM2 antibodies are particularly advantageous.

[0018] Anti-TREM2 antibodies used in the methods and uses of the present disclosure are disclosed in W02020 / 079580 which is hereby incorporated by reference.

[0019] In some embodiments, the methods provided herein comprise intravenously administering to the patient the anti-TREM2 antibody at a dose of about 1 mg / kg to about 60 mg / kg.

[0020] In a further embodiment, the methods provided herein comprise administering to the individual an anti-TREM2 antibody (e.g., monoclonal, chimeric, humanized antibody, antigen-binding fragment, etc.) at a dose of at least about 1 mg / kg intravenously, e.g., at least 1 mg / kg intravenously, wherein the antibody comprises: a) a heavy chain variable region CDR1 comprising, e.g., consisting of, SEQ ID NO: 4; a heavy chain variable region CDR2 comprising, e.g., consisting of, SEQ ID NO: 5; a heavy chain variable region CDR3 comprising, e.g., consisting of, SEQ ID NO: 6; a light chain variable region CDR1 comprising, e.g., consisting of, SEQ ID NO: 17; a light chain variable region CDR2 comprising, e.g., consisting of, SEQ ID NO: 18; and a light chain variable region CDR3 comprising, e.g., consisting of, SEQ ID NO: 19, as defined by the Combined numbering system; b) a heavy chain variable region CDR1 comprising, e.g., consisting of, SEQ ID NO: 7; a heavy chain variable region CDR2 comprising, e.g., consisting of, SEQ ID NO: 5; a heavy chain variable region CDR3 comprising, e.g., consisting of, SEQ ID NO: 6; a light chain variable region CDR1 comprising, e.g., consisting of, SEQ ID NO: 17; a light chain variable region CDR2 comprising, e.g., consisting of, SEQ ID NO: 18; and a light chain variable region CDR3 comprising, e.g., consisting of, SEQ ID NO: 19, as defined by the Kabat numbering system; Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) c) a heavy chain variable region CDR1 of SEQ ID NO: 8; a heavy chain variable region CDR2 comprising, e.g., consisting of, SEQ ID NO: 9; a heavy chain variable region CDR3 comprising, e.g., consisting of, SEQ ID NO: 6; a light chain variable region CDR1 comprising, e.g., consisting of, SEQ ID NO: 20; a light chain variable region CDR2 comprising, e.g., consisting of, SEQ ID NO: 21 ; and a light chain variable region CDR3 comprising, e.g., consisting of, SEQ ID NO: 22, as defined by the Chothia numbering system; or d) a heavy chain variable region CDR1 comprising, e.g., consisting of, SEQ ID NO: 10; a heavy chain variable region CDR2 comprising, e.g., consisting of, SEQ ID NO: 11; a heavy chain variable region CDR3 comprising, e.g., consisting of, SEQ ID NO: 12; a light chain variable region CDR1 comprising, e.g., consisting of, SEQ ID NO: 23; a light chain variable region CDR2 comprising, e.g., consisting of, SEQ ID NO: 21; and a light chain variable region CDR3 comprising, e.g., consisting of, SEQ ID NO: 19, as defined by the IMGT numbering system.

[0021] In a further embodiment, the methods provided herein comprise administering to the individual an anti-TREM2 antibody (e.g., monoclonal, chimeric, humanized antibody, antigen-binding fragment, etc.) at a dose of at least about 3 mg / kg intravenously, e.g., at least 3 mg / kg intravenously, wherein the antibody comprises: a) a heavy chain variable region CDR1 comprising, e.g., consisting of, SEQ ID NO: 4; a heavy chain variable region CDR2 comprising, e.g., consisting of, SEQ ID NO: 5; a heavy chain variable region CDR3 comprising, e.g., consisting of, SEQ ID NO: 6; a light chain variable region CDR1 comprising, e.g., consisting of, SEQ ID NO: 17; a light chain variable region CDR2 comprising, e.g., consisting of, SEQ ID NO: 18; and a light chain variable region CDR3 comprising, e.g., consisting of, SEQ ID NO: 19, as defined by the Combined numbering system;; b) a heavy chain variable region CDR1 comprising, e.g., consisting of, SEQ ID NO: 7; a heavy chain variable region CDR2 comprising, e.g., consisting of, SEQ ID NO: 5; a heavy chain variable region CDR3 comprising, e.g., consisting of, SEQ ID NO: 6; a light chain variable region CDR1 comprising, e.g., consisting of, SEQ ID NO: 17; a light chain variable region CDR2 comprising, e.g., consisting of, SEQ ID NO: 18; and Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) a light chain variable region CDR3 comprising, e.g., consisting of, SEQ ID NO: 19, as defined by the Kabat numbering system; c) a heavy chain variable region CDR1 of SEQ ID NO: 8; a heavy chain variable region

[0022] CDR2 comprising, e.g., consisting of, SEQ ID NO: 9; a heavy chain variable region

[0023] CDR3 comprising, e.g., consisting of, SEQ ID NO: 6; a light chain variable region

[0024] CDR1 comprising, e.g., consisting of, SEQ ID NO: 20; a light chain variable region

[0025] CDR2 comprising, e.g., consisting of, SEQ ID NO: 21 ; and a light chain variable region CDR3 comprising, e.g., consisting of, SEQ ID NO: 22, as defined by the Chothia numbering system; or d) a heavy chain variable region CDR1 comprising, e.g., consisting of, SEQ ID NO: 10; a heavy chain variable region CDR2 comprising, e.g., consisting of, SEQ ID NO: 11; a heavy chain variable region CDR3 comprising, e.g., consisting of, SEQ ID NO: 12; a light chain variable region CDR1 comprising, e.g., consisting of, SEQ ID NO: 23; a light chain variable region CDR2 comprising, e.g., consisting of, SEQ ID NO: 21; and a light chain variable region CDR3 comprising, e.g., consisting of, SEQ ID NO: 19, as defined by the IMGT numbering system;

[0026] In some embodiments, the methods provided herein comprise administering to the individual an anti-TREM2 antibody (e.g., monoclonal, chimeric, humanized antibody, antigen-binding fragment, etc.) at a dose of at least about 10 mg / kg intravenously, e.g., at least 10 mg / kg intravenously, wherein the antibody comprises: a) a heavy chain variable region CDR1 comprising, e.g., consisting of, SEQ ID NO: 4; a heavy chain variable region CDR2 comprising, e.g., consisting of, SEQ ID NO: 5; a heavy chain variable region CDR3 comprising, e.g., consisting of, SEQ ID NO: 6; a light chain variable region CDR1 comprising, e.g., consisting of, SEQ ID NO: 17; a light chain variable region CDR2 comprising, e.g., consisting of, SEQ ID NO: 18; and a light chain variable region CDR3 comprising, e.g., consisting of, SEQ ID NO: 19, as defined by the Combined numbering system; or b) a heavy chain variable region CDR1 comprising, e.g., consisting of, SEQ ID NO: 7; a heavy chain variable region CDR2 comprising, e.g., consisting of, SEQ ID NO: 5; a heavy chain variable region CDR3 comprising, e.g., consisting of, SEQ ID NO: 6; a light chain variable region CDR1 comprising, e.g., consisting of, SEQ ID NO: 17; a light chain variable region CDR2 comprising, e.g., consisting of, SEQ ID NO: 18; and Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) a light chain variable region CDR3 comprising, e.g., consisting of, SEQ ID NO: 19, as defined by the Kabat numbering system; c) a heavy chain variable region CDR1 of SEQ ID NO: 8; a heavy chain variable region CDR2 comprising, e.g., consisting of, SEQ ID NO: 9; a heavy chain variable region CDR3 comprising, e.g., consisting of, SEQ ID NO: 6; a light chain variable region CDR1 comprising, e.g., consisting of, SEQ ID NO: 20; a light chain variable region CDR2 comprising, e.g., consisting of, SEQ ID NO: 21 ; and a light chain variable region CDR3 comprising, e.g., consisting of, SEQ ID NO: 22, as defined by the Chothia numbering system; or d) a heavy chain variable region CDR1 comprising, e.g., consisting of, SEQ ID NO: 10; a heavy chain variable region CDR2 comprising, e.g., consisting of, SEQ ID NO: 11; a heavy chain variable region CDR3 comprising, e.g., consisting of, SEQ ID NO: 12; a light chain variable region CDR1 comprising, e.g., consisting of, SEQ ID NO: 23; a light chain variable region CDR2 comprising, e.g., consisting of, SEQ ID NO: 21; and a light chain variable region CDR3 comprising, e.g., consisting of, SEQ ID NO: 19, as defined by the IMGT numbering system.

[0027] In some embodiments, the methods provided herein comprise administering to the patient an anti-TREM2 antibody (e.g., monoclonal, chimeric, humanized antibody, antigen-binding fragment, etc.) at a dose of at least about 30 mg / kg intravenously, e.g., at least 30 mg / kg intravenously, wherein the antibody comprises: a) a heavy chain variable region CDR1 comprising, e.g., consisting of, SEQ ID NO: 4; a heavy chain variable region CDR2 comprising, e.g., consisting of, SEQ ID NO: 5; a heavy chain variable region CDR3 comprising, e.g., consisting of, SEQ ID NO: 6; a light chain variable region CDR1 comprising, e.g., consisting of, SEQ ID NO: 17; a light chain variable region CDR2 comprising, e.g., consisting of, SEQ ID NO: 18; and a light chain variable region CDR3 comprising, e.g., consisting of, SEQ ID NO: 19, as defined by the Combined numbering system; or b) a heavy chain variable region CDR1 comprising, e.g., consisting of, SEQ ID NO: 7; a heavy chain variable region CDR2 comprising, e.g., consisting of, SEQ ID NO: 5; a heavy chain variable region CDR3 comprising, e.g., consisting of, SEQ ID NO: 6; a light chain variable region CDR1 comprising, e.g., consisting of, SEQ ID NO: 17; a light chain variable region CDR2 comprising, e.g., consisting of, SEQ ID NO: 18; and Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) a light chain variable region CDR3 comprising, e.g., consisting of, SEQ ID NO: 19, as defined by the Kabat numbering system; c) a heavy chain variable region CDR1 of SEQ ID NO: 8; a heavy chain variable region CDR2 comprising, e.g., consisting of, SEQ ID NO: 9; a heavy chain variable region CDR3 comprising, e.g., consisting of, SEQ ID NO: 6; a light chain variable region CDR1 comprising, e.g., consisting of, SEQ ID NO: 20; a light chain variable region CDR2 comprising, e.g., consisting of, SEQ ID NO: 21 ; and a light chain variable region CDR3 comprising, e.g., consisting of, SEQ ID NO: 22, as defined by the Chothia numbering system; or d) a heavy chain variable region CDR1 comprising, e.g., consisting of, SEQ ID NO: 10; a heavy chain variable region CDR2 comprising, e.g., consisting of, SEQ ID NO: 11; a heavy chain variable region CDR3 comprising, e.g., consisting of, SEQ ID NO: 12; a light chain variable region CDR1 comprising, e.g., consisting of, SEQ ID NO: 23; a light chain variable region CDR2 comprising, e.g., consisting of, SEQ ID NO: 21; and a light chain variable region CDR3 comprising, e.g., consisting of, SEQ ID NO: 19, as defined by the IMGT numbering system.

[0028] In some embodiments, the dose of the anti-TREM2 antibody is between about 1 mg / kg to about 60 mg / kg. In some embodiments, the dose is about 1 mg / kg, about 1.5 mg / kg, about 2 mg / kg, about 3 mg / kg, about 3.6 mg / kg, about 4 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 55 mg / kg, or about 60 mg / kg.

[0029] In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of at least about 1 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of at least about 1.5 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of at least about 2 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of at least about 3 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of at least about 3.6 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of at least about 4 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of at least about 5 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) of at least about 10 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of about 15 mg / kg. In some embodiments, the anti- TREM2 antibody is administered about once every four weeks at a dose of about 20 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of about 25 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of about 30 mg / kg. In some embodiments, the anti- TREM2 antibody is administered about once every four weeks at a dose of about 35 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of about 40 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of about 45 mg / kg. In some embodiments, the anti- TREM2 antibody is administered about once every four weeks at a dose of about 50 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of about 55 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of about 60 mg / kg.

[0030] In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of at least 1 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of at least 1.5 mg / kg. In some embodiments, the anti- TREM2 antibody is administered about once every four weeks at a dose of at least 2 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of at least 3 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of at least 3.6 mg / kg. In some embodiments, the anti- TREM2 antibody is administered about once every four weeks at a dose of at least 4 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of at least 5 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of at least 10 mg / kg. In some embodiments, the anti- TREM2 antibody is administered about once every four weeks at a dose of at least 15 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of at least 20 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of at least 25 mg / kg. In some embodiments, the anti- TREM2 antibody is administered about once every four weeks at a dose of at least 30 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of at least 35 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of at least 40 mg / kg. In some embodiments, the anti- Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)

[0031] TREM2 antibody is administered about once every four weeks at a dose of at least 45 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of at least 50 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of at least 55 mg / kg. In some embodiments, the anti- TREM2 antibody is administered about once every four weeks at a dose of at least 60 mg / kg.

[0032] In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of about 1 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of about 1.5 mg / kg. In some embodiments, the anti- TREM2 antibody is administered about once every four weeks at a dose of about 2 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of about 3 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of about 3.6 mg / kg. In some embodiments, the anti- TREM2 antibody is administered about once every four weeks at a dose of about 4 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of about 5 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of about 10 mg / kg. In some embodiments, the anti- TREM2 antibody is administered about once every four weeks at a dose of about 15 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of about 20 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of about 25 mg / kg. In some embodiments, the anti- TREM2 antibody is administered about once every four weeks at a dose of about 30 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of about 35 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of about 40 mg / kg. In some embodiments, the anti- TREM2 antibody is administered about once every four weeks at a dose of about 45 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of about 50 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of about 55 mg / kg. In some embodiments, the anti- TREM2 antibody is administered about once every four weeks at a dose of about 60 mg / kg.

[0033] In some embodiments, an antibody or antigen-binding fragment thereof of the present disclosure comprises: a) a heavy chain variable region CDR1 comprising, e.g., consisting of, SEQ ID NO: 41 or SEQ ID NO: 44 or SEQ ID NO: 45 or SEQ ID NO: 47; a heavy chain variable region CDR2 Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) comprising, e.g., consisting of, SEQ ID NO: 42 or SEQ ID NO: 46, or SEQ ID NO: 48; a heavy chain variable region CDR3 comprising, e.g., consisting of, SEQ ID NO: 43 or SEQ ID NO: 49; a light chain variable region CDR1 comprising, e.g., consisting of, SEQ ID NO: 54 or SEQ ID NO: 57 or SEQ ID NO: 60; a light chain variable region CDR2 comprising, e.g., consisting of, SEQ ID NO: 55 or SEQ ID NO: 58; and a light chain variable region CDR3 comprising, e.g., consisting of, SEQ ID NO: 56 or SEQ ID NO: 59; or b) a heavy chain variable region CDR1 comprising, e.g., consisting of, SEQ ID NO: 4 or SEQ ID NO: 7 or SEQ ID NO: 8 or SEQ ID NO: 10; a heavy chain variable region CDR2 comprising, e.g., consisting of, SEQ ID NO: 5 or SEQ ID NO: 9 or SEQ ID NO: 11; a heavy chain variable region CDR3 comprising, e.g., consisting of, SEQ ID NO: 6 or SEQ ID NO: 12; a light chain variable region CDR1 comprising, e.g., consisting of, SEQ ID NO: 17 or SEQ ID NO: 20 or SEQ ID NO: 23; a light chain variable region CDR2 comprising, e.g., consisting of, SEQ ID NO: 18 or SEQ ID NO: 21; and a light chain variable region CDR3 comprising, e.g., consisting of, SEQ ID NO: 19 or SEQ ID NO: 22; or c) a heavy chain variable region CDR1 comprising, e.g., consisting of, SEQ ID NO: 4 or SEQ ID NO: 7 or SEQ ID NO: 8 or SEQ ID NO: 10; a heavy chain variable region CDR2 comprising, e.g., consisting of, SEQ ID NO: 5 or SEQ ID NO: 9 or SEQ ID NO: 11; a heavy chain variable region CDR3 comprising, e.g., consisting of, SEQ ID NO: 6 or SEQ ID NO: 12; a light chain variable region CDR1 comprising, e.g., consisting of, SEQ ID NO: 17 or SEQ ID NO: 20 or SEQ ID NO: 23; a light chain variable region CDR2 comprising, e.g., consisting of, SEQ ID NO: 18 or SEQ ID NO: 21; and a light chain variable region CDR3 comprising, e.g., consisting of, SEQ ID NO: 78 or SEQ ID NO: 79.

[0034] In some embodiments, the antibody or antigen-binding fragment thereof of the present disclosure comprises: a) a heavy chain variable region (VH) comprising, e.g., consisting of, SEQ ID NO: 13 and a light chain variable region (VL) comprising, e.g., consisting of, SEQ ID NO: 24; or b) a VH comprising, e.g., consisting of, SEQ ID NO: 50 and a VL comprising, e.g., consisting of, SEQ ID NO: 61; or c) a VH comprising, e.g., consisting of, a sequence having at least 95% homology to SEQ ID NO: 13 and a VL comprising, e.g., consisting of, a sequence having at least 95% homology to SEQ ID NO: 24; or Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) d) a VH comprising, e.g., consisting of, a sequence having at least 95% homology to SEQ ID NO: 50 and a VL comprising, e.g., consisting of, a sequence having at least 95% homology to SEQ ID NO: 61; or e) a VH comprising, e.g., 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, e.g., consisting of, a sequence that differs by at least 1, 2, 3, 4, 5, or 6 amino acids from SEQ ID NO: 24; or f) a VH comprising, e.g., 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, e.g., consisting of, a sequence that differs by at least 1, 2, 3, 4, 5, or 6 amino acids from SEQ ID NO: 61; or g) a VH comprising, e.g., consisting of, SEQ ID NO: 13 and a VL comprising, e.g., consisting of, SEQ ID NO: 80; or h) a VH comprising, e.g., consisting of, a sequence having at least 95% homology to SEQ ID NO: 13 and a VL comprising, e.g., consisting of, a sequence having at least 95% homology to SEQ ID NO: 80; or i) a VH comprising, e.g., 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, e.g., consisting of, a sequence that differs by at least 1, 2, 3, 4, 5, or 6 amino acids from SEQ ID NO: 80.

[0035] In some embodiments, the antibody or antigen-binding fragment thereof of the present disclosure comprises: a) a heavy chain sequence comprising, e.g., consisting of, SEQ ID NO: 15 and a light chain sequence comprising, e.g., consisting of, SEQ ID NO: 26; b) a heavy chain sequence comprising, e.g., consisting of, SEQ ID NO: 29 and a light chain sequence comprising, e.g., consisting of, SEQ ID NO: 26; c) a heavy chain sequence comprising, e.g., consisting of, SEQ ID NO: 33 and a light chain sequence comprising, e.g., consisting of, SEQ ID NO: 26; d) a heavy chain sequence comprising, e.g., consisting of, SEQ ID NO: 35 and a light chain sequence comprising, e.g., consisting of, SEQ ID NO: 26; e) a heavy chain sequence comprising, e.g., consisting of, SEQ ID NO: 37 and a light chain sequence comprising, e.g., consisting of, SEQ ID NO: 26; Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) f) a heavy chain sequence comprising, e.g., consisting of, SEQ ID NO: 39 and a light chain sequence comprising, e.g., consisting of, SEQ ID NO: 26; g) a heavy chain sequence comprising, e.g., consisting of, SEQ ID NO: 52 and a light chain sequence comprising, e.g., consisting of, SEQ ID NO: 63; h) a heavy chain sequence comprising, e.g., consisting of, SEQ ID NO: 66 and light chain sequence comprising, e.g., consisting of, SEQ ID NO: 63; i) a heavy chain sequence comprising, e.g., consisting of, SEQ ID NO: 70 and light chain sequence comprising, e.g., consisting of, SEQ ID NO: 63; j) a heavy chain sequence comprising, e.g., consisting of, SEQ ID NO: 72 and light chain sequence comprising, e.g., consisting of, SEQ ID NO: 63; k) a heavy chain sequence comprising, e.g., consisting of, SEQ ID NO: 74 and light chain sequence comprising, e.g., consisting of, SEQ ID NO: 63; l) a heavy chain sequence comprising, e.g., consisting of, SEQ ID NO: 76 and light chain sequence comprising, e.g., consisting of, SEQ ID NO: 63; or m) a heavy chain sequence comprising, e.g., consisting of, SEQ ID NO: 15 and light chain sequence comprising, e.g., consisting of, SEQ ID NO: 82.

[0036] In some embodiments, the antibody comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 13 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 24.

[0037] In some embodiments, the antibody has a human IgGl isotype.

[0038] In some embodiments, the antibody has a human IgGl isotype and comprises M428L / N434S (LS) and / or D265A / P329A (DAP A) amino acid substitutions in the Fc region, wherein the numbering of the residues is according to EU numbering.

[0039] In some embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 37, and a light chain comprising the amino acid sequence of SEQ ID NO: 26.

[0040] In some embodiments, the dose of the anti-TREM2 antibody is between about 1 mg / kg to about 60 mg / kg. In some embodiments, the dose is about 1 mg / kg, 1.5 mg / kg, about 2 mg / kg, about 3 mg / kg, about 3.6 mg / kg, about 4 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 55 mg / kg, or about 60 mg / kg.

[0041] In some embodiments, the dose of the anti-TREM2 antibody is about 10 mg / kg to about 30 mg / kg. In some embodiments, the dose of the anti-TREM2 antibody is about 10 mg / kg. In some embodiments, the dose of the anti-TREM2 antibody is about 30 mg / kg.

[0042] In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of at least about 1 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of at least about 1.5 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of at least about 2 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of at least about 3 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of at least about 3.6 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of at least about 4 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of at least about 5 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of at least about 10 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of about 15 mg / kg. In some embodiments, the anti- TREM2 antibody is administered about once every four weeks at a dose of about 20 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of about 25 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of about 30 mg / kg. In some embodiments, the anti- TREM2 antibody is administered about once every four weeks at a dose of about 35 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of about 40 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of about 45 mg / kg. In some embodiments, the anti- TREM2 antibody is administered about once every four weeks at a dose of about 50 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of about 55 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of about 60 mg / kg.

[0043] In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of at least 1 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of at least 1.5 mg / kg. In some embodiments, the anti- Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)

[0044] TREM2 antibody is administered about once every four weeks at a dose of at least 2 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of at least 3 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of at least 3.6 mg / kg. In some embodiments, the anti- TREM2 antibody is administered about once every four weeks at a dose of at least 4 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of at least 5 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of at least 10 mg / kg. In some embodiments, the anti- TREM2 antibody is administered about once every four weeks at a dose of at least 15 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of at least 20 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of at least 25 mg / kg. In some embodiments, the anti- TREM2 antibody is administered about once every four weeks at a dose of at least 30 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of at least 35 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of at least 40 mg / kg. In some embodiments, the anti- TREM2 antibody is administered about once every four weeks at a dose of at least 45 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of at least 50 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of at least 55 mg / kg. In some embodiments, the anti- TREM2 antibody is administered about once every four weeks at a dose of at least 60 mg / kg.

[0045] In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of about 1 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of about 1.5 mg / kg. In some embodiments, the anti- TREM2 antibody is administered about once every four weeks at a dose of about 2 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of about 3 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of about 3.6 mg / kg. In some embodiments, the anti- TREM2 antibody is administered about once every four weeks at a dose of about 4 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of about 5 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of about 10 mg / kg. In some embodiments, the anti- TREM2 antibody is administered about once every four weeks at a dose of about 15 mg / kg. In Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of about 20 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of about 25 mg / kg. In some embodiments, the anti- TREM2 antibody is administered about once every four weeks at a dose of about 30 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of about 35 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of about 40 mg / kg. In some embodiments, the anti- TREM2 antibody is administered about once every four weeks at a dose of about 45 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of about 50 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every four weeks at a dose of about 55 mg / kg. In some embodiments, the anti- TREM2 antibody is administered about once every four weeks at a dose of about 60 mg / kg.

[0046] In some embodiments, the anti-TREM2 antibody is administered once every four weeks at a dose of at least about 1 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every four weeks at a dose of at least about 1.5 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every four weeks at a dose of at least about 2 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every four weeks at a dose of at least about 3 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every four weeks at a dose of at least about 3.6 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every four weeks at a dose of at least about 4 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every four weeks at a dose of at least about 5 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every four weeks at a dose of at least about 10 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every four weeks at a dose of about 15 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every four weeks at a dose of about 20 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every four weeks at a dose of about 25 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every four weeks at a dose of about 30 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every four weeks at a dose of about 35 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every four weeks at a dose of about 40 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every four weeks at a dose of about 45 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every four weeks at a dose of about 50 mg / kg. In Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) some embodiments, the anti-TREM2 antibody is administered once every four weeks at a dose of about 55 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every four weeks at a dose of about 60 mg / kg.

[0047] In some embodiments, the anti-TREM2 antibody is administered once every four weeks at a dose of at least 1 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every four weeks at a dose of at least 1.5 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every four weeks at a dose of at least 2 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every four weeks at a dose of at least 3 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every four weeks at a dose of at least 3.6 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every four weeks at a dose of at least 4 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every four weeks at a dose of at least 5 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every four weeks at a dose of at least 10 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every four weeks at a dose of at least 15 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every four weeks at a dose of at least 20 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every four weeks at a dose of at least 25 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every four weeks at a dose of at least 30 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every four weeks at a dose of at least 35 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every four weeks at a dose of at least 40 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every four weeks at a dose of at least 45 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every four weeks at a dose of at least 50 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every four weeks at a dose of at least 55 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every four weeks at a dose of at least 60 mg / kg.

[0048] In some embodiments, the anti-TREM2 antibody is administered once every four weeks at a dose of about 1 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every four weeks at a dose of about 1.5 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every four weeks at a dose of about 2 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every four weeks at a dose of about 3 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) four weeks at a dose of about 3.6 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every four weeks at a dose of about 4 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every four weeks at a dose of about 5 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every four weeks at a dose of about 10 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every four weeks at a dose of about 15 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every four weeks at a dose of about 20 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every four weeks at a dose of about 25 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every four weeks at a dose of about 30 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every four weeks at a dose of about 35 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every four weeks at a dose of about 40 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every four weeks at a dose of about 45 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every four weeks at a dose of about 50 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every four weeks at a dose of about 55 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every four weeks at a dose of about 60 mg / kg.

[0049] In some embodiments, the anti-TREM2 antibody is administered about once every month at a dose of at least about 1 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every month at a dose of at least about 1.5 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every month at a dose of at least about 2 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every month at a dose of at least about 3 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every month at a dose of at least about 3.6 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every month at a dose of at least about 4 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every month at a dose of at least about 5 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every month at a dose of at least about 10 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every month at a dose of about 15 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every month at a dose of about 20 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every month at a dose of about 25 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every month at a dose of about 30 mg / kg. In Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) some embodiments, the anti-TREM2 antibody is administered about once every month at a dose of about 35 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every month at a dose of about 40 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every month at a dose of about 45 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every month at a dose of about 50 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every month at a dose of about 55 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every month at a dose of about 60 mg / kg.

[0050] In some embodiments, the anti-TREM2 antibody is administered about once every month at a dose of at least 1 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every month at a dose of at least 1.5 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every month at a dose of at least 2 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every month at a dose of at least 3 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every month at a dose of at least 3.6 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every month at a dose of at least 4 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every month at a dose of at least 5 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every month at a dose of at least 10 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every month at a dose of at least 15 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every month at a dose of at least 20 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every month at a dose of at least 25 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every month at a dose of at least 30 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every month at a dose of at least 35 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every month at a dose of at least 40 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every month at a dose of at least 45 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every month at a dose of at least 50 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every month at a dose of at least 55 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every month at a dose of at least 60 mg / kg. Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)

[0051] In some embodiments, the anti-TREM2 antibody is administered about once every month at a dose of about 1 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every month at a dose of about 1.5 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every month at a dose of about 2 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every month at a dose of about 3 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every month at a dose of about 3.6 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every month at a dose of about 4 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every month at a dose of about 5 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every month at a dose of about 10 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every month at a dose of about 15 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every month at a dose of about 20 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every month at a dose of about 25 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every month at a dose of about 30 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every month at a dose of about 35 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every month at a dose of about 40 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every month at a dose of about 45 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every month at a dose of about 50 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every month at a dose of about 55 mg / kg. In some embodiments, the anti-TREM2 antibody is administered about once every month at a dose of about 60 mg / kg.

[0052] In some embodiments, the anti-TREM2 antibody is administered once every month at a dose of at least about 1 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every month at a dose of at least about 1.5 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every month at a dose of at least about 2 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every month at a dose of at least about 3 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every month at a dose of at least about 3.6 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every month at a dose of at least about 4 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every month at a dose of at least about 5 mg / kg. Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)

[0053] In some embodiments, the anti-TREM2 antibody is administered once every month at a dose of at least about 10 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every month at a dose of about 15 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every month at a dose of about 20 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every month at a dose of about 25 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every month at a dose of about 30 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every month at a dose of about 35 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every month at a dose of about 40 mg / kg. In some embodiments, the anti- TREM2 antibody is administered once every month at a dose of about 45 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every month at a dose of about 50 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every month at a dose of about 55 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every month at a dose of about 60 mg / kg.

[0054] In some embodiments, the anti-TREM2 antibody is administered once every month at a dose of at least 1 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every month at a dose of at least 1.5 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every month at a dose of at least 2 mg / kg. In some embodiments, the anti- TREM2 antibody is administered once every month at a dose of at least 3 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every month at a dose of at least 3.6 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every month at a dose of at least 4 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every month at a dose of at least 5 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every month at a dose of at least 10 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every month at a dose of at least 15 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every month at a dose of at least 20 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every month at a dose of at least 25 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every month at a dose of at least 30 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every month at a dose of at least 35 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every month at a dose of at least 40 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every month at a dose of at least 45 mg / kg. In some embodiments, the anti-TREM2 Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) antibody is administered once every month at a dose of at least 50 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every month at a dose of at least 55 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every month at a dose of at least 60 mg / kg.

[0055] In some embodiments, the anti-TREM2 antibody is administered once every month at a dose of about 1 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every month at a dose of about 1.5 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every month at a dose of about 2 mg / kg. In some embodiments, the anti- TREM2 antibody is administered once every month at a dose of about 3 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every month at a dose of about 3.6 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every month at a dose of about 4 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every month at a dose of about 5 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every month at a dose of about 10 mg / kg. In some embodiments, the anti- TREM2 antibody is administered once every month at a dose of about 15 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every month at a dose of about 20 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every month at a dose of about 25 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every month at a dose of about 30 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every month at a dose of about 35 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every month at a dose of about 40 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every month at a dose of about 45 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every month at a dose of about 50 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every month at a dose of about 55 mg / kg. In some embodiments, the anti- TREM2 antibody is administered once every month at a dose of about 60 mg / kg.

[0056] In some embodiments, the anti-TREM2 antibody is administered once every 25-31 days at a dose of at least about 1 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every 25-31 days at a dose of at least about 1.5 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every 25-31 days at a dose of at least about 2 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every 25-31 days at a dose of at least about 3 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every 25-31 days at a dose of at least about 3.6 mg / kg. In some Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) embodiments, the anti-TREM2 antibody is administered once every 25-31 days at a dose of at least about 4 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every 25-31 days at a dose of at least about 5 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every 25-31 days at a dose of at least about 10 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every 25-31 days at a dose of about 15 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every 25-31 days at a dose of about 20 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every 25-31 days at a dose of about 25 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every 25-31 days at a dose of about 30 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every 25-31 days at a dose of about 35 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every 25-31 days at a dose of about 40 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every 25-31 days at a dose of about 45 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every 25-31 days at a dose of about 50 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every 25-31 days at a dose of about 55 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every 25-31 days at a dose of about 60 mg / kg.

[0057] In some embodiments, the anti-TREM2 antibody is administered once every 25-31 days at a dose of at least 1 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every 25-31 days at a dose of at least 1.5 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every 25-31 days at a dose of at least 2 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every 25-31 days at a dose of at least 3 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every 25- 31 days at a dose of at least 3.6 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every 25-31 days at a dose of at least 4 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every 25-31 days at a dose of at least 5 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every 25-31 days at a dose of at least 10 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every 25-31 days at a dose of at least 15 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every 25-31 days at a dose of at least 20 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every 25-31 days at a dose of at least 25 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every 25-31 days at a dose of at least 30 mg / kg. In some embodiments, the anti-TREM2 antibody is Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) administered once every 25-31 days at a dose of at least 35 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every 25-31 days at a dose of at least 40 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every 25-31 days at a dose of at least 45 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every 25-31 days at a dose of at least 50 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every 25-31 days at a dose of at least 55 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every 25-31 days at a dose of at least 60 mg / kg.

[0058] In some embodiments, the anti-TREM2 antibody is administered once every 25-31 days at a dose of about 1 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every 25-31 days at a dose of about 1.5 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every 25-31 days at a dose of about 2 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every 25-31 days at a dose of about 3 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every 25-31 days at a dose of about 3.6 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every 25-31 days at a dose of about 4 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every 25-31 days at a dose of about 5 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every 25-31 days at a dose of about 10 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every 25-31 days at a dose of about 15 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every 25-31 days at a dose of about 20 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every 25-31 days at a dose of about 25 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every 25-31 days at a dose of about 30 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every 25-31 days at a dose of about 35 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every 25-31 days at a dose of about 40 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every 25-31 days at a dose of about 45 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every 25-31 days at a dose of about 50 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every 25-31 days at a dose of about 55 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every 25-31 days at a dose of about 60 mg / kg.

[0059] In some embodiments, the anti-TREM2 antibody is administered once every 25-31 days, e.g., once every 25, 26, 27, 28, 29, 30, 31 days at a dose of about 10 mg / kg. In some embodiments, Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) the anti-TREM2 antibody is administered once every 25-31 days, e.g., once every 25, 26, 27, 28, 29, 30, 31 days at a dose of 10 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every 25-31 days, e.g., once every 25, 26, 27, 28, 29, 30, 31 days at a dose of about 30 mg / kg. In some embodiments, the anti-TREM2 antibody is administered once every 25-31 days, e.g., once every 25, 26, 27, 28, 29, 30, 31 days at a dose of 30 mg / kg. In some embodiments, the interval between any two consecutive doses (i.e. one dose and the very next dose scheduled for the treatment) can be 25, 26, 27, 28, 29, 30, or 31 days. In some embodiments, the interval between any two consecutive doses can be 25, 26, 27, 28, 29, 30, or 31 days. In some embodiments, the interval between any two consecutive doses is 28 days.

[0060] In some embodiments, the disease or disorder is selected from the group consisting of Alzheimer’s disease, frontotemporal dementia, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), Huntington’s disease, Nasu-Hakola disease, multiple sclerosis, a demyelination disorder, vascular dementia, progressive supranuclear palsy (PSP), multisystem atrophy (MSA), Lewy Body dementia (LBD), cortico-basal dementia (CBD), adrenoleukodystrophy (ALD), adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), a tauopathy disease, anti-NMDA receptor encephalitis, brain lupus (NP-SLE), chemo-induced peripheral neuropathy (CIPN), postherpetic neuralgia, chronic inflammatory demyelinating polyneuropathy (CIDP), Guillain-Barre Syndrome (GBS), inclusion body myositis, lysosomal storage diseases, sphingomyelinlipidose (Niemann-Pick C), mucopolysaccharidose II / IIIB, metachromatic leukodystrophy, multifocal motor neuropathy, myasthenia gravis, Neuro-Behcet’s Disease, neuromyelitis optica (NMO), optic neuritis, polymyositis, dermatomyositis, Rasmussen’s encephalitis, Rett’s Syndrome, stroke, transverse myelitis, cognitive deficit, memory loss, traumatic brain injury, spinal cord injury, viral encephalitis, and bacterial meningitis.

[0061] In some embodiments, the disease or disorder is Alzheimer's disease. In some embodiments, the disease or disorder is lateral sclerosis (ALS). In some embodiments, the disease or disorder is multiple sclerosis (MS).

[0062] In some embodiments, the methods provided herein also comprise measuring the levels of one or more biomarkers of neuroinflammation in a sample of blood, plasma, and / or cerebrospinal fluid from the individual before and after the individual has received one or more doses of the anti-TREM2 antibody. Exemplary markers of neuroinflammation include SPP1 or sCSFIR. In some embodiments, a further dose of the anti-TREM2 antibody is administered based on the measured level and / or change in the level of one or more biomarkers of neuroinflammation. In Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) certain embodiments, a decline in the level of one or more biomarkers of neuroinflammation indicates that the treatment is having the desired effect (i.e. a beneficial effect), in which case a decision can be made to continue with the treatment, for example by administering one or more further doses of the anti-TREM2 antibody.

[0063] In some embodiments, the methods provided herein also comprise measuring the levels of one or more biomarkers of neurodegeneration in a sample of blood, plasma, and / or cerebrospinal fluid from the individual before and after the individual has received one or more doses of the anti-TREM2 antibody. In some embodiments, a further dose of the anti-TREM2 antibody is administered based on the measured level and / or change in the level of one or more biomarkers of neurodegeneration. In certain embodiments, a decline in the level of one or more biomarkers of neurodegeneration indicates that the treatment is having the desired effect (i.e. a beneficial effect), in which case a decision can be made to continue with the treatment, for example by administering one or more further doses of the anti-TREM2 antibody.

[0064] In some embodiments, the one or more biomarkers of neurodegeneration is neurofilament light (NfL).

[0065] In some embodiments, the methods provided herein also comprise measuring the expression levels of sTREM2, soluble CSF1R (Colony-stimulating factor 1 receptor), SPP1 (osteopontin), or CCL3 in a sample of blood, plasma, and / or cerebrospinal fluid from the individual before and after the individual has received one or more doses of the anti-TREM2 antibody (e.g., monoclonal, chimeric, humanized antibody, antigen-binding fragment, etc). In some embodiments, the expression levels of sTREM2, soluble CSF1R, SPP1 (osteopontin), and / or CCL3 refer to mRNA expression levels. In some embodiments, the expression levels of sTREM2, soluble CSF1R, SPP1 (osteopontin) and / or CCL3 refer to protein expression levels. In some embodiments, the method comprises measuring protein expression levels of sTREM2. or soluble CSFIR in the sample of blood, plasma, and / or cerebrospinal fluid from the individual before and after the individual has received one or more doses of the anti-TREM2 antibody. In some embodiments, the methods provided herein also comprise measuring the levels of one or more biomarkers of AD in a sample of cerebrospinal fluid from the individual before and after the individual has received one or more doses of the anti-TREM2 antibody. In some embodiments, the methods provided herein also comprise measuring the levels of one or more biomarkers of AD in a sample of blood from the individual before and after the individual has received one or more doses of the anti-TREM2 antibody. In some embodiments, the methods provided herein also comprise measuring the levels of one or more biomarkers of AD in a Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) sample of plasma from the individual before and after the individual has received one or more doses of the anti-TREM2 antibody. In some embodiments, the one or more biomarkers of AD comprise one or more of YKL-40, IL6, IL-18, CXCL10, CCL2, TIMP and NfL, in CSF. In some embodiments, the methods provided herein also comprise measuring the levels of one or more biomarkers of microglia function in a sample of cerebrospinal fluid from the individual before and after the individual has received one or more doses of the anti-TREM2 antibody. In some embodiments, the methods provided herein also comprise measuring the levels of one or more biomarkers of microglia function in a sample of blood from the individual before and after the individual has received one or more doses of the anti-TREM2 antibody. In some embodiments, the methods provided herein also comprise measuring the levels of one or more biomarkers of microglia function in a sample of plasma from the individual before and after the individual has received one or more doses of the anti-TREM2 antibody. In some embodiments, the one or more biomarkers of microglia function are CSF1R, SPP1 (osteopontin) and / or CCL3.

[0066] In some embodiments, the methods provided herein also comprise measuring in CSF the expression levels of Ap40, Ap42, Ap42 / Ap40 ratio, total-tau, p-tau species, neurogranin. In some embodiments, the methods provided herein also comprise determining a change from baseline in the Clinical Dementia Rating scale - Sum of Boxes (CDR-SB).

[0067] In some embodiments, the methods provided herein also comprise determining changes from baseline in ADAS-Cogl4 over time, e.g., over 18 months.

[0068] In some embodiments, the methods provided herein also comprise determining changes from baseline in instrumental activities of daily living (iADL) on the ADCS-ADL scale over time, e.g., over 18 months.

[0069] In some embodiments, the methods provided herein also comprise determining changes from baseline in volumes of specific brain regions as measured by MR, e.g., until Month 18.

[0070] In some embodiments, the methods provided herein also comprise determining the anti- TREM2 antibody, in particular VHB937, serum PK concentration, preferably at Day 1, Week 4, Week 12, Week 24, Week 48, Week 68, Week 72 and Week 96.

[0071] In some embodiments, the methods provided herein also comprise determining the anti- TREM2 antibody, in particular VHB937, concentration in CSF at Week 12 and Week 68 in a Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) sub-set of participants (sub-study). In some embodiments, the methods provided herein also comprise determining the ratio of VHB937 concentration in CSF to serum at the timepoints where concentrations are available.

[0072] In some embodiments, the methods provided herein also comprise determining changes from baseline in ADAS-Cogl3, modified ADAS-Cogl4 and MMSE over time, e.g., until Month 18.

[0073] In some embodiments, the methods provided herein also comprise determining changes from baseline in ADAS-Cogl3, modified ADAS-Cogl4 and MMSE over time, e.g., until Month 18.

[0074] In some embodiments, the methods provided herein also comprise determining changes from baseline in the Neuropsychiatric Inventory 12-item Scale (NPI-12) over time, e.g., until Month 18.

[0075] In some embodiments, the methods provided herein also comprise determining changes from baseline in the Functional Activities Questionnaire (FAQ) over time, e.g., until Month 18.

[0076] In some embodiments, the methods provided herein also comprise determining change from baseline to Month 18 on brain amyloid levels as measured by amyloid PET in a subset of participants (sub-study).

[0077] In some embodiments, the methods provided herein also comprise determining changes from baseline in blood p-tau, NfL, GFAP and other biomarkers.

[0078] In some embodiments, the methods provided herein also comprise measuring the levels of one or more biomarkers of AD, including but not limited to any of the biomarkers described herein, before and after the patient has received one or more doses of the anti-TREM2 antibody.

[0079] In some embodiments, the patient is not homozygous for the APOE4 gene.

[0080] In some embodiments, the patient is heterozygous for the APOE4 gene.

[0081] In some embodiments, the patient tested for APOE4 status prior to treatment.

[0082] In some embodiments, the patient is assessed for Amyloid related imaging abnormalities (ARIA) during the treatment, optionally where the ARIA assessment is through magnetic Resonance Imaging (MRI). Typically, the patient assessed for ARIA is a patient that has Alzheimer’s disease. In some embodiments, a patient who develops asymptomatic and radiographically mild ARIA-E or ARIA-H on MRI continues to be administered the anti- TREM2 antibody. In some embodiments, a patient who develops mild to moderate symptoms Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) or radiographically moderate / severe ARIA-E will not be administered at least the next scheduled dose of the anti-TREM2 antibody. In some embodiments, a patient who develops mild / moderate symptoms or radiographically moderate ARIA-H will not be administered at least the next scheduled dose of the anti-TREM2 antibody. In some embodiments, a patient who develops radiographically severe ARIA-H regardless of symptoms, will not be administered any further doses of the anti-TREM2 antibody.

[0083] In some embodiments, the anti-TREM2 antibody of the pharmaceutical composition comprises a heavy chain variable region comprising a CDR-H1, CDR-H2, and CDR-H3 and a light chain variable region comprising a CDR-L1, CDR-L2, and CDR-L3, wherein:

[0084] (i) the CDR-H1 comprises the amino acid sequence SEQ ID NO: 4, the CDR-H2 comprises the amino acid sequence SEQ ID NO: 5, the CDR-H3 comprises the amino acid sequence SEQ ID NO: 6, the CDR-L1 comprises the amino acid sequence SEQ ID NO: 17, the CDR-L2 comprises the amino acid sequence SEQ ID NO: 18, and the CDR-L3 comprises the amino acid sequence SEQ ID NO: 19, as defined by the Combined numbering system; or

[0085] (ii) the CDR-H1 comprises the amino acid sequence SEQ ID NO: 7, the CDR-H2 comprises the amino acid sequence SEQ ID NO: 5, the CDR-H3 comprises the amino acid sequence SEQ ID NO: 6, the CDR-L1 comprises the amino acid sequence SEQ ID NO: 17, the CDR-L2 comprises the amino acid sequence SEQ ID NO: 18, and the CDR-L3 comprises the amino acid sequence SEQ ID NO: 19, as defined by the Kabat numbering system; or

[0086] (iii) the CDR-H1 comprises the amino acid sequence SEQ ID NO: 8, the CDR-H2 comprises the amino acid sequence SEQ ID NO: 9, the CDR-H3 comprises the amino acid sequence SEQ ID NO: 6, the CDR-L1 comprises the amino acid sequence SEQ ID NO: 20, the CDR-L2 comprises the amino acid sequence SEQ ID NO: 21, and the CDR-L3 comprises the amino acid sequence SEQ ID NO: 22, as defined by the Chothia numbering system; or

[0087] (iv) the CDR-H1 comprises the amino acid sequence SEQ ID NO: 10, the CDR-H2 comprises the amino acid sequence SEQ ID NO: 11, the CDR-H3 comprises the amino acid sequence SEQ ID NO: 12, the CDR-L1 comprises the amino acid sequence SEQ ID NO: 23, the CDR-L2 comprises the amino acid sequence SEQ ID NO: 21, and the CDR-L3 comprises the amino acid sequence SEQ ID NO: 19, as defined by the IMGT numbering system.

[0088] In some embodiments, the anti-TREM2 antibody of the pharmaceutical composition comprises a heavy chain variable region comprising a CDR-H1, CDR-H2, and CDR-H3 and a light chain variable region comprising a CDR-L1, CDR-L2, and CDR-L3, wherein the CDR-H1 comprises Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) the amino acid sequence SEQ ID NO: 7, the CDR-H2 comprises the amino acid sequence SEQ ID NO: 5, the CDR-H3 comprises the amino acid sequence SEQ ID NO: 6, the CDR-L1 comprises the amino acid sequence SEQ ID NO: 17, the CDR-L2 comprises the amino acid sequence SEQ ID NO: 18, and the CDR-L3 comprises the amino acid sequence SEQ ID NO: 19, as defined by the Kabat numbering system. In some embodiments, the antibody comprises a heavy chain variable region comprising a CDR-H1, CDR-H2, and CDR-H3 and a light chain variable region comprising a CDR-L1, CDR-L2, and CDR-L3, wherein the CDR-H1 comprises the amino acid sequence SEQ ID NO: 10, the CDR-H2 comprises the amino acid sequence SEQ ID NO: 11, the CDR-H3 comprises the amino acid sequence SEQ ID NO: 12, the CDR- L1 comprises the amino acid sequence SEQ ID NO: 23, the CDR-L2 comprises the amino acid sequence SEQ ID NO: 21, and the CDR-L3 comprises the amino acid sequence SEQ ID NO: 19 as defined by the IMGT numbering system. In some embodiments, the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 13 and the light chain variable region comprising the amino acid sequence of SEQ ID NO: 24. In some embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 37 and a light chain comprising the amino acid sequence of SEQ ID NO: 26.

[0089] In some embodiments, the pharmaceutical composition comprises: (i) 150 mg / mL of the anti- TREM2 antibody, wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 37 and a light chain comprising the amino acid sequence of SEQ ID NO: 26, (ii) 20 mM histidine, (iii) 220 mM sucrose, and (iv) 0.4 mM polysorbate-20.

[0090] In some embodiments, the pharmaceutical composition has a pH of 5.0 to 6.0. In some embodiments, the pH of the pharmaceutical composition is 5.5.

[0091] In some embodiments, the pharmaceutical composition comprises: (i) about 150 mg / mL of the anti-TREM2 antibody; (ii) about 20 mM histidine; (iii) about 220 mM sucrose; and (iv) about 0.4 mg / mL polysorbate-20.

[0092] In some embodiments, the pharmaceutical composition comprises: (i) 135 mg / mL to 165 mg / mL of an anti-TREM2 antibody; (ii) 2.79 to 3.41 mg / mL histidine, (iii) 67.78 mg / mL to 82.84 mg / mL sucrose, and (iv) 0.2 mg / mL to 0.6 mg / mL polysorbate-20.

[0093] In some embodiments, the pharmaceutical composition comprises (i)150 mg / mL of an anti- TREM2 antibody; (ii) 20 mM histidine; (iii) 220 mM sucrose; and (iv) 0.4 mg / mL polysorbate- 20. Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)

[0094] In some embodiments, provided herein is a pharmaceutical composition comprising (i) about 150 mg / mL of an anti-TREM2 antibody; (ii) about 20 mM histidine; (iii) about 220 mM sucrose; and (iv) about 0.4 mg / mL polysorbate-20.

[0095] In some embodiments, provided herein is a pharmaceutical composition comprising: (i) 135 mg / mL to 165 mg / mL of an anti-TREM2 antibody; (ii) 2.79 to 3.41 mg / mL histidine, (iii) 67.78 mg / mL to 82.84 mg / mL sucrose, and (iv) 0.2 mg / mL to 0.6 mg / mL polysorbate-20.

[0096] In some embodiments, provided herein is a pharmaceutical composition comprising (i)150 mg / mL of an anti-TREM2 antibody; (ii)20 mM histidine; (iii)220 m sucrose; and (iv) 0.4 mg / mL polysorbate-20.

[0097] In some embodiments, the anti-TREM2 antibody of the pharmaceutical composition comprises a heavy chain variable region comprising a CDR-H1, CDR-H2, and CDR-H3 and a light chain variable region comprising a CDR-L1, CDR-L2, and CDR-L3, wherein:

[0098] (i) the CDR-H1 comprises the amino acid sequence SEQ ID NO: 4, the CDR-H2 comprises the amino acid sequence SEQ ID NO: 5, the CDR-H3 comprises the amino acid sequence SEQ ID NO: 6, the CDR-L1 comprises the amino acid sequence SEQ ID NO: 17, the CDR-L2 comprises the amino acid sequence SEQ ID NO: 18, and the CDR-L3 comprises the amino acid sequence SEQ ID NO: 19, as defined by the Combined numbering system; or

[0099] (ii) the CDR-H1 comprises the amino acid sequence SEQ ID NO: 7, the CDR-H2 comprises the amino acid sequence SEQ ID NO: 5, the CDR-H3 comprises the amino acid sequence SEQ ID NO: 6, the CDR-L1 comprises the amino acid sequence SEQ ID NO: 17, the CDR-L2 comprises the amino acid sequence SEQ ID NO: 18, and the CDR-L3 comprises the amino acid sequence SEQ ID NO: 19, as defined by the Kabat numbering system; or

[0100] (iii) the CDR-H1 comprises the amino acid sequence SEQ ID NO: 8, the CDR-H2 comprises the amino acid sequence SEQ ID NO: 9, the CDR-H3 comprises the amino acid sequence SEQ ID NO: 6, the CDR-L1 comprises the amino acid sequence SEQ ID NO: 20, the CDR-L2 comprises the amino acid sequence SEQ ID NO: 21, and the CDR-L3 comprises the amino acid sequence SEQ ID NO: 22, as defined by the Chothia numbering system; or

[0101] (iv) the CDR-H1 comprises the amino acid sequence SEQ ID NO: 10, the CDR-H2 comprises the amino acid sequence SEQ ID NO: 11, the CDR-H3 comprises the amino acid sequence SEQ ID NO: 12, the CDR-L1 comprises the amino acid sequence SEQ ID NO: 23, the CDR- L2 comprises the amino acid sequence SEQ ID NO: 21, and the CDR-L3 comprises the amino acid sequence SEQ ID NO: 19, as defined by the IMGT numbering system. Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)

[0102] In some embodiments, the antibody comprises a heavy chain variable region comprising a CDR-H1, CDR-H2, and CDR-H3 and a light chain variable region comprising a CDR-L1, CDR-L2, and CDR-L3, wherein: the CDR-H1 comprises the amino acid sequence SEQ ID NO: 7, the CDR-H2 comprises the amino acid sequence SEQ ID NO: 5, the CDR-H3 comprises the amino acid sequence SEQ ID NO: 6, the CDR-L1 comprises the amino acid sequence SEQ ID NO: 17, the CDR-L2 comprises the amino acid sequence SEQ ID NO: 18, and the CDR-L3 comprises the amino acid sequence SEQ ID NO: 19, as defined by the Kabat numbering system.

[0103] In some embodiments, the antibody of the pharmaceutical composition comprises a heavy chain variable region comprising a CDR-H1, CDR-H2, and CDR-H3 and a light chain variable region comprising a CDR-L1, CDR-L2, and CDR-L3, wherein: the CDR-H1 comprises the amino acid sequence SEQ ID NO: 10, the CDR-H2 comprises the amino acid sequence SEQ ID NO: 11, the CDR-H3 comprises the amino acid sequence SEQ ID NO: 12, the CDR-L1 comprises the amino acid sequence SEQ ID NO: 23, the CDR-L2 comprises the amino acid sequence SEQ ID NO: 21, and the CDR-L3 comprises the amino acid sequence SEQ ID NO: 19 as defined by the IMGT numbering system.

[0104] In some embodiments, the antibody of the pharmaceutical composition comprises a heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 13 and the light chain variable region comprising the amino acid sequence of SEQ ID NO: 24.

[0105] In some embodiments, the antibody of the pharmaceutical composition comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 37 and a light chain comprising the amino acid sequence of SEQ ID NO: 26.

[0106] In some embodiments, provided herein is a pharmaceutical composition comprising: A pharmaceutical composition comprising: (i) about 150 mg / mL of an anti-TREM2 antibody, wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 37 and a light chain comprising the amino acid sequence of SEQ ID NO: 26, (ii) about 20 mM histidine, (iii) about 220 mM sucrose, and (iv) about 0.4 mg / mL polysorbate-20.

[0107] In some embodiments, provided herein is a pharmaceutical composition comprising: A pharmaceutical composition comprising: (i) 150 mg / mL of an anti-TREM2 antibody, wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 37 and a light chain comprising the amino acid sequence of SEQ ID NO: 26, (ii) 20 mM histidine, (iii) 220 mM sucrose, and (iv) 0.4 mg / mL polysorbate-20. Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)

[0108] In some embodiments, the pharmaceutical composition has a pH of 5.0 to 6.0.

[0109] In some embodiments, the pharmaceutical composition has a pH of 5.4 to 6.0.

[0110] In some embodiments, the pharmaceutical composition has a pH of 5.5.

[0111] In some embodiments, the pharmaceutical composition is an aqueous formulation. In some embodiments, the pharmaceutical composition is formulated for intravenous administration.

[0112] Any pharmaceutical composition disclosed herein may be used in a method disclosed herein, e.g., in a method of treating Alzheimer’s disease (AD). In some embodiments, the pharmaceutical composition is used in the manufacture of a medicament for treating Alzheimer’s disease (AD).

[0113] BRIEF DESCRIPTION OF THE DRAWINGS

[0114] FIG. 1: Transcriptome change of human iPS microglia cells after treatment with VHB937 vs. isotype antibody.

[0115] FIG. 2: Effect of single acute treatment with VHB937 on SPP1 in the brain parenchyma of KI- TREM2 mice in a cuprizone model. *p=0.3.

[0116] FIG. 3: Release of SPP1 from iPS derived microglial cells after treatment with VHB937 vs. idiotype control antibody.

[0117] FIG. 4A: Image analysis results of the APP23-PS45 amyloidosis model in humanized TREM2 mice and a representative microscopy picture for each group. Example pictures for Methoxy- X04 and APP staining in the cortex, 40X.

[0118] FIG. 4B: Results of the APP23-PS45 amyloidosis model in humanized TREM2 mice.

[0119] FIG. 5: Quantification of P-tau in hTREM2-KIxTau58.4 mice.

[0120] FIG. 6: Study schematic diagram. DMC = data monitoring committee.

[0121] FIG. 7: sTREM2 ratios in cerebrospinal fluid (CSF) after VHB937 treatment vs. placebo.

[0122] FIG. 8: SPP1 ratios in cerebrospinal fluid (CSF) after VHB937 treatment vs. placebo.

[0123] FIG. 9: sCSFIR ratios in cerebrospinal fluid (CSF) after VHB937 treatment vs. placebo.

[0124] FIG. 10: CCL3 ratios in cerebrospinal fluid (CSF) after VHB937 treatment vs. placebo. Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)

[0125] DETAILED DESCRIPTION OF THE INVENTION

[0126] TREM2 is expressed in microglia and certain tissue macrophages, pre-osteoclasts and dendritic cells in the periphery (Bouchon et al 2001, Sessa et al 2004, Lue et al 2005). Normally at low levels in homeostatic microglia cells, upon CNS injury TREM2 is upregulated and activated, to promote a disease-associated microglia (DAM) state that is a physiological, neuroprotective response aimed at restoration of homeostasis (Keren-Shaul et al 2017). However, microglia can also become neurotoxic and pro-inflammatory, particularly with sustained activation in neurodegenerative diseases (Paolicelli et al 2022). Activation of TREM2 might reduce the appearance of pro-inflammatory microglia and support microglial survival, chemotaxis, phagocytosis (e.g., of myelin), improve metabolic fitness and skew microglia towards a neuroprotective and anti-inflammatory phenotype (Yeh et al 2017, Song and Colonna 2018).

[0127] Microglia play a central role in a number of neurodegenerative and neuroinflammatory diseases. TREM2 activation on microglia enables these cells to leave the homeostatic state and become disease-associated microglia (DAM, Wang, Colonna 2019). DAMs are found in a variety of neurodegenerative diseases and are the physiological response of microglia to insults in the brain (Wang et al 2015). Preclinical experimental evidence indicates that the effects of VHB937 on TREM2 cell surface expression, direct activation of TREM2 and signaling in microglia cells might attenuate the disease course across neurodegenerative disorders, including AD.

[0128] VHB937 is a human monoclonal antibody (mAh) and a highly selective agonist that stabilizes and activates TREM2. The mAh is a selective activator of TREM2 and increases TREM2 cell surface abundance by reducing shedding of TREM2. Activating TREM2 drives microglia towards a neuroprotective and pro-resolution phenotype:

[0129] VHB937 was shown (e.g., in WO-A-2020 / 079580) to support key functions of human induced pluripotent stem cells (iPS) derived-microglia cells like chemotaxis and phagocytosis in vitro. Further, anti-inflammatory subclusters of human iPS-derived microglia were expanded at the expense of pro-inflammatory subclusters. In vivo, VHB937 displayed efficacy in five different animal models that recapitulate pathological features of neurodegenerative and neuroinflammatory diseases (i.e., MPTP, cuprizone, TAU58.4, EAE and amyloidosis models). The change to a neuroprotective microglia phenotype after VHB937 treatment promoted neuronal health (reduction of dystrophic neurites) and ameliorated astrogliosis, indicating promising efficacy beyond microglia on other cells in the CNS. In line with this neuroprotective Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) activity, a treatment dependent reduction of pro-inflammatory markers like SPP1 was observed in vitro and in vivo. Thus, this mechanism can delay progression in neuroinflammatory and neurodegenerative conditions such as AD.

[0130] Therefore, interventions that increase microglial TREM2 activity could have a benefit in slowing AD disease progression.

[0131] The present disclosure provides potentially disease-modifying therapies for disorder or diseases, in particular for neurological and neurodegenerative disorders, and more particularly for AD, said therapies are well tolerated, convenient for patients, and induce a high rate of response, which is also maintained after end of the treatment period.

[0132] In one aspect, the present disclosure provides a method of treating AD, especially in a subject in need thereof, comprising administering, especially in a therapeutically effective amount, a molecule that activates TREM2. In one embodiment, the molecule that activates TREM2 is an antibody against TREM2 (anti-TREM2 antibody) or antigen-binding fragment thereof. In one further embodiment such anti-TREM2 antibody binds the IgSF domain. In one further embodiment such anti-TREM2 antibody binds sTREM2. In one further embodiment such anti- TREM2 antibody or antigen-binding fragment binds soluble TREM2 (sTREM2). In some embodiments, sTREM2 comprises the amino acids 19-157 of any one of SEQ ID NOs: 1, 2, and 3. In some embodiments, sTREM2 consists of the amino acids 19-157 of any one of SEQ ID NOs: 1, 2, and 3.

[0133] Human TREM2 encodes a TREM2 protein consisting of a leading signal peptide (amino acids 1-18), a single V-type IgSF extracellular region (amino acids 19-132), a stalk 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 is mapped to chromosomal location 6p21.1, and the genomic sequence of TREM2 gene can be found in GenBank (Gene ID: 54209). Due to alternative splicing, three TREM2 isoforms are present in the human (protein sequences available in ENSEMBL under IDs ENSP00000362205, ENSP00000342651 , and ENSP00000362214). The protein and mRNA sequences for the longest human TREM2 isoform are:

[0134] Triggering receptor expressed on myeloid cells 2 precursor isoform 1 precursor [Homo sapiens] (NP_061838.1)

[0135] MEPLRLLILLFVTELSGAHNTTVFQGVAGQSLQVSCPYDSMKHWGRRKAWCRQLGE

[0136] KGPCQRVVSTHNLWLLSFLRRWNGSTAITDDTLGGTLTITLRNLQPHDAGLYQCQSL Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)

[0137] HGSEADTLRKVLVEVLADPLDHRDAGDLWFPGESESFEDAHVEHSISRSLLEGEIPFP

[0138] PTSILLLLACIFLIKILAASALWAAAWHGQKPGTHPPSELDCGHDPGYQLQTLPGLRD

[0139] T

[0140] (SEQ ID NO: 1)

[0141] In some embodiments, human TREM2 isoform 2 comprises an amino acid sequence of SEQ ID NO: 2 and human isoform 3 comprises an amino acid sequence of SEQ ID NO: 3 (see also W02020 / 0079580, herein incorporated by reference).

[0142] MEPLRLLILLFVTELSGAHNTTVFQGVAGQSLQVSCPYDSMKHWGRRKAWCRQLGE KGPCQRVVSTHNLWLLSFLRRWNGSTAITDDTLGGTLTITLRNLQPHDAGLYQCQSL HGSEADTLRKVLVEVLADPLDHRDAGDLWFPGESESFEDAHVEHSISRAERHVKED DGRKSPGEVPPGTSPACILATWPPGLLVLLWQETTLPEHCFSWTLEAGTG

[0143] (SEQ ID NO: 2)

[0144] MEPLRLLILLFVTELSGAHNTTVFQGVAGQSLQVSCPYDSMKHWGRRKAWCRQLGE KGPCQRVVSTHNLWLLSFLRRWNGSTAITDDTLGGTLTITLRNLQPHDAGLYQCQSL HGSEADTLRKVLVEVLADPLDHRDAGDLWFPGESESFEDAHVEHSISRPSQGSHLPS CLSKEPLGRRNPLPTHFHPSPPGLHLSHQDSSSQRPLGCSLAWTEARDTSTQ

[0145] (SEQ ID NO: 3)

[0146] In some embodiments, human TREM2 protein also encompasses proteins that have over its full length at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity with any of SEQ ID NOs: 1, 2, or 3, wherein such proteins still have the ligand binding, intracellular signaling, facilitating phagocytosis and degradation of phagocytic material, and other regulatory function of TREM2. The sequences of murine, cynomolgus (cyno), and other animal TREM2 proteins are known in the art (for example, NP_112544.1 and NP_001259007.1 for murine TREM2 protein).

[0147] The present disclosure provides methods using an isolated monoclonal antibody or antigen binding region thereof comprising a heavy chain CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 4, 7, 8, 10, 41, 44, 45, and 47; a heavy chain CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 5, 9, 11, 42, 46, and 48; a heavy chain CDR3 comprising an amino acid sequence selected Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) from the group consisting of SEQ ID NOs: 6, 12, 43, and 49; a light chain CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 17, 20, 23, 54, 57, and 60; a light chain CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 18, 21, 55, and 58; and a light chain CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 19, 22, 56, 59, and 56; wherein the antibody specifically binds human TREM2.

[0148] In certain embodiments, an antibody that specifically binds to human TREM2 is an antibody or antigen-binding fragment that is described in Table 1. In some embodiments, the antibody or antigen binding region thereof that specifically binds to human TREM2 comprises a heavy chain complementary determining region 1 (HCDR1) comprising the amino acid sequence of SEQ ID NO: 4, 7, 8, or 10; a heavy chain complementary determining region 2 (HCDR2) comprising the amino acid sequence of SEQ ID NO: 5, 9, or 11 ; a heavy chain complementary determining region 3 (HCDR3) comprising the amino acid sequence of SEQ ID NO: 6 or 12; a light chain complementary determining region 1 (LCDR1) comprising the amino acid sequence of SEQ ID NO: 17, 20, or 23; a light chain complementary determining region 2 (LCDR2) comprising the amino acid sequence of SEQ ID NO: 18 or 21; and a light chain complementary determining region 3 (LCDR3) comprising the amino acid sequence of SEQ ID NO: 19 or 22.

[0149] In some embodiments, the antibody or 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; an HCDR2 comprising the amino acid sequence of SEQ ID NO: 42, 46, or 48; an 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.

[0150] In some embodiments, the antibody or antigen binding region thereof that specifically binds to human TREM2 comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 13 (or a sequence at least about 90%, 95%, 99%, or more identical thereto, and / or having one, two, three or more substitutions, insertions, deletions, or modifications, optionally twelve or fewer substitutions, insertions, deletions, or modifications), and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 24 (or a sequence at least about 90%, 95%, 99% or more identical thereto, and / or having one, two, Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) three or more substitutions, insertions, deletions, or modifications, optionally ten or fewer substitutions, insertions, deletions, or modifications).

[0151] In some embodiments, the antibody or antigen binding region thereof that specifically binds to human TREM2 comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 50 (or a sequence at least about 90%, 95%, 99%, or more identical thereto, and / or having one, two, three or more substitutions, insertions, deletions, or modifications, optionally twelve or fewer substitutions, insertions, deletions, or modifications), and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 61 (or a sequence at least about 90%, 95%, 99% or more identical thereto, and / or having one, two, three or more substitutions, insertions, deletions, or modifications, optionally ten or fewer substitutions, insertions, deletions, or modifications).

[0152] In some embodiments, the antibody that specifically binds to 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 thereto, and / or having one, two, three or more substitutions, insertions, deletions, or modifications, optionally twelve or fewer substitutions, insertions, deletions, or modifications), and a light chain comprising the amino acid sequence of SEQ ID NO: 26 (or a sequence at least about 90%, 95%, 99%, or more identical thereto, and / or having one, two, three or more substitutions, insertions, deletions, or modifications, optionally ten or fewer substitutions, insertions, deletions, or modifications).

[0153] In some embodiments, the antibody that specifically binds to 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 thereto, and / or having one, two, three or more substitutions, insertions, deletions, or modifications, optionally twelve or fewer substitutions, insertions, deletions, or modifications), and a light chain comprising the amino acid sequence of SEQ ID NO: 26 (or a sequence at least about 90%, 95%, 99% or more identical thereto, and / or having one, two, three or more substitutions, insertions, deletions, or modifications, optionally ten or fewer substitutions, insertions, deletions, or modifications).

[0154] In some embodiments, the antibody that specifically binds to 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 thereto, and / or having one, two, three or more substitutions, insertions, deletions, or modifications, optionally twelve or fewer substitutions, insertions, deletions, or modifications), and a light chain comprising the amino acid sequence Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) of SEQ ID NO: 26 (or a sequence at least about 90%, 95%, 99% or more identical thereto, and / or having one, two, three or more substitutions, insertions, deletions, or modifications, optionally ten or fewer substitutions, insertions, deletions, or modifications).

[0155] In some embodiments, the antibody that specifically binds to 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 thereto, and / or having one, two, three or more substitutions, insertions, deletions, or modifications, optionally twelve or fewer substitutions, insertions, deletions, or modifications), and a light chain comprising the amino acid sequence of SEQ ID NO: 26 (or a sequence at least about 90%, 95%, 99%, or more identical thereto, and / or having one, two, three or more substitutions, insertions, deletions, or modifications, optionally ten or fewer substitutions, insertions, deletions, or modifications).

[0156] In some embodiments, the antibody that specifically binds to 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 thereto, and / or having one, two, three or more substitutions, insertions, deletions, or modifications, optionally twelve or fewer substitutions, insertions, deletions, or modifications), and a light chain comprising the amino acid sequence of SEQ ID NO: 26 (or a sequence at least about 90%, 95%, 99%, or more identical thereto, and / or having one, two , three or more substitutions, insertions, deletions, or modifications, optionally ten or fewer substitutions, insertions, deletions, or modifications).

[0157] In some embodiments, the antibody that specifically binds to 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 thereto, and / or having one, two, three or more substitutions, insertions, deletions, or modifications, optionally twelve or fewer substitutions, insertions, deletions, or modifications), and a light chain comprising the amino acid sequence of SEQ ID NO: 26 (or a sequence at least about 90%, 95%, 99%, or more identical thereto, and / or having one, two, three or more substitutions, insertions, deletions, or modifications, optionally ten or fewer substitutions, insertions, deletions, or modifications).

[0158] In some embodiments, the antibody that specifically binds to 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 thereto, and / or having one, two, three or more substitutions, insertions, deletions, or modifications, optionally twelve or fewer substitutions, insertions, deletions, or modifications), and a light chain comprising the amino acid sequence Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) of SEQ ID NO: 63 (or a sequence at least about 90%, 95%, 99%, or more identical thereto, and / or having one, two, three or more substitutions, insertions, deletions, or modifications, optionally ten or fewer substitutions, insertions, deletions, or modifications).

[0159] In some embodiments, the antibody that specifically binds to 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 thereto, and / or having one, two, three or more substitutions, insertions, deletions, or modifications, optionally twelve or fewer substitutions, insertions, deletions, or modifications), and a light chain comprising the amino acid sequence of SEQ ID NO: 63 (or a sequence at least about 90%, 95%, 99%, or more identical thereto, and / or having one, two, three or more substitutions, insertions, deletions, or modifications, optionally ten or fewer substitutions, insertions, deletions, or modifications).

[0160] In some embodiments, the antibody that specifically binds to 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 thereto, and / or having one, two, three or more substitutions, insertions, deletions, or modifications, optionally twelve or fewer substitutions, insertions, deletions, or modifications), and a light chain comprising the amino acid sequence of SEQ ID NO: 63 (or a sequence at least about 90%, 95%, 99%, or more identical thereto, and / or having one, two, three or more substitutions, insertions, deletions, or modifications, optionally ten or fewer substitutions, insertions, deletions, or modifications).

[0161] In some embodiments, the antibody that specifically binds to 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 thereto, and / or having one, two, three or more substitutions, insertions, deletions, or modifications, optionally twelve or fewer substitutions, insertions, deletions, or modifications), and a light chain comprising the amino acid sequence of SEQ ID NO: 63 (or a sequence at least about 90%, 95%, 99% or more identical thereto, and / or having one, two, three or more substitutions, insertions, deletions, or modifications, optionally ten or fewer substitutions, insertions, deletions, or modifications).

[0162] In some embodiments, the antibody that specifically binds to 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 thereto, and / or having one, two, three or more substitutions, insertions, deletions, or modifications, optionally twelve or fewer substitutions, insertions, deletions, or modifications), and a light chain comprising the amino acid sequence Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) of SEQ ID NO: 63 (or a sequence at least about 90%, 95%, 99%, or more identical thereto, and / or having one, two, three or more substitutions, insertions, deletions, or modifications, optionally ten or fewer substitutions, insertions, deletions, or modifications).

[0163] In some embodiments, the antibody that specifically binds to 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 thereto, and / or having one, two, three or more substitutions, insertions, deletions, or modifications, optionally twelve or fewer substitutions, insertions, deletions, or modifications), and a light chain comprising the amino acid sequence of SEQ ID NO: 63 (or a sequence at least about 90%, 95%, 99%, or more identical thereto, and / or having one, two, three or more substitutions, insertions, deletions, or modifications, optionally ten or fewer substitutions, insertions, deletions, or modifications).

[0164] In one embodiment, the anti-TREM2 antibody or antigen-binding fragment thereof comprises HCDR1, HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NO: 7, SEQ ID NO: 5, and SEQ ID NO: 6, and LCDR1, LCDR2, and LCDR3 having the amino acid sequences of SEQ ID NO: 17, SEQ ID NO: 18, and SEQ ID NO: 19, respectively.

[0165] In one embodiment, the anti-TREM2 antibody or antigen-binding fragment thereof comprises HCDR1, HCDR2, and HCDR3 having the amino acid sequences of SEQ ID NO: 10, SEQ ID NO: 11, and SEQ ID NO: 12, and LCDR1, LCDR2, and LCDR3 having the amino acid sequences of SEQ ID NO: 23, SEQ ID NO: 21, and SEQ ID NO: 19, respectively.

[0166] In one embodiment, the anti-TREM2 antibody or antigen-binding fragment thereof comprises VH having the amino acid sequences of SEQ ID NO: 13 and VL having the amino acid sequences of SEQ ID NO: 24, respectively.

[0167] In one embodiment, the anti-TREM2 antibody or antigen-binding fragment comprises a heavy chain having the amino acid sequences of SEQ ID NO: 37 and a light chain having the amino acid sequences of SEQ ID NO: 26, respectively.

[0168] In some embodiments, the TREM2-binding molecule comprises a human IgGl constant region. In some embodiments, the human IgGl constant region comprises an Fc region.

[0169] In one embodiment, the Fc region is altered by replacing at least one amino acid residue with a different amino acid residue to alter the effector functions of the antibody. For example, one or more amino acids can be replaced with a different amino acid residue such that the antibody has an altered affinity for an effector ligand but retains the antigen-binding ability of the parent antibody. The effector ligand to which affinity is altered can be, for example, an Fc receptor or Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) the Cl component of complement. This approach is described in further detail in U.S. Pat. Nos. 5,624,821 and 5,648,260, both by Winter et al.

[0170] In another embodiment, the Fc region is altered by replacing at least one amino acid residue with a different amino acid residue such that the antibody has altered Clq binding and / or reduced or abolished complement dependent cytotoxicity (CDC). This approach is described in further detail in U.S. Pat. No. 6,194,551 by Idusogie et al.

[0171] In another embodiment, one or more amino acid residues are altered to thereby alter the ability of the antibody to fix complement. This approach is described further in PCT Publication WO 94 / 29351 by Bodmer et al.

[0172] In some embodiments, the Fc region of the TREM2-binding molecule includes one or more mutations mediating reduced or no antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC). In some embodiments, amino acid residues L234 and L235 of the IgGl constant region are substituted to A234 and A235. In some embodiments, amino acid residue N267 of the IgGl constant region is substituted to A267. In some embodiments, amino acid residues D265 and P329 of the IgGl constant region are substituted to A265 and A329. In certain embodiments, the Fc region optionally comprises a mutation or combination of mutations conferring reduced effector function selected from any of D265A, P329A, P329G, N297A, D265A / P329A, D265A / N297A, L234 / L235A,

[0173] P329A / L234A / L235A, and P329G / L234A / L235A. In certain embodiments, the Fc region optionally comprises a mutation or combination of mutations conferring reduced effector function selected from any of D265A, P329A, P329G, N297A, M428L, N434S, D265A / P329A, D265A / N297A, L234 / L235A, P329A / L234A / L235A, P329G / L234A / L235A and M428L / N434S. In some embodiments, the Fc region comprises a mutation or combination of mutations conferring reduced effector function selected from any of D265 A, P329A, P329G, N297A, D265A / P329A, D265A / N297A, L234 / L235A, P329A / L234A / L235A, and P329G / L234A / L235A. In some embodiments, the Fc region comprises a mutation or combination of mutations conferring reduced effector function selected from any of D265A, P329A, P329G, N297A, M428L, N434S, D265A / P329A, D265A / N297A, L234 / L235A, P329A / L234A / L235A, P329G / L234A / L235A and M428L / N434S. (All positions by EU numbering). In some embodiments, the Fc region comprises M428L / N434S (LS) amino acid substitutions in the Fc region (all positions by EU numbering). In some embodiments, the Fc region comprises D265A / P329A (DAP A) amino acid substitutions in the Fc region (all positions by EU numbering). In some embodiments, the Fc region comprises M428L / N434S Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)

[0174] (LS) and D265A / P329A (DAP A) amino acid substitutions in the Fc region (all positions by EU numbering).

[0175] In yet another embodiment, the Fc region is modified to increase the ability of the antibody to mediate antibody dependent cellular cytotoxicity (ADCC) and / or to increase the affinity of the antibody for an Fc-gamma receptor by modifying one or more amino acids. This approach is described further in PCT Publication WO 00 / 42072 by Presta. Moreover, the binding sites on human IgGl for Fc-gamma RI, Fc-gamma RII, Fc-gamma RIII and FcRn have been mapped and variants with improved binding have been described (see Shields, R. E. et al., 2001 J. Biol. Chen. 276:6591-6604). For example, the Fc region can comprise a mutation or combination of mutations conferring increased effector function selected from any of S239D, I332E, A330E, S298A, E333A, E333S, K334A, K236A, K236W, F243E, P247I, D280H, K290S, R292P, S298D, S298V, Y300E, V305I, A339D, A339Q, A339T, P396E (all positions by EU numbering).

[0176] In some embodiments, the TREM2-binding molecule is an antibody. In some embodiments, the antibody has an IgGl isotype with one or more mutations (e.g., relative to a wild-type Fc region of the same isotype). In some embodiments, the one or more mutations are selected from N297A, N297Q (BoltS et al. (1993) Eur J Immunol 23:403-411), D265A, L234A, L235A (McEarchern et al., (2007) Blood, 109:1185-1192), C226S, C229S (McEarchern et al., (2007) Blood, 109:1185-1192), P238S (Davis et al., (2007) J Rheumatol, 34:2204-2210), E233P, L234V (McEarchern et al., (2007) Blood, 109:1185-1192), P238A, A327Q, A327G, P329A (Shields RL. et al., (2001) J Biol Chem. 276(9):6591-604), K322A, L234F, L235E (Hezareh et al., (2001) J Viral 75, 12161-12168; Oganesyan et al., (2008). Acta Crystallographica 64, 700- 704), P331S (Oganesyan et al., (2008) Acta Crystallographica 64, 700-704), T394D (Wilkinson et al. (2013) MAbs 5(3): 406-417), A330E, M252Y, S254T, and / or T256E, where the amino acid position is according to the EU or Kabat numbering convention. In certain embodiments, the Fc region further includes an amino acid deletion at a position corresponding to glycine 236 according to the EU or Kabat numbering convention.

[0177] In some embodiments, the antibody has an IgGl isotype with a heavy chain constant region that contains a C220S mutation according to the EU or Kabat numbering convention.

[0178] In some embodiments, the Fc region further contains one or more additional mutations selected from A330L, L234F, L235E, and / or P331S according to EU or Kabat numbering convention. Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)

[0179] In certain embodiments, the antibody has an IgG2 isotype. In some embodiments, the antibody contains a human IgG2 constant region. In some embodiments, the human IgG2 constant region includes an Fc region. In some embodiments, the Fc region contains one or more modifications. For example, in some embodiments, the Fc region contains one or more mutations (e.g., relative to a wild-type Fc region of the same isotype). In some embodiments, the one or more mutations are selected from V234A, G237A, H268E, V309L, N297A, N297Q, A330S, P331S, C232S, C233S, M252Y, S254T, and / or T256E, where the amino acid position is according to the EU or Kabat numbering convention.

[0180] In certain embodiments, the antibody has an IgG4 isotype. In some embodiments, the antibody contains a human IgG4 constant region. In some embodiments, the human IgG4 constant region includes an Fc region. In some embodiments, the Fc region contains one or more modifications. For example, in some embodiments, the Fc region contains one or more mutations (e.g., relative to a wild-type Fc region of the same isotype). In some embodiments, the one or more mutations are selected from E233P, F234V, L235A, G237A, E318A (Hutchins et al. (1995) Proc Nat / A cad Sci USA, 92:11980-11984), S228P, L236E, S241P, L248E (Reddy et al., (2000) J Immuno / , 164:1925-1933; Angal et al., (1993) Mol Immunol. 30(l):105-8; US 8614299 B2), T394D, M252Y, S254T, T256E, N297A, and / or N297Q, where the amino acid position is according to the EU or Kabat numbering convention.

[0181] In some embodiments, the Fc region further contains one or more additional mutations selected from a M252Y, S254T, and / or T256E, where the amino acid position is according to the EU or Kabat numbering convention.

[0182] In some embodiments, one or more of the IgGl variants described herein may be combined with an A330L mutation (Lazaret al., (2006) Proc Natl Acad Sci USA, 103:4005-4010), or one or more of L234F, L235E, and / or P331S mutations (Sazinsky et al., (2008) Proc Natl Acad Sci USA, 105:20167-20172), where the amino acid position is according to the EU or Kabat numbering convention, to eliminate complement activation. In some embodiments, the IgG variants described herein may be combined with one or more mutations to enhance the antibody half-life in human serum (e.g., M252Y, S254T, T256E mutations according to the EU or Kabat numbering convention) (Dall’ Acqua et al., (2006) J Biol Chem, 281:23514-23524; and Strohl e al., (2009) Current Opinion in Biotechnology, 20:685-691).

[0183] In some embodiments, an IgG4 variant of the present disclosure may be combined with an S228P mutation according to the EU or Kabat numbering convention (Angal et al., (1993) Mol Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)

[0184] Immunol, 30:105-108) and / or with one or more mutations described in Peters et al., (2012) J Biol Chem. 13;287(29):24525-33) to enhance antibody stabilization.

[0185] In some embodiments, the antibody has an Fc region selected from an IgG2 Fc region, an IgG4 Fc region, or an IgG2 / IgG4 hybrid Fc region.

[0186] In some embodiments, the anti-TREM2 antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising a CDR-H1, CDR-H2, and CDR-H3 (used herein interchangeably as HCDR1, HCDR2, and HCDR3, respectively) and a light chain variable region comprising a CDR-L1, CDR-L2, and CDR-L3 (used herein interchangeably as LCDR1, LCDR2, and LCDR3, respectively), wherein the CDR-H1 comprises the amino acid sequence SEQ ID NO: 4, the CDR-H2 comprises the amino acid sequence SEQ ID NO: 5, the CDR-H3 comprises the amino acid sequence SEQ ID NO: 6, the CDR-L1 comprises the amino acid sequence SEQ ID NO: 17, the CDR-L2 comprises the amino acid sequence SEQ ID NO: 18, and the CDR-L3 comprises the amino acid sequence SEQ ID NO: 19, as defined by the Combined numbering system.

[0187] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising a CDR-H1, CDR-H2, and CDR-H3 and a light chain variable region comprising a CDR-L1, CDR-L2, and CDR-L3, wherein the CDR-H1 comprises the amino acid sequence SEQ ID NO: 7, the CDR-H2 comprises the amino acid sequence SEQ ID NO: 5, the CDR-H3 comprises the amino acid sequence SEQ ID NO: 6, the CDR-L1 comprises the amino acid sequence SEQ ID NO: 17, the CDR-L2 comprises the amino acid sequence SEQ ID NO: 18, and the CDR-L3 comprises the amino acid sequence SEQ ID NO: 19, as defined by the Kabat numbering system.

[0188] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising a CDR-H1, CDR-H2, and CDR-H3 and a light chain variable region comprising a CDR-L1, CDR-L2, and CDR-L3, wherein the CDR-H1 comprises the amino acid sequence SEQ ID NO: 8, the CDR-H2 comprises the amino acid sequence SEQ ID NO: 9, the CDR-H3 comprises the amino acid sequence SEQ ID NO: 6, the CDR-L1 comprises the amino acid sequence SEQ ID NO: 20, the CDR-L2 comprises the amino acid sequence SEQ ID NO: 21, and the CDR-L3 comprises the amino acid sequence SEQ ID NO: 22, as defined by the Chothia numbering system.

[0189] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising a CDR-H1, CDR-H2, and CDR-H3 and a light chain variable Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) region comprising a CDR-L1, CDR-L2, and CDR-L3, wherein the CDR-H1 comprises the amino acid sequence SEQ ID NO: 10, the CDR-H2 comprises the amino acid sequence SEQ ID NO: 11, the CDR-H3 comprises the amino acid sequence SEQ ID NO: 12, the CDR-L1 comprises the amino acid sequence SEQ ID NO: 23, the CDR-L2 comprises the amino acid sequence SEQ ID NO: 21, and the CDR-L3 comprises the amino acid sequence SEQ ID NO: 19, as defined by the IMGT numbering system.

[0190] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 13 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 24.

[0191] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising a CDR-H1, CDR-H2, and CDR-H3 and a light chain variable region comprising a CDR-L1, CDR-L2, and CDR-L3, wherein the CDR-H1 comprises the amino acid sequence SEQ ID NO: 4, the CDR-H2 comprises the amino acid sequence SEQ ID NO: 5, the CDR-H3 comprises the amino acid sequence SEQ ID NO: 6, the CDR-L1 comprises the amino acid sequence SEQ ID NO: 17, the CDR-L2 comprises the amino acid sequence SEQ ID NO: 18, and the CDR-L3 comprises the amino acid sequence SEQ ID NO: 19, as defined by the Combined numbering system, and wherein the Fc region comprises M428L / N434S (LS) and D265A / P329A (DAP A) amino acid substitutions in the Fc region (all positions by EU numbering).

[0192] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising a CDR-H1, CDR-H2, and CDR-H3 and a light chain variable region comprising a CDR-L1, CDR-L2, and CDR-L3, wherein the CDR-H1 comprises the amino acid sequence SEQ ID NO: 7, the CDR-H2 comprises the amino acid sequence SEQ ID NO: 5, the CDR-H3 comprises the amino acid sequence SEQ ID NO: 6, the CDR-L1 comprises the amino acid sequence SEQ ID NO: 17, the CDR-L2 comprises the amino acid sequence SEQ ID NO: 18, and the CDR-L3 comprises the amino acid sequence SEQ ID NO: 19, as defined by the Kabat numbering system, and wherein the Fc region comprises M428L / N434S (LS) and D265A / P329A (DAP A) amino acid substitutions in the Fc region (all positions by EU numbering).

[0193] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising a CDR-H1, CDR-H2, and CDR-H3 and a light chain variable region comprising a CDR-L1, CDR-L2, and CDR-L3, wherein the CDR-H1 comprises the Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) amino acid sequence SEQ ID NO: 8, the CDR-H2 comprises the amino acid sequence SEQ ID NO: 9, the CDR-H3 comprises the amino acid sequence SEQ ID NO: 6, the CDR-L1 comprises the amino acid sequence SEQ ID NO: 20, the CDR-L2 comprises the amino acid sequence SEQ ID NO: 21, and the CDR-L3 comprises the amino acid sequence SEQ ID NO: 22, as defined by the Chothia numbering system, and wherein the Fc region comprises M428L / N434S (LS) and D265A / P329A (DAP A) amino acid substitutions in the Fc region (all positions by EU numbering).

[0194] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising a CDR-H1, CDR-H2, and CDR-H3 and a light chain variable region comprising a CDR-L1, CDR-L2, and CDR-L3, wherein the CDR-H1 comprises the amino acid sequence SEQ ID NO: 10, the CDR-H2 comprises the amino acid sequence SEQ ID NO: 11, the CDR-H3 comprises the amino acid sequence SEQ ID NO: 12, the CDR-L1 comprises the amino acid sequence SEQ ID NO: 23, the CDR-L2 comprises the amino acid sequence SEQ ID NO: 21, and the CDR-L3 comprises the amino acid sequence SEQ ID NO: 19, as defined by the IMGT numbering system, and wherein the Fc region comprises M428L / N434S (LS) and D265A / P329A (DAP A) amino acid substitutions in the Fc region (all positions by EU numbering).

[0195] In some embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 13 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 24, and wherein the Fc region comprises M428L / N434S (LS) and D265A / P329A (DAP A) amino acid substitutions in the Fc region (all positions by EU numbering). In one embodiment, the anti- TREM-2 antibody or an antigen-binding fragment thereof is VHB937 or an antigen-binding fragment of VHB937. In some embodiments, the anti-TREM2 antibody is VHB937. Sequences of VHB937 are disclosed in PCT Application No. PCT / IB2019 / 058769 (published as WO-A- 2020 / 079580), which is incorporated herein by reference in its entirety. As used herein, VHB937 is also equally referred to as MOR044698E or MOR44698E.VHB937 is a human monoclonal antibody (mAh) with targeted silenced functions and with a half-life extension mutation that prolongs its half-life. Without being bound by theory, the mAh is a selective activator of TREM2 and increases TREM2 cell surface abundance by reducing shedding of TREM2. Activating TREM2 drives microglia towards a neuroprotective and pro-resolution phenotype: VHB937 was shown to support key functions of human iPS derived-microglia cells like chemotaxis and phagocytosis in vitro (see also WO-A-2020 / 079580). Further, anti- Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) inflammatory subclusters of human iPS-derived microglia were expanded at the expense of pro-inflammatory subclusters. In vivo, VHB937 displayed efficacy in different animal models that recapitulate pathological features of neurodegenerative and neuroinflammatory diseases (MPTP, cuprizone, TAU58.4 and amyloidosis models). The neuroprotective phenotype that emerged in microglia in vivo after VHB937 treatment promoted neuronal health (reduction of dystrophic neurites) and ameliorated astrogliosis, indicating promising efficacy beyond microglia on other neuronal cells. In line with this neuroprotective activity, a treatment dependent reduction of pro-inflammatory markers like osteopontin (SPP-1) was observed in vitro and in vivo. Thus, this mechanism could delay progression in neuroinflammatory and neurodegenerative conditions such as AD.

[0196] Preclinical experimental evidence indicates that the effects of VHB937 on TREM2 cell surface expression, direct activation of TREM2 and signaling in microglia cells might attenuate the disease course across neurological and neurodegenerative disorders, including AD.

[0197] In the First-In-Human (FIH) study CVHB937A02101, VHB937 showed a bi-exponential disposition and non-linear PK with higher clearance at lowest VHB937 dose levels, potentially due to target mediated drug clearance after intravenous (i.v.) single dose administration in healthy volunteers. This PK profile is in-line with the expectations for a typical human IgGl immunoglobulin targeting a cellular receptor like TREM2. Following single dose i.v. administration of VHB937 in doses ranging from 0.003 mg / to 30 mg / kg, Cmax values increased in a dose-proportional manner over the dose range, while AUCs increased in a greater than dose proportional manner, which is in line with assumed target mediated drug clearance. Consequently, a dose-dependent increase of the half-life of VHB937 was determined up to currently about 34 days at 10 mg / kg dose level. Peak serum VHB937 concentrations were observed shortly after the end of the i.v. infusion (mean Tmax ranging from about 2 hours to 6 hours across the dose levels) with Cmax concentrations comparable to predictions. In the cerebrospinal fluid (CSF), VHB937 was detected across all dose cohorts with CSF collection (Cohorts 6 to 9) at 168 h (Day 8) post-dose based on preliminary data. At 168 h (Day 8) postdose, the VHB937 CSF to serum concentration ratio was approximately 0.2% - 0.3%.

[0198] In one embodiment, the anti-TREM-2 antibody or a fragment thereof, especially VHB937, is administered to a patient, especially in need thereof, at a dose of about 3 mg / kg to about 60 mg / kg, about 10 mg / kg to about 30 mg / kg. In a preferred embodiment, the dose is about 10 Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) mg / kg. Preferably, the dose is 10 mg / kg. In yet another preferred embodiment, the dose is 30 mg / kg. More preferably, the dose is about 30 mg / kg.

[0199] In one embodiment, the anti-TREM2 antibody or antigen-binding fragment thereof, especially VHB937, or antigen-binding fragment thereof, is administered to a patient, especially in need thereof, once every 4 weeks (q4w, monthly, + / - 3 days).

[0200] In one embodiment, the antibody is VHB937, wherein VHB937 is administered to a subject, especially in need thereof, at a dose of about 10 mg / kg intravenously, once every four weeks (q4w, monthly, + / - 3 days).

[0201] In some embodiments, the antibody is VHB937, wherein VHB937 is administered to a subject, especially in need thereof, at a dose of about 10 mg / kg intravenously. In some embodiments, the antibody is administered to the subject in need thereof once every four weeks. In some embodiments, the antibody is administered to the subject in need thereof once every month. In some embodiments, the antibody is administered to the subject in need thereof once every 25- 31 days. For example, the antibody may be administered to a patient once every 25 days, every 26 days, every 27 days, every 28 days, every 29 days, every 30 days, or every 31 days. In some embodiments, the antibody is administered to a patient at a frequency within the range of every 25-31 days, the interval between one dose and the following dose (i.e. the very next dose scheduled for the treatment) can be any of 25, 26, 27, 28, 29, 30, or 31 days. As used herein, “interval between” refers to the time between two events, for example, if a first dose is on day 1 and a second dose is on day 29, the interval between the first and second doses is 28 days. In some embodiments, the antibody is administered to a patient at a frequency of every 24-32 days, the interval between one dose and the following dose (i.e. the very next dose scheduled for the treatment) can be any of 24, 25, 26, 27, 28, 29, 30, 31, or 32 days. As used herein for consistency and not intended as limiting, the first week of dosing is referred to as week 0, and the first day of dosing is referred to as day 1. In some embodiments, the antibody is administered to a patient at every 4 weeks, e.g., during week 0, week 4, week 8, and so on. In some embodiments, the antibody is administered to a patient every 4 weeks, e.g., on day 1, day 29, day 57, day 85, and so on. In some embodiments, the antibody is administered to a patient every 4 weeks, e.g., on or approximately on day 1, day 29, day 57, day 85, and so on, wherein each date after day 1 can be + / - 3 days, for example, second dose between day 26 and day 32 (including day 26 and day 32), third dose between day 54 and day 60 (including day 54 and day 60), and so on. In some embodiments, the antibody is administered to a patient every 4 weeks, e.g., on or approximately on day 1, day 29, day 57, day 85, and so on, wherein each Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) date after day 1 can be + / - 2 days. In some embodiments, the antibody is administered to a patient every 4 weeks, e.g., on or approximately on day 1, day 29, day 57, day 85, and so on, wherein each date after day 1 can be + / - 1 day. It will be understood that, in some embodiments, dosing monthly or dosing every 4 weeks need not be provided at an exact time point of each week, as long as it is provided in the appropriate week. For example, a dose due approximately on day 29 could be provided, e.g., between day 29 and day 35 (including day 29 and day 35). In some embodiments, the antibody is administered to the subject in need thereof once every four weeks. In some embodiments, the antibody is administered to the subject in need thereof once every month. In some embodiments, the antibody is administered to the subject in need thereof once every 25-31 days. For example, the antibody may be administered to a patient once every 25 days, every 26 days, every 27 days, every 28 days, every 29 days, every 30 days, or every 31 days. In some embodiments, the antibody is administered to a patient at a frequency within the range of every 25-31 days, the interval between one dose and the following dose (i.e. the very next dose scheduled for the treatment) can be any of 25, 26, 27, 28, 29, 30, or 31 days. In some embodiments, the antibody is VHB937, wherein VHB937 is administered to a subject in need thereof, at a dose of about 10 mg / kg intravenously. In some embodiments, the antibody is VHB937, wherein VHB937 is administered to a subject in need thereof, at a dose of 10 mg / kg intravenously.

[0202] In one embodiment, the antibody is VHB937, wherein VHB937 is administered to a subject, especially in need thereof, at a dose of about 10 mg / kg intravenously, once every four weeks (q4w, monthly, + / - 3 days). In one embodiment, the antibody is VHB937, wherein VHB937 is administered to a subject, especially in need thereof, at a dose of about 10 mg / kg intravenously, once every four weeks. In one embodiment, the antibody is VHB937, wherein VHB937 is administered to a subject, especially in need thereof, at a dose of about 10 mg / kg intravenously, once every 25-31 days. For example, the antibody may be administered to a patient once every 25 days, every 26 days, every 27 days, every 28 days, every 29 days, every 30 days, or every 31 days. In some embodiments, the antibody is administered to a patient at a frequency within the range of every 25-31 days, the interval between one dose and the following dose (i.e. the very next dose scheduled for the treatment) can be any of 25, 26, 27, 28, 29, 30, or 31 days.

[0203] In some embodiments, the antibody is VHB937, wherein VHB937 is administered to a subject, especially in need thereof, at a dose of about 30 mg / kg intravenously. In some embodiments, the antibody is administered to the subject in need thereof once every four weeks. In some embodiments, the antibody is administered to the subject in need thereof once every month. In Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) some embodiments, the antibody is administered to the subject in need thereof once every 25- 31 days. For example, the antibody may be administered to a patient once every 25 days, every 26 days, every 27 days, every 28 days, every 29 days, every 30 days, or every 31 days. In some embodiments, the antibody is administered to a patient at a frequency within the range of every 25-31 days, the interval between one dose and the following dose (i.e. the very next dose scheduled for the treatment) can be any of 25, 26, 27, 28, 29, 30, or 31 days. In some embodiments, the antibody is administered to a patient at a frequency of every 24-32 days, the interval between one dose and the following dose (i.e. the very next dose scheduled for the treatment) can be any of 24, 25, 26, 27, 28, 29, 30, 31, or 32 days. As used herein for consistency and not intended as limiting, the first week of dosing is referred to as week 0, and the first day of dosing is referred to as day 1. In some embodiments, the antibody is administered to a patient at every 4 weeks, e.g., during week 0, week 4, week 8, and so on. In some embodiments, the antibody is administered to a patient every 4 weeks, e.g., on day 1, day 29, day 57, day 85, and so on. In some embodiments, the antibody is administered to a patient every 4 weeks, e.g., on or approximately on day 1, day 29, day 57, day 85, and so on, wherein each date after day 1 can be + / - 3 days, for example, second dose between day 26 and day 32 (including day 26 and day 32), third dose between day 54 and day 60 (including day 54 and day 60), and so on. In some embodiments, the antibody is administered to a patient every 4 weeks, e.g., on or approximately on day 1, day 29, day 57, day 85, and so on, wherein each date after day 1 can be + / - 2 days. In some embodiments, the antibody is administered to a patient every 4 weeks, e.g., on or approximately on day 1, day 29, day 57, day 85, and so on, wherein each date after day 1 can be + / - 1 day. It will be understood that, in some embodiments, dosing monthly or dosing every 4 weeks need not be provided at an exact time point of each week, as long as it is provided in the appropriate week. For example, a dose due approximately on day 29 could be provided, e.g., between day 29 and day 35 (including day 29 and day 35). In some embodiments, the antibody is administered to the subject in need thereof once every four weeks. In some embodiments, the antibody is administered to the subject in need thereof once every month. In some embodiments, the antibody is administered to the subject in need thereof once every 25-31 days. For example, the antibody may be administered to a patient once every 25 days, every 26 days, every 27 days, every 28 days, every 29 days, every 30 days, or every 31 days. In some embodiments, the antibody is administered to a patient at a frequency within the range of every 25-31 days, the interval between one dose and the following dose (i.e. the very next dose scheduled for the treatment) can be any of 25, 26, 27, 28, 29, 30, or 31 days. In some embodiments, the antibody is VHB937, wherein VHB937 is administered to a Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) subject in need thereof, at a dose of about 30 mg / kg intravenously. In some embodiments, the antibody is VHB937, wherein VHB937 is administered to a subject in need thereof, at a dose of 30 mg / kg intravenously.

[0204] In some embodiments, the antibody is VHB937, wherein VHB937 is administered to a subject, especially in need thereof, at a dose of 30 mg / kg intravenously. In some embodiments, the antibody is administered to the subject in need thereof once every four weeks. In some embodiments, the antibody is administered to the subject in need thereof once every month. In some embodiments, the antibody is administered to the subject in need thereof once every 25- 31 days. For example, the antibody may be administered to a patient once every 25 days, every 26 days, every 27 days, every 28 days, every 29 days, every 30 days, or every 31 days. In some embodiments, the antibody is administered to a patient at a frequency within the range of every 25-31 days, the interval between one dose and the following dose (i.e. the very next dose scheduled for the treatment) can be any of 25, 26, 27, 28, 29, 30, or 31 days.

[0205] In one embodiment, the molecule that activates TREM2, especially the anti-TREM2 antibody or antigen-binding fragment thereof, especially VHB937, is administered to a subject, especially in need thereof, as a monotherapy. The patient does not receive any other treatment during the time period of being treated with the antibody or antigen-binding fragment thereof, e.g., VHB937. In one embodiment, the patient has not received an anti-amyloid antibody treatment prior to the treatment with the anti-TREM2 antibody or antigen-binding fragment thereof, e.g., VHB937. In one embodiment, the patient does not receive an anti-amyloid antibody treatment during the time period of being treated with the anti-TREM2 antibody or antigen-binding fragment thereof, e.g., VHB937.

[0206] In one embodiment, a pharmaceutical composition is provided comprising a therapeutically effective amount of the antibody for use in the methods of the present disclosure and one or more pharmaceutically acceptable carriers.

[0207] In one embodiment, the route of administration of the anti-TREM2 antibody or antigen-binding fragment thereof is intravenous.

[0208] In one embodiment, the dose is about 1 mg / kg to about 60 mg / kg of the anti-TREM2 antibody or antigen-binding fragment thereof. In some embodiments, the dose is administered every four weeks (or monthly), every six weeks, every eight weeks (once every two months), or every twelve weeks (once every three months). In some embodiments, the dose is administered every 25-31 days, preferably every 28 days. In some embodiments, the dose is administered every Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)

[0209] 39-45 days, preferably every 42 days. In some embodiments, the dose is administered every 53-59 days, preferably every 56 days. In some embodiments, the dose is administered every 81-87 days, preferably every 84 days.

[0210] In one embodiment, the dose is about 1 mg / kg of the anti-TREM2 antibody or antigen-binding fragment thereof. In some embodiments, the dose is administered every four weeks, every six weeks, every eight weeks, or every twelve weeks. In some embodiments, the dose is administered every 25-31 days, preferably every 28 days. In some embodiments, the dose is administered every 39-45 days, preferably every 42 days. In some embodiments, the dose is administered every 53-59 days, preferably every 56 days. In some embodiments, the dose is administered every 81-87 days, preferably every 84 days.

[0211] In one embodiment, the dose is about 1.2 mg / kg of the anti-TREM2 antibody or antigenbinding fragment thereof. In some embodiments, the dose is administered every four weeks, every six weeks, every eight weeks, or every twelve weeks. In some embodiments, the dose is administered every 25-31 days, preferably every 28 days. In some embodiments, the dose is administered every 39-45 days, preferably every 42 days. In some embodiments, the dose is administered every 53-59 days, preferably every 56 days. In some embodiments, the dose is administered every 81-87 days, preferably every 84 days.

[0212] In one embodiment, the dose is about 1.5 mg / kg of the anti-TREM2 antibody or antigenbinding fragment thereof. In some embodiments, the dose is administered every four weeks, every six weeks, every eight weeks, or every twelve weeks. In some embodiments, the dose is administered every 25-31 days, preferably every 28 days. In some embodiments, the dose is administered every 39-45 days, preferably every 42 days. In some embodiments, the dose is administered every 53-59 days, preferably every 56 days. In some embodiments, the dose is administered every 81-87 days, preferably every 84 days.

[0213] In one embodiment, the dose is about 2 mg / kg of the anti-TREM2 antibody or antigen-binding fragment thereof. In some embodiments, the dose is administered every four weeks, every six weeks, every eight weeks, or every twelve weeks. In some embodiments, the dose is administered every 25-31 days, preferably every 28 days. In some embodiments, the dose is administered every 39-45 days, preferably every 42 days. In some embodiments, the dose is administered every 53-59 days, preferably every 56 days. In some embodiments, the dose is administered every 81-87 days, preferably every 84 days. Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)

[0214] In one embodiment, the dose is about 3 mg / kg of the anti-TREM2 antibody or antigen-binding fragment thereof. In some embodiments, the dose is administered every four weeks, every six weeks, every eight weeks, or every twelve weeks. In some embodiments, the dose is administered every 25-31 days, preferably every 28 days. In some embodiments, the dose is administered every 39-45 days, preferably every 42 days. In some embodiments, the dose is administered every 53-59 days, preferably every 56 days. In some embodiments, the dose is administered every 81-87 days, preferably every 84 days.

[0215] In one embodiment, the dose is about 3.6 mg / kg of the anti-TREM2 antibody or antigenbinding fragment thereof. In some embodiments, the dose is administered every four weeks, every six weeks, every eight weeks, or every twelve weeks. In some embodiments, the dose is administered every 25-31 days, preferably every 28 days. In some embodiments, the dose is administered every 39-45 days, preferably every 42 days. In some embodiments, the dose is administered every 53-59 days, preferably every 56 days. In some embodiments, the dose is administered every 81-87 days, preferably every 84 days.

[0216] In one embodiment, the dose is about 4 mg / kg of the anti-TREM2 antibody or antigen-binding fragment thereof. In some embodiments, the dose is administered every four weeks, every six weeks, every eight weeks, or every twelve weeks. In some embodiments, the dose is administered every 25-31 days, preferably every 28 days. In some embodiments, the dose is administered every 39-45 days, preferably every 42 days. In some embodiments, the dose is administered every 53-59 days, preferably every 56 days. In some embodiments, the dose is administered every 81-87 days, preferably every 84 days.

[0217] In one embodiment, the dose is about 5 mg / kg of the anti-TREM2 antibody or antigen-binding fragment thereof. In some embodiments, the dose is administered every four weeks, every six weeks, every eight weeks, or every twelve weeks. In some embodiments, the dose is administered every 25-31 days, preferably every 28 days. In some embodiments, the dose is administered every 39-45 days, preferably every 42 days. In some embodiments, the dose is administered every 53-59 days, preferably every 56 days. In some embodiments, the dose is administered every 81-87 days, preferably every 84 days.

[0218] In one embodiment, the dose is about 10 mg / kg of the anti-TREM2 antibody or antigen-binding fragment thereof. In some embodiments, the dose is administered every four weeks, every six weeks, every eight weeks, or every twelve weeks. In some embodiments, the dose is administered every 25-31 days, preferably every 28 days. In some embodiments, the dose is Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) administered every 39-45 days, preferably every 42 days. In some embodiments, the dose is administered every 53-59 days, preferably every 56 days. In some embodiments, the dose is administered every 81-87 days, preferably every 84 days.

[0219] In one embodiment, the dose is about 15 mg / kg of the anti-TREM2 antibody or antigen-binding fragment thereof. In some embodiments, the dose is administered every four weeks, every six weeks, every eight weeks, or every twelve weeks. In some embodiments, the dose is administered every 25-31 days, preferably every 28 days. In some embodiments, the dose is administered every 39-45 days, preferably every 42 days. In some embodiments, the dose is administered every 53-59 days, preferably every 56 days. In some embodiments, the dose is administered every 81-87 days, preferably every 84 days.

[0220] In one embodiment, the dose is about 20 mg / kg of the anti-TREM2 antibody or antigen-binding fragment thereof. In some embodiments, the dose is administered every four weeks, every six weeks, every eight weeks, or every twelve weeks. In some embodiments, the dose is administered every 25-31 days, preferably every 28 days. In some embodiments, the dose is administered every 39-45 days, preferably every 42 days. In some embodiments, the dose is administered every 53-59 days, preferably every 56 days. In some embodiments, the dose is administered every 81-87 days, preferably every 84 days.

[0221] In one embodiment, the dose is about 25 mg / kg of the anti-TREM2 antibody or antigen-binding fragment thereof. In some embodiments, the dose is administered every four weeks, every six weeks, every eight weeks, or every twelve weeks. In some embodiments, the dose is administered every 25-31 days, preferably every 28 days. In some embodiments, the dose is administered every 39-45 days, preferably every 42 days. In some embodiments, the dose is administered every 53-59 days, preferably every 56 days. In some embodiments, the dose is administered every 81-87 days, preferably every 84 days.

[0222] In one embodiment, the dose is about 30 mg / kg of the anti-TREM2 antibody or antigen-binding fragment thereof. In some embodiments, the dose is administered every four weeks, every six weeks, every eight weeks, or every twelve weeks. In some embodiments, the dose is administered every 25-31 days, preferably every 28 days. In some embodiments, the dose is administered every 39-45 days, preferably every 42 days. In some embodiments, the dose is administered every 53-59 days, preferably every 56 days. In some embodiments, the dose is administered every 81-87 days, preferably every 84 days. Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)

[0223] In one embodiment, the dose is about 35 mg / kg of the anti-TREM2 antibody or antigen-binding fragment thereof. In some embodiments, the dose is administered every four weeks, every six weeks, every eight weeks, or every twelve weeks. In some embodiments, the dose is administered every 25-31 days, preferably every 28 days. In some embodiments, the dose is administered every 39-45 days, preferably every 42 days. In some embodiments, the dose is administered every 53-59 days, preferably every 56 days. In some embodiments, the dose is administered every 81-87 days, preferably every 84 days.

[0224] In one embodiment, the dose is about 40 mg / kg of the anti-TREM2 antibody or antigen-binding fragment thereof. In some embodiments, the dose is administered every four weeks, every six weeks, every eight weeks, or every twelve weeks. In some embodiments, the dose is administered every 25-31 days, preferably every 28 days. In some embodiments, the dose is administered every 39-45 days, preferably every 42 days. In some embodiments, the dose is administered every 53-59 days, preferably every 56 days. In some embodiments, the dose is administered every 81-87 days, preferably every 84 days.

[0225] In one embodiment, the dose is about 45 mg / kg of the anti-TREM2 antibody or antigen-binding fragment thereof. In some embodiments, the dose is administered every four weeks, every six weeks, every eight weeks, or every twelve weeks. In some embodiments, the dose is administered every 25-31 days, preferably every 28 days. In some embodiments, the dose is administered every 39-45 days, preferably every 42 days. In some embodiments, the dose is administered every 53-59 days, preferably every 56 days. In some embodiments, the dose is administered every 81-87 days, preferably every 84 days.

[0226] In one embodiment, the dose is about 50 mg / kg of the anti-TREM2 antibody or antigen-binding fragment thereof. In some embodiments, the dose is administered every four weeks, every six weeks, every eight weeks, or every twelve weeks. In some embodiments, the dose is administered every 25-31 days, preferably every 28 days. In some embodiments, the dose is administered every 39-45 days, preferably every 42 days. In some embodiments, the dose is administered every 53-59 days, preferably every 56 days. In some embodiments, the dose is administered every 81-87 days, preferably every 84 days.

[0227] In one embodiment, the dose is about 55 mg / kg of the anti-TREM2 antibody or antigen-binding fragment thereof. In some embodiments, the dose is administered every four weeks, every six weeks, every eight weeks, or every twelve weeks. In some embodiments, the dose is administered every 25-31 days, preferably every 28 days. In some embodiments, the dose is Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) administered every 39-45 days, preferably every 42 days. In some embodiments, the dose is administered every 53-59 days, preferably every 56 days. In some embodiments, the dose is administered every 81-87 days, preferably every 84 days.

[0228] In one embodiment, the dose is about 60 mg / kg of the anti-TREM2 antibody or antigen-binding fragment thereof. In some embodiments, the dose is administered every four weeks, every six weeks, every eight weeks, or every twelve weeks. In some embodiments, the dose is administered every 25-31 days, preferably every 28 days. In some embodiments, the dose is administered every 39-45 days, preferably every 42 days. In some embodiments, the dose is administered every 53-59 days, preferably every 56 days. In some embodiments, the dose is administered every 81-87 days, preferably every 84 days.

[0229] In one embodiment, the dose is about 1 mg / kg to about 60 mg / kg active ingredient. The dose may be given every four weeks (or monthly, every six weeks, every eight weeks (once every two months), or every twelve weeks (once every three months).

[0230] In one embodiment, the dose is about 1 mg / kg active ingredient. The dose may be given every four weeks, every six weeks, every eight weeks, or every twelve weeks.

[0231] In one embodiment, the dose is about 1.5 mg / kg active ingredient. The dose may be given every four weeks, every six weeks, every eight weeks, or every twelve weeks.

[0232] In one embodiment, the dose is about 2 mg / kg active ingredient. The dose may be given every four weeks, every six weeks, every eight weeks, or every twelve weeks.

[0233] In one embodiment, the dose is about 3 mg / kg active ingredient. The dose may be given every four weeks, every six weeks, every eight weeks, or every twelve weeks.

[0234] In one embodiment, the dose is about 3.6 mg / kg active ingredient. The dose may be given every four weeks, every six weeks, every eight weeks, or every twelve weeks.

[0235] In one embodiment, the dose is about 4 mg / kg active ingredient. The dose may be given every four weeks, every six weeks, every eight weeks, or every twelve weeks.

[0236] In one embodiment, the dose is about 5 mg / kg active ingredient. The dose may be given every four weeks, every six weeks, every eight weeks, or every twelve weeks.

[0237] In one embodiment, the dose is about 10 mg / kg active ingredient. The dose may be given every four weeks, every six weeks, every eight weeks, or every twelve weeks. Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)

[0238] In one embodiment, the dose is about 15 mg / kg active ingredient. The dose may be given every four weeks, every six weeks, every eight weeks, or every twelve weeks.

[0239] In one embodiment, the dose is about 20 mg / kg active ingredient. The dose may be given every four weeks, every six weeks, every eight weeks, or every twelve weeks.

[0240] In one embodiment, the dose is about 25 mg / kg active ingredient. The dose may be given every four weeks, every six weeks, every eight weeks, or every twelve weeks.

[0241] In one embodiment, the dose is about 30 mg / kg active ingredient. The dose may be given every four weeks, every six weeks, every eight weeks, or every twelve weeks.

[0242] In one embodiment, the dose is about 35 mg / kg active ingredient. The dose may be given every four weeks, every six weeks, every eight weeks, or every twelve weeks.

[0243] In one embodiment, the dose is about 40 mg / kg active ingredient. The dose may be given every four weeks, every six weeks, every eight weeks, or every twelve weeks.

[0244] In one embodiment, the dose is about 45 mg / kg active ingredient. The dose may be given every four weeks, every six weeks, every eight weeks, or every twelve weeks.

[0245] In one embodiment, the dose is about 50 mg / kg active ingredient. The dose may be given every four weeks, every six weeks, every eight weeks, or every twelve weeks.

[0246] In one embodiment, the dose is about 55 mg / kg active ingredient. The dose may be given every four weeks, every six weeks, every eight weeks, or every twelve weeks.

[0247] In one embodiment, the dose is about 60 mg / kg active ingredient. The dose may be given every four weeks, every six weeks, every eight weeks, or every twelve weeks.

[0248] In some embodiments, the active ingredient is the anti-TREM2 antibody or antigen-binding fragment thereof disclosed herein. In some embodiments, the active ingredient is VHB937.

[0249] In one embodiment, the treatment is for any disease or disorder.

[0250] In one embodiment, the treatment is for neurological disorders.

[0251] In one embodiment, the treatment is for neurodegenerative disorders.

[0252] In one embodiment, the disorder is Alzheimer’s disease (AD).

[0253] In one embodiment, the disorder is multiple sclerosis.

[0254] In one embodiment, the disorder is ALS. Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)

[0255] In one embodiment, the patient has not received a prior treatment, e.g., an anti-amyloid antibody treatment, prior to administration of the anti-TREM2 antibody or antigen-binding fragment thereof, e.g., VHB937. In one embodiment, the patient does not receive an additional treatment, e.g., an anti-amyloid antibody treatment, in the time course of administration of the anti-TREM2 antibody or antigen-binding fragment thereof, e.g., VHB937.

[0256] In one embodiment, the anti-TREM2 antibody or antigen-binding fragment thereof, e.g., VHB937, is administered to a patient as a monotherapy, wherein the patient had an insufficient response after an initial prior treatment regimen. In some embodiments, the initial prior treatment regimen is a treatment for AD. In some embodiments, the initial prior treatment regimen comprises one or more of an anti-amyloid antibody (e.g., donanemab, lecanemab), a cholinesterase inhibitor (e.g., benzgalantamine, donepezil, galantamine, rivas tigmine), and a glutamate regulator (e.g., memantine).

[0257] In one embodiment, the anti-TREM2 antibody, or antigen-binding fragment thereof, especially VHB937, is administered to a subject, wherein subject receives the initial treatment, or at the same time when the initial treatment is started, after diagnosed with the disorder. In some embodiments, the initial prior treatment regimen is a treatment for AD. In some embodiments, the initial prior treatment regimen comprises one or more of an anti-amyloid antibody (e.g., donanemab, lecanemab), a cholinesterase inhibitor (e.g., benzgalantamine, donepezil, galantamine, rivas tigmine), and a glutamate regulator (e.g., memantine).

[0258] In one embodiment, the anti-TREM2 antibody, or antigen-binding fragment thereof, especially VHB937, is administered to a subject, in combination with the initial treatment, for the treatment of the disorder. In some embodiments, the initial prior treatment regimen is a treatment for AD. In some embodiments, the initial prior treatment regimen comprises one or more of an anti-amyloid antibody (e.g., donanemab, lecanemab), a cholinesterase inhibitor (e.g., benzgalantamine, donepezil, galantamine, rivastigmine), and a glutamate regulator (e.g., memantine).

[0259] In one embodiment, the present disclosure provides an anti-TREM2 antibody or antigenbinding fragment thereof, e.g., VHB937, for use, in the combination with the initial treatment, for the treatment of the disorder. In some embodiments, the initial prior treatment regimen is a treatment for AD. In some embodiments, the initial prior treatment regimen comprises one or more of an anti-amyloid antibody (e.g., donanemab, lecanemab), a cholinesterase inhibitor Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)

[0260] (e.g., benzgalantamine, donepezil, galantamine, rivastigmine), and a glutamate regulator (e.g., memantine).

[0261] The initial treatment may be administered according to the approved doses.

[0262] In one preferred embodiment, the dose is about 10 mg / kg of an anti-TREM2 antibody or antigen-binding fragment thereof, e.g., VHB937. In another preferred embodiment, the dose is about 30 mg / kg of an anti-TREM2 antibody or antigen-binding fragment thereof, e.g., VHB937. In yet another preferred embodiment, the dose is about 10 mg / kg of an anti-TREM2 antibody or antigen-binding fragment thereof, e.g., VHB937, and may be given every four weeks. In yet another preferred embodiment, the dose is about 30 mg / kg of an anti-TREM2 antibody or antigen-binding fragment thereof, e.g., VHB937, and may be given every four weeks. In one embodiment, the dose of the anti-TREM2 antibody or antigen-binding fragment thereof is administered intravenously.

[0263] In one preferred embodiment, the dose is 10 mg / kg of an anti-TREM2 antibody or antigenbinding fragment thereof, e.g., VHB937. In another preferred embodiment, the dose is 30 mg / kg of an anti-TREM2 antibody or antigen-binding fragment thereof, e.g., VHB937. In yet another preferred embodiment, the dose is 10 mg / kg of an anti-TREM2 antibody or antigenbinding fragment thereof, e.g., VHB937, and may be given every four weeks. In yet another preferred embodiment, the dose is 30 mg / kg of an anti-TREM2 antibody or antigen-binding fragment thereof, e.g., VHB937, and may be given every four weeks. In one embodiment, the dose of the anti-TREM2 antibody or antigen-binding fragment thereof is administered intravenously.

[0264] In one embodiment, the anti-TREM2 antibody or antigen-binding fragment thereof, e.g., VHB937, is administered through a loading dosing and a maintenance dosing. In one embodiment, the loading dosing is administered via subcutaneous injections of a first dose, and the maintenance dosing is administered via subcutaneous injections of a second dose. The first dose may be the same as the second dose or higher than the second dose.

[0265] In one embodiment the loading dose is 10 mg / kg, and the maintenance dose is 30 mg / kg.

[0266] In one embodiment, the anti-TREM2 antibody treatment results in an improvement in one or more of: amount of total soluble Triggering receptor expressed on myeloid cells 2 (sTREM2); amount of one or more inflammatory biomarkers in a bodily fluid typically serum, plasma or CSF, optionally wherein the one or more inflammatory biomarkers comprise one or more of CSF sCSFIR or CSF SPP1 (osteopontin), or CSF CCE3, or wherein the one or more Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) inflammatory biomarkers additionally or alternatively comprise one or more: CSF biomarkers , amount of one or more biomarkers of neurodegeneration in a bodily fluid typically serum, plasma, CSF or urine, optionally wherein the one or more biomarkers of neurodegeneration comprise one or more of Neurofilament Light (NfL) in CSF.

[0267] In one embodiment, anti-TREM2 antibody treatment results in a change in one or more of: ratio to baseline in Neurofilament Light (NfL) concentration in serum, as a biomarker for neurodegeneration.

[0268] In some embodiments, treatment with the anti-TREM2 antibody or antigen-binding fragment thereof, e.g., VHB937, increases the amount of sTREM2 in serum, plasma, or CSF of the patient as compared to baseline prior to the treatment.

[0269] In some embodiments, treatment with the anti-TREM2 antibody or antigen-binding fragment thereof, e.g., VHB937 reduces the level of one or more pro-inflammatory biomarkers in serum, plasma, or CSF in the patient compared to baseline prior to the treatment.

[0270] In some embodiments, treatment with the anti-TREM2 antibody or antigen-binding fragment thereof, e.g., VHB937, results in statistically significant decline in the level of one or more pro- inflammatory biomarkers in serum, plasma, or CSF of the patient as compared to baseline prior to the treatment. In some embodiments, the one or more proinflammatory biomarkers comprise SPP1, sCSFIR, CCL3, YKL-40, IL6, IL-18, CXCL10, CCL2, or TIMP-1. in some embodiments, the pro-inflammatory marker is SPP1. in some embodiments, the pro- inflammatory marker is cSFIR.

[0271] In practicing some of the methods of treatment or uses of the present disclosure, a therapeutically effective amount of the anti-TREM2 antibody or antigen-binding fragment thereof, e.g., VHB937, especially is administered to a patient, e.g., a mammal (e.g., a human). While it is understood that the disclosed methods provide for treatment of patients using the anti-TREM2 antibody, or antigen-binding fragment thereof, e.g., VHB937, this does not preclude that, if the patient is to be ultimately treated with an anti-TREM2 antibody, or antigenbinding fragment thereof, e.g., VHB937, is necessarily a monotherapy. Indeed, if a patient is selected for treatment with an anti-TREM2 antibody, or antigen-binding fragment thereof, e.g., VHB937 may be administered in accordance with the methods of the disclosure either alone or in combination with other agents and therapies.

[0272] In preferred embodiments, the anti-TREM2 antibody binds the IgSF domain of human TREM2. Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)

[0273] In preferred embodiments, the anti-TREM2 antibody binds soluble TREM2 (sTREM2).

[0274] In yet preferred embodiments, the anti TREM2 antibody is VHB937, or antigen-binding fragment thereof.

[0275] It will also be understood that intravenous administration (e.g., for VHB937) may be less frequent than monthly dosing, e.g., dosing every six weeks, every eight weeks (every two months), quarterly (every twelve weeks or every three months), etc.

[0276] Accordingly, the methods provided herein advantageously permit safe and relatively infrequent administration of an anti-TREM2 antibody or antigen-binding fragment thereof of the disclosure, which is particularly beneficial for patients with neurodegenerative diseases, such as AD, that typically affect patients for long periods of time and thus require regular treatment over the course of many months or years. As intravenous administration of antibody therapeutics cannot be done at home, patients must be transported to infusion centers, which is a burden on both the patient and caregiver. Finally, the memory loss, mood swings, physical condition caused by muscle wasting as well as aggression, and other behavioral symptoms of these diseases make patient compliance difficult.

[0277] All references cited herein, including patents, patent applications and publications, are hereby incorporated by reference in their entirety.

[0278] Definitions

[0279] The following definitions, in addition to others already provided, serve to define particular, preferred meanings of features and language used in the present disclosure description and claims, where any one or more or all of more general terms can be replaced with the particular meaning(s), leading to special invention embodiments

[0280] As used in the specification and claims, the singular form “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise. For example, the term “a cell” includes a plurality of cells, including mixtures thereof.

[0281] The term “about” in relation to a numerical value X means, X ± 15%, including all the values within this range. It also is to be understood, although not always explicitly stated, that the reagents described herein are merely examples and that equivalents of such are known in the art. Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)

[0282] Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising," are used herein in their open-ended and non-limiting sense unless otherwise noted.

[0283] When used herein "consisting of" excludes any element, step, or ingredient not specified in the aspect, embodiment and / or claim element. When used herein, "consisting essentially of" does not exclude materials or steps that do not materially affect the basic and novel characteristics of the aspect, embodiment, and / or claim.

[0284] As used herein, “TREM2” (also known as “triggering receptor expressed on myeloid cells 2”, TREM2, TREM2a, TREM2b, or TREM2c) refers to a transmembrane glycoprotein that belongs to the immunoglobulin superfamily (IgSF).

[0285] 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 human TREM2 protein can include the amino acid residues 19 to 172 of SEQ ID NO: 1.

[0286] Cleavage site is reported to be between amino acid H157 and S158 (Feuerbach et al., Neurosci. Lett. 660 (2017): 109-114). In some embodiments, the ectodomain of hTREM2 comprises the amino acids 19-157 of any one of SEQ ID NOs: 1, 2, or 3.

[0287] The term soluble TREM2 or sTREM2 refers to the portion of the extracellular domain of TREM2 that is released after sheddase cleavage. Cleavage site is reported to be between amino acid H157 and S158 (Feuerbach et al. 2017, see also Zhong et al., 2019). Therefore, sTREM2 will typically consist of the amino acids 19-157 of any one of SEQ ID NOs: 1, 2, and 3.

[0288] The term “total sTREM2 refers to the sum of free sTREM2 and sTREM2 bound to VHB937.

[0289] The term “IgSF domain” refers to a part of the extracellular domain of TREM2 containing an immunoglobulin (Ig)-type fold and thus belonging to the immunoglobulin superfamily. In human, for example, the IgSF domain consists of the amino acid residues 19 to 132 of any one of SEQ ID NOs: 1, 2 and 3.

[0290] The term “stalk region” of TREM2 refers to a portion of the extracellular domain of TREM2 that connects the V-type immunoglobulin (IgSF) domain and the transmembrane domain. For example, the stalk region of human TREM2 isoform 1 protein can include amino acids 133- 172 of SEQ ID NO: 1. Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)

[0291] 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).

[0292] 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 the lipid bilayer of a cell. Methods for determining the cytoplasmic tail of a protein are known in the art (Elofsson et al. (2007) and Bernsel et al. (2005)).

[0293] The term “stabilize” as used herein refers to the maintenance, restoration or increase of TREM2 cell surface level in a TREM2-expressing cell, e.g., to the TREM2 level in a corresponding TREM2-expressing cell in a healthy subject without inflammatory or neurodegenerative disease. This may be accomplished, for example, by reducing or inhibiting the shedding of TREM2 ectodomain, or by increasing cell surface expression of TREM2. TREM2 cell surface level can be assessed by flow cytometry / FACS or by TREM2 cell surface immunoprecipitation or by the reduction of soluble TREM2 over time. TREM2 cell surface expression can also be detected by enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), bioassays (e.g., increase in phagocytosis), Western Blot assay, flow cytometry, immunohistochemistry, immunofluorescent assay, homogeneous time resolved fluorescence (HTRF), or positron emission tomography (PET).

[0294] The term “activate” herein refers to the initiation or preservation of downstream signaling of TREM2 expressed at the cell surface, e.g., in TREM2-expressing cells in healthy subjects or individuals with inflammatory or neurodegenerative diseases where proper TREM2 dependent activities are impaired. This may be accomplished but is not limited phosphorylation of TREM2 associated DAP 12 or DAP 10, leading via different intracellular signaling cascades to enhancement of Syk phosphorylation, phagocytosis, increased target-directed cellular motility (chemotaxis), increased cellular survival, modulating cytokine or chemokine release of cells expressing TREM2, increasing degradation of intracellular phagocytosed material, or changes in gene expression. Increased TREM2 dependent DAP12 or Syk phosphorylation can be assessed by Western blot, ELISA or flow cytometry / FACS. Directed motility of cells, e.g., 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 on the mRNA level or by Western blot or flow cytometry at the protein level. Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)

[0295] The term “facilitate” herein refers to the enhancement or restoration of disease impaired TREM2 dependent activities. These activities may comprise phagocytosis, increased target- directed cellular motility (chemotaxis), increased cellular survival, modulating cytokine or chemokine release of cells expressing TREM2, increasing degradation of intracellular phagocytosed material, modulating cellular responses of neighbouring cells (astrocytes / neurons) or changes in gene expression.

[0296] 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, multiple or single chain, or intact immunoglobulins, and may be derived from natural sources or from recombinant sources. A naturally occurring “antibody” is a glycoprotein comprising at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region is comprised of three domains, CHI, CH2 and CH3. Each light chain is comprised of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region is comprised of one domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), 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 amino-terminus to 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 the antibodies may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system. An antibody can be a monoclonal antibody, human antibody, humanized antibody, camelised antibody, or chimeric antibody. The antibodies can be of any isotype (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgGl, IgG2, IgG3, IgG4, IgAl and IgA2) or subclass. Throughout this document, the term “antibody” or “antibody molecule” also includes any fragments thereof and any derivatives thereof, unless the context indicates otherwise.

[0297] The term “antigen-binding fragment” or “antigen binding region” used herein interchangeably refers to at least one portion of an antibody, that retains the ability to specifically interact with (e.g., by binding, steric hindrance, stabilizing / destabilizing, spatial distribution) an epitope of an antigen. Examples of antigen-binding fragments include, but are not limited to, Fab, Fab', Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)

[0298] F(ab')2, Fv fragments, scFv antigen-binding fragments, disulfide-linked Fvs (sdFv), a Fd fragment consisting of the VH and CHI domains, linear antibodies, single domain antibodies such as sdAb (either VL or VH), camelid VHH domains, multi- specific antibodies formed from antigen-binding 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 fragments of an antibody. An antigen binding fragment can also be incorporated into single domain antibodies, maxibodies, minibodies, nanobodies, intrabodies, diabodies, triabodies, tetrabodies, v-NAR and bis-scFv (see, e.g., Hollinger and Hudson, Nature Biotechnology 23:1126-1136, 2005). Antigen binding fragments can also be grafted into scaffolds based on polypeptides such as a fibronectin type III (Fn3) (see U.S. Patent No.: 6,703,199, which describes fibronectin polypeptide minibodies). The term “scFv” refers to a fusion protein comprising at least one antigen-binding fragment comprising a variable region of a light chain and at least one antigen-binding fragment comprising a variable region of a heavy chain, wherein the light and heavy chain variable regions are contiguously linked, e.g., via a synthetic linker, e.g., a short flexible polypeptide linker, and capable of being expressed as a single-chain polypeptide, and wherein the scFv retains the specificity of the intact antibody from which it is derived. Unless specified, as used herein an scFv may have the VL and VH variable regions in either order, e.g., with respect to the N-terminal and C-terminal ends of the polypeptide, the scFv may comprise VL-linker-VH or may comprise VH-linker-VL.

[0299] The terms “complementarity determining region” or “CDR,” as used herein, refer to the sequences of amino acids within antibody variable regions which confer antigen specificity and binding affinity. For example, in general, there are three CDRs in each heavy chain variable region (e.g., HCDR1, HCDR2, and HCDR3, also referred to herein as CDR-H1, CDR-H2, and CDR-H3, respectively) and three CDRs in each light chain variable region (LCDR1, LCDR2, and LCDR3, also referred to herein as CDR-L1, CDR-L2, and CDR-L3, respectively). The precise amino acid sequence boundaries of a given CDR can be determined using any of a number of well-known 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 thereof, and ImMunoGenTics (IMGT) numbering (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) (“IMGT” numbering scheme). In a combined Kabat and Chothia numbering scheme for a given Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)

[0300] CDR region (for example, HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 or LCDR3), in some embodiments, the CDRs correspond to the 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 herein, the CDRs defined according to the “Chothia” number scheme are also sometimes referred to as “hypervariable loops.” Under IMGT, the CDR regions of an antibody can be determined using the program IMGT / DomainGap Align. Generally, unless specifically indicated, the antibody molecules can include any combination of one or more Kabat CDRs and / or Chothia CDRs.

[0301] The term “epitope” includes any protein determinant capable of specific binding to an immunoglobulin or otherwise interacting with a molecule. Epitopic determinants generally consist of chemically active surface groupings of molecules such as amino acids or carbohydrate or sugar side chains and can have specific three-dimensional structural characteristics, as well as specific charge characteristics. An epitope may be “linear” or “conformational.” Conformational and linear epitopes are distinguished for example in that the binding to the former but not the latter is lost in the presence of denaturing solvents.

[0302] "Binds the same epitope as" means the ability of an antibody, antigen-binding fragment or other antigen-binding moiety to bind to a specific antigen and binding to the same epitope as the exemplified antibody when using the same epitope mapping technique for comparing 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 spatial conformation of amino acids such as by, e.g., hydrogen / deuterium exchange, x-ray crystallography and two- dimensional nuclear magnetic resonance.

[0303] In another embodiment, the present disclosure refers to methods of treatment using an antibody or antigen-binding fragment that cross-competes with an antibody described in Table 1.

[0304] In one embodiment the present disclosure refers to methods of treatment using an antibody or antigen-binding fragment, wherein said antibody or antigen-binding fragment cross-competes with an antibody or antigen-binding fragment comprising 6 CDRs defined by any of the Kabat, Chothia, IMGT, or combined Kabat / Chothia method of one or more of the antibodies in Table 1.

[0305] In another embodiment, the present disclosure refers to methods of treatment using an antibody or antigen-binding fragment described in Table 1. Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)

[0306] In another embodiment, the present disclosure refers to methods of treatment using an antibody or antigen-binding fragment that binds to (e.g., by binding, and / or activating) the same epitope as one of the antibodies in Table 1.

[0307] In a further embodiment, methods of treatment using said antibody or antigen-binding fragment thereof which binds to (e.g., by binding and / or activating) an epitope overlapping the epitope of an antibody or antigen-binding fragment comprising 6 CDRs defined by any one of the Kabat, Chothia, IMGT, or combined Kabat / Chothia methods of any one of the antibodies in Table 1.

[0308] The phrases “monoclonal antibody” or “monoclonal antibody composition” as used herein refers to antibodies, bispecific antibodies, etc., that have substantially identical amino acid sequence or are derived from the same genetic source. This term also includes preparations of antibody molecules of single molecular composition. A monoclonal antibody composition displays a single binding specificity and affinity for a particular epitope.

[0309] The phrase “human antibody,” as used herein, includes antibodies having variable regions in which both the framework and CDR regions are derived from sequences of human origin. The constant region is also derived from human sequences, e.g., human germline sequences, or mutated versions of human germline sequences or antibody containing consensus framework sequences derived from human framework sequences analysis, for example, as described in Knappik, et al. (2000) J Mol Biol 296, 57-86). The structures and locations of immunoglobulin variable domains, e.g., CDRs, may be defined using well-known numbering schemes, e.g., the Kabat numbering scheme, the Chothia numbering scheme, or a combination of Kabat and Chothia, and ImMunoGenTics (IMGT) numbering (see, e.g., 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 Al-Lazikani et al., (1997) J. Mai. 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.

[0310] The human antibodies used in the methods of the disclosure may include amino acid residues not encoded by human sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo, or a conservative substitution to promote Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) stability or manufacturing). However, the term “human antibody” as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.

[0311] 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 (e.g., a mouse) that is transgenic or transchromosomal for human immunoglobulin genes or a hybridoma prepared therefrom, antibodies isolated from a host cell transformed to express the human antibody, e.g., from a transfectoma, antibodies isolated from a recombinant, combinatorial human antibody library, and antibodies prepared, expressed, created or isolated by any other means that involve splicing of 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. In certain embodiments, however, such recombinant human antibodies can be subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while derived from and related to human germline VH and VL sequences, may not naturally exist within the human antibody germline repertoire in vivo.

[0312] Antibody "effector functions" refer to those biological activities attributable to the Fc region (a native sequence Fc region or amino acid sequence variant Fc region) of an antibody, and vary with the antibody isotype. The term "Fc region" herein is used to define a C-terminal region of an immunoglobulin heavy chain, including native- sequence Fc regions and variant Fc regions. Although the boundaries of the Fc region of an immunoglobulin heavy chain might vary, the human IgG heavy-chain Fc region is usually defined to stretch from an amino acid residue at position Cys226, or from Pro230, to the carboxyl-terminus thereof. The C-terminal lysine (residue 447 according to the EU numbering system) of the Fc region may be removed, for example, during production or purification of the antibody, or by recombinantly engineering the nucleic acid encoding a heavy chain of the antibody. Accordingly, a composition of intact antibodies may comprise antibody populations with all K447 residues removed, antibody populations with no K447 residues removed, and antibody populations having a mixture of antibodies with and without the K447 residue. Suitable native-sequence Fc regions for use in the antibodies of the present disclosure include human IgGl, IgG2, IgG3 and IgG4. Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)

[0313] Alternatively, the term “Fc region” as used herein refers to a polypeptide comprising the CH3, CH2 and at least a portion of the hinge region of a constant domain of an antibody. Optionally, an Fc region may include a CH4 domain, present in some antibody classes. An Fc region may comprise the entire hinge region of a constant domain of an antibody. In one embodiment, the disclosure comprises an Fc region and a CHI region of an antibody. In one embodiment, the disclosure comprises an Fc region CH3 region of an antibody. In another embodiment, the disclosure comprises an Fc region, a CHI region and a Ckappa / lambda region from the constant domain of an antibody. In one embodiment, a binding molecule of the disclosure comprises a constant region, e.g., a heavy chain constant region. In one embodiment, such a constant region is modified compared to a wild-type constant region. That is, the polypeptides of the disclosure disclosed herein may comprise alterations or modifications to one or more of the three heavy chain constant domains (CHI, CH2 or CH3) and / or to the light chain constant region domain (CL). Example 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.

[0314] A "native sequence Fc region" comprises an amino acid sequence identical to the amino acid sequence of an Fc region found in nature. Native sequence human Fc regions include a native sequence human IgGl Fc region (non- A and A allotypes); native sequence human IgG2 Fc region; native sequence human IgG3 Fc region; and native sequence human IgG4 Fc region as well as naturally occurring variants thereof. A "variant Fc region" comprises an amino acid sequence which differs from that of a native sequence Fc region by virtue of at least one amino acid modification, preferably one or more amino acid substitution(s). Preferably, the variant Fc region has at least one amino acid substitution compared to a native sequence Fc region, e.g., from about one to about ten amino acid substitutions, and preferably from about one to about five amino acid substitutions in a native sequence Fc region. The variant Fc region herein will preferably possess at least about 80% homology with a native sequence Fc region, and most preferably at least about 90% homology there with, more preferably at least about 95% homology therewith. "Fc receptor" or "FcR" describes a receptor that binds to the Fc region of an antibody. The preferred FcR is a native sequence human FcR. Moreover, a preferred FcR is one which binds an IgG antibody (a gamma receptor) and includes receptors of the FcyRI, FcyRII, and FcyRIII subclasses, including allelic variants and alternatively spliced forms of these receptors, FcyRII receptors include FcyRIIA (an "activating receptor") and FcyRIIB (an "inhibiting receptor"), which have similar amino acid sequences that differ Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) primarily in the cytoplasmic domains thereof. Activating receptor FcyRIIA contains an immunoreceptor tyrosine-based activation motif ("IT AM") in its cytoplasmic domain.

[0315] Inhibiting receptor FcyRIIB contains an immunoreceptor tyrosine-based inhibition motif ("ITIM") in its cytoplasmic domain (see, e.g., M. Daeron, Annu. Rev. Immunol. 15:203-234 (1997)). FcRs are reviewed in Ravetch and Kinet, Annu. Rev. Immunol. 9:457-92 (1991); Capel et al., Immunomethods 4:25-34 (1994); and de Haas et al., J Lab. Clin. Med. 126: 330- 41 (1995). Other FcRs are encompassed by the term "FcR" herein. FcRs can also increase the serum half-life of antibodies.

[0316] Binding to FcR in vivo and serum half-life of human FcR high-affinity binding polypeptides can be assayed, e.g., in transgenic mice or transfected human cell lines expressing human FcR, or in primates to which the polypeptides having a variant Fc region are administered. WO 2004 / 42072 (Presta) describes antibody variants with improved or diminished binding to FcRs. See also, e.g., Shields et al., J Biol. Chem 9(2):6591-6604 (2001).

[0317] As used herein, the term “affinity” refers to the strength of interaction between antibody and antigen at single antigenic sites. Within each antigenic site, the variable regions of the antibody interact through weak non-covalent 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 (e.g., a Fab fragment) refers to an antibody having an affinity of 10"8M or less, 10"9M or less, or IO"10M, or 10"11M or less, or 10"12M or less, or 10"13M or less for a target antigen. However, high affinity binding can vary for other antibody isotypes. For example, high affinity binding for an IgM isotype refers to an antibody having an affinity of 10’7M or less, or 10’8M or less.

[0318] As used herein, the terms "Kassoc," "Ka," or “Kon” are intended to refer to the association rate of a particular antibody-antigen interaction, whereas the term "Kdis," "Kd," or “Koff” are intended to refer to the dissociation rate of a particular antibody-antigen interaction. In one embodiment, the term "KD" (or “KD”), as used herein, is intended to refer to the dissociation constant, which is obtained from the ratio of Kd to Ka (i.e. Kd / Ka) and is expressed as a molar concentration (M). KD values for antibodies can be determined using methods well established in the art. A method for determining the KD of an antibody is by using surface plasmon resonance or using a biosensor system such as a Biacore® system.

[0319] 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 major factors: antibody Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) epitope affinity; the valency of both the antigen and antibody; and the structural arrangement of the interacting parts. Ultimately these factors define the specificity of the antibody, that is, the likelihood that the particular antibody is binding to a precise antigen epitope.

[0320] The term “binding specificity” or “specifically binds” as used herein refers to the ability of an individual antibody combining site to react with one antigenic determinant and not with a different antigenic determinant. The combining site of the antibody is located in the Fab portion of the molecule and is constructed from the hypervariable regions of the heavy and light chains. 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 attractive and repulsive forces operating between the antigenic determinant and the combining site of the antibody.

[0321] The terms “treat” and “treatment” refer to therapeutic treatment, wherein the object is to slow down or slow progression of an undesired physiological change or disorder. For purpose of this disclosure, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0322] The term “patient” refers to an animal, human or non-human, preferably human to whom treatment according to the methods of the present disclosure is provided. As used herein, a patient is a person who is receiving medical care, or who is cared for by a particular doctor when necessary. Veterinary and non-veterinary applications are contemplated. The term includes, but is not limited to, mammals, e.g., humans, other primates, pigs, rodents such as mice and rats, rabbits, guinea pigs, hamsters, cows, horses, cats, dogs, sheep and goats. Typical patients include humans, farm animals, and domestic pets such as cats and dogs. In some preferred embodiments, the subject is a human. The term “subject” or “individual” can be used interchangeably with the term “patient”.

[0323] For AD, the term “patient” encompasses a patient with early AD.

[0324] As used herein “early AD” is defined by mild cognitive impairment (MCI) due to AD or mild AD, preferably according to the 2018 NIA AA diagnostic criteria and evidence of amyloid pathology. Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)

[0325] An “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 can be the same or different from a prophylactically effective amount, which is an amount necessary to prevent onset of disease or disease symptoms. An effective amount can be administered in one or more administrations, applications or dosages. A “therapeutically effective amount” of a therapeutic compound (i.e., 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, including once every other day. The skilled artisan will appreciate that certain factors may influence the dosage and timing required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health and / or age of the subject, and other diseases present. Moreover, 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.

[0326] The term “nucleic acid” or “polynucleotide” refers to deoxyribonucleic acids (DNA) or ribonucleic acids (RNA) and polymers thereof in either single- or double-stranded form. Unless specifically limited, the term encompasses nucleic acids containing known analogues of natural nucleotides that have similar binding properties as the reference nucleic acid and are metabolized in a manner similar to naturally occurring nucleotides. Unless otherwise indicated, a particular nucleic acid sequence also implicitly encompasses conservatively modified variants thereof (e.g., degenerate codon substitutions), alleles, orthologs, SNPs, and complementary sequences as well as the sequence explicitly indicated. Specifically, degenerate codon substitutions may be achieved by generating sequences in which the third position of one or more selected (or all) codons is substituted with mixed-base and / or deoxyinosine residues (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)).

[0327] 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 no limitation is placed on the maximum number of amino acids that can comprise a protein’s or peptide’s sequence. Polypeptides include any peptide or protein comprising two or more amino acids joined to each other by peptide bonds. As used herein, the term refers to both short chains, which also commonly are referred to in the art as peptides, oligopeptides and oligomers, for example, and to longer chains, which generally are referred to in the art as proteins, of which there are many types. Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)

[0328] “Polypeptides” include, for example, biologically active fragments, substantially homologous polypeptides, oligopeptides, homodimers, heterodimers, variants of polypeptides, modified polypeptides, derivatives, analogs, fusion proteins, among others. A polypeptide includes a natural peptide, a recombinant peptide, or a combination thereof.

[0329] The term “conservative sequence modifications” refers to amino acid modifications that do not significantly affect or alter the binding characteristics of the antibody or antigen-binding fragment containing the amino acid sequence. Such conservative modifications may include amino acid substitutions, additions and deletions. Modifications can be introduced into an antibody or antigen-binding fragment of the disclosure by standard techniques known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis. Conservative amino acid substitutions are ones 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 (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Thus, one or more amino acid residues within an antibody or an antigen-binding fragment thereof of the disclosure can be replaced with other amino acid residues from the same side chain family and the altered antibody or antigen-binding fragment can be tested using the functional assays described herein.

[0330] The term “identical” refers to the subunit sequence identity between two polymeric molecules, e.g., between two nucleic acid molecules, such as, two DNA molecules or two RNA molecules, or between two polypeptide molecules. When a subunit position in both of the two molecules is occupied by the same monomeric subunit, e.g., if a position in each of two DNA molecules is occupied by adenine, then they are identical at that position. The identity between two sequences is a direct function of the number of matching or homologous positions, e.g., if half (e.g., five positions in a polymer ten subunits in length) of the positions in two sequences are identical, the two sequences are 50% identical; if 90% of the positions (e.g., 9 of 10) are matched, the two sequences are 90% identical. Percentage of “sequence identity” can be determined by comparing two optimally aligned sequences over a comparison window, where the fragment of the amino acid sequence in the comparison window may comprise additions or Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) deletions (e.g., gaps or overhangs) as compared to the reference sequence (which does not comprise 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 yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison, and multiplying the result by 100 to yield the percentage of sequence identity. The output is the percent identity of the subject sequence with respect to the query sequence.

[0331] The term “isolated” means altered or removed from the natural state. For example, a nucleic acid or a peptide naturally present in a living animal is not “isolated,” but the same nucleic acid or peptide partially or completely separated from the coexisting materials of its natural state is “isolated.” An isolated nucleic acid or protein can exist in substantially purified form, or 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 (e.g., an isolated antibody that specifically binds TREM2 is substantially free of antibodies that specifically bind antigens other than TREM2). An isolated antibody that specifically binds a target molecule may, however, have cross-reactivity to the same antigens from other species, e.g., an isolated antibody that specifically binds TREM2 may bind TREM2 molecules from other species. An isolated antibody may be a monoclonal antibody. An isolated antibody may be a recombinant monoclonal antibody. Moreover, an isolated antibody may be substantially free of other cellular material and / or chemicals.

[0332] Examples of TREM-2 antibodies:

[0333] VHB937 (MOR44698E) Heavy chain: SEQ ID NO: 37

[0334] QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYHMSWVRQAPGQGLEWMGVINPVSGNTV YAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARIPSYTYAFDYWGQGTLVTVSSAS TKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSL SSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPK PKDTLMISRTPEVTCVVVAVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLT VLHQDWLNGKEYKCKVSNKALAAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLV KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVLHEA LHSHYTQKSLSLSPGK Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)

[0335] VHB937 (MOR044698E) Light chain: SEQ ID NO: 26

[0336] DIQMTQSPSSLSASVGDRVTITCRASQDISNYLAWYQQKPGKAPKLLIYRASSLQSGVPSRFS

[0337] GSGSGTDFTLTISSLQPEDFATYYCFQYRHMPSQTFGQGTKVEIKRTVAAPSVFIFPPSDEQLK

[0338] SGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYE

[0339] KHKVYACEVTHQGLSSPVTKSFNRGEC

[0340] VHB937 (MOR044698E) Variable Domain of Heavy Chain (VH): SEQ ID NO: 13

[0341] QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYHMSWVRQAPGQGLEWMGVINPVSGNTV

[0342] YAQKFQGRVTMTRDTSISTAYMELSRLRSEDTAVYYCARIPSYTYAFDYWGQGTLVTVSS

[0343] VHB937 (MOR44698E) Variable Domain of Light Chain (VL): SEQ ID NO: 24

[0344] DIQMTQSPSSLSASVGDRVTITCRASQDISNYLAWYQQKPGKAPKLLIYRASSLQSGVPSRFS

[0345] GSGSGTDFTLTISSLQPEDFATYYCFQYRHMPSQTFGQGTKVEIK

[0346] VHB937 (MOR44698E) comprises the following Complementarity Determining Regions (CDRs):

[0347] Heavy Chain CDRs

[0348] CDR-IMGT Heavy Chain (H):

[0349] H-CDR1 GYTFTGYH SEQ ID NO: 10

[0350] H-CDR2 INPVSGNT SEQ ID NO: 11

[0351] H-CDR3 ARIPSYTYAFDY SEQ ID NO: 12

[0352] CDR-Kabat Heavy Chain (H)

[0353] H-CDR1 GYHMS SEQ ID NO: 7

[0354] H-CDR2 VINPVSGNTVYAQKFQG SEQ ID NO:5

[0355] H-CDR3 IPSYTYAFDY SEQ ID NO:6 Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)

[0356] Light Chain CDRs:

[0357] CDR-IMGT Light Chain (L)

[0358] L- CDR1 QDISNY SEQ ID NO: 23

[0359] L-CDR2 RAS SEQ ID NO: 21

[0360] L-CDR3 FQYRHMPSQT SEQ ID NO: 19

[0361] CDR-Kabat Light Chain (L)

[0362] L-CDR1 RASQDISNYLA SEQ ID NO: 17

[0363] L-CDR2 RASSLQS SEQ ID NO: 18

[0364] L-CDR3 FQYRHMPSQT SEQ ID NO: 19

[0365] As used herein, the term “inhibit”, "inhibition" or “inhibiting” refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0366] As used herein, the term “treat,” “treating," or "treatment" of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development or progression of the disease or at least one of the clinical symptoms thereof). In another embodiment “treat,” "treating," or "treatment" refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient. In yet another embodiment, “treat,” "treating," or "treatment" refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. More specifically, the term “treating” the disease refers to slowing the progression of the disease.

[0367] In some embodiments, treatment refers to, in adults diagnosed with AD, preferably with early AD, as described herein.

[0368] In some embodiments, treatment can mean slower progression of the disease as measure by changes in scores such as CDR-SB, ADAS-Cogl4, and ADCS-ADL.

[0369] The term “change” in these scores refers to a slower decline, or a slower rate of change of a decreased slope when plotting the score over time, or a smaller decline, in an AD patient. Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)

[0370] As used herein, a patient is “in need of’ a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.

[0371] As used herein, the term "a,” "an,” "the,” and similar terms used in the context of the present invention (especially in the context of the claims) are to be construed to cover both the singular and plural unless otherwise indicated herein or clearly contradicted by the context.

[0372] As used herein in certain embodiments, the term "about,” unless otherwise defined, includes a variation of ±10%, or ±5% from the value given.

[0373] The term “pharmaceutically acceptable” means a nontoxic material that does not interfere with the effectiveness of the biological activity of the active ingredient(s).

[0374] As used herein, the term "administration" or "administering" of the subject compound means providing a compound of the disclosure and prodrugs thereof to a subject in need of treatment. Administration “in combination with” one or more further therapeutic agents includes simultaneous (concurrent) and consecutive administration in any order, and in any route of administration. One administration may be a single injection, or multiple injections delivered in conjunction with each other, depending on how much drug substance needs to be administered to achieve therapeutic effect.

[0375] As used herein, a “therapeutically effective amount” refers to an amount of an anti-TREM2 antibody or antigen binding fragment thereof, e.g., VHB937, that is effective, upon single or multiple dose administration to a patient (such as a human) for treating, preventing, preventing the onset of, curing, delaying, slowing the progression of, reducing the severity of, ameliorating at least one symptom of a disorder or recurring disorder, or prolonging the survival of the patient beyond that expected in the absence of such treatment. When applied to an individual active ingredient (e.g., an anti-TREM2 antibody, e.g., VHB937) administered alone, the term refers to that ingredient alone. When applied to a combination, the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially or simultaneously.

[0376] The phrase “therapeutic regimen” means the regimen used to treat an illness, e.g., the dosing protocol used during the treatment of the disease or disorder. A therapeutic regimen may include a loading regimen (or loading dosing), followed by a maintenance regimen (or maintenance dosing).

[0377] The phrase “loading regimen" or “loading period” refers to a treatment regimen (or the portion of a treatment regimen) that is used for the initial treatment of a disease. In some embodiments, Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) the disclosed methods, uses, kits, processes and regimens (e.g., methods of treating a disease or disorder) employ a loading regimen (or loading dosing). In some cases, the loading period is the period until maximum efficacy is reached. The general goal of a loading regimen is to provide a high level of drug to a patient during the initial period of a treatment regimen. A loading regimen may include administering a greater dose of the drug than a physician would employ during maintenance regimen, administering a drug more frequently than a physician would administer the drug during a maintenance regimen, or both. Dose escalation may occur during or after the loading regimen.

[0378] The phrase “maintenance regimen" or “maintenance period” refers to a treatment regimen (or the portion of a treatment regimen) that is used for the maintenance of a patient during treatment of an illness, e.g., to keep the patient in remission for long periods of time (months or years) following the loading regimen or period. In some embodiments, the disclosed methods, uses and regimens employ a maintenance regimen. A maintenance regimen may employ continuous therapy (e.g., administering a drug at regular intervals, e.g., weekly, bi-weekly or monthly (every 4 weeks), yearly, etc.) or intermittent therapy (e.g., interrupted treatment, intermittent treatment, treatment at relapse, or treatment upon achievement of a particular predetermined criteria [e.g., pain, disease manifestation, etc.]). Dose escalation may occur during a maintenance regimen. The term “in combination with” is understood as the two or more drugs are administered subsequently or simultaneously, which is either in separate dose or in a fixed dose. Alternatively, the term “in combination with” is understood that two or more drugs are administered in the manner that the effective therapeutical concentration of the drugs are expected to be overlapping for a majority of the period of time within the patient’s body. The two or more drugs may be administered independently at the same time or separately within time intervals, especially where these time intervals allow that the combination partners show a cooperative, e.g., synergistic effect. The terms “co-administration” or “combined administration” or the like as utilized herein are meant to encompass administration of the selected combination partner to a single subject in need thereof (e.g., a patient), and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time. The drug administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient and the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein. Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)

[0379] The phrase “means for administering” is used to indicate any available implement for systemically administering a drug to a patient, including, but not limited to, a pre-filled syringe, a vial and syringe, an injection pen, an autoinjector, an i.v. drip and bag, a pump, a patch pump, etc. With such items, a patient may self-administer the drug (i.e., administer the drug on their own behalf) or a physician may administer the drug.

[0380] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. Although methods and materials similar or equivalent to those described herein can be used to practice the disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, prevail. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

[0381] The details of one or more embodiments of the disclosure are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the disclosure will be apparent from the description and drawings, and from the claims.

[0382] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as”) provided herein is intended merely to better illuminate the disclosure and does not pose a limitation on the scope of the invention otherwise claimed. However, it may relate to preferable features.

[0383] Disclosure embodiments and their hierarchical relationship to each other are also defined in the claims which are to be regarded as included here.

[0384] Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)

[0385] Examples of TREM-2 Antibodies:

[0386] In some embodiments, the antibody is any antibody from Table 1.

[0387] In one embodiment, the antibody is MOR44698A as described by the CDRs, VH and VL, heavy chain and light chain sequences in Table 1.

[0388] In one embodiment, the antibody is MOR44698B as described by the CDRs, VH and VL, heavy chain and light chain sequences in Table 1.

[0389] In one embodiment, the antibody is MOR44698C as described by the CDRs, VH and VL, heavy chain and light chain sequences in Table 1.

[0390] In one embodiment, the antibody is MOR44698D as described by the CDRs, VH and VL, heavy chain and light chain sequences in Table 1.

[0391] In one embodiment, the antibody is MOR44698E as described by the CDRs, VH and VL, heavy chain and light chain sequences in Table 1.

[0392] In one embodiment, the antibody is MOR44698F as described by the CDRs, VH and VL, heavy chain and light chain sequences in Table 1.

[0393] In one embodiment, the antibody is MOR44746A as described by the CDRs, VH and VL, heavy chain and light chain sequences in Table 1.

[0394] In one embodiment, the antibody is MOR44746B as described by the CDRs, VH and VL, heavy chain and light chain sequences in Table 1.

[0395] In one embodiment, the antibody is MOR44746C as described by the CDRs, VH and VL, heavy chain and light chain sequences in Table 1.

[0396] In one embodiment, the antibody is MOR44746D as described by the CDRs, VH and VL, heavy chain and light chain sequences in Table 1.

[0397] In one embodiment, the antibody is MOR44746F as described by the CDRs, VH and VL, heavy chain and light chain sequences in Table 1.

[0398] In one embodiment, the antibody is MOR42596 as described by the CDRs, VH and VL, heavy chain and light chain sequences in Table 1. Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)

[0399] Table 1: Sequences of Exemplary Monoclonal Antibodies That Bind Human TREM2 Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)

[0400] Nasu-Hakola disease

[0401] Nasu-Hakola disease (NHD), which may alternatively be referred to as polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), is a rare inherited leukodystrophy characterized by progressive presenile dementia associated with recurrent bone fractures due to polycystic osseous lesions of the lower and upper extremities. NHD disease course is generally divided into four stages: latent, osseous, early neurologic, and late neurologic. After a normal development during childhood (latent stage), NHD starts manifesting during adolescence or young adulthood (typical age of onset 20-30 years) with pain in the hands, wrists, ankles, and feet. Patients then start suffering from recurrent bone fractures due to polycystic osseous and osteroporotic lesions in the limb bones (osseous stage). During the third or fourth decade of life (early neurologic stage), patients present with pronounced personality changes (e.g., euphoria, lack of concentration, loss of judgment, and social inhibitions) characteristic of a frontal lobe syndrome. Patients also typically suffer from progressive memory disturbances. Epileptic seizures are also frequently observed. Finally (late Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) neurologic stage), patients progress to profound dementia, are unable to speak and move, and usually die by the age of 50.

[0402] In some embodiments, administering an anti-TREM2 antibody of the present disclosure can treat and / or delay Nasu-Hakola disease (NHD). In some embodiments, administering an anti- TREM2 antibody may promote or increase microglial activity in an individual having NHD, e.g., compared to baseline. In some embodiments, administering an anti-TREM2 antibody may induce or increase one or more TREM2 activities (e.g., DAP12 phosphorylation, PBK activation, increased expression of one or more anti-inflammatory mediators, and reduced expression of one or more pro-inflammatory mediators) in an individual having NHD.

[0403] Parkinson's disease

[0404] Parkinson's disease (PD), which may be referred to as idiopathic or primary parkinsonism, hypokinetic rigid syndrome (HRS), or paralysis agitans, is a neurodegenerative brain disorder that affects motor system control. The progressive death of dopamine-producing cells in the brain leads to the major symptoms of Parkinson's. Most often, Parkinson's disease is diagnosed in people over 50 years of age Parkinson’s disease is idiopathic (having no known cause) in most people. However, genetic factors also play a role in the disease. Symptoms of Parkinson's disease include, without limitation, tremors of the hands, arms, legs, jaw, and face, muscle rigidity in the limbs and trunk, slowness of movement (bradykinesia), postural instability, difficulty walking, neuropsychiatric problems, changes in speech or behavior, depression, anxiety, pain, psychosis, dementia, hallucinations, and sleep problems.

[0405] In some embodiments, administering an anti-TREM2 antibody of the present disclosure can treat and / or delay PD. In some embodiments, administering an anti-TREM2 antibody may promote or increase microglial activity in an individual having PD, e.g., compared to baseline. In some embodiments, administering an anti-TREM2 antibody may induce or increase one or more TREM2 activities (e.g., DAP12phosphorylation, PBK activation, increased expression of one or more anti-inflammatory mediators, and reduced expression of one or more pro- inflammatory mediators) in an individual having PD. Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)

[0406] Huntington's disease

[0407] Huntington's disease (HD) is an inherited neurodegenerative disease caused by an autosomal dominant mutation in the Huntingtin gene (HTT). Expansion of a cytokine-adenine-guanine (CAG) triplet repeat within the Huntingtin gene results in production of a mutant form of the Huntingtin protein (Htt) encoded by the gene. This mutant Huntingtin protein (mHtt) is toxic and contributes to neuronal death. Symptoms of Huntington's disease most commonly appear between the ages of 3 5 and 44, although they can appear at any age. Symptoms of Huntington's disease, include, without limitation, motor control problems, jerky, random movements (chorea), abnormal eye movements, impaired balance, seizures, difficulty chewing, difficulty swallowing, cognitive problems, altered speech, memory deficits, thinking difficulties, insomnia, fatigue, dementia, changes in personality, depression, anxiety, and compulsive behavior. In some embodiments, administering an anti-TREM2 antibody of the present disclosure can treat and / or delay HD. In some embodiments, administering an anti-TREM2 antibody may promote, change, or increase microglial activity in an individual having HD, e.g., compared to baseline. In some embodiments, administering an anti-TREM2 antibody may induce or increase one or more TREM2 activities (e.g., DAP12phosphorylation, PBK activation, increased expression of one or more anti-inflammatory mediators, and reduced expression of one or more pro-inflammatory mediators) in an individual having HD.

[0408] Tauopathy disease

[0409] Tauopathy diseases, or Tauopathies, are a class of neurodegenerative disease caused by aggregation of the microtubule-associated protein tau within the brain. Alzheimer's disease (AD) is the most well-known tauopathy disease and involves an accumulation of tau protein within neurons in the form of insoluble neurofibrillary tangles (NFTs). Other tauopathy diseases and disorders include progressive supranuclear palsy, dementia pugilistica (chromic traumatic encephalopathy), frontotemporal dementia (FTD) and parkinsonism linked to chromosome 17, Lytico-Bodig disease (Parkinson-dementia complex of Guam), tangle- predominant dementia, ganglioglioma and gangliocytoma, meningioangiomatosis, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, Hallervorden-Spatz disease, lipofuscinosis, Pick's disease, corticobasal degeneration, Argyrophilic grain disease (AGD), Huntington's disease, frontotemporal dementia, and frontotemporal lobar degeneration. Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)

[0410] In some embodiments, administering an anti-TREM2 antibody of the present disclosure can treat and / or delay tauopathy disease. In some embodiments, administering an anti-TREM2 antibody may promote or increase microglial activity in an individual having tauopathy disease, e.g., compared to baseline. In some embodiments, administering an anti-TREM2 antibody may induce or increase one or more TREM2 activities (e.g., DAP12 phosphorylation, PBK activation, increased expression of one or more anti-inflammatory mediators, and reduced expression of one or more pro-inflammatory mediators) in an individual having tauopathy disease.

[0411] Multiple sclerosis

[0412] Multiple sclerosis (MS) can also be referred to as disseminated sclerosis or encephalomyelitis disseminata. MS is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms. MS affects the ability of nerve cells in the brain and spinal cord to communicate with each other effectively. Nerve cells communicate by sending electrical signals called action potentials down long fibers called axons, which are contained within an insulating substance called myelin. In MS, the body's own immune system attacks and damages the myelin. When myelin is lost, the axons can no longer effectively conduct signals. MS onset usually occurs in young adults and is more common in women.

[0413] Symptoms of MS include, without limitation, changes in sensation, such as loss of sensitivity or tingling; pricking or numbness, such as hypoesthesia and paresthesia; muscle weakness; clonus; muscle spasms; difficulty in moving; difficulties with coordination and balance, such as ataxia; problems in speech, such as dysarthria, or in swallowing, such as dysphagia; visual problems, such as nystagmus, optic neuritis including phosphenes, and diplopia; fatigue; acute or chronic pain; and bladder and bowel difficulties; cognitive impairment of varying degrees; emotional symptoms of depression or unstable mood; Uhthoff’s phenomenon, which is an exacerbation of extant symptoms due to an exposure to higher than usual ambient temperatures; and Lhermitte's sign, which is an electrical sensation that runs down the back when bending the neck. Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)

[0414] Clinical Assessments

[0415] In some embodiments of the methods of treatment provided herein, the method comprises determining a score of one or more clinical assessments of the individual before and after the individual has received one or more doses of the anti-TREM2 antibody. In some embodiments, the clinical assessments are selected from Clinical Dementia Rating scale - Sum of Boxes (CDR-SB), changes from baseline in ADAS-Cogl4, changes from baseline in instrumental activities of daily living (iADL) on the ADCS-ADL scale, changes from baseline in ADAS- Cogl3, modified ADAS-Cogl4 and MMSE, changes from baseline in the Neuropsychiatric Inventory 12-item Scale (NPI-12), changes from baseline in the Functional Activities Questionnaire (FAQ) .In some embodiments, administration of an antibody of the disclosure results in an improvement or change in a score of the one or more clinical assessments compared to prior to administration of the anti-TREM2 antibody.

[0416] Soluble TREM2 Levels

[0417] As used herein, "soluble TREM2" or "sTREM2" refer to any form of TREM2 that results from processing, e.g., cleavage, of a TREM2 protein, resulting in a soluble, processed form of TREM2 as described herein. In some embodiments, sTREM2 refers to the portion of extra the extracellular domain of TREM2 that is released after sheddase cleavage.

[0418] The TREM2 cleavage site has been identified as occurring on the C-terminal side of Histidine 157 (see WO 2018 / 015573), and cleavage at that site leads to shedding of the relevant portion of the TREM2 extracellular domain, detectable as an increase in soluble TREM2 (sTREM2) corresponding to that portion of TREM2. In some embodiments, the sheddase cleavage site is between amino acids H157 and S158.

[0419] In some aspects, methods of the present disclosure comprise administering an anti-TREM2 antibody to an individual (e.g., an individual that has AD) intravenously, wherein administration of the anti-TREM2 antibody to the individual results in an increase in the levels of soluble TREM2 in the cerebrospinal fluid of the individual, compared to the levels of soluble TREM2 in the cerebrospinal fluid of the individual prior to administration of the anti- TREM2 antibody. In some embodiments, administration of the anti-TREM2 antibody to the individual (e.g., an individual that has AD) results in an increase of any of at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) at least about 85%, at least about 90%, at least about 95%, at least about 99%, or 100% in the levels of soluble TREM2 in the cerebrospinal fluid of the individual, compared to the levels of soluble TREM2 in the cerebrospinal fluid of the individual prior to administration of the anti- TREM2 antibody.

[0420] In some embodiments, administration of the anti-TREM2 antibody to the individual (e.g., an individual that has AD) results in an increase of any of at least about 110%, at least about 115%, at least about 120%, at least about 125%, at least about 130%, at least about 135%, at least about 140%, at least about 145%, at least about 150%, at least about 155%, at least about 160%, at least about 165%, at least about 170%, at least about 175%, at least about 180%, at least about 185%, at least about 190%, at least 195%, or at least about 200% in the levels of soluble TREM2 in the cerebrospinal fluid of the individual, compared to the levels of soluble TREM2 in the cerebrospinal fluid of the individual prior to administration of the anti-TREM2 antibody.

[0421] In some embodiments, the increase in the levels of soluble TREM2 in the cerebrospinal fluid of the individual compared to the levels of soluble TREM2 in the cerebrospinal fluid of the individual prior to administration of the anti-TREM2 antibody is present at about 2 days to about 12 days (e.g., any of 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, or 12 days) after administration of the antibody.

[0422] The levels of sTREM2 in the cerebrospinal fluid of the individual may be measured using any method known in the art, such as ELISA, immunoassays, immunoblotting, and mass spectrometry.

[0423] SPP1 (osteopontin) Levels

[0424] In some aspects, methods of the present disclosure comprise administering an anti-TREM2 antibody to an individual (e.g., an individual that has AD) intravenously, wherein administration of the anti-TREM2 antibody to the individual results in a decrease in the levels of SPP1 in the cerebrospinal fluid of the individual, compared to the levels of SPP1 in the cerebrospinal fluid of the individual prior to administration of the anti-TREM2 antibody. In some embodiments, administration of the anti-TREM2 antibody results in a decrease of any of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or about 100% in the levels of SPP1 in the cerebrospinal fluid of the individual, compared to the levels of SPP1 in the cerebrospinal fluid of the individual prior to administration of the anti- TREM2 antibody.

[0425] In some embodiments, the decrease in the levels of SPP1 in the cerebrospinal fluid of the individual, compared to the levels of SPP1 in the cerebrospinal fluid of the individual prior to administration of the anti-TREM2 antibody is present at about 2 days to about 12 days (e.g., any of 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, or 12 days) administration of the antibody.

[0426] The levels of SPP1 in the cerebrospinal fluid of the individual may be measured using any method known in the art, such as ELISA (e.g., an ELISA assay from R&D Systems), immunoassays, and immunoblotting.

[0427] Soluble CSF1R Levels

[0428] As used herein, "soluble CSF1R" or "sCSFIR" refer to any form of CSF IR that results from processing, e.g., cleavage, of CSF1R protein, resulting in a soluble, processed form of CSF1R.

[0429] In some aspects, methods of the present disclosure comprise administering an anti-TREM2 antibody to an individual (e.g., an individual that has AD) intravenously, wherein administration of the anti-TREM2 antibody to the individual results in a decrease in the levels of soluble CSF1R in the cerebrospinal fluid of the individual, compared to the levels of soluble CSF1R in the cerebrospinal fluid of the individual prior to administration of the anti- TREM2 antibody. In some embodiments, administration of the anti-TREM2 antibody results in a decrease of any of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or about 100% in the levels of soluble CSF1R in the cerebrospinal fluid of the individual, compared to the levels of soluble CSF1R in the cerebrospinal fluid of the individual prior to administration of the anti-TREM2 antibody.

[0430] In some embodiments, the decrease in the levels of soluble CSF1R in the cerebrospinal fluid of the individual, compared to the levels of soluble CSF1R in the cerebrospinal fluid of the individual prior to administration of the anti-TREM2 antibody is present at about 2 days to Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) about 12 days (e.g., any of 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, or 12 days) administration of the antibody.

[0431] The levels of sCSFIR in the cerebrospinal fluid of the individual may be measured using any method known in the art, such as ELISA (e.g., an ELISA assay from R&D Systems), immunoassays, immunoblotting.

[0432] CCL3 (MIP-la) Levels

[0433] In some aspects, methods of the present disclosure comprise administering an anti-TREM2 antibody to an individual (e.g., an individual that has AD) intravenously, wherein administration of the anti-TREM2 antibody to the individual results in a decrease in the levels of CCL3 in the cerebrospinal fluid of the individual, compared to the levels of CCL3 in the cerebrospinal fluid of the individual prior to administration of the anti-TREM2 antibody. In some embodiments, administration of the anti-TREM2 antibody results in a decrease of any of at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or about 100% in the levels of CCL3 in the cerebrospinal fluid of the individual, compared to the levels of CCL3 in the cerebrospinal fluid of the individual prior to administration of the anti-TREM2 antibody.

[0434] In some embodiments, the decrease in the levels of CCL3 in the cerebrospinal fluid of the individual, compared to the levels of CCL3 in the cerebrospinal fluid of the individual prior to administration of the anti-TREM2 antibody is present at about 2 days to about 12 days (e.g., any of 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, or 12 days) administration of the antibody.

[0435] The levels of CCL3 in the cerebrospinal fluid of the individual may be measured using any method known in the art, such as ELISA (e.g., an ELISA assay from R&D Systems), immunoassays, immunoblotting. Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)

[0436] Pharmaceutical Compositions

[0437] Therapeutic antibodies are typically formulated either in aqueous form ready for administration or as lyophilisate for reconstitution with a suitable diluent prior to administration. An anti- TREM2 antibody may be formulated either as a lyophilisate, or as an aqueous composition (solution), for example in pre-filled syringes. The formulation is also called drug product (DP).

[0438] Suitable formulation can provide an aqueous pharmaceutical composition (solution) or a lyophilisate which can be reconstituted to give a solution with a high concentration of the antibody active ingredient and a low level of antibody aggregation for delivery to a patient. High concentrations of antibody are useful as they reduce the amount of material which must be delivered to a patient. Reduced dosing volumes minimize the time taken to deliver a fixed dose to the patient. The aqueous compositions of the disclosure with high concentration of anti- TREM2 antibodies are particularly suitable for intravenous administration.

[0439] Thus, the disclosure provides an aqueous pharmaceutical composition, suitable for administration in a subject, e.g., for intravenous administration, comprising an antibody of the present disclosure, in particular VHB937.

[0440] An anti-TREM2 antibody disclosed herein may be used as a pharmaceutical composition when combined with a pharmaceutically acceptable carrier. Such a composition may contain, in addition to an anti-TREM2 antibody such as VHB937, carriers, various diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art. Accordingly, the anti-TREM2 antibody, e.g., VHB937, disclosed herein, may be formulated in a pharmaceutical composition suitable for administration to a subject, e.g., a human subject. In some embodiments, the pharmaceutical composition comprises the anti-TREM2 antibody and a pharmaceutically acceptable carrier. Suitable pharmaceutically acceptable carriers include any material that, when combined with an antibody disclosed herein, allows that antibody to retain its function and is generally non-reactive with the patient's immune system. Pharmaceutically acceptable carriers may include one or more diluents, fillers, salts, buffers, stabilizers, solubilizers, solvents, surfactants, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and other materials well known in the art.

[0441] A pharmaceutically acceptable carrier may be a carrier that is approved or approvable by a regulatory agency, e.g., of the Federal or a state government (e.g., EMA, US-FDA), or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia, for use in animals, and more particularly in humans. Examples of pharmaceutically acceptable carriers include but are Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) not limited to water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, mesylate salt, and the like, as well as combinations thereof. In some embodiments, the pharmaceutically acceptable carrier comprises isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride. Pharmaceutically acceptable carriers may further comprise auxiliary substances such as wetting or emulsifying agents, preservatives, or buffers, which enhance the shelf life or effectiveness of the antibody. In some embodiments, the characteristics of the carrier will depend on the route of administration. The pharmaceutical compositions for use in the disclosed methods may also contain additional therapeutic agents for treatment of the particular targeted disorder, e.g., Alzheimer’s disease (AD).

[0442] The pharmaceutical compositions described herein may be in a variety of forms. These include, for example, liquid, semi-solid, and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes, and suppositories. The preferred form depends on the intended mode of administration and therapeutic application. In some embodiments, the pharmaceutical composition is a liquid solution.

[0443] In some embodiments, components, concentrations of the same, and specific pH of the formulation(s) for the pharmaceutical composition comprising anti-TREM2 antibody or antigen-binding fragment thereof, e.g., VHB937, may be selected based on desired features, for example, stability over time, e.g., over 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more weeks, e.g., after 4 months of storage, or stability under certain conditions such as physical conditions (e.g., shaking), or freeze / thaw cycles.

[0444] In some embodiments, the present disclosure provides a pharmaceutical composition comprising an anti-TREM2 antibody described herein (e.g., VHB937), wherein the antibody is present in the pharmaceutical composition at a concentration of about 150 mg / mL. In some embodiments, the pharmaceutical composition comprises 150 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises 142.5 mg / mL to 157.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises 135 mg / mL mg / mL to 165 mg / mL of the anti-TREM2 antibody. In some embodiments, the anti-TREM2 antibody is VHB937. In some embodiments, the pharmaceutical composition comprises 127.5 mg / mL to 172.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises 128 mg / mL to 172 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises 128.5 mg / mL to 171.5 mg / mL of the anti-TREM2 antibody. In some embodiments, Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) the pharmaceutical composition comprises 129 mg / mL to 171 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises 129.5 mg / mL to

[0445] 170.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises 130 mg / mL to 170 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises 130.5 mg / mL to 169.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises 131 mg / mL to 169 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises 131.5 mg / mL to 168.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises 132 mg / mL to 168 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises

[0446] 132.5 mg / mL to 167.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises 133 mg / mL to 167 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises 133.5 mg / mL to

[0447] 166.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises 134 mg / mL to 166 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises 134.5 mg / mL to 165.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises 135 mg / mL to 165 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises 135.5 mg / mL to 164.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises 136 mg / mL to 164 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises

[0448] 136.5 mg / mL to 163.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises 137 mg / mL to 163 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises 137.5 mg / mL to

[0449] 162.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises 138 mg / mL to 162 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises 138.5 mg / mL to 161.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises 139 mg / mL to 161 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises 139.5 mg / mL to 160.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises 140 mg / mL to 160 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises

[0450] 140.5 mg / mL to 159.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises 141 mg / mL to 159 mg / mL of the anti-TREM2 Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) antibody. In some embodiments, the pharmaceutical composition comprises 141.5 mg / mL to

[0451] 158.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises 142 mg / mL to 158 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises 142.5 mg / mL to 157.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises 143 mg / mL to 157 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises 143.5 mg / mL to 156.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises 144 mg / mL to 156 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises

[0452] 144.5 mg / mL to 155.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises 145 mg / mL to 155 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises 145.5 mg / mL to

[0453] 154.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises 146 mg / mL to 154 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises 146.5 mg / mL to 153.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises 147 mg / mL to 153 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises 147.5 mg / mL to 152.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises 148 mg / mL to 152 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises

[0454] 148.5 mg / mL to 151.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises 149 mg / mL to 151 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises 149.5 mg / mL to

[0455] 150.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the anti-TREM2 antibody is VHB937. In some embodiments, the pharmaceutical composition comprises about 127.5 mg / mL to about 172.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about 128 mg / mL to about 172 mg / mL of the anti- TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about

[0456] 128.5 mg / mL to about 171.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about 129 mg / mL to about 171 mg / mL of the anti- TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about

[0457] 129.5 mg / mL to about 170.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about 130 mg / mL to about 170 mg / mL of the anti- TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)

[0458] 130.5 mg / mL to about 169.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about 131 mg / mL to about 169 mg / mL of the anti- TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about

[0459] 131.5 mg / mL to about 168.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about 132 mg / mL to about 168 mg / mL of the anti- TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about

[0460] 132.5 mg / mL to about 167.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about 133 mg / mL to about 167 mg / mL of the anti- TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about

[0461] 133.5 mg / mL to about 166.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about 134 mg / mL to about 166 mg / mL of the anti- TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about

[0462] 134.5 mg / mL to about 165.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about 135 mg / mL to about 165 mg / mL of the anti- TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about

[0463] 135.5 mg / mL to about 164.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about 136 mg / mL to about 164 mg / mL of the anti- TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about

[0464] 136.5 mg / mL to about 163.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about 137 mg / mL to about 163 mg / mL of the anti- TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about

[0465] 137.5 mg / mL to about 162.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about 138 mg / mL to about 162 mg / mL of the anti- TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about

[0466] 138.5 mg / mL to about 161.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about 139 mg / mL to about 161 mg / mL of the anti- TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about

[0467] 139.5 mg / mL to about 160.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about 140 mg / mL to about 160 mg / mL of the anti- TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about

[0468] 140.5 mg / mL to about 159.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about 141 mg / mL to about 159 mg / mL of the anti- TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about

[0469] 141.5 mg / mL to about 158.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) pharmaceutical composition comprises about 142 mg / mL to about 158 mg / mL of the anti- TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about

[0470] 142.5 mg / mL to about 157.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about 143 mg / mL to about 157 mg / mL of the anti- TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about

[0471] 143.5 mg / mL to about 156.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about 144 mg / mL to about 156 mg / mL of the anti- TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about

[0472] 144.5 mg / mL to about 155.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about 145 mg / mL to about 155 mg / mL of the anti- TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about

[0473] 145.5 mg / mL to about 154.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about 146 mg / mL to about 154 mg / mL of the anti- TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about

[0474] 146.5 mg / mL to about 153.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about 147 mg / mL to about 153 mg / mL of the anti- TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about

[0475] 147.5 mg / mL to about 152.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about 148 mg / mL to about 152 mg / mL of the anti- TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about

[0476] 148.5 mg / mL to about 151.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about 149 mg / mL to about 151 mg / mL of the anti- TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about

[0477] 149.5 mg / mL to about 150.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the anti-TREM2 antibody is VHB937.

[0478] In some embodiments, the pharmaceutical composition comprises 130 mg / mL of the anti- TREM2 antibody. In some embodiments, the pharmaceutical composition comprises 132.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises 135 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises 137.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises 140 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises 142.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises 145 mg / mL of the Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises

[0479] 147.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises 150 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises 152.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises 155 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises 157.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises 160 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises 162.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises 165 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises 167.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises 170 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises

[0480] 172.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about 130 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about 132.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about 135 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about 137.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about 140 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about 142.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about 145 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about 147.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about 150 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about 152.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about 155 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about 157.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about 160 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about 162.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about 165 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about 167.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) composition comprises about 170 mg / mL of the anti-TREM2 antibody. In some embodiments, the pharmaceutical composition comprises about 172.5 mg / mL of the anti-TREM2 antibody. In some embodiments, the anti-TREM2 antibody is VHB937. In some embodiments, the pharmaceutical composition comprises about 150 mg / mL of the anti-TREM2 antibody, In some embodiments, the pharmaceutical composition comprises 150 mg / mL of the anti-TREM2 antibody. In some embodiments, the anti-TREM2 antibody is VHB937.

[0481] In some embodiments, the pharmaceutical composition comprising an anti-TREM2 antibody described herein comprises or further comprises one or more surfactants or excipients. In some embodiments, the pharmaceutical composition comprises polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.2 mM to about 0.6 mM polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.2 mM, about 0.3 mM, about 0.4 mM, about 0.5 mM, or about 0.6 mM of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises about 0.2 mM to about 0.4 mM polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.4 mM to about 0.6 mM polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.3 mM to about 0.5 mM polysorbate-20.

[0482] In some embodiments, the pharmaceutical composition comprises about 0.16 mM of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.17 mM of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.18 mM of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.19 mM of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.2 mM of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.21 mM of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.22 mM of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.23 mM of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.24 mM of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.25 mM of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.26 mM of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.27 mM of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.28 mM of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.29 mM of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.3 mM of Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.31 mM of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.32 mM of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.33 mM of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.34 mM of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.35 mM of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.36 mM of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.37 mM of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.38 mM of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.39 mM of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.4 mM of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.41 mM of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.42 mM of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.43 mM of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.44 mM of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.45 mM of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.46 mM of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.47 mM of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.48 mM of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.49 mM of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.16 mM of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises 0.17 mM of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises 0.18 mM of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises 0.19 mM of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises 0.2 mM of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.21 mM of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises 0.22 mM of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises 0.23 mM of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises 0.24 mM of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises 0.25 mM of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises 0.26 mM of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises 0.27 mM of polysorbate- 20. In some Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) embodiments, the pharmaceutical composition comprises 0.28 mM of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises 0.29 mM of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises 0.3 mM of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.31 mM of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises 0.32 mM of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises 0.33 mM of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises 0.34 mM of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises 0.35 mM of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises 0.36 mM of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises 0.37 mM of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises 0.38 mM of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises 0.39 mM of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises 0.4 mM of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.41 mM of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises 0.42 mM of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises 0.43 mM of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises 0.44 mM of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises 0.45 mM of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises 0.46 mM of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises 0.47 mM of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises 0.48 mM of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises 0.49 mM of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises about 0.32 mM of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.32+ / - 10% mM of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.32 + / -5% mM of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.32 mM of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.33 mM of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.33+ / -10% mM of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.33 + / -5% mM of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.33 mM of polysorbate-20.

[0483] In some embodiments, the pharmaceutical composition comprises 0.16 mM to 0.49 mM of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.17 mM to Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)

[0484] 0.48 mM of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.18 mM to 0.47 mM of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises 0.19 mM to 0.46 mM of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.2 mM to 0.45 mM of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.21 mM to 0.44 mM of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises 0.22 mM to 0.43 mM of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.23 mM to 0.42 mM of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.24 mM to 0.41 mM of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises 0.25 mM to 0.4 mM of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.26 mM to 0.39 mM of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.27 mM to 0.38 mM of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises 0.28 mM to 0.37 mM of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.29 mM to 0.36 mM of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.3 mM to 0.35 mM of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.31 mM to 0.34 mM of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.32 mM to 0.33 mM of polysorbate-20.

[0485] A skilled person can appreciate that the concentration of a component of the pharmaceutical composition described herein, e.g., the active ingredient anti-TREM2 antibody, or any excipient, surfactant, or carrier, can be presented and described in any formats or units known in the art and is capable of converting the concentration of a component presented in one unit to its equivalent in another format or unit with, e.g., molecular weight of the component, for example, from mM to mg / mL, from mg / mL to w / v%, and vice versa, such equivalents of which are encompassed herein.

[0486] Accordingly, in some embodiments, the pharmaceutical composition comprises about 0.2 mg / mL to about 0.6 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.2 mg / mL, about 0.3 mg / mL, about 0.4 mg / mL, about 0.5 mg / mL, or about 0.6 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.4 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.4 + / -10% mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.4 + / -5% mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.4 mg / mL of polysorbate- Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)

[0487] 20. In some embodiments, the pharmaceutical composition comprises about 0.49 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.49 + / -10% mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.49 + / -5% mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.49 mg / mL of polysorbate-20.

[0488] In some embodiments, the pharmaceutical composition comprises about 0.17 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.18 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.19 mg / mL of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises about 0.2 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.21 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.22 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.23 mg / mL of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises about 0.24 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.25 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.26 mg / mL of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises about 0.27 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.28 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.29 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.3 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.31 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.32 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.33 mg / mL of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises about 0.34 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.35 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.36 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.37 mg / mL of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises about 0.38 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.39 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.4 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) comprises about 0.41 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.42 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.43 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.44 mg / mL of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises about 0.45 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.46 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.47 mg / mL of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises about 0.48 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.49 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.5 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.51 mg / mL of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises about 0.52 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.53 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.54 mg / mL of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises about 0.55 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.56 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.57 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.58 mg / mL of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises about 0.59 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.6 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.61 mg / mL of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises about 0.62 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.63 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.64 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.65 mg / mL of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises about 0.66 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.67 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.68 mg / mL of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises about 0.69 mg / mL of polysorbate-20. Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)

[0489] In some embodiments, the pharmaceutical composition comprises 0.17 mg / mL of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises 0.18 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.19 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.2 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.21 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.22 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.23 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.24 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.25 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.26 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.27 mg / mL of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises 0.28 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.29 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.3 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.31 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.32 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.33 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.34 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.35 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.36 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.37 mg / mL of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises 0.38 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.39 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.4 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.41 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.42 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.43 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.44 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.45 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.46 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.47 mg / mL of polysorbate- Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)

[0490] 20. In some embodiments, the pharmaceutical composition comprises 0.48 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.49 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.5 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.51 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.52 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.53 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.54 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.55 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.56 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.57 mg / mL of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises 0.58 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.59 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.6 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.61 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.62 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.63 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.64 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.65 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.66 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.67 mg / mL of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises 0.68 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.69 mg / mL of polysorbate-20.

[0491] In some embodiments, the pharmaceutical composition comprises 0.17 mg / mL to 0.63 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.18 mg / mL to 0.62 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.19 mg / mL to 0.61 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.2 mg / mL to 0.6 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.21 mg / mL to 0.59 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.22 mg / mL to 0.58 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) comprises 0.23 mg / mL to 0.57 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.24 mg / mL to 0.56 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.25 mg / mL to 0.55 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.26 mg / mL to 0.54 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.27 mg / mL to 0.53 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.28 mg / mL to 0.52 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.29 mg / mL to 0.51 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.3 mg / mL to 0.5 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.31 mg / mL to 0.49 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.32 mg / mL to 0.48 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.33 mg / mL to 0.47 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.34 mg / mL to 0.46 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.35 mg / mL to 0.45 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.36 mg / mL to 0.44 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.37 mg / mL to 0.43 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.38 mg / mL to 0.42 mg / mL of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.39 mg / mL to 0.41 mg / mL of polysorbate-20.

[0492] Concentration of a pharmaceutical composition component may also be described in w / v%. As used herein, a w / v percentage refers to the percentage of a component in the formulation calculated by weight of such component divided by formulation volume. A skilled person is capable of converting a concentration in another unit, e.g., mg / mL, to a w / v percentage concentration. For example, a concentration of 0.1 mg / mL is the equivalent of 0.01% (w / v). In some embodiments, the pharmaceutical composition comprises about 0.02% to about 0.06% of polysorbate-20(w / v). In some embodiments, the pharmaceutical composition comprises about 0.02%, about 0.03%, about 0.04%, about 0.05%, or 0.06% of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.04% of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.04% of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.049% of polysorbate- 20. Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)

[0493] In some embodiments, the pharmaceutical composition comprises about 0.017% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.018% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.019% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.02% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.021% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.022% (w / v) of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises about 0.023% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.024% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.025% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.026% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.027% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.028% (w / v) of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises about 0.029% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.03% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.031% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.032% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.033% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.034% (w / v) of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises about 0.035% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.036% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.037% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.038% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.039% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.04% (w / v) of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises about 0.041% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.042% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.043% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.044% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.045% (w / v) of polysorbate-20. In some Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) embodiments, the pharmaceutical composition comprises about 0.046% (w / v) of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises about 0.047% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.048% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.049% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.05% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.051% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.052% (w / v) of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises about 0.053% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.054% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.055% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.056% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.057% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.058% (w / v) of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises about 0.059% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.06% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.061% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.062% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.063% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.064% (w / v) of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises about 0.065% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.066% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.067% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.068% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises about 0.069% (w / v) of polysorbate-20.

[0494] In some embodiments, the pharmaceutical composition comprises 0.017% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.018% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.019% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.02% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) composition comprises 0.021% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.022% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.023% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.024% (w / v) of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises 0.025% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.026% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.027% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.028% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.029% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.03% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.031% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.032% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.033% (w / v) of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises 0.034% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.035% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.036% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.037% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.038% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.039% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.04% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.041% (w / v) of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises 0.042% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.043% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.044% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.045% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.046% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.047% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.048% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.049% (w / v) of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises 0.05% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.051% Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)

[0495] (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.052% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.053% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.054% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.055% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.056% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.057% (w / v) of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises 0.058% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.059% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.06% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.061% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.062% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.063% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.064% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.065% (w / v) of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises 0.066% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.067% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.068% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.069% (w / v) of polysorbate- 20.

[0496] In some embodiments, the pharmaceutical composition comprises 0.017% (w / v) to 0.063% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.018% (w / v) to 0.062% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.019% (w / v) to 0.061% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.02% (w / v) to 0.06% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.021% (w / v) to 0.059% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.022% (w / v) to 0.058% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.023% (w / v) to 0.057% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.024% (w / v) to 0.056% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.025% (w / v) to 0.055% (w / v) of polysorbate-20. In some Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) embodiments, the pharmaceutical composition comprises 0.026% (w / v) to 0.054% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.027% (w / v) to 0.053% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.028% (w / v) to 0.052% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.029% (w / v) to 0.051% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.03% (w / v) to 0.05% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.031% (w / v) to 0.049% (w / v) of polysorbate- 20. In some embodiments, the pharmaceutical composition comprises 0.032% (w / v) to 0.048% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.033% (w / v) to 0.047% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.034% (w / v) to 0.046% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.035% (w / v) to 0.045% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.036% (w / v) to 0.044% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.037% (w / v) to 0.043% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.038% (w / v) to 0.042% (w / v) of polysorbate-20. In some embodiments, the pharmaceutical composition comprises 0.039% (w / v) to 0.041% (w / v) of polysorbate-20.

[0497] In some embodiments, the pharmaceutical composition comprising an anti-TREM2 antibody described herein comprises histidine, wherein the histidine is present in the pharmaceutical composition at a concentration of 10 mM to 50 mM. In some embodiments, the pharmaceutical composition comprises 20 mM to 50 m histidine. In some embodiments, the pharmaceutical composition comprises 10 mM to 40 mM histidine. In some embodiments, the pharmaceutical composition comprises 10 mM to 30 mM histidine. In some embodiments, the pharmaceutical composition comprises 10 mM to 35 mM histidine. In some embodiments, the pharmaceutical composition comprises 20 mM to 40 mM histidine. In some embodiments, the pharmaceutical composition comprises 15 mM to 35 mM histidine. In some embodiments, the pharmaceutical composition comprises lOmM to 30 mM histidine. In some embodiments, the pharmaceutical composition comprises 15mM to 25mM histidine. In some embodiments, the pharmaceutical composition comprises 18 mM to 22 mM histidine. In some embodiments, the pharmaceutical composition comprises 19 mM to 21 mM histidine. In some embodiments, the pharmaceutical composition comprises about 10 mM, about 15 mM, about 20 mM, about 25 mM, about 30 Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) mM, about 35 mM, about 40 mM, about 45 mM, or about 50 mM histidine. In some embodiments, the pharmaceutical composition comprises 10 mM, 15 mM, 20 mM, 25 mM, 30 mM, 35 mM, 40 mM, 45 mM, or 50 mM histidine. In some embodiments, the pharmaceutical composition comprises 10 + / -10% mM, 15 + / -10% mM, 20 + / -10% mM, 25 + / -10% mM, 30 + / -10% mM, 35 + / -10% mM, 40 + / -10% mM, 45 + / -10% mM, or 50 + / -10% mM histidine. In some embodiments, the pharmaceutical composition comprises 10 + / -5% mM, 15 + / -5% mM, 20 +1-5% mM, 25 +1-5% mM, 30 +1-5% mM, 35 +1-5% mM, 40 +1-5% mM, 45 +1-5% mM, or 50 + / -5% mM histidine. In some embodiments, the pharmaceutical composition comprises about 22 mM, about 21 mM, about 20 mM, about 19 mM, or about 18 mM histidine. In some embodiments, the pharmaceutical composition comprises 22 mM, 21 mM, 20 mM, 19 mM, or 18 mM histidine. In some embodiments, the pharmaceutical composition comprises 22+ / -10% mM, 21+ / -10% mM, 20+ / -10% mM, 19+ / -10% mM, or 18 + / -10% mM histidine. In some embodiments, the pharmaceutical composition comprises 22+ / -5% mM, 21+ / -5% mM, 20+ / - 5% mM, 19+ / -5% mM, or 18 + / -5% mM histidine. In some embodiments, the pharmaceutical composition comprises about 20 mM histidine. In some embodiments, the pharmaceutical composition comprises 20 + / -10% mM histidine. In some embodiments, the pharmaceutical composition comprises 20 + / -5% mM histidine. In some embodiments, the pharmaceutical composition comprises 20 mM histidine.

[0498] In some embodiments, the pharmaceutical composition comprises 3.1 mg / mL to 7.76 mg / mL histidine. In some embodiments, the pharmaceutical composition comprises 1.55 mg / mL to 6.21 mg / mL histidine. In some embodiments, the pharmaceutical composition comprises 1.55 mg / mL to 4.65 mg / mL histidine. In some embodiments, the pharmaceutical composition comprises 1.55 mg / mL to 5.43 mg / mL histidine. In some embodiments, the pharmaceutical composition comprises 3.1 mg / mL to 6.21 mg / mL histidine. In some embodiments, the pharmaceutical composition comprises 2.33 mg / mL to 5.43 mg / mL histidine. In some embodiments, the pharmaceutical composition comprises 1.55 mg / mL to 4.65 mg / mL histidine. In some embodiments, the pharmaceutical composition comprises 2.33 mg / mL to 3.88 mg / mL histidine. In some embodiments, the pharmaceutical composition comprises 2.79 mg / mL to 3.41 mg / mL histidine. In some embodiments, the pharmaceutical composition comprises 2.95 mg / mL to 3.26 mg / mL histidine. In some embodiments, the pharmaceutical composition comprises about 1.55 mg / mL, about 2.33 mg / mL, about 3.1 mg / mL, about 3.88 mg / mL, about 4.65 mg / mL, about 5.43 mg / mL, about 6.21 mg / mL, about 6.98 mg / mL, or about 7.76 mg / mL histidine. Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)

[0499] In some embodiments, the pharmaceutical composition comprises 2.95 mg / mL to 3.26 mg / mL histidine. In some embodiments, the pharmaceutical composition comprises about 1.55 mg / mL, about 2.33 mg / mL, about 3.1 mg / mL, about 3.88 mg / mL, about 4.65 mg / mL, about 5.43 mg / mL, about 6.21 mg / mL, about 6.98 mg / mL, or about 7.76 mg / mL histidine.

[0500] In some embodiments, the pharmaceutical composition...

Claims

1. Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)CLAIMS1. A method of treating a disease or disorder in a patient comprising intravenously administering to the patient a therapeutically effective amount of an anti-TREM2 antibody at a dose of about 1 mg / kg to about 60 mg / kg.

2. The method of claim 1 , wherein the anti-TREM2 antibody binds to the immunoglobulin superfamily (IgSF) domain of human TREM2.

3. The method of claim 1 or 2, wherein the anti-TREM2 antibody binds soluble TREM2 (sTREM2).

4. The method of anyone of claims 1-3, wherein the antibody comprises a heavy chain variable region comprising a CDR-H1, CDR-H2, and CDR-H3 and a light chain variable region comprising a CDR-L1, CDR-L2, and CDR-L3, wherein:(i) the CDR-H1 comprises the amino acid sequence SEQ ID NO: 4, the CDR-H2 comprises the amino acid sequence SEQ ID NO: 5, the CDR-H3 comprises the amino acid sequence SEQ ID NO: 6, the CDR-L1 comprises the amino acid sequence SEQ ID NO: 17, the CDR-L2 comprises the amino acid sequence SEQ ID NO: 18, and the CDR-L3 comprises the amino acid sequence SEQ ID NO: 19, as defined by the Combined numbering system; or(ii) the CDR-H1 comprises the amino acid sequence SEQ ID NO: 7, the CDR-H2 comprises the amino acid sequence SEQ ID NO: 5, the CDR-H3 comprises the amino acid sequence SEQ ID NO: 6, the CDR-L1 comprises the amino acid sequence SEQ ID NO: 17, the CDR-L2 comprises the amino acid sequence SEQ ID NO: 18, and the CDR-L3 comprises the amino acid sequence SEQ ID NO: 19, as defined by the Kabat numbering system; or(iii) the CDR-H1 comprises the amino acid sequence SEQ ID NO: 8, the CDR-H2 comprises the amino acid sequence SEQ ID NO: 9, the CDR-H3 comprises the amino acid sequence SEQ ID NO: 6, the CDR-L1 comprises the amino acid sequence SEQ ID NO: 20, the CDR-L2 comprises the amino acid sequence SEQ ID NO: 21, and the CDR-L3 comprises the amino acid sequence SEQ ID NO: 22, as defined by the Chothia numbering system; or(iv) the CDR-H1 comprises the amino acid sequence SEQ ID NO: 10, the CDR-H2 comprises the amino acid sequence SEQ ID NO: 11, the CDR-H3 comprises the amino acid sequence SEQ ID NO: 12, the CDR-L1 comprises the amino acid sequence SEQ ID NO: 23, the CDR-L2 comprises the amino acid sequence SEQ ID NO: 21, and the CDR-L3 comprises the amino acid sequence SEQ ID NO: 19, as defined by the IMGT numbering system.Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)5. The method of any one of claims 1-4, wherein the dose is about 10 mg / kg to about 30 mg / kg.

6. The method of any one of claims 1-5, wherein the dose is about 10 mg / kg.

7. The method of any one of claims 1-5, wherein the dose is about 30 mg / kg.

8. The method of any one of claims 1-7, wherein the anti-TREM2 antibody is administered about once every four weeks.

9. The method of any one of claims 1-7, wherein the anti-TREM2 antibody is administered about once every month.

10. The method of any one of claims 1-7, wherein the anti-TREM2 antibody is administered once every four weeks.

11. The method of any one of claims 1-7, wherein the anti-TREM2 antibody is administered once every month.

12. The method of any one of claims 1-7, wherein the anti-TREM2 antibody is administered once every 25-31 days.

13. The method of any one of claims 1-6 or 8, wherein the anti-TREM2 antibody is administered about once every four weeks at a dose of about 10 mg / kg.

14. The method of any one of claims 1-6 or 9, wherein the anti-TREM2 antibody is administered about once every month at a dose of about 10 mg / kg.

15. The method of any one of claims 1-6 or 12, wherein the anti-TREM2 antibody is administered once every 25-31 days at a dose of about 10 mg / kg.

16. The method of any one of claims 1-6, 7 or 8, wherein the anti-TREM2 antibody is administered about once every four weeks at a dose of about 30 mg / kg.

17. The method of any one of claims 1-6, 7 or 9, wherein the anti-TREM2 antibody is administered about once every month at a dose of about 30 mg / kg.

18. The method of any one of claims 1-6, 7 or 12, wherein the anti-TREM2 antibody is administered once every 25-31 days at a dose of about 30 mg / kg.Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)19. The method of any one of claims 1-18, wherein the antibody comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 13 and a light chain variable region (VL) comprising the amino acid sequence of SEQ ID NO: 24.

20. The method of any one of claims 1-19, wherein the antibody has a human IgGl isotype.

21. The method of any one of claims 1-20, wherein the antibody has a human IgGl isotype and comprises M428L / N434S (LS) and / or D265A / P329A (DAP A) amino acid substitutions in the Fc region, wherein the numbering of the residues is according to EU numbering.

22. The method of any one of claims 1-21, wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 37, and a light chain comprising the amino acid sequence of SEQ ID NO: 26.

23. The method of any one of claims 1-22, wherein the disease or disorder is a neurological disease or disorder.

24. The method of any one of claims 1-23, wherein the neurological disease or disorder is a neurodegenerative disease or disorder.

25. The method according to any of claims 1-24, wherein the disease or disorder is selected from the group consisting of Alzheimer’s disease, frontotemporal dementia, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), Huntington’s disease, Nasu-Hakola disease, multiple sclerosis, a demyelination disorder, vascular dementia, progressive supranuclear palsy (PSP), multi-system atrophy (MSA), Lewy Body dementia (LBD), cortico-basal dementia (CBD), adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), a tauopathy disease, anti-NMDA receptor encephalitis, brain lupus (NP-SLE), chemo-induced peripheral neuropathy (CIPN), postherpetic neuralgia, chronic inflammatory demyelinating polyneuropathy (CIDP), Guillain-Barre Syndrome (GBS), inclusion body myositis, lysosomal storage diseases, sphingomyelinlipidose (Niemann-Pick C), mucopolysaccharidose II / IIIB, metachromatic leukodystrophy, multifocal motor neuropathy, myasthenia gravis, NeuroBehcet’s Disease, neuromyelitis optica (NMO), optic neuritis, polymyositis, dermatomyositis, Rasmussen’s encephalitis, Rett’s Syndrome, stroke, transverse myelitis, traumatic brain injury, spinal cord injury, viral encephalitis, and bacterial meningitis.Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)26. The method of any one of claims 1-25, wherein the disease or disorder is Alzheimer’s disease (AD).

27. The method of claim 26, wherein the disease or disorder is early AD.

28. The method of claim 26 or 27, wherein the patient has symptoms of Alzheimer's disease prior to administration of the anti-TREM2 antibody.

29. The method of any one of claims 26-28, wherein the patient is diagnosed with mild cognitive impairment (MCI) due to AD or mild AD.

30. The method of any one of claims 26-29, wherein the patient is heterozygous or homozygous for a mutation in TREM2.

31. The method of any one of claims 26-30, wherein the patient comprises an amino acid substitution in a human TREM2 protein at residue position R47H, R62H, or both compared to a wildtype hTREM2 protein.

32. The method of any one of claims 26-31, wherein the anti-TREM2 antibody treatment results in a change from baseline in the Clinical Dementia Rating scale - Sum of Boxes (CDR- SB).

33. The method of any of claims 26-32, wherein the wherein the anti-TREM2 antibody treatment results in one or more of: changes from baseline in ADAS-Cogl4; or changes from baseline in instrumental activities of daily living (iADL) on the ADCS- ADL scale.

34. The method of any one of claims 26-33, wherein the anti-TREM2 antibody treatment results in one or more of: changes from baseline in ADAS-Cogl3, modified ADAS-Cogl4 and MMSE; changes from baseline in the Neuropsychiatric Inventory 12-item Scale (NPI-12); or changes from baseline in the Functional Activities Questionnaire (FAQ).

35. The method of any one of claims 26-34, wherein the anti-TREM2 antibody treatment results in a change in one or more of:Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) amount of total soluble Triggering receptor expressed on myeloid cells 2 (sTREM2) in a bodily fluid typically serum, plasma or CSF, preferably serum; amount of one or more inflammatory biomarkers in a bodily fluid typically serum, plasma or CSF, optionally wherein the one or more inflammatory biomarkers comprise one or more of CSF sCSFIR or CSF SPP1 (osteopontin) or CSF CCL3, or wherein the one or more inflammatory biomarkers additionally or alternatively comprise one or more: CSF biomarkers YKL-40, IL6, IL-18, CXCL10, CCL2, TIMP-1; amount of one or more inflammatory biomarkers in a bodily fluid typically serum, plasma or CSF, optionally wherein the one or more inflammatory biomarkers comprise one or more of blood p-tau, NfL, and GFAP; and amount of one or more of CSF levels of Ap40, Ap42, Ap42 / Ap40 ratio, total-tau, p- tau species, neurogranin.

36. The method of any of claims 26-35, wherein the anti-TREM2 antibody treatment results in changes from baseline in volumes of specific brain regions as measured by MRI.

37. The method of any one of claims 26-36, further comprising performing tau or amyloid positron emission tomography (PET) imaging assessments in the patient before and after the patient has received one or more doses of the anti-TREM2 antibody.

38. The method of any one of claims 26-37, further comprising assessing the patient for Amyloid Related Imaging Abnormality (ARIA), vasogenic brain edema, or new cerebral micro-hemorrhage.

39. The method of any one of claims 1-38, further comprising measuring the levels of soluble TREM2 in a sample of blood, plasma, and / or cerebrospinal fluid from the patient before and after the patient has received one or more doses of the anti-TREM2 antibody.

40. The method of any one of claims 1-39, further comprising measuring the levels of soluble CSF1R in a sample of blood, plasma, and / or cerebrospinal fluid from the patient before and after the patient has received one or more doses of the anti-TREM2 antibody.

41. The method of claim 40, wherein the levels of soluble CSF1R in the cerebrospinal fluid of the patient are measured in a sample of cerebrospinal fluid obtained from the patient using an ELISA assay.Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)42. The method of any one of claims 1-41, further comprising measuring the level of SPP1 (osteopontin) in a sample of cerebrospinal fluid from the patient before and after the patient has received one or more doses of the anti-TREM2 antibody.

43. The method of any one of claims 1-42, further comprising measuring the levels of one or more biomarkers of neurodegeneration in a sample of blood, plasma, serum and / or cerebrospinal fluid from the patient before and after the patient has received one or more doses of the anti-TREM2 antibody.

44. The method of claim 43, wherein the one or more biomarkers of neurodegeneration comprises or consists of neurofilament light (NfL).

45. The method of any one of claims 1-44, further comprising measuring the levels of one or more biomarkers of AD in a sample of blood, plasma, and / or cerebrospinal fluid from the patient before and after the patient has received one or more doses of the anti-TREM2 antibody.

46. The method of claim 45, wherein said one or more biomarkers comprises one or more of:YKL-40, IL6, IL-18, CXCL10, CCL2, TIMP-1; blood p-tau, NfL, GFAP; andCSF levels of Ap40, Ap42, AP42 / AP40 ratio, total-tau, p-tau species, neurogranin.

47. The method of any one of claims 1-46, wherein the anti-TREM2 antibody treatment results in soluble TREM2 (sTREM2) bound to the antibody in the cerebrospinal fluid and / or serum of the patient.

48. The method of any one of claims 1-47, wherein the anti-TREM2 antibody treatment results in an increase in soluble TREM2 (sTREM2) in the cerebrospinal fluid, blood, serum or plasma of the patient, optionally wherein anti-TREM2 antibody treatment results in a sTREM2 level that is about 10%, 15%, 20%, 25%, 30%, 35%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% higher as compared to the sTREM2 level in the cerebrospinal fluid, blood, serum or plasma of the patient prior to the treatment.

49. The method of claim 47 or 48, wherein the total levels of soluble TREM2, being the sum of free sTREM2 and sTREM2 bound to the anti-TREM2 antibody, in the serum and / or cerebrospinal fluid of the patient are measured using an electrochemiluminescent assay on a sample of cerebrospinal fluid and / or serum obtained from the patient.Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)50. The method of any one of claims 1-49, wherein the anti-TREM2 antibody treatment results in a decrease, optionally by at least 5%, in the levels of soluble CSF1R in the cerebrospinal fluid of the patient, compared to the levels of soluble CSF1R in the cerebrospinal fluid of the patient prior to administration of the anti-TREM2 antibody.

51. The method of any one of claims 1-49, wherein the anti-TREM2 antibody treatment results in a decrease in the levels of soluble CSF1R in the cerebrospinal fluid, blood, serum or plasma of the patient, by 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more compared to the levels of soluble CSF1R in the cerebrospinal fluid, blood, serum or plasma of the patient prior to administration of the anti- TREM2 antibody.

52. The method of any one of claims 1-49, wherein the anti-TREM2 antibody treatment results in a decrease in the levels of SSP1 (osteopontin) in the cerebrospinal fluid, blood, serum or plasma of the patient, by 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more compared to the levels of SSP1 in the cerebrospinal fluid, blood, serum or plasma of the patient prior to administration of the anti- TREM2 antibody.

53. The method of any one of claims 1-49, wherein the anti-TREM2 antibody treatment results in a decrease in the levels of CCL3 (MIPla) in the cerebrospinal fluid, blood, serum or plasma of the patient, by 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more compared to the levels of CCL3 in the cerebrospinal fluid, blood, serum or plasma of the patient prior to administration of the anti-TREM2 antibody.

54. The method of any one of claims 32-53, wherein the treatment results are after 40 weeks, after 60 weeks or more, or 100 weeks or more.

55. The method of any one of claims 32-53, wherein the treatment results are after 18 months or more after administration.

56. The method of any one of claims 54-55, wherein the decrease in the levels of CCL3 or SSP1 in the cerebrospinal fluid, blood, serum or plasma of the patient is present at about 12 weeks after administration of the anti-TREM2 antibody.Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)57. The method of claim 54 or 55, wherein the increase in the levels of sTREM2 in the cerebrospinal fluid, blood, serum or plasma of the patient is present at about 12 weeks after administration of the anti-TREM2 antibody.

58. The method of any one of claims 1-57, wherein the administration is about every four weeks.

59. The method of any one of claims 1-57, wherein the administration is about every month.

60. The method of any one of claims 1-57, wherein the administration is every 25-31 days.

61. The method of any one of claims 1-60, wherein the anti-TREM2 antibody is administered by intravenous infusion at a dose of about 30 mg / kg at a frequency of about once every four weeks, wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 37, and a light chain comprising the amino acid sequence of SEQ ID NO: 26, and wherein the disease or disorder is Alzheimer’s disease.

62. The method of any one of claims 1-60, wherein the antibody is administered by intravenous infusion at a dose of about 10 mg / kg at a frequency of about once every four weeks, wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 37, and a light chain comprising the amino acid sequence of SEQ ID NO: 26, and wherein the disease or disorder is Alzheimer’s disease.

63. The method of any one of claims 1-60, wherein the anti-TREM2 antibody is administered by intravenous infusion at a dose of about 30 mg / kg at a frequency of once every four weeks, wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 37, and a light chain comprising the amino acid sequence of SEQ ID NO: 26, and wherein the disease or disorder is Alzheimer’s disease.

64. The method of any one of claims 1-60, wherein the antibody is administered by intravenous infusion at a dose of about 10 mg / kg at a frequency of once every four weeks, wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 37, and a light chain comprising the amino acid sequence of SEQ ID NO: 26, and wherein the disease or disorder is Alzheimer’s disease.

65. The method of any one of claims 1-60, wherein the anti-TREM2 antibody is administered by intravenous infusion at a dose of about 30 mg / kg at a frequency of once everyAttorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) month, wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 37, and a light chain comprising the amino acid sequence of SEQ ID NO: 26, and wherein the disease or disorder is Alzheimer’s disease.

66. The method of any one of claims 1-60, wherein the antibody is administered by intravenous infusion at a dose of about 10 mg / kg at a frequency of once every month, wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 37, and a light chain comprising the amino acid sequence of SEQ ID NO: 26, and wherein the disease or disorder is Alzheimer’s disease.

67. The method of any one of claims 1-60, wherein the anti-TREM2 antibody is administered by intravenous infusion at a dose of about 30 mg / kg at a frequency of once every 25-31 days, wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 37, and a light chain comprising the amino acid sequence of SEQ ID NO: 26, and wherein the disease or disorder is Alzheimer’s disease.

68. The method of any one of claims 1-60, wherein the antibody is administered by intravenous infusion at a dose of about 10 mg / kg at a frequency of once every 25-31 days, wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 37, and a light chain comprising the amino acid sequence of SEQ ID NO: 26, and wherein the disease or disorder is Alzheimer’s disease.

69. A method of monitoring the treatment of a patient being administered an anti-TREM2 antibody, comprising measuring the levels of soluble TREM2 (sTREM2) in a sample of cerebrospinal fluid, blood, serum or plasma from the patient before and after the patient has received one or more doses of an anti-TREM2 antibody, wherein an increase in total sTREM2 is indicative of treatment.

70. A method of monitoring the treatment of a patient being administered an anti-TREM2 antibody, comprising measuring the levels of soluble CSF1R in a sample of cerebrospinal fluid, blood, serum or plasma from the patient before and after the patient has received one or more doses of an anti-TREM2 antibody, wherein the anti-TREM2 antibody is determined to be active in the patient if the levels of soluble CSF1R in the sample of cerebrospinal fluid, blood, serum or plasma are decreased after the patient has received one or more doses of the anti- TREM2 antibody, compared to the levels of soluble CSF1R in the sample of cerebrospinal fluid, blood, serum or plasma before the patient received a dose of the anti-TREM2 antibody.Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)71. A method of monitoring the treatment of a patient being administered an anti-TREM2 antibody, comprising measuring the levels of SPP1 (osteopontin) in a sample of cerebrospinal fluid, blood, or plasma from the patient before and after the patient has received one or more doses of an anti-TREM2 antibody, wherein the anti-TREM2 antibody is determined to be active in the patient if the levels of SPP1 in the sample of cerebrospinal fluid, blood, serum or plasma are decreased after the patient has received one or more doses of the anti-TREM2 antibody, compared to the levels of SPP1 in the sample of cerebrospinal fluid, blood, or plasma before the patient received a dose of the anti-TREM2 antibody.

72. A method of monitoring the treatment of a patient being administered an anti-TREM2 antibody, comprising measuring the levels of CCL3 (MIPla) in a sample of cerebrospinal fluid, blood, serum or plasma from the patient before and after the patient has received one or more doses of an anti-TREM2 antibody, wherein the anti-TREM2 antibody is determined to be active in the patient if the levels of CCL3 in the sample of cerebrospinal fluid, blood, or plasma are decreased after the patient has received one or more doses of the anti-TREM2 antibody, compared to the levels of CCL3 in the sample of cerebrospinal fluid, blood, or plasma before the patient received a dose of the anti-TREM2 antibody.

73. The method of any one of claims 1-72, wherein the anti-TREM2 antibody activates TREM2.

74. The method of any one of claims 1-73, wherein the antibody is a monoclonal antibody.

75. A method of treating a disease or disorder in a patient according to any of claims 1 to74, wherein the patient is not homozygous for the APOE4 gene.

76. A method of treating a disease or disorder in a patient according to any of claims 1 to75, wherein the patient is heterozygous for the APOE4 gene.

77. A method of treating a disease or disorder in a patient according to any of claims 1 to76, wherein the patient is tested for APOE4 homozygosity prior to treatment.

78. A method of treating a disease or disorder in a patient according to any of claims 1 to77, wherein the patient is assessed for Amyloid related imaging abnormalities (ARIA) during the treatment, optionally where the ARIA assessment is through magnetic resonance imaging (MRI).Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)79. The method of any one of claims 75-78, wherein the patient has Alzheimer’s disease.

80. The method of claim 79, wherein the patient develops asymptomatic and radiographically mild ARIA-E or ARIA-H on MRI and continues to be administered the anti- TREM2 antibody.

81. The method of claim 79, wherein the patient that develops mild to moderate symptoms or radiographically moderate / severe ARIA-E will not be administered at least the next scheduled dose of the anti-TREM2 antibody.

82. The method of claim 79, wherein the patient that develops mild / moderate symptoms OR radiographically moderate ARIA-H will not be administered at least the next scheduled dose of the anti-TREM2 antibody.

83. The method of claim 79, wherein the patient that develops radiographically severe ARIA-H regardless of symptoms will not be administered at least the next scheduled dose of the anti-TREM2 antibody.

84. A pharmaceutical composition comprising:(i) an anti-TREM2 antibody at a concentration of 150 mg / mL,(ii) histidine at a concentration of 20 mM,(iii) sucrose at a concentration of 220 mM, and(iv) polysorbate-20 at a concentration of 0.4 mM.

85. A pharmaceutical composition according to claim 84, wherein the composition has a pH of 5.5.

86. A pharmaceutical composition of claim 84 or 85, wherein the antibody comprises a heavy chain variable region comprising a CDR-H1, CDR-H2, and CDR-H3 and a light chain variable region comprising a CDR-L1, CDR-L2, and CDR-L3, wherein:(i) the CDR-H1 comprises the amino acid sequence SEQ ID NO: 4, the CDR-H2 comprises the amino acid sequence SEQ ID NO: 5, the CDR-H3 comprises the amino acid sequence SEQ ID NO: 6, the CDR-L1 comprises the amino acid sequence SEQ ID NO: 17, the CDR-L2 comprises the amino acid sequence SEQ ID NO: 18, and the CDR-L3 comprises the amino acid sequence SEQ ID NO: 19, as defined by the Combined numbering system; orAttorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)(ii) the CDR-H1 comprises the amino acid sequence SEQ ID NO: 7, the CDR-H2 comprises the amino acid sequence SEQ ID NO: 5, the CDR-H3 comprises the amino acid sequence SEQ ID NO: 6, the CDR-L1 comprises the amino acid sequence SEQ ID NO: 17, the CDR-L2 comprises the amino acid sequence SEQ ID NO: 18, and the CDR-L3 comprises the amino acid sequence SEQ ID NO: 19, as defined by the Kabat numbering system; or(iii) the CDR-H1 comprises the amino acid sequence SEQ ID NO: 8, the CDR-H2 comprises the amino acid sequence SEQ ID NO: 9, the CDR-H3 comprises the amino acid sequence SEQ ID NO: 6, the CDR-L1 comprises the amino acid sequence SEQ ID NO: 20, the CDR-L2 comprises the amino acid sequence SEQ ID NO: 21, and the CDR-L3 comprises the amino acid sequence SEQ ID NO: 22, as defined by the Chothia numbering system; or(iv) the CDR-H1 comprises the amino acid sequence SEQ ID NO: 10, the CDR-H2 comprises the amino acid sequence SEQ ID NO: 11, the CDR-H3 comprises the amino acid sequence SEQ ID NO: 12, the CDR-L1 comprises the amino acid sequence SEQ ID NO: 23, the CDR-L2 comprises the amino acid sequence SEQ ID NO: 21, and the CDR-L3 comprises the amino acid sequence SEQ ID NO: 19, as defined by the IMGT numbering system.

87. An anti-TREM2 antibody for use in a method of treating a patient according to a method of any one of claims 1-86.

88. Use of an anti-TREM2 antibody in the manufacture of a medicament for treating a patient according to a method of any one of claims 1-86.

89. A pharmaceutical composition for use in a method of any one of claims 1-83.

90. A pharmaceutical composition comprising:(i) about 150 mg / mL of an anti-TREM2 antibody;(ii) about 20 mM histidine;(iii) about 220 mM sucrose; and(iv) about 0.4 mg / mL polysorbate-20.

91. A pharmaceutical composition comprising:(i) 135 mg / mL to 165 mg / mL of an anti-TREM2 antibody;(ii) 2.79 to 3.41 mg / mL histidine,(iii) 67.78 mg / mL to 82.84 mg / mL sucrose, and(iv) 0.2 mg / mL to 0.6 mg / mL polysorbate-20.

92. A pharmaceutical composition comprising:Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)(i) 150 mg / mL of an anti-TREM2 antibody;(ii) 20 m histidine;(iii) 220 mM sucrose; and(iv) 0.4 mg / mL polysorbate-20.

93. The pharmaceutical composition of any one of claims 90-92, wherein the antibody comprises a heavy chain variable region comprising a CDR-H1, CDR-H2, and CDR-H3 and a light chain variable region comprising a CDR-L1, CDR-L2, and CDR-L3, wherein:(i) the CDR-H1 comprises the amino acid sequence SEQ ID NO: 4, the CDR-H2 comprises the amino acid sequence SEQ ID NO: 5, the CDR-H3 comprises the amino acid sequence SEQ ID NO: 6, the CDR-L1 comprises the amino acid sequence SEQ ID NO: 17, the CDR-L2 comprises the amino acid sequence SEQ ID NO: 18, and the CDR-L3 comprises the amino acid sequence SEQ ID NO: 19, as defined by the Combined numbering system; or(ii) the CDR-H1 comprises the amino acid sequence SEQ ID NO: 7, the CDR-H2 comprises the amino acid sequence SEQ ID NO: 5, the CDR-H3 comprises the amino acid sequence SEQ ID NO: 6, the CDR-L1 comprises the amino acid sequence SEQ ID NO: 17, the CDR-L2 comprises the amino acid sequence SEQ ID NO: 18, and the CDR-L3 comprises the amino acid sequence SEQ ID NO: 19, as defined by the Kabat numbering system; or(iii) the CDR-H1 comprises the amino acid sequence SEQ ID NO: 8, the CDR-H2 comprises the amino acid sequence SEQ ID NO: 9, the CDR-H3 comprises the amino acid sequence SEQ ID NO: 6, the CDR-L1 comprises the amino acid sequence SEQ ID NO: 20, the CDR-L2 comprises the amino acid sequence SEQ ID NO: 21, and the CDR-L3 comprises the amino acid sequence SEQ ID NO: 22, as defined by the Chothia numbering system; or(iv) the CDR-H1 comprises the amino acid sequence SEQ ID NO: 10, the CDR-H2 comprises the amino acid sequence SEQ ID NO: 11, the CDR-H3 comprises the amino acid sequence SEQ ID NO: 12, the CDR-L1 comprises the amino acid sequence SEQ ID NO: 23, the CDR-L2 comprises the amino acid sequence SEQ ID NO: 21, and the CDR-L3 comprises the amino acid sequence SEQ ID NO: 19, as defined by the IMGT numbering system.

94. The pharmaceutical composition of any one of claims 90-92, wherein the antibody comprises a heavy chain variable region comprising a CDR-H1, CDR-H2, and CDR-H3 and a light chain variable region comprising a CDR-L1, CDR-L2, and CDR-L3, wherein: the CDR-H1 comprises the amino acid sequence SEQ ID NO: 7, the CDR-H2 comprises the amino acid sequence SEQ ID NO: 5, the CDR-H3 comprises the amino acidAttorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304) sequence SEQ ID NO: 6, the CDR-L1 comprises the amino acid sequence SEQ ID NO: 17, the CDR-L2 comprises the amino acid sequence SEQ ID NO: 18, and the CDR-L3 comprises the amino acid sequence SEQ ID NO: 19, as defined by the Kabat numbering system.

95. The pharmaceutical composition of any one of claims 90-92, wherein the antibody comprises a heavy chain variable region comprising a CDR-H1, CDR-H2, and CDR-H3 and a light chain variable region comprising a CDR-L1, CDR-L2, and CDR-L3, wherein: the CDR-H1 comprises the amino acid sequence SEQ ID NO: 10, the CDR-H2 comprises the amino acid sequence SEQ ID NO: 11, the CDR-H3 comprises the amino acid sequence SEQ ID NO: 12, the CDR-L1 comprises the amino acid sequence SEQ ID NO: 23, the CDR-L2 comprises the amino acid sequence SEQ ID NO: 21, and the CDR-L3 comprises the amino acid sequence SEQ ID NO: 19 as defined by the IMGT numbering system.

96. The pharmaceutical composition of any one of claims 93-95, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 13 and the light chain variable region comprising the amino acid sequence of SEQ ID NO: 24.

97. The pharmaceutical composition of any one of claims 90-96, wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 37 and a light chain comprising the amino acid sequence of SEQ ID NO: 26.

98. A pharmaceutical composition comprising:(i) 150 mg / mL of an anti-TREM2 antibody, wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 37 and a light chain comprising the amino acid sequence of SEQ ID NO: 26,(ii) 20 m histidine,(iii) 220 mM sucrose, and(iv) 0.4 mg / mL polysorbate-20.

99. The pharmaceutical composition of any one of claims 90-98, wherein the pharmaceutical composition has a pH of 5.0 to 6.0.

100. The pharmaceutical composition of any one of claims 90-99, wherein the pharmaceutical composition has a pH of 5.4 to 6.0.

101. The pharmaceutical composition of claim 100, wherein the pH of the pharmaceutical composition is 5.5.Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)102. The pharmaceutical composition of any one of claims 90-101, wherein the pharmaceutical composition is an aqueous formulation.

103. The pharmaceutical composition of any one of claims 90-102, wherein the pharmaceutical composition is formulated for intravenous administration.

104. The pharmaceutical composition of any one of claims 90-103 for use in a method of treating Alzheimer’s Disease (AD).

105. Use of a pharmaceutical composition of any one of claims 90-103 in the manufacture of a medicament for treating Alzheimer’s Disease (AD).

106. A method of treating Alzheimer’s Disease (AD) in a patient in need thereof, the method comprising administering to the patient in need thereof the pharmaceutical composition of any one of claims 90-103.

107. The method of claim 106, wherein the pharmaceutical composition is administered at a dose of about 1 mg / kg to about 60 mg / kg of the anti-TREM2 antibody.

108. The method of claim 107, wherein the pharmaceutical composition is administered at a dose of about 10 mg / kg to about 30 mg / kg of the anti-TREM2 antibody.

109. The method of claim 108, wherein the pharmaceutical composition is administered at a dose of about 10 mg / kg of the anti-TREM2 antibody.

110. The method of claim 108, wherein the pharmaceutical composition is administered at a dose of about 30 mg / kg of the anti-TREM2 antibody.

111. The method of claim 108, wherein the pharmaceutical composition is administered at a dose of 10 mg / kg of the anti-TREM2 antibody.

112. The method of claim 108, wherein the pharmaceutical composition is administered at a dose of 30 mg / kg of the anti-TREM2 antibody.

113. The method of any one of claims 106-112, wherein the pharmaceutical composition is administered about once every four weeks.

114. The method of any one of claims 106-112, wherein the pharmaceutical composition is administered about once every month.

115. The method of any one of claims 106-112, wherein the pharmaceutical composition is administered once every four weeks.Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)116. The method of any one of claims 106-112, wherein the pharmaceutical composition is administered once every month.

117. The method of any one of claims 106-112, wherein the pharmaceutical composition is administered once every 25-31 days.

118. The method of any one of claims 106-117, further comprising measuring the levels of(i) total sTREM2,(ii) soluble CSF1R,(iii) SSPl, or(iv) CCL3 in a sample of blood, plasma, and / or cerebrospinal fluid from the patient before and after the patient has received one or more doses of the pharmaceutical composition.

119. The method of any one of claims 106-118, further comprising determining a change or score of one or more clinical assessments of the patient after the patient has received one or more doses of the anti-TREM2 antibody compared to baseline prior to the treatment, wherein the one or more clinical assessments are selected from the group consisting of:Clinical Dementia Rating scale - Sum of Boxes (CDR-SB);ADAS-Cogl4; instrumental activities of daily living (iADL) on the ADCS-ADL scale;ADAS-Cogl3, modified ADAS-Cogl4 and MMSE;Neuropsychiatric Inventory 12-item Scale (NPI-12); andFunctional Activities Questionnaire (FAQ).

120. The method of any one of claims 106- 119, wherein the anti-TREM2 antibody treatment results in an improvement in one or more of:Clinical Dementia Rating scale - Sum of Boxes (CDR-SB);ADAS-Cogl4; instrumental activities of daily living (iADL) on the ADCS-ADL scale;ADAS-Cogl3, modified ADAS-Cogl4 and MMSE;Neuropsychiatric Inventory 12-item Scale (NPI-12); andFunctional Activities Questionnaire (FAQ).Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)121. The method of any one of claims 106-120, wherein the anti-TREM2 antibody treatment results in an increase in soluble TREM2 (sTREM2) in the cerebrospinal fluid, blood, serum or plasma of the patient, optionally wherein anti-TREM2 antibody treatment results in a sTREM2 level that is about 10%, 15%, 20%, 25%, 30%, 35%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% higher as compared to the sTREM2 level in the cerebrospinal fluid, blood, serum or plasma of the patient prior to the treatment, optionally wherein the total sTREM2 is determined by the sum of free sTREM2 and sTREM2 bound to the anti-TREM2 antibody, in the serum and / or cerebrospinal fluid of the patient are measured using an electrochemiluminescent assay on a sample of cerebrospinal fluid and / or serum obtained from the patient.

122. The method of any one of claims 106-121, wherein the anti-TREM2 antibody treatment results in a decrease in the levels of soluble CSF1R in the cerebrospinal fluid, blood, serum or plasma of the patient, by 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more compared to the levels of soluble CSF1R in the cerebrospinal fluid, blood, serum or plasma of the patient prior to administration of the anti- TREM2 antibody, optionally wherein the levels of soluble CSF1R in the cerebrospinal fluid of the patient are measured in a sample of cerebrospinal fluid obtained from the patient using an ELISA assay.

123. The method of any one of claims 106- 122, wherein the anti-TREM2 antibody treatment results in a decrease in the levels of SSP1 (osteopontin) in the cerebrospinal fluid, blood, serum or plasma of the patient, by 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more compared to the levels of SSP1 in the cerebrospinal fluid, blood, serum or plasma of the patient prior to administration of the anti- TREM2 antibody.

124. The method of any one of claims 106- 123, wherein the anti-TREM2 antibody treatment results in a decrease in the levels of CCL3 (MIPla) in the cerebrospinal fluid, blood, serum or plasma of the patient, by 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more compared to the levels of CCL3 in the cerebrospinal fluid, blood, serum or plasma of the patient prior to administration of the anti-TREM2 antibody.

125. The method of any one of claims 121-124, wherein the increase in the levels of sTREM2 in the cerebrospinal fluid, blood, serum or plasma of the patient is present at about 12 weeks after administration of the anti-TREM2 antibody.Attorney Reference: PAT059764-PCT-SEC01 (14452.0120-00304)126. The method of claim 122, wherein the decrease in the levels of soluble CSF1R in the cerebrospinal fluid of the patient is present at about 12 weeks after administration of the anti- TREM2 antibody.

127. The method of any one of claims 123-124, wherein the decrease in the levels of CCL3 or SSP1 in the cerebrospinal fluid, blood, serum or plasma of the patient is present at about 12 weeks after administration of the anti-TREM2 antibody.

128. The method of any one of claims 106-127, wherein the treatment results are after 40 weeks, after 60 weeks or more, or 100 weeks or more.

129. A method of treatment of Alzheimer’s disease in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of an anti-TREM2 antibody at a dose of about 10 mg / kg, wherein the anti-TREM2 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 37 and a light chain comprising the sequence of SEQ ID NO: 26, and wherein the administering is performed intravenously every four weeks.

130. A method of treatment of Alzheimer’s disease in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of an anti-TREM2 antibody at a dose of about 30 mg / kg, wherein the anti-TREM2 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 37 and a light chain comprising the sequence of SEQ ID NO: 26, and wherein the administering is performed intravenously every four weeks.

131. The method of claim 129 or 130, wherein the anti-TREM2 antibody is formulated in an aqueous formulation, wherein the aqueous formulation comprises (i) 150 mg / mL of the anti- TREM2 antibody (ii) 20 mM histidine (iii) 220 mM sucrose and (iv) 0.4 mg / mL polysorbate- 20 and has a pH of 5.5.

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