Anti-TREM2 antibodies and uses thereof

Abstract

The present invention provides anti-TREM2 antibodies, formulations thereof, and methods of using same.

Description

[Technical Field]

[0001] The present invention provides anti-TREM2 antibodies, formulations thereof, and methods of use thereof for treating adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in human patients. [Background technology]

[0002] Mutations in triggering receptor expressed on myeloid cells 2 (TREM2), a receptor with expression restricted to microglia in the central nervous system, increase the risk of neurodegenerative diseases such as Alzheimer's disease and frontotemporal dementia (Ulland and Colonna, Nature Reviews, 14, 2018). The TREM2 receptor influences microglial status and function through interactions with various ligands, which are important for sensing tissue damage and minimizing neuropathogenesis (Deczkowska, Cell, 181, 2020). Furthermore, TREM2 receptor agonism is required for the progression of microglia to a neuroprotective disease-associated (DAM) phenotype (Keren-Shaul, Cell, 169, 2017). Summary of the Invention

[0003] Disclosed herein are compositions and methods for using an anti-triggering receptor 2 (TREM2) antibody expressed on myeloid cells. The response of microglial cells to changes in the CNS environment is activated via TREM2 and its associated protein kinase complex, DAP12. TREM2 / DAP12 signaling functions as a key regulator, converting microglia from homeostasis to a neurological disease-related state and producing anti-inflammatory responses and neurotrophic factors to protect injured neurons and enable neural tissue regeneration. In one embodiment, the anti-TREM2 antibody is "Ab-1," a monoclonal antibody capable of binding to TREM2, also referred to herein as VGL101. The anti-TREM2 antibody "Ab-1" may be useful for modulating the activity of such cells without suppressing or impairing the immune system. Without intending to be bound by any particular theory, the anti-TREM2 antibody "Ab-1" activates TREM2, delaying disease progression and enhancing nervous system tissue repair mechanisms regulated by microglia.

[0004] Thus, in one aspect, the present invention provides a liquid formulation of an anti-TREM2 antibody. In one embodiment, the anti-TREM2 antibody is "Ab-1," and the liquid formulation further comprises a pharmaceutically acceptable excipient and / or carrier. In some embodiments, the liquid formulation of the present invention comprises sodium acetate. In some embodiments, the liquid formulation of the present invention comprises sucrose. In some embodiments, the liquid formulation of the present invention comprises polysorbate 80.

[0005] In another aspect, the present invention provides a method for treating or preventing adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a human patient, comprising administering a therapeutically effective amount of an anti-TREM2 antibody to a patient in need thereof. In some embodiments, the anti-TREM2 antibody is anti-TREM2 antibody "Ab-1." In some embodiments, the method of the present invention comprises administering a liquid formulation containing the anti-TREM2 antibody "Ab-1" described herein to a patient in need thereof. In some embodiments, the method of the present invention comprises administering "Ab-1" to a patient in need thereof at a dose of 10 to 75 mg / kg by intravenous infusion every 2 to 6 weeks. In a preferred embodiment, the method of the present invention comprises administering "Ab-1" to a subject in need thereof at a dose of 20 mg / kg by intravenous infusion every 28±7 days, for example, for a total of at least 13 doses, as described in the Examples. In a preferred embodiment, the methods of the invention comprise administering Ab-1 to a subject in need thereof by intravenous infusion every 28±7 days, e.g., at a dose of 40 mg / kg, for a total of at least 13 doses, as described in the Examples.

[0006] Based on preclinical data, Ab-1 administered according to the methods described herein should exhibit a favorable safety and tolerability profile in patients with ALSP. Ab-1 administered according to the methods described herein should also exhibit favorable effects on imaging and biomarkers of disease progression in subjects with ALSP. Ab-1 administered according to the methods described herein should demonstrate signs of clinical efficacy for the treatment of ALSP in patients with ALSP. Ab-1 administered according to the methods described herein should exhibit favorable pharmacokinetics in subjects with ALSP. DETAILED DESCRIPTION OF THE INVENTION

[0007] Detailed Description of the Invention 1. General Description of Certain Embodiments of the Invention In vitro cytokine release assays found that, at concentrations up to 10 μg / mL, anti-TREM2 antibody "Ab-1" had no effect on the release of granulocyte colony-stimulating factor, monocyte chemoattractant protein-1 (MCP-1), 10 kDa interferon gamma-inducible protein (IP-10), interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-10, IL-12p40, IL-13, and IFN-γ. A minimal but dose-related increase in tumor necrosis factor-α release was observed at the two highest concentrations (4 and 10 μg / mL). However, this increase was within the range reported for other commercially available monoclonal antibodies, and no increase in TNF-α was observed in vivo in GLP nonhuman primate (NHP) studies at any dose tested.

[0008] The anti-TREM2 antibody "Ab-1" was well tolerated in NHPs at repeated weekly IV doses up to 200 mg / kg for 1 month. No test article-related effects were observed on clinical signs, body weight, food consumption, ophthalmologic examination, or clinical pathology parameters (serum chemistry, hematology, coagulation, and urinalysis). Macroscopic and microscopic examinations revealed no adverse findings or effects on organ weights. GLP toxicity studies in NHPs included safety pharmacology parameters in accordance with the International Council for Harmonization (ICH) Tripartite Committee on Technical Requirements for Registration of Pharmaceuticals for Human Use (GCP) S6 Guidance. Detailed neurobehavioral testing did not reveal any CNS effects, and electrocardiograms (ECGs) showed no anti-TREM2 antibody "Ab-1"-related findings.

[0009] The no observed adverse effect level (NOAEL) is considered to be 200 mg / kg. Exposures observed after the fourth dose of 200 mg / kg, once every seven days (q7d), were as follows: At 200 mg / kg on Day 22, serum area under the curve from pre-dose (time 0) to the time of quantifiable concentration at 168 hours (AUC0-168h): 838,000 h*μg / mL At 200 mg / kg on day 22, maximum serum / cerebrospinal fluid concentration (Cmax) was 8320 μg / mL

[0010] Doses were administered q7d for 29 days to cynomolgus monkeys. The planned dosing regimen administered to humans as part of the MAD portion of the study is once every 28 days. To calculate the NOAEL limit, based on q7d dosing in cynomolgus monkeys, the AUC0-168hr on day 22 was multiplied by 4 (the number of doses the monkeys received over 28 days); the Cmax NOAEL limit remains unchanged: NOAEL limit for the area under the serum or CSF concentration-time curve from extrapolated pre-dose (time 0) to infinity (AUClast+Clast / λz) (AUC0-∞): 838,000 h*μg / mL x 4 = 3,350,000 h*μg / mL NOAEL limit for Cmax: 8,320 μg / mL The NHP NOAEL of 200 mg / kg is the predicted Cmax and AUC at a starting dose of 1 mg / kg in healthy volunteers. INF This also provides a safety margin for 344X and 337X.

[0011] Thus, in one aspect, the invention provides a liquid formulation comprising the anti-TREM2 antibody "Ab-1" and a pharmaceutically acceptable excipient and / or carrier. In some embodiments, the pharmaceutically acceptable excipient and / or carrier of the invention is selected from those described herein.

[0012] In another aspect, the invention provides methods for treating adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a human patient, comprising administering a therapeutically effective amount of an anti-TREM2 antibody to a patient in need thereof. In some embodiments, the methods of the invention comprise administering a therapeutically effective amount of a liquid formulation described herein to a patient in need thereof.

[0013] In another aspect, the invention provides methods for preventing or delaying the onset or recurrence of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a human patient, comprising administering a therapeutically effective amount of an anti-TREM2 antibody to a patient in need thereof. In some embodiments, the methods of the invention comprise administering a therapeutically effective amount of a liquid formulation described herein to a patient in need thereof.

[0014] In some embodiments, the anti-hTREM2 antibody comprises a light chain variable region comprising CDRL1 having the amino acid sequence according to SEQ ID NO:2, CDRL2 having the amino acid sequence according to SEQ ID NO:3, and CDRL3 having the amino acid sequence according to SEQ ID NO:4, and a heavy chain variable region comprising CDRH1 having the amino acid sequence according to SEQ ID NO:6, CDRH2 having the amino acid sequence according to SEQ ID NO:7, and CDRH3 having the amino acid sequence according to SEQ ID NO:8.

[0015] In some embodiments, the anti-hTREM2 antibody comprises a light chain variable region having an amino acid sequence according to SEQ ID NO:1 and a heavy chain variable region having an amino acid sequence according to SEQ ID NO:5.

[0016] In some embodiments, the anti-hTREM2 antibody is an IgG, optionally an IgG1.

[0017] In some embodiments, the anti-hTREM2 antibody comprises a kappa light constant region.

[0018] In some embodiments, the anti-hTREM2 antibody is an IgG1 comprising a variant constant region having one or more mutations selected from R292C, N297G, V302C, D356E, or L358M, according to EU numbering.

[0019] In some embodiments, the anti-hTREM2 antibody is anti-TREM2 antibody "Ab-1."

[0020] 2.Definition As used herein, the term "anti-TREM2 antibody Ab-1" refers to the anti-TREM2 antibody "Ab-1" comprising a light chain having the amino acid sequence of SEQ ID NO: 9 and a heavy chain having the amino acid sequence of SEQ ID NO: 10. "Ab-1" is used interchangeably with VGL101 to describe the antibody having CAS number 2733621-19-5, which has the amino acid sequence summarized in Table 1 below. [Table 1]

[0021] In some embodiments, the anti-TREM2 antibody is an anti-TREM2 antibody cited in one or more of WO2018 / 195506, U.S. Patent No. 8,231,878, U.S. Patent Publication No. 2019 / 0010230, WO2017 / 062672, WO2019 / 028292, WO2018 / 015573, WO2019 / 055841, WO2019 / 118513, WO2020 / 055975, WO2020 / 079580, or Korean Patent Publication No. KR20200048069, each of which is incorporated by reference in its entirety. In some embodiments, the anti-TREM2 antibody is AL002. In some embodiments, the anti-TREM2 antibody is DNL919. In some embodiments, the anti-TREM2 antibody is not Ab-1.

[0022] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is suitable, within the scope of sound medical judgment, for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, etc., and that is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, and 2-hydroxy-ethanesulfonate. Examples of suitable salts include sulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate.

[0023] Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N + (C 1~4Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharmaceutically acceptable salts include non-toxic ammonium cations, quaternary ammonium cations, and amine cations, formed where appropriate using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0024] Unless otherwise stated, structures depicted herein are also intended to include all isomeric forms of the structure (e.g., enantiomers, diastereomers, and geometric (or conformational) forms), such as the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E stereoisomers. Accordingly, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, replacement of hydrogen by deuterium or tritium, or 13 C or 14 Compounds having this structure including the replacement of a carbon with a C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents according to the present invention.

[0025] As used herein, the term "about" or "approximately" means within 20% of a given value or range. In some embodiments, the term "about" refers to within 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of a given value.

[0026] 3. Description of Exemplary Embodiments antibody The present invention relates to an antibody that specifically binds to TREM2, particularly human TREM2. In humans, the TREM2 gene is located within the TREM gene cluster on chromosome 6p21.1. The TREM gene cluster encodes four TREM proteins (TREM1, TREM2, TREM4, and TREM5) and two TREM-like proteins (TLT-1 and TLT-2). The TREM2 gene encodes a 230-amino acid protein consisting of an extracellular domain, a transmembrane region, and a short cytoplasmic tail (Paradowska-Gorycka et al., Human Immunology, Vol. 74: 730-737, 2013). The extracellular domain contains a single V-type Ig superfamily domain with three potential N-glycosylation sites. The wild-type human TREM2 amino acid sequence (NCBI Reference Sequence: NP_061838.1) is provided below as SEQ ID NO: 354.

[0027] Amino acids 1-18 of the wild-type human TREM2 protein (SEQ ID NO:354) are a signal peptide, which is generally removed from the mature protein. The mature human TREM2 protein contains an extracellular domain at amino acids 19-174 of SEQ ID NO:354, a transmembrane domain at amino acids 175-195 of SEQ ID NO:354, and a cytoplasmic domain at amino acids 196-230 of SEQ ID NO:354. The amino acid sequence of the extracellular domain of human TREM2 (including the signal peptide) is provided in the table below as SEQ ID NO:355.

[0028] The term "human triggering receptor 2 expressed on myeloid cells" or "human TREM2" may refer to the polypeptide of SEQ ID NO:354, the polypeptide of SEQ ID NO:355, the polypeptide of SEQ ID NO:354 or SEQ ID NO:355 minus the signal peptide (amino acids 1-18), an allelic variant of human TREM2, or a splice variant of human TREM2. In some embodiments, the term "human TREM2" includes naturally occurring variants of TREM2, such as the mutations R47H, Q33X (where X is a stop codon), Y38C, T66M, D87N, H157Y, R98W, and S116C. [Table 2]

[0029] In one aspect, the invention provides a method of treating ALSP in a human patient, the method comprising administering to the patient an effective amount of an antigen-binding protein or antibody, or antigen-binding fragment thereof, thereby increasing the activity of TREM2. In some embodiments, the antibody is a TREM2 agonist. In some embodiments, the antibody is a TREM2 agonist that specifically binds to and activates human TREM2. In some embodiments, the antibody is the anti-human TREM2 antibody VGL101.

[0030] A TREM2 agonist antibody may be directed to human TREM2 (SEQ ID NO: 354) or to the extracellular domain (ECD) of human TREM2 (e.g., the ECD shown in SEQ ID NO: 355), e.g., with an equilibrium dissociation constant (K D ) specifically binds with less than 50 nM, less than 25 nM, less than 10 nM, or less than 5 nM. In some embodiments, the TREM2 agonist antibody does not cross-react with other TREM proteins, such as human TREM1. In some embodiments, the TREM2 agonist antibody does not bind to human TREM1.

[0031] In some embodiments, the TREM2 antibody specifically binds to human TREM2 residues 19-174 (SEQ ID NO: 354). In some embodiments, the TREM2 antibody specifically binds to the IgV region of human TREM2, for example, human TREM2 residues 19-140 (SEQ ID NO: 354).

[0032] In certain embodiments, anti-TREM2 antibodies of the present disclosure bind to one or more amino acids within amino acid residues 29-112 of human TREM2 (SEQ ID NO: 354), or within the amino acid residues on the TREM2 protein that correspond to amino acid residues 29-112 of SEQ ID NO: 354. In some embodiments, anti-TREM2 antibodies of the present disclosure bind to one or more amino acids within amino acid residues 29-41 of human TREM2 (SEQ ID NO: 354), or within the amino acid residues on the TREM2 protein that correspond to amino acid residues 29-41 of SEQ ID NO: 354. In some embodiments, anti-TREM2 antibodies of the present disclosure bind to one or more amino acids within amino acid residues 47-69 of human TREM2 (SEQ ID NO: 354), or within the amino acid residues on the TREM2 protein that correspond to amino acid residues 47-69 of SEQ ID NO: 354. In some embodiments, anti-TREM2 antibodies of the present disclosure bind to one or more amino acids within amino acid residues 76-86 of human TREM2 (SEQ ID NO: 354), or within the amino acid residues on the TREM2 protein that correspond to amino acid residues 76-86 of SEQ ID NO: 354. In some embodiments, anti-TREM2 antibodies of the present disclosure bind to one or more amino acids within amino acid residues 91-100 of human TREM2 (SEQ ID NO: 354), or within the amino acid residues on the TREM2 protein that correspond to amino acid residues 91-100 of SEQ ID NO: 354. In some embodiments, anti-TREM2 antibodies of the present disclosure bind to one or more amino acids within amino acid residues 99-115 of human TREM2 (SEQ ID NO: 354), or within the amino acid residues on the TREM2 protein that correspond to amino acid residues 99-115 of SEQ ID NO: 354. In some embodiments, anti-TREM2 antibodies of the present disclosure bind to one or more amino acids within amino acid residues 104-112 of human TREM2 (SEQ ID NO: 354), or within the amino acid residues on the TREM2 protein that correspond to amino acid residues 104-112 of SEQ ID NO: 354. In some embodiments, anti-TREM2 antibodies of the present disclosure bind to one or more amino acids within amino acid residues 114-118 of human TREM2 (SEQ ID NO: 354), or within the amino acid residues on the TREM2 protein that correspond to amino acid residues 114-118 of SEQ ID NO: 354.In some embodiments, anti-TREM2 antibodies of the present disclosure bind to one or more amino acids within amino acid residues 130-171 of human TREM2 (SEQ ID NO: 354), or within the amino acid residues on the TREM2 protein that correspond to amino acid residues 130-171 of SEQ ID NO: 354. In some embodiments, anti-TREM2 antibodies of the present disclosure bind to one or more amino acids within amino acid residues 139-153 of human TREM2 (SEQ ID NO: 354), or within the amino acid residues on the TREM2 protein that correspond to amino acid residues 139-153 of SEQ ID NO: 354. In some embodiments, anti-TREM2 antibodies of the present disclosure bind to one or more amino acids within amino acid residues 139-146 of human TREM2 (SEQ ID NO: 354), or within the amino acid residues on the TREM2 protein that correspond to amino acid residues 139-146 of SEQ ID NO: 354. In some embodiments, anti-TREM2 antibodies of the present disclosure bind to one or more amino acids within amino acid residues 130-144 of human TREM2 (SEQ ID NO: 354), or within amino acid residues on the TREM2 protein that correspond to amino acid residues 130-144 of SEQ ID NO: 354. In some embodiments, anti-TREM2 antibodies of the present disclosure bind to one or more amino acids within amino acid residues 158-171 of human TREM2 (SEQ ID NO: 354), or within amino acid residues on the TREM2 protein that correspond to amino acid residues 158-171 of SEQ ID NO: 354.

[0033] In some embodiments, anti-TREM2 antibodies of the present disclosure bind to one or more amino acids within amino acid residues 43-50 of human TREM2 (SEQ ID NO: 354), or within the amino acid residues on the TREM2 protein that correspond to amino acid residues 43-50 of SEQ ID NO: 354. In some embodiments, anti-TREM2 antibodies of the present disclosure bind to one or more amino acids within amino acid residues 49-57 of human TREM2 (SEQ ID NO: 354), or within the amino acid residues on the TREM2 protein that correspond to amino acid residues 49-57 of SEQ ID NO: 354. In some embodiments, anti-TREM2 antibodies of the present disclosure bind to one or more amino acids within amino acid residues 139-146 of human TREM2 (SEQ ID NO: 354), or within the amino acid residues on the TREM2 protein that correspond to amino acid residues 139-146 of SEQ ID NO: 354. In some embodiments, an anti-TREM2 antibody of the present disclosure binds to one or more amino acids within amino acid residues 140-153 of human TREM2 (SEQ ID NO: 354), or within amino acid residues on the TREM2 protein that correspond to amino acid residues 140-153 of SEQ ID NO: 354. In some embodiments, the TREM2 antibody specifically binds to the stalk region of human TREM2, e.g., amino acid residues 145-174 of human TREM2.

[0034] In some embodiments, the antibody, or antigen-binding fragment thereof, specifically binds to TREM2 and prevents degradation or cleavage of TREM2.

[0035] In some embodiments, the antibody is a polyclonal antibody. In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the antibody is a chimeric antibody. In some embodiments, the antibody is a humanized antibody. In some embodiments, the antibody is a human antibody, particularly a fully human antibody. In some embodiments, the antibody is a bispecific or other multivalent antibody. In some embodiments, the antibody is a single chain antibody.

[0036] In some embodiments, the TREM2 activating antibody comprises a light chain variable region comprising complementarity determining regions CDRL1, CDRL2, and CDRL3, and a heavy chain variable region comprising complementarity determining regions CDRH1, CDRH2, and CDRH3, as described herein.

[0037] In certain embodiments, the TREM2 agonist antigen binding proteins of the invention comprise at least one light chain variable region comprising CDRL1, CDRL2, and CDRL3, and at least one heavy chain variable region comprising CDRH1, CDRH2, and CDRH3, from an anti-TREM2 agonist antibody described herein.

[0038] In some embodiments, the TREM2 activating antibody comprises a light chain variable region and a heavy chain variable region described herein. The light and heavy chain variable regions or CDRs may be from any of the anti-TREM2 antibodies or variants thereof described herein. A. PCT Patent Application Publication No. WO2018 / 195506A1

[0039] In some embodiments, the TREM2 agonist is an antigen-binding protein or antibody, or an antigen-binding fragment thereof, as described in PCT Patent Application Publication No. WO2018 / 195506A1, which is incorporated herein by reference in its entirety.

[0040] In some embodiments, the TREM2 agonist antigen binding protein comprises CDRL1 or a variant thereof having one, two, three, or four amino acid substitutions, CDRL2 or a variant thereof having one, two, three, or four amino acid substitutions, CDRL3 or a variant thereof having one, two, three, or four amino acid substitutions, CDRH1 or a variant thereof having one, two, three, or four amino acid substitutions, CDRH2 or a variant thereof having one, two, three, or four amino acid substitutions, and CDRH3 or a variant thereof having one, two, three, or four amino acid substitutions, wherein the amino acid sequences of CDRL1, CDRL2, CDRL3, CDRH1, CDRH2, and CDRH3, along with exemplary light chain regions and variable regions, are provided in Tables 1A and 1B below. [Table 3-1] [Table 3-2] [Table 3-3] [Table 4-1] [Table 4-2] [Table 4-3]

[0041] As noted above, the TREM2 agonist antigen binding protein may comprise one or more of the CDRs presented in Table 1 (VGL101), Table 1A (light chain CDRs, i.e., CDRLs), or Table 1B (heavy chain CDRs, i.e., CDRHs).

[0042] In some embodiments, the TREM2 agonist antigen binding protein comprises one or more light chain CDRs selected from (i) a CDRL1 selected from SEQ ID NOs: 11-18 or 356-361, (ii) a CDRL2 selected from SEQ ID NOs: 19-30, and (iii) a CDRL3 selected from SEQ ID NOs: 31-45, and (iv) a CDRL of (i), (ii), and (iii) that contains one or more, e.g., one, two, three, four or more amino acid substitutions (e.g., conservative amino acid substitutions), or no more than five, four, three, two, or one amino acid deletions or insertions. In these and other embodiments, the TREM2 agonist antigen binding protein comprises one or more heavy chain CDRs selected from (i) a CDRH1 selected from SEQ ID NOs: 77-86, (ii) a CDRH2 selected from SEQ ID NOs: 87-94, and (iii) a CDRH3 selected from SEQ ID NOs: 95-109, and (iv) a CDRH of (i), (ii), and (iii) that contains one or more, e.g., one, two, three, four or more amino acid substitutions (e.g., conservative amino acid substitutions), or no more than five, four, three, two, or one amino acid deletions or insertions.

[0043] In some embodiments, the TREM2 agonist antigen binding protein may comprise variant forms of one, two, three, four, five, or six of the CDRs listed in Tables 1A and 1B, each having at least 80%, 85%, 90%, or 95% sequence identity to the CDR sequences listed in Tables 1A and 1B. In some embodiments, the TREM2 agonist antigen binding protein comprises one, two, three, four, five, or six of the CDRs listed in Tables 1A and 1B, each differing by no more than one, two, three, four, or five amino acids from the CDRs listed in these tables.

[0044] In some embodiments, the TREM2 agonist antigen binding protein comprises a CDRL1 comprising a sequence selected from SEQ ID NOs: 11-18 or 356-361, or a variant thereof having one, two, three, or four amino acid substitutions; a CDRL2 comprising a sequence selected from SEQ ID NOs: 19-30, or a variant thereof having one, two, three, or four amino acid substitutions; a CDRL3 comprising a sequence selected from SEQ ID NOs: 31-45, or a variant thereof having one, two, three, or four amino acid substitutions; a CDRH1 comprising a sequence selected from SEQ ID NOs: 77-86, or a variant thereof having one, two, three, or four amino acid substitutions; a CDRH2 comprising a sequence selected from SEQ ID NOs: 87-94, or a variant thereof having one, two, three, or four amino acid substitutions; and a CDRH3 comprising a sequence selected from SEQ ID NOs: 95-109, or a variant thereof having one, two, three, or four amino acid substitutions.

[0045] In some embodiments, the TREM2 agonist antigen binding proteins of the invention comprise a CDRL1 comprising a sequence selected from SEQ ID NOs: 11-18 or 356-361, a CDRL2 comprising a sequence selected from SEQ ID NOs: 19-30, a CDRL3 comprising a sequence selected from SEQ ID NOs: 31-45, a CDRH1 comprising a sequence selected from SEQ ID NOs: 77-86, a CDRH2 comprising a sequence selected from SEQ ID NOs: 87-94, and a CDRH3 comprising a sequence selected from SEQ ID NOs: 95-109.

[0046] In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising CDRL1, CDRL2, and CDRL3; (a) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 356, 19, and 31, respectively; (b) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 357, 20, and 32, respectively; (c) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 357, 21, and 33, respectively; (d) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 357, 20, and 33, respectively; (e) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 358, 22, and 34, respectively; (f) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 359, 22, and 35, respectively; (g) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 360, 22, and 36, respectively; (h) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 361, 23, and 37, respectively; (i) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 11, 23, and 38, respectively; (j) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 12, 24, and 39, respectively; (k) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 13, 25, and 40, respectively; (l) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 14, 26, and 41, respectively; (m) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 15, 27, and 42, respectively; (n) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 16, 28, and 43, respectively; (o) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 17, 29, and 44, respectively; or (p) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 18, 30, and 45, respectively.

[0047] In some embodiments, the TREM2 agonist antigen binding protein comprises a heavy chain variable region comprising CDRH1, CDRH2, and CDRH3; (a) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 77, 87, and 95, respectively; (b) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 78, 88, and 96, respectively; (c) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 78, 88, and 97, respectively; (d) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 78, 89, and 96, respectively; (e) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 77, 90, and 98, respectively; (f) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 79, 90, and 99, respectively; (g) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 80, 91, and 100, respectively; (h) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 81, 91, and 101, respectively; (i) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 82, 92, and 102, respectively; (j) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 81, 91, and 103, respectively; (k) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 81, 91, and 104, respectively; (l) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 83, 93, and 105, respectively; (m) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 84, 91, and 106, respectively; (n) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 85, 91, and 107, respectively; (o) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 86, 94, and 108, respectively; or (p) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 85, 91, and 109, respectively.

[0048] In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising CDRL1, CDRL2, and CDRL3, and a heavy chain variable region comprising CDRH1, CDRH2, and CDRH3; (a) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 356, 19, and 31, respectively, and CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 77, 87, and 95, respectively; (b) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 357, 20, and 32, respectively, and CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 78, 88, and 96, respectively; (c) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 357, 21, and 33, respectively, and CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 78, 88, and 97, respectively; (d) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 357, 20, and 33, respectively, and CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 78, 88, and 97, respectively; (e) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 357, 20, and 33, respectively, and CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 78, 89, and 96, respectively; (f) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 358, 22, and 34, respectively, and CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 77, 87, and 95, respectively; (g) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 359, 22, and 35, respectively, and CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 77, 90, and 98, respectively; (h) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 360, 22, and 36, respectively, and CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 79, 90, and 99, respectively; (i) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 361, 23, and 37, respectively, and CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 80, 91, and 100, respectively; (j) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 361, 23, and 37, respectively, and CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 81, 91, and 101, respectively; (k) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 11, 23, and 38, respectively, and CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 82, 92, and 102, respectively; (l) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 12, 24, and 39, respectively, and CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 81, 91, and 103, respectively; (m) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 13, 25, and 40, respectively, and CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 81, 91, and 104, respectively; (n) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 14, 26, and 41, respectively, and CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 83, 93, and 105, respectively; (o) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 15, 27, and 42, respectively, and CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 84, 91, and 106, respectively; (p) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 16, 28, and 43, respectively, and CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 85, 91, and 107, respectively; (q) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 17, 29, and 44, respectively, and CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 86, 94, and 108, respectively; or (r) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 18, 30, and 45, respectively, and CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 85, 91, and 109, respectively.

[0049] In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising CDRL1, CDRL2, and CDRL3, and a heavy chain variable region comprising CDRH1, CDRH2, and CDRH3, wherein CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 361, 23, and 37, respectively, and wherein CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 80, 91, and 100, respectively. In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising CDRL1, CDRL2, and CDRL3, and a heavy chain variable region comprising CDRH1, CDRH2, and CDRH3, wherein CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 361, 23, and 37, respectively, and wherein CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 81, 91, and 101, respectively. In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising CDRL1, CDRL2, and CDRL3, and a heavy chain variable region comprising CDRH1, CDRH2, and CDRH3, wherein CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 15, 27, and 42, respectively, and wherein CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 84, 91, and 106, respectively. In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising CDRL1, CDRL2, and CDRL3, and a heavy chain variable region comprising CDRH1, CDRH2, and CDRH3, wherein CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 16, 28, and 43, respectively, and wherein CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 85, 91, and 107, respectively. In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising CDRL1, CDRL2, and CDRL3, and a heavy chain variable region comprising CDRH1, CDRH2, and CDRH3, wherein CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 17, 29, and 44, respectively, and CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 86, 94, and 108, respectively.In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising CDRL1, CDRL2, and CDRL3, and a heavy chain variable region comprising CDRH1, CDRH2, and CDRH3, wherein CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 359, 22, and 35, respectively, and CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 77, 90, and 98, respectively.

[0050] In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising a sequence selected from SEQ ID NOs: 46-63, and a heavy chain variable region comprising a sequence selected from SEQ ID NOs: 110-126. In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO: 46, and a heavy chain variable region comprising the sequence of SEQ ID NO: 110. In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO: 47, and a heavy chain variable region comprising the sequence of SEQ ID NO: 111. In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO: 48, and a heavy chain variable region comprising the sequence of SEQ ID NO: 112. In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO: 49, and a heavy chain variable region comprising the sequence of SEQ ID NO: 113. In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO:50, and a heavy chain variable region comprising the sequence of SEQ ID NO:114. In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO:51, and a heavy chain variable region comprising the sequence of SEQ ID NO:110. In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO:53, and a heavy chain variable region comprising the sequence of SEQ ID NO:116. In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO:54, and a heavy chain variable region comprising the sequence of SEQ ID NO:117. In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO:55, and a heavy chain variable region comprising the sequence of SEQ ID NO:118. In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO:56, and a heavy chain variable region comprising the sequence of SEQ ID NO:119. In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO:57 and a heavy chain variable region comprising the sequence of SEQ ID NO:120.In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO:58, and a heavy chain variable region comprising the sequence of SEQ ID NO:121. In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO:59, and a heavy chain variable region comprising the sequence of SEQ ID NO:122. In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO:60, and a heavy chain variable region comprising the sequence of SEQ ID NO:123. In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO:61, and a heavy chain variable region comprising the sequence of SEQ ID NO:124. In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO:62, and a heavy chain variable region comprising the sequence of SEQ ID NO:125. In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO:63, and a heavy chain variable region comprising the sequence of SEQ ID NO:126. In yet another embodiment, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO:52 and a heavy chain variable region comprising the sequence of SEQ ID NO:115.

[0051] In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region selected from LV-01, LV-02, LV-03, LV-04, LV-05, LV-06, LV-07, LV-08, LV-09, LV-10, LV-11, LV-12, LV-13, LV-14, LV-15, LV-16, LV-17, and LV-18, as shown in Table 1A, and / or a light chain variable region selected from the group consisting of LV-01, LV-02, LV-03, LV-04, LV-05, LV-06, LV-07, LV-08, LV-09, LV-10, LV-11, LV-12, LV-13, LV-14, LV-15, LV-16, LV-17, and LV-18, as shown in Table 1A. 1B, and functional fragments, derivatives, muteins, and variants of these light and heavy chain variable regions.

[0052] In some embodiments, each of the light chain variable regions listed in Table 1A may be combined with any of the heavy chain variable regions listed in Table 1B to form the anti-TREM2 binding domain of an antigen binding protein of the invention. Examples of such combinations include, but are not limited to, the following: LV-01 (SEQ ID NO:46) and HV-01 (SEQ ID NO:110), LV-02 (SEQ ID NO:47) and HV-02 (SEQ ID NO:111), LV-03 (SEQ ID NO:48) and HV-03 (SEQ ID NO:112), LV-04 (SEQ ID NO:49) and HV-04 (SEQ ID NO:113), LV-05 (SEQ ID NO:50) and HV-05 (SEQ ID NO:114), LV-06 (SEQ ID NO:51) and HV-01 (SEQ ID NO:110), LV-07 (SEQ ID NO:52) and HV-06 (SEQ ID NO:115), LV-08 (SEQ ID NO:53) and HV-07 (SEQ ID NO:116), LV-09 (SEQ ID NO:54) and HV- 08 (SEQ ID NO: 117), LV-10 (SEQ ID NO: 55) and HV-09 (SEQ ID NO: 118), LV-11 (SEQ ID NO: 56) and HV-10 (SEQ ID NO: 119), LV-12 (SEQ ID NO: 57) and HV-11 (SEQ ID NO: 120), LV-13 (SEQ ID NO: 58) and HV-12 (SEQ ID NO: 121), LV-14 (SEQ ID NO: 59) and HV-13 (SEQ ID NO: 122), LV-15 (SEQ ID NO: 60) and HV-14 (SEQ ID NO: 123), LV-16 (SEQ ID NO: 61) and HV-15 (SEQ ID NO: 124), LV-17 (SEQ ID NO: 62) and HV-16 (SEQ ID NO: 125), and LV-18 (SEQ ID NO: 63) and HV-17 (SEQ ID NO: 126).

[0053] In certain embodiments, TREM2 agonist antigen binding proteins of the present invention comprise a light chain variable region comprising the sequence of LV-09 (SEQ ID NO: 54) and a heavy chain variable region comprising the sequence of HV-08 (SEQ ID NO: 117). In some embodiments, TREM2 agonist antigen binding proteins of the present invention comprise a light chain variable region comprising the sequence of LV-10 (SEQ ID NO: 55) and a heavy chain variable region comprising the sequence of HV-09 (SEQ ID NO: 118). In other embodiments, TREM2 agonist antigen binding proteins of the present invention comprise a light chain variable region comprising the sequence of LV-15 (SEQ ID NO: 60) and a heavy chain variable region comprising the sequence of HV-14 (SEQ ID NO: 123). In yet other embodiments, TREM2 agonist antigen binding proteins of the present invention comprise a light chain variable region comprising the sequence of LV-16 (SEQ ID NO: 61) and a heavy chain variable region comprising the sequence of HV-15 (SEQ ID NO: 124). In some embodiments, the TREM2 agonist antigen binding protein of the invention comprises a light chain variable region comprising the sequence of LV-17 (SEQ ID NO: 62) and a heavy chain variable region comprising the sequence of HV-16 (SEQ ID NO: 125). In certain embodiments, the TREM2 agonist antigen binding protein of the invention comprises a light chain variable region comprising the sequence of LV-07 (SEQ ID NO: 52) and a heavy chain variable region comprising the sequence of HV-06 (SEQ ID NO: 115).

[0054] In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising a sequence of contiguous amino acids that differs by only 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues from a light chain variable region sequence in Table 1A, i.e., a VL selected from LV-01, LV-02, LV-03, LV-04, LV-05, LV-06, LV-07, LV-08, LV-09, LV-10, LV-11, LV-12, LV-13, LV-14, LV-15, LV-16, LV-17, or LV-18, wherein each such sequence difference is independently either a deletion, insertion, or substitution of a single amino acid, and wherein the deletion, insertion, and / or substitution results in no more than 15 amino acid changes compared to the aforementioned variable domain sequence. The light chain variable region in some TREM2 agonist antigen binding proteins comprises a sequence of amino acids that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NOs: 46-63 (i.e., the light chain variable region in Table 1A). In one embodiment, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising a sequence that is at least 90% identical to a sequence selected from SEQ ID NOs: 46-63. In another embodiment, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising a sequence that is at least 95% identical to a sequence selected from SEQ ID NOs: 46-63. In yet another embodiment, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising a sequence selected from SEQ ID NOs: 46-63. In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO: 54. In other embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO: 55. In yet other embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO: 60. In yet other embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO: 61.In certain embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO: 62. In other embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO: 52.

[0055] In these and other embodiments, the TREM2 agonist antigen binding protein comprises a heavy chain variable region comprising a sequence of contiguous amino acids that differs by only 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acid residues from a heavy chain variable region sequence in Table 1B, i.e., a VH selected from HV-01, HV-02, HV-03, HV-04, HV-05, HV-06, HV-07, HV-08, HV-09, HV-10, HV-11, HV-12, HV-13, HV-14, HV-15, HV-16, or HV-17, wherein each such sequence difference is independently either a deletion, insertion, or substitution of a single amino acid, and wherein the deletion, insertion, and / or substitution results in 15 or fewer amino acid changes compared to the aforementioned variable domain sequence. The heavy chain variable region in some TREM2 agonist antigen binding proteins comprises a sequence of amino acids that has at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NOs: 110-126 (i.e., the heavy chain variable region in Table 1B). In one embodiment, the TREM2 agonist antigen binding protein comprises a heavy chain variable region comprising a sequence that is at least 90% identical to a sequence selected from SEQ ID NOs: 110-126. In another embodiment, the TREM2 agonist antigen binding protein comprises a heavy chain variable region comprising a sequence that is at least 95% identical to a sequence selected from SEQ ID NOs: 110-126. In yet another embodiment, the TREM2 agonist antigen binding protein comprises a heavy chain variable region comprising a sequence selected from SEQ ID NOs: 110-126. In some embodiments, the TREM2 agonist antigen binding protein comprises a heavy chain variable region comprising the sequence of SEQ ID NO: 117. In other embodiments, the TREM2 agonist antigen binding protein comprises a heavy chain variable region comprising the sequence of SEQ ID NO: 118. In yet other embodiments, the TREM2 agonist antigen binding protein comprises a heavy chain variable region comprising the sequence of SEQ ID NO: 123. In yet other embodiments, the TREM2 agonist antigen binding protein comprises a heavy chain variable region comprising the sequence of SEQ ID NO: 124.In certain embodiments, the TREM2 agonist antigen binding protein comprises a heavy chain variable region comprising the sequence of SEQ ID NO: 125. In other embodiments, the TREM2 agonist antigen binding protein comprises a heavy chain variable region comprising the sequence of SEQ ID NO: 115.

[0056] In some embodiments, variants of anti-TREM2 antibodies can be generated by substituting one or more amino acids in the light or heavy chain variable regions to address chemical trends (e.g., aspartic acid isomerization, asparagine deamidation, tryptophan and methionine oxidation) or precise covariance violations (see, e.g., WO 2012 / 125495, which is incorporated herein by reference in its entirety). Such variants can have improved biophysical, expression, and / or stability properties compared to the parent antibody. In some embodiments, the TREM2 agonist antigen binding proteins of the invention comprise a light chain variable region and / or a heavy chain variable region with one or more of the amino acid substitutions set forth in any of Tables 2A-2F below.

[0057] In some embodiments, additional variants of the anti-TREM2 antibodies described herein can be generated by adjusting the affinity of any of the anti-TREM2 antibodies described herein. An "affinity-adjusted antibody" is an antibody that contains one or more amino acid substitutions in its light chain variable region sequence and / or heavy chain variable region sequence, thereby increasing or decreasing the affinity of the antibody for a target antigen compared to a parent antibody that does not contain the amino acid substitutions. Methods for tuning antibody affinity are known to those skilled in the art and include CDR walking mutagenesis (Yang et al., J. Mol. Biol., 254, 392-403, 1995), chain shuffling (Marks et al., Bio / Technology, 10, 779-783, 1992), use of mutant strains of E. coli (Low et al., J. Mol. Biol., 250, 350-368, 1996), DNA shuffling (Patten et al., Curr. Opin. Biotechnol., 1997, 8:724-733), phage display (Thompson et al., J. Mol. Biol., 1996, 256:7-88), PCR techniques (Crameri, et al., Nature, 1998, 391:288-291), and other mutagenesis strategies (Barbas et al., Proc Nat. Acad. Sci. USA 91:3809-3813,1994; Schier et al., Gene 169:147-155 1995; Yelton et al., J. Immunol.155:1994-2004,1995; Jackson et al., J. Immunol.154(7):3310-9,1995; and Hawkins et al., J. Mol. Biol.,1992,226:889-896). Methods of affinity modulation are described in Hoogenboom, Trends in Biotechnology,1995,15:62-70, and Vaughan et al., Nature Biotechnology,1998,16535-539.One particular method for generating affinity-tuned variants of the anti-TREM2 antibodies described herein is the use of a yeast-displayed Fab mutagenesis library.

[0058] In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region that is a variant of the light chain variable region of any of the anti-TREM2 antibodies described herein. Thus, in some embodiments, the light chain variable region of the TREM2 agonist antigen binding protein comprises a sequence that is at least 90% identical, at least 91% identical, at least 92% identical, at least 93% identical, at least 94% identical, or at least 95% identical to a sequence selected from SEQ ID NOs: 46-63. In some embodiments, the TREM2 agonist antigen binding protein can comprise a light chain variable region from any of the engineered anti-TREM2 antibody variants shown in Tables 2A-2F below.

[0059] In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO: 54 with a mutation at one or more amino acid positions 64, 79, 80, 85, 94, and / or 100. In some such embodiments, the mutations are V64G, V64A, Q79E, Q79D, S80P, S80A, F85V, F85L, F85A, F85D, F85I, F85L, F85M, F85T, W94F, W94Y, W94S, W94T, W94A, W94H, W94I, W94Q, P100R, P100Q, P100G, or a combination thereof. In another embodiment, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO: 55 with a mutation at one or more amino acid positions 64, 79, 80, 94, and / or 100. Such mutations may include V64G, V64A, Q79E, Q79D, S80P, S80A, W94F, W94Y, W94S, W94T, W94A, W94H, W94I, W94Q, P100R, P100Q, P100G, or a combination thereof. In a specific embodiment, the mutation is V64G, V64A, Q79E, S80P, S80A, W94Y, W94S, P100R, P100Q, or a combination thereof. In another embodiment, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO: 60 with a mutation at one or more amino acid positions 60, 92, and / or 93. In such an embodiment, the mutations may be selected from L60S, L60P, L60D, L60A, D92E, D92Q, D92T, D92N, S93A, S93N, S93Q, S93V, or a combination thereof. In yet another embodiment, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO: 61 with a mutation at one or more amino acid positions 56, 57, 92, and / or 93. In such embodiments, the mutation may be N56S, N56T, N56Q, N56E, G57A, G57V, D92E, D92Q, D92T, D92N, S93A, S93N, S93Q, S93V, or a combination thereof. In certain embodiments, the mutation is N56S, N56Q, G57A, D92E, D92Q, S93A, or a combination thereof.In yet another embodiment, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO: 62 with a mutation at amino acid position 36, 46, 61, and / or 100. Such mutations may include F36Y, S46L, S46R, S46V, S46F, K61R, P100Q, P100G, P100R, or a combination thereof. In a specific embodiment, the mutation is F36Y, K61R, P100Q, or a combination thereof. In another embodiment, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO: 52 with a mutation at amino acid position 91, which can be selected from F91V, F91I, F91T, F91L, or F91D. In one embodiment, the mutation is F91V.

[0060] In some embodiments, the TREM2 agonist antigen binding protein comprises a heavy chain variable region that is a variant of a heavy chain variable region from any of the anti-TREM2 antibodies described herein. Thus, in some embodiments, the heavy chain variable region of the TREM2 agonist antigen binding protein comprises a sequence that is at least 90% identical, at least 91% identical, at least 92% identical, at least 93% identical, at least 94% identical, or at least 95% identical to a sequence selected from SEQ ID NOs: 110-126. For example, the TREM2 agonist antigen binding protein can comprise a heavy chain variable region from any of the engineered anti-TREM2 antibody variants described in Tables 2A-2F below. In one embodiment, the TREM2 agonist antigen binding protein comprises a heavy chain variable region comprising the sequence of SEQ ID NO: 117 with mutations at one or more amino acid positions 19, 55, 56, 57, 58, and / or 104. In some such embodiments, the mutation is M19K, M19R, M19T, M19E, M19N, M19Q, D55E, D55Q, D55N, D55T, S56A, S56Q, S56V, D57S, D57E, D57Q, T58A, T58V, W104F, W104Y, W104T, W104S, W104A, W104H, W104I, W104Q, or a combination thereof. In another embodiment, the TREM2 agonist antigen binding protein comprises a heavy chain variable region comprising the sequence of SEQ ID NO: 118 with a mutation at one or more amino acid positions 19, 55, 56, 57, 58, and / or 104. Such mutations may include M19K, M19R, M19T, M19E, M19N, M19Q, D55E, D55Q, D55N, D55T, S56A, S56Q, S56V, D57S, D57E, D57Q, T58A, T58V, W104F, W104Y, W104T, W104S, W104A, W104H, W104I, W104Q, or a combination thereof. In certain embodiments, the mutation is M19K, D55E, S56A, D57E, T58A, W104Y, W104T, or a combination thereof.In another embodiment, the TREM2 agonist antigen binding protein comprises a heavy chain variable region comprising the sequence of SEQ ID NO: 123 with a mutation at one or more amino acid positions 27, 55, 56, 57, 58, 105, and / or 106. In some embodiments, the mutations are selected from H27Y, H27D, H27F, H27N, D55E, D55Q, D55N, D55T, S56A, S56Q, S56V, D57S, D57E, D57Q, T58A, T58V, D105E, D105Q, D105T, D105N, D105G, S106A, S106Q, S106V, S106T, or a combination thereof. In yet another embodiment, the TREM2 agonist antigen binding protein comprises a heavy chain variable region comprising the sequence of SEQ ID NO: 124 with a mutation at one or more amino acid positions 55, 56, 57, 58, 105, and / or 106. The mutations in such embodiments may be selected from D55E, D55Q, D55N, D55T, S56A, S56Q, S56V, D57S, D57E, D57Q, T58A, T58V, D105E, D105Q, D105T, D105N, D105G, S106A, S106Q, S106V, S106T, or a combination thereof. In a particular embodiment, the mutation is D55E, D55Q, S56A, D57E, T58A, D105E, D105N, S106A, or a combination thereof. In yet another embodiment, the TREM2 agonist antigen binding protein comprises a heavy chain variable region comprising the sequence of SEQ ID NO: 125 with a mutation at one or more amino acid positions 43, 76, 85, 99, 100, and / or 116. Such mutations may include L43Q, L43K, L43H, I76T, R85S, R85G, R85N, R85D, D99E, D99Q, D99S, D99T, G100A, G100Y, G100V, T116L, T116M, T116P, T116R, or a combination thereof. In a particular embodiment, the mutation is L43Q, R85S, D99E, G100A, G100Y, T116L, or a combination thereof. In another embodiment, the TREM2 agonist antigen binding protein comprises a heavy chain variable region comprising the sequence of SEQ ID NO: 115 with mutations at amino acid positions 62 and / or 63.In such embodiments, the mutations can be selected from D62E, D62Q, D62T, D62N, S63A, S63Q, S63V, or a combination thereof. In some embodiments, the mutations are D62E, D62Q, S63A, or a combination thereof. In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region and / or a heavy chain variable region from any of the anti-TREM2 variant antibodies set forth in Tables 2A, 2B, 3A, 3B, and 19. Thus, in some embodiments, the light chain variable region of the TREM2 agonist antigen binding protein comprises a sequence that is at least 90% identical, at least 91% identical, at least 92% identical, at least 93% identical, at least 94% identical, or at least 95% identical to a sequence selected from SEQ ID NOs: 61, 153-162, and 295-300. In these and other embodiments, the heavy chain variable region of the TREM2 agonist antigen binding protein comprises a sequence that is at least 90% identical, at least 91% identical, at least 92% identical, at least 93% identical, at least 94% identical, or at least 95% identical to a sequence selected from SEQ ID NOs: 124, 180-190, and 307-312.

[0061] In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO: 54 with a mutation at one or more amino acid positions 64, 79, 80, 85, 94, and / or 100. Such mutations may include V64G, V64A, Q79E, Q79D, S80P, S80A, F85V, F85L, F85A, F85D, F85I, F85L, F85M, F85T, W94F, W94Y, W94S, W94T, W94A, W94H, W94I, W94Q, P100R, P100Q, P100G, or a combination thereof. In these and other embodiments, the TREM2 agonist antigen binding protein comprises a heavy chain variable region comprising the sequence of SEQ ID NO: 117 with a mutation at one or more amino acid positions 19, 55, 56, 57, 58, and / or 104. In certain embodiments, the mutations are selected from M19K, M19R, M19T, M19E, M19N, M19Q, D55E, D55Q, D55N, D55T, S56A, S56Q, S56V, D57S, D57E, D57Q, T58A, T58V, W104F, W104Y, W104T, W104S, W104A, W104H, W104I, W104Q, or a combination thereof.

[0062] In other embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO: 55 with a mutation at one or more amino acid positions 64, 79, 80, 94, and / or 100. In some embodiments, the mutations are selected from V64G, V64A, Q79E, Q79D, S80P, S80A, W94F, W94Y, W94S, W94T, W94A, W94H, W94I, W94Q, P100R, P100Q, P100G, or a combination thereof. In certain embodiments, the mutations are selected from V64G, V64A, Q79E, S80P, S80A, W94Y, W94S, P100R, P100Q, or a combination thereof. For example, in some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO: 55 with one or more mutations selected from V64G, Q79E, S80P, W94Y, and P100Q. In these and other embodiments, the TREM2 agonist antigen binding protein comprises a heavy chain variable region comprising the sequence of SEQ ID NO: 118 with mutations at one or more amino acid positions 19, 55, 56, 57, 58, and / or 104. Such mutations may include M19K, M19R, M19T, M19E, M19N, M19Q, D55E, D55Q, D55N, D55T, S56A, S56Q, S56V, D57S, D57E, D57Q, T58A, T58V, W104F, W104Y, W104T, W104S, W104A, W104H, W104I, W104Q, or a combination thereof. In certain embodiments, the mutation is selected from M19K, D55E, S56A, D57E, T58A, W104Y, W104T, or a combination thereof.

[0063] In certain other embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO: 60 with a mutation at one or more amino acid positions 60, 92, and / or 93. The mutations may be selected from L60S, L60P, L60D, L60A, D92E, D92Q, D92T, D92N, S93A, S93N, S93Q, S93V, or a combination thereof. In these and other embodiments, the TREM2 agonist antigen binding protein comprises a heavy chain variable region comprising the sequence of SEQ ID NO: 123 with a mutation at one or more amino acid positions 27, 55, 56, 57, 58, 105, and / or 106. In some embodiments, the mutation is selected from H27Y, H27D, H27F, H27N, D55E, D55Q, D55N, D55T, S56A, S56Q, S56V, D57S, D57E, D57Q, T58A, T58V, D105E, D105Q, D105T, D105N, D105G, S106A, S106Q, S106V, S106T, or a combination thereof.

[0064] In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO: 61 with mutations at one or more amino acid positions 56, 57, 92, and / or 93. In certain embodiments, the mutations are selected from N56S, N56T, N56Q, N56E, G57A, G57V, D92E, D92Q, D92T, D92N, S93A, S93N, S93Q, S93V, or a combination thereof. In some embodiments, the mutations are selected from N56S, N56Q, G57A, D92E, D92Q, S93A, or a combination thereof. In certain embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO: 61 with one or more mutations selected from N56S, D92E, and S93A. In these and other embodiments, the TREM2 agonist antigen binding protein comprises a heavy chain variable region comprising the sequence of SEQ ID NO: 124 with a mutation at one or more amino acid positions 55, 56, 57, 58, 105, and / or 106. The mutations can be selected from D55E, D55Q, D55N, D55T, S56A, S56Q, S56V, D57S, D57E, D57Q, T58A, T58V, D105E, D105Q, D105T, D105N, D105G, S106A, S106Q, S106V, S106T, or a combination thereof. In certain embodiments, the mutation is D55E, D55Q, S56A, D57E, T58A, D105E, D105N, S106A, or a combination thereof. In some embodiments, the TREM2 agonist antigen binding protein comprises a heavy chain variable region comprising the sequence of SEQ ID NO: 124 with one or more mutations selected from D55E, S56A, D57E, D105E, and S106A.

[0065] In other embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO: 62 with mutations at amino acid positions 36, 46, 61, and / or 100. In certain embodiments, the mutations are selected from F36Y, S46L, S46R, S46V, S46F, K61R, P100Q, P100G, P100R, or combinations thereof. In some embodiments, the mutations are F36Y, K61R, P100Q, or combinations thereof. In some embodiments, the mutations are S46L, P100Q, or combinations thereof. In these and other embodiments, the TREM2 agonist antigen binding protein comprises a heavy chain variable region comprising the sequence of SEQ ID NO: 125 with mutations at one or more amino acid positions 43, 76, 85, 99, 100, and / or 116. The mutations can be selected from L43Q, L43K, L43H, I76T, R85S, R85G, R85N, R85D, D99E, D99Q, D99S, D99T, G100A, G100Y, G100V, T116L, T116M, T116P, T116R, or a combination thereof. In certain embodiments, the mutations are L43Q, I76T, R85S, D99E, G100A, G100Y, T116L, or a combination thereof.

[0066] In still other embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO: 52 with a mutation at amino acid position 91. The mutation can be selected from F91V, F91I, F91T, F91L, or F91D. In one embodiment, the mutation is F91V. In these and other embodiments, the TREM2 agonist antigen binding protein comprises a heavy chain variable region comprising the sequence of SEQ ID NO: 115 with a mutation at amino acid position 62 and / or 63. In certain embodiments, the mutation is selected from D62E, D62Q, D62T, D62N, S63A, S63Q, S63V, or a combination thereof. In some embodiments, the mutation is selected from D62E, D62Q, S63A, or a combination thereof. [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10]

[0067] In some embodiments, the TREM2 agonist antigen binding protein comprises one or more CDRs of an anti-TREM2 antibody variant described herein, hi some embodiments, the TREM2 agonist antigen binding protein may comprise one or more CDRs of an anti-TREM2 antibody variant shown in Tables 3A, 3B, 3C, 3D, and 3E below.

[0068] In certain embodiments, the TREM2 agonist antigen binding proteins of the invention comprise a light chain variable region and / or a heavy chain variable region from an affinity-tuned variant of the 6E7 antibody. For example, in some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region and / or a heavy chain variable region with one or more of the amino acid substitutions shown in Table 2G. [Table 11-1] [Table 11-2] [Table 11-3]

[0069] In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the sequence of SEQ ID NO: 61 with a mutation at one or more amino acid positions 24, 31, 50, 52, 54, 56, 89, 92, 93, 94, and / or 96. In certain embodiments, the mutations are selected from R24A, S31R, A50S, A50G, S52G, L54R, N56K, N56R, N56L, N56T, Q89G, D92V, S93R, F94Y, F94L, R96H, R96L, or a combination thereof. In these and other embodiments, the TREM2 agonist antigen binding protein comprises a heavy chain variable region comprising the sequence of SEQ ID NO: 124 with a mutation at one or more amino acid positions 27, 28, 30, 32, 50, 54, 58, 60, 61, 63, 66, 99, 101, 103, 104, and / or 110. In some embodiments, the mutations are selected from Y27S, S28G, S28H, T30N, T30G, T30E, T30A, Y32E, I50T, G54S, T58V, Y60L, S61A, S63G, S63E, G66D, Q99G, Q99S, Q99M, T101G, Y103R, Y104G, F110S, or a combination thereof. The amino acid sequences for the light and heavy chain variable regions and relevant CDRs of exemplary variants of the 6E7 antibody with improved affinity are shown in Tables 3A and 3B below, respectively. The amino acid sequences for the light and heavy chain variable regions and relevant CDRs of exemplary variants of the 6E7 antibody with reduced affinity are shown in Tables 3C and 3D below, respectively. The corresponding sequences for the 6E7 antibody are listed for comparison. [Table 12-1] [Table 12-2] [Table 13-1] [Table 13-2] [Table 13-3]

[0070] In some embodiments, the TREM2 agonist antigen binding proteins of the present invention may comprise one or more of the CDRs from the affinity-improved variants presented in Table 3A (light chain CDRs, i.e., CDRLs) and Table 3B (heavy chain CDRs, i.e., CDRHs). In some embodiments, the TREM2 agonist antigen binding protein comprises a consensus CDR sequence derived from an affinity-improved variant. For example, in some embodiments, the TREM2 agonist antigen binding protein comprises a CDRL2 consensus sequence of X1ASSX2QX3 (SEQ ID NO: 139), where X1 is A or G, X2 is L or R, and X3 is N, K, R, L, or T. In another embodiment, the TREM2 agonist antigen binding protein comprises a CDRL3 consensus sequence of X1QADX2X3PX4T (SEQ ID NO: 140), where X1 is Q or G, X2 is S or R, X3 is F, L, or Y, and X4 is R or H. In yet another embodiment, the TREM2 agonist antigen binding protein comprises a CDRH2 consensus sequence of X1IYPGDSDX2RX3X4PX5FQX6 (SEQ ID NO: 141), where X1 is I or T, X2 is T or V, X3 is Y or L, X4 is S or A, X5 is S, G, or E, and X6 is G or D. In some embodiments, the TREM2 agonist antigen binding protein comprises a CDRH3 consensus sequence of X1RTFYYDSSDYX2DY (SEQ ID NO: 142), where X1 is Q, G, S, or M, and X2 is F or S.

[0071] In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising complementarity determining regions CDRL1, CDRL2, and CDRL3, and a heavy chain variable region comprising complementarity determining regions CDRH1, CDRH2, and CDRH3, wherein CDRL1 comprises the sequence of SEQ ID NO: 16, CDRL2 comprises the consensus sequence of SEQ ID NO: 139, CDRL3 comprises the consensus sequence of SEQ ID NO: 140, CDRH1 comprises the sequence of SEQ ID NO: 85, CDRH2 comprises the consensus sequence of SEQ ID NO: 141, and CDRH3 comprises the consensus sequence of SEQ ID NO: 142.

[0072] In some embodiments, the TREM2 agonist antigen binding protein comprises a CDRL1 comprising the sequence of SEQ ID NO: 16, a CDRL2 comprising a sequence selected from SEQ ID NOs: 26 and 143-147, a CDRL3 comprising a sequence selected from SEQ ID NOs: 43 and 148-152, a CDRH1 comprising the sequence of SEQ ID NO: 85, a CDRH2 comprising a sequence selected from SEQ ID NOs: 91 and 170-175, and a CDRH3 comprising a sequence selected from SEQ ID NOs: 176-179.

[0073] In certain embodiments, the TREM2 agonist antigen binding protein of the invention comprises a light chain variable region comprising CDRL1, CDRL2, and CDRL3; (a) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 16, 143, and 148, respectively; (b) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 16, 144, and 149, respectively; (c) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 16, 145, and 43, respectively; (d) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 16, 146, and 148, respectively; (e) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 16, 26, and 150, respectively; (f) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 16, 143, and 151, respectively; (g) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 16, 145, and 148, respectively; (h) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 16, 145, and 152, respectively; (i) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 16, 144, and 43, respectively; or (j) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 16, 147, and 43, respectively.

[0074] In a related embodiment, the TREM2 agonist antigen binding protein of the invention comprises a heavy chain variable region comprising CDRH1, CDRH2, and CDRH3; (a) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 85, 170, and 176, respectively; (b) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 85, 171, and 177, respectively; (c) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 85, 172, and 177, respectively; (d) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 85, 171, and 178, respectively; (e) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 85, 171, and 179, respectively; (f) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 85, 173, and 177, respectively; (g) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 85, 91, and 176, respectively; (h) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 85, 174, and 176, respectively; (i) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 85, 175, and 178, respectively; or (j) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 85, 91, and 178, respectively.

[0075] In some embodiments, the TREM2 agonist antigen binding protein of the invention comprises a light chain variable region comprising CDRL1, CDRL2, and CDRL3, and a heavy chain variable region comprising CDRH1, CDRH2, and CDRH3; (a) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 16, 143, and 148, respectively, and CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 85, 170, and 176, respectively; (b) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 16, 144, and 149, respectively, and CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 85, 171, and 177, respectively; (c) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 16, 145, and 43, respectively, and CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 85, 172, and 177, respectively; (d) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 16, 146, and 148, respectively, and CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 85, 171, and 178, respectively; (e) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 16, 26, and 150, respectively, and CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 85, 171, and 179, respectively; (f) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 16, 143, and 151, respectively, and CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 85, 173, and 177, respectively; (g) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 16, 145, and 148, respectively, and CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 85, 91, and 176, respectively; (h) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 16, 145, and 152, respectively, and CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 85, 171, and 178, respectively; (i) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 16, 143, and 151, respectively, and CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 85, 174, and 176, respectively; (j) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 16, 144, and 43, respectively, and CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 85, 175, and 178, respectively; or (k) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 16, 147, and 43, respectively, and CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 85, 91, and 178, respectively.

[0076] In some embodiments, a TREM2 agonist antigen binding protein of the invention may comprise a light chain variable region selected from LV-101, LV-102, LV-103, LV-104, LV-105, LV-106, LV-107, LV-108, LV-109, and LV-110, as shown in Table 3A, and / or a heavy chain variable region selected from HV-101, HV-102, HV-103, HV-104, HV-105, HV-106, HV-107, HV-108, HV-109, HV-110, and HV-111, as shown in Table 3B, or a sequence that is at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical to any of the sequences in Tables 3A and 3B. For example, in some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising (i) a sequence at least 90% identical to a sequence selected from SEQ ID NOs: 153-162, (ii) a sequence at least 95% identical to a sequence selected from SEQ ID NOs: 153-162, or (iii) a sequence selected from SEQ ID NOs: 153-162. In related embodiments, the TREM2 agonist antigen binding protein comprises a heavy chain variable region comprising (i) a sequence at least 90% identical to a sequence selected from SEQ ID NOs: 180-190, (ii) a sequence at least 95% identical to a sequence selected from SEQ ID NOs: 180-190, or (iii) a sequence selected from SEQ ID NOs: 180-190.

[0077] Each of the light chain variable regions listed in Table 3A may be combined with any of the heavy chain variable regions listed in Table 3B to form the anti-TREM2 binding domain of an antigen binding protein of the invention. Examples of such combinations include, but are not limited to, the following: LV-101 (SEQ ID NO: 153) and HV-101 (SEQ ID NO: 180), LV-102 (SEQ ID NO: 154) and HV-102 (SEQ ID NO: 181), LV-103 (SEQ ID NO: 155) and HV-103 (SEQ ID NO: 182), LV-104 (SEQ ID NO: 156) and HV-104 (SEQ ID NO: 183), LV-105 (SEQ ID NO: 157) and HV-105 (SEQ ID NO: 184), LV-106 (SEQ ID NO: 158) and HV-106 (SEQ ID NO: 185), LV-107 (SEQ ID NO: 159) and HV-107 (SEQ ID NO: 190), LV-108 (SEQ ID NO: 191) and HV-108 (SEQ ID NO: 192), LV-109 (SEQ ID NO: 193) and HV-109 (SEQ ID NO: 194), LV-110 (SEQ ID NO: 115) and HV-110 (SEQ ID NO: 195), LV-111 (SEQ ID NO: 116) and HV-111 (SEQ ID NO: 196), LV-112 (SEQ ID NO: 117) and HV-112 (SEQ ID NO: 197), LV-113 (SEQ ID NO: 118) and HV-113 (S 6 (SEQ ID NO: 158) and HV-106 (SEQ ID NO: 185), LV-107 (SEQ ID NO: 159) and HV-107 (SEQ ID NO: 186), LV-108 (SEQ ID NO: 160) and HV-108 (SEQ ID NO: 187), LV-106 (SEQ ID NO: 158) and HV-109 (SEQ ID NO: 188), LV-109 (SEQ ID NO: 161) and HV-110 (SEQ ID NO: 189), and LV-110 (SEQ ID NO: 162) and HV-111 (SEQ ID NO: 190). [Table 14] [Table 15-1] [Table 15-2]

[0078] In some embodiments, the TREM2 agonist antigen binding proteins of the present invention may comprise one or more of the CDRs from the affinity-reduced variants presented in Table 3C (light chain CDRs, i.e., CDRLs) and Table 3D (heavy chain CDRs, i.e., CDRHs). In some embodiments, the TREM2 agonist antigen binding protein comprises consensus CDR sequences derived from affinity-reduced variants. For example, in one embodiment, the TREM2 agonist antigen binding protein comprises a CDRL1 consensus sequence of X1ASQGISX2WLA (SEQ ID NO: 284), where X1 is R or A and X2 is S or R. In another embodiment, the TREM2 agonist antigen binding protein comprises a CDRL2 consensus sequence of X1AX2SLQN (SEQ ID NO: 285), where X1 is A or S and X2 is S or G. In another embodiment, the TREM2 agonist antigen binding protein comprises a CDRH3 consensus sequence of QQAX1SFPX2T (SEQ ID NO: 286), where X1 is D or V and X2 is R or L. In another embodiment, the TREM2 agonist antigen binding protein comprises a CDRH1 consensus sequence of SX1WIA (SEQ ID NO: 287), where X1 is Y or E. In yet another embodiment, the TREM2 agonist antigen binding protein comprises a CDRH2 consensus sequence of IIYPX1DSDTRYSPSFQG (SEQ ID NO: 288), where X1 is G or S. In yet another embodiment, the TREM2 agonist antigen binding protein comprises a CDRH3 consensus sequence of QRX1FX2X3DSSDYFDY (SEQ ID NO: 289), where X1 is T or G, X2 is Y or R, and X3 is Y or G.In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising complementarity determining regions CDRL1, CDRL2, and CDRL3, and a heavy chain variable region comprising complementarity determining regions CDRH1, CDRH2, and CDRH3, wherein CDRL1 comprises the sequence of SEQ ID NO: 284, CDRL2 comprises the consensus sequence of SEQ ID NO: 285, CDRL3 comprises the consensus sequence of SEQ ID NO: 286, CDRH1 comprises the sequence of SEQ ID NO: 287, CDRH2 comprises the consensus sequence of 288, and CDRH3 comprises the consensus sequence of 289.

[0079] In some embodiments, the TREM2 agonist antigen binding proteins of the present invention comprise a CDRL1 comprising a sequence selected from SEQ ID NOs: 16, 290, and 291; a CDRL2 comprising a sequence selected from SEQ ID NOs: 28, 292, and 293; a CDRL3 comprising a sequence selected from SEQ ID NOs: 43, 294, and 271; a CDRH1 comprising the sequence of SEQ ID NO: 85 or SEQ ID NO: 302; a CDRH2 comprising the sequence of SEQ ID NO: 91 or SEQ ID NO: 303; and a CDRH3 comprising a sequence selected from SEQ ID NOs: 107 and 304-306.

[0080] In some embodiments, the TREM2 agonist antigen binding protein of the present invention comprises a light chain variable region comprising CDRL1, CDRL2, and CDRL3; (a) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 16, 28, and 43, respectively; (b) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 16, 292, and 43, respectively; (c) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 16, 28, and 294, respectively; (d) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 290, 28, and 43, respectively; (e) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 16, 293, and 43, respectively; (f) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 16, 28, and 271, respectively; or (g) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 291, 28, and 43, respectively.

[0081] In a related embodiment, the TREM2 agonist antigen binding protein of the invention comprises a heavy chain variable region comprising CDRH1, CDRH2, and CDRH3; (a) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 85, 91, and 304, respectively; (b) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 85, 91, and 107, respectively; (c) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 85, 91, and 305, respectively; (d) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 85, 303, and 107, respectively; (e) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 85, 91, and 306, respectively; or (f) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 302, 91, and 107, respectively.

[0082] In some embodiments, the TREM2 agonist antigen binding protein of the invention comprises a light chain variable region comprising CDRL1, CDRL2, and CDRL3, and a heavy chain variable region comprising CDRH1, CDRH2, and CDRH3; (a) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 16, 28, and 43, respectively, and CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 85, 91, and 304, respectively; (b) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 16, 292, and 43, respectively, and CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 85, 91, and 107, respectively; (c) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 16, 28, and 294, respectively, and CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 85, 91, and 107, respectively; (d) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 16, 28, and 43, respectively, and CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 85, 91, and 107, respectively; (e) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 16, 28, and 43, respectively, and CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 85, 91, and 305, respectively; (f) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 16, 28, and 43, respectively, and CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 85, 303, and 107, respectively; (g) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 290, 28, and 43, respectively, and CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 85, 91, and 107, respectively; (h) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 16, 28, and 43, respectively, and CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 85, 91, and 306, respectively; (i) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 16, 293, and 43, respectively, and CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 85, 91, and 107, respectively; (j) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 16, 28, and 271, respectively, and CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 85, 91, and 107, respectively; or (k) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 291, 28, and 43, respectively, and CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 302, 91, and 107, respectively.

[0083] In some embodiments, a TREM2 agonist antigen binding protein of the invention may comprise a light chain variable region selected from LV-16, LV-201, LV-202, LV-203, LV-204, LV-205, and LV-206, as shown in Table 3C, and / or a heavy chain variable region selected from HV-15, HV-201, HV-202, HV-203, HV-204, HV-205, and HV-206, as shown in Table 3D, or a sequence that is at least 80% identical, at least 85% identical, at least 90% identical, or at least 95% identical to any of the sequences in Tables 3C and 3D. For example, in certain embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising (i) a sequence at least 90% identical to a sequence selected from SEQ ID NOs: 61 and 295-300, (ii) a sequence at least 95% identical to a sequence selected from SEQ ID NOs: 61 and 295-300, or (iii) a sequence selected from SEQ ID NOs: 61 and 295-300. In related embodiments, the TREM2 agonist antigen binding protein comprises a heavy chain variable region comprising (i) a sequence at least 90% identical to a sequence selected from SEQ ID NOs: 124 and 307-312, (ii) a sequence at least 95% identical to a sequence selected from SEQ ID NOs: 124 and 307-312, or (iii) a sequence selected from SEQ ID NOs: 124 and 307-312.

[0084] In some embodiments, each of the light chain variable regions listed in Table 3C may be combined with any of the heavy chain variable regions listed in Table 3D to form the anti-TREM2 binding domain of an antigen binding protein of the invention. Examples of such combinations include, but are not limited to, the following: LV-16 (SEQ ID NO:61) and HV-201 (SEQ ID NO:307), LV-201 (SEQ ID NO:295) and HV-15 (SEQ ID NO:124), LV-202 (SEQ ID NO:296) and HV-15 (SEQ ID NO:124), LV-16 (SEQ ID NO:61) and HV-202 (SEQ ID NO:308), LV-16 (SEQ ID NO:61) and HV-202 (SEQ ID NO:308). 03 (SEQ ID NO: 309), LV-16 (SEQ ID NO: 61) and HV-204 (SEQ ID NO: 310), LV-203 (SEQ ID NO: 297) and HV-15 (SEQ ID NO: 124), LV-16 (SEQ ID NO: 61) and HV-205 (SEQ ID NO: 311), LV-204 (SEQ ID NO: 298) and HV-15 (SEQ ID NO: 124), LV-205 (SEQ ID NO: 299) and HV-15 (SEQ ID NO: 124), and LV-206 (SEQ ID NO: 300) and HV-206 (SEQ ID NO: 312).

[0085] In some embodiments, the TREM2 agonist antigen binding protein comprises one or more CDRs of an anti-TREM2 antibody variant shown in Table 3E. In some embodiments, the TREM2 agonist antigen binding protein comprises the light chain variable region and the heavy chain variable region of an anti-TREM2 antibody variant shown in Table 3E. [Table 16]

[0086] In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising CDRL1, CDRL2, and CDRL3; (a) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 16, 369, and 370, respectively; (b) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 361, 23, and 372, respectively; or (c) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 357, 21, and 33, respectively; (d) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 357, 20, and 33, respectively.

[0087] In some embodiments, the TREM2 agonist antigen binding protein comprises a heavy chain variable region comprising CDRH1, CDRH2, and CDRH3; (a) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 77, 368, and 98, respectively; (b) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 85, 371, and 107, respectively; (c) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 81, 373, and 374, respectively; or (d) CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 86, 94, and 375, respectively.

[0088] In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising CDRL1, CDRL2, and CDRL3, and a heavy chain variable region comprising CDRH1, CDRH2, and CDRH3; (a) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 359, 22, and 35, respectively, and CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 77, 368, and 98, respectively; (b) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 16, 369, and 370, respectively, and CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 85, 371, and 107, respectively; (c) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 361, 23, and 372, respectively, and CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 81, 373, and 374, respectively; or (d) CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 17, 29, and 44, respectively, and CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 86, 94, and 375, respectively.

[0089] Thus, in some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising CDRL1, CDRL2, and CDRL3, and a heavy chain variable region comprising CDRH1, CDRH2, and CDRH3, wherein CDRL1, CDRL2, and CDRL3 have the sequences of SEQ ID NOs: 361, 23, and 372, respectively, and CDRH1, CDRH2, and CDRH3 have the sequences of SEQ ID NOs: 81, 373, and 374, respectively.

[0090] In some embodiments, the invention therefore provides a method of treating ALSP in a human patient, the method comprising administering to the patient an effective amount of a TREM2 agonist antigen binding protein comprising CDRL1, CDRL2, and CDRL3 having the sequences of SEQ ID NOs: 361, 23, and 372, respectively, and CDRH1, CDRH2, and CDRH3 having the sequences of SEQ ID NOs: 81, 373, and 374, respectively. In certain embodiments, the antibody is human. In some embodiments, the TREM2 agonist antigen binding protein is (a) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 326, and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 327; (b) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 328, and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 329; (c) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 330 and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 331; or (d) a light chain variable region comprising the amino acid sequence of SEQ ID NO: 332, and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 333.

[0091] In some embodiments, the TREM2 agonist antigen binding protein comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:330, and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:331.

[0092] In some embodiments, the invention therefore provides a method of treating ALSP in a human patient, the method comprising administering to the patient an effective amount of a TREM2 agonist antigen binding protein comprising a light chain variable region comprising the amino acid sequence of SEQ ID NO: 330, and a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 331. In certain embodiments, the antibody is human.

[0093] In some embodiments, TREM2 agonist antigen binding proteins of the invention comprise a light chain variable region consisting of, or consisting essentially of, the amino acid sequence of SEQ ID NO: 326, 328, 330, or 332. In some embodiments, TREM2 agonist antigen binding proteins of the invention comprise a heavy chain variable region consisting of, or consisting essentially of, the amino acid sequence of SEQ ID NO: 327, 329, 331, or 333. In specific embodiments, TREM2 agonist antigen binding proteins of the invention comprise a light chain variable region and a heavy chain variable region, wherein the light chain variable region consists of, or consists essentially of, the amino acid sequence of SEQ ID NO: 326, and the heavy chain variable region consists of, or consists essentially of the amino acid sequence of SEQ ID NO: 327. In specific embodiments, TREM2 agonist antigen binding proteins of the invention comprise a light chain variable region and a heavy chain variable region, wherein the light chain variable region consists of, or consists essentially of, the amino acid sequence of SEQ ID NO: 328, and the heavy chain variable region consists of, or consists essentially of the amino acid sequence of SEQ ID NO: 329. In certain embodiments, the TREM2 agonist antigen binding proteins of the invention comprise a light chain variable region and a heavy chain variable region, wherein the light chain variable region consists of or consists essentially of the amino acid sequence of SEQ ID NO: 330 and the heavy chain variable region consists of or consists essentially of the amino acid sequence of SEQ ID NO: 331. In certain embodiments, the TREM2 agonist antigen binding proteins of the invention comprise a light chain variable region and a heavy chain variable region, wherein the light chain variable region consists of or consists essentially of the amino acid sequence of SEQ ID NO: 332 and the heavy chain variable region consists of or consists essentially of the amino acid sequence of SEQ ID NO: 333.

[0094] In some embodiments, each of the light chain variable regions disclosed in Tables 1A, 3A, 3C, and 3E, and each of the heavy chain variable regions disclosed in Tables 1B, 3B, 3D, and 3E, may be joined to a light chain constant region and a heavy chain constant region to form complete antibody light and heavy chains, respectively, as further discussed below. Furthermore, each of the generated heavy and light chain sequences may be combined to form complete antibody structures. It should be understood that the heavy and light chain variable regions provided herein may also be joined to other constant domains having sequences different from the exemplary sequences listed herein.

[0095] In some embodiments, exemplary TREM2 agonist antibodies having a light chain variable region with a light chain constant domain and a heavy chain variable region with a heavy chain constant domain are disclosed in Table 3F. [Table 17-1] [Table 17-2] [Table 17-3]

[0096] In some embodiments, TREM2 agonist antigen binding proteins of the invention comprise a light chain comprising the sequence of SEQ ID NO: 334 and a heavy chain comprising the sequence of SEQ ID NO: 335. In some embodiments, TREM2 agonist antigen binding proteins of the invention comprise a light chain comprising the sequence of SEQ ID NO: 334 and a heavy chain comprising the sequence of SEQ ID NO: 336. In some embodiments, TREM2 agonist antigen binding proteins of the invention comprise a light chain comprising the sequence of SEQ ID NO: 337 and a heavy chain comprising the sequence of SEQ ID NO: 338. In some embodiments, TREM2 agonist antigen binding proteins of the invention comprise a light chain comprising the sequence of SEQ ID NO: 339 and a heavy chain comprising the sequence of SEQ ID NO: 340. In some embodiments, TREM2 agonist antigen binding proteins of the invention comprise a light chain comprising the sequence of SEQ ID NO: 341 and a heavy chain comprising the sequence of SEQ ID NO: 342. In some embodiments, TREM2 agonist antigen binding proteins of the invention comprise a light chain comprising the sequence of SEQ ID NO: 343 and a heavy chain comprising the sequence of SEQ ID NO: 344. In some embodiments, a TREM2 agonist antigen binding protein of the invention comprises a light chain comprising the sequence of SEQ ID NO: 343, and a heavy chain comprising the sequence of SEQ ID NO: 345. In some embodiments, a TREM2 agonist antigen binding protein of the invention comprises a light chain comprising the sequence of SEQ ID NO: 346, and a heavy chain comprising the sequence of SEQ ID NO: 347. In some embodiments, a TREM2 agonist antigen binding protein of the invention comprises a light chain comprising the sequence of SEQ ID NO: 348, and a heavy chain comprising the sequence of SEQ ID NO: 349. In some embodiments, a TREM2 agonist antigen binding protein of the invention comprises a light chain comprising the sequence of SEQ ID NO: 350, and a heavy chain comprising the sequence of SEQ ID NO: 351.

[0097] In some embodiments, the invention provides a method of treating ALSP in a human patient, the method comprising administering to the patient an effective amount of a TREM2 agonist antigen binding protein comprising a light chain comprising the sequence of SEQ ID NO: 334 and a heavy chain comprising the sequence of SEQ ID NO: 335. In some embodiments, the invention provides a method of treating ALSP in a human patient, the method comprising administering to the patient an effective amount of a TREM2 agonist antigen binding protein comprising a light chain comprising the sequence of SEQ ID NO: 334 and a heavy chain comprising the sequence of SEQ ID NO: 336. In some embodiments, the invention provides a method of treating ALSP in a human patient, the method comprising administering to the patient an effective amount of a TREM2 agonist antigen binding protein comprising a light chain comprising the sequence of SEQ ID NO: 337 and a heavy chain comprising the sequence of SEQ ID NO: 338. In some embodiments, the invention provides a method of treating ALSP in a human patient, the method comprising administering to the patient an effective amount of a TREM2 agonist antigen binding protein comprising a light chain comprising the sequence of SEQ ID NO: 339 and a heavy chain comprising the sequence of SEQ ID NO: 340. In some embodiments, the invention provides a method of treating ALSP in a human patient, the method comprising administering to the patient an effective amount of a TREM2 agonist antigen binding protein comprising a light chain comprising the sequence of SEQ ID NO: 341 and a heavy chain comprising the sequence of SEQ ID NO: 342. In some embodiments, the invention provides a method of treating ALSP in a human patient, the method comprising administering to the patient an effective amount of a TREM2 agonist antigen binding protein comprising a light chain comprising the sequence of SEQ ID NO: 343 and a heavy chain comprising the sequence of SEQ ID NO: 344. In some embodiments, the invention provides a method of treating ALSP in a human patient, the method comprising administering to the patient an effective amount of a TREM2 agonist antigen binding protein comprising a light chain comprising the sequence of SEQ ID NO: 343 and a heavy chain comprising the sequence of SEQ ID NO: 345. In some embodiments, the invention provides a method of treating ALSP in a human patient, the method comprising administering to the patient an effective amount of a TREM2 agonist antigen binding protein comprising a light chain comprising the sequence of SEQ ID NO: 346 and a heavy chain comprising the sequence of SEQ ID NO: 347.In some embodiments, the invention therefore provides a method of treating ALSP in a human patient, the method comprising administering to the patient an effective amount of a TREM2 agonist antigen binding protein comprising a light chain comprising the sequence of SEQ ID NO: 348 and a heavy chain comprising the sequence of SEQ ID NO: 349. In some embodiments, the invention provides a method of treating ALSP in a human patient, the method comprising administering to the patient an effective amount of a TREM2 agonist antigen binding protein comprising a light chain comprising the sequence of SEQ ID NO: 350 and a heavy chain comprising the sequence of SEQ ID NO: 351. In some embodiments, the invention provides a method of treating ALSP in a human patient, the method comprising administering to the patient an effective amount of a TREM2 agonist antigen binding protein comprising a light chain comprising the sequence of SEQ ID NO: 352 and a heavy chain comprising the sequence of SEQ ID NO: 353.

[0098] In some embodiments, the TREM2 agonist antigen binding proteins of the invention comprise a light chain consisting of, or consisting essentially of, the amino acid sequence of SEQ ID NO: 334, 337, 339, or 341. In some embodiments, the TREM2 agonist antigen binding proteins of the invention comprise a light chain consisting of, or consisting essentially of, the amino acid sequence of SEQ ID NO: 343, 346, 348, or 350. In some embodiments, the TREM2 agonist antigen binding proteins of the invention comprise a heavy chain consisting of, or consisting essentially of, the amino acid sequence of SEQ ID NO: 335, 336, 338, 340, or 342. In some embodiments, the TREM2 agonist antigen binding proteins of the invention comprise a heavy chain consisting of, or consisting essentially of the amino acid sequence of SEQ ID NO: 344, 345, 347, 349, or 351. In certain embodiments, the TREM2 agonist antigen binding proteins of the invention comprise a light chain and a heavy chain, (a) the light chain consists of or consists essentially of the amino acid sequence of SEQ ID NO: 334 and the heavy chain consists of or consists essentially of the amino acid sequence of SEQ ID NO: 335; (b) the light chain consists of or consists essentially of the amino acid sequence of SEQ ID NO: 334 and the heavy chain consists of or consists essentially of the amino acid sequence of SEQ ID NO: 336; (c) the light chain consists of or consists essentially of the amino acid sequence of SEQ ID NO: 337 and the heavy chain consists of or consists essentially of the amino acid sequence of SEQ ID NO: 338; (d) the light chain consists of or consists essentially of the amino acid sequence of SEQ ID NO: 339 and the heavy chain consists of or consists essentially of the amino acid sequence of SEQ ID NO: 340; or (e) the light chain consists of or consists essentially of the amino acid sequence of SEQ ID NO: 341 and the heavy chain consists of or consists essentially of the amino acid sequence of SEQ ID NO: 342.

[0099] In certain embodiments, the TREM2 agonist antigen binding protein of the invention comprises a light chain and a heavy chain, (a) the light chain consists of or consists essentially of the amino acid sequence of SEQ ID NO: 343 and the heavy chain consists of or consists essentially of the amino acid sequence of SEQ ID NO: 344; (b) the light chain consists of or consists essentially of the amino acid sequence of SEQ ID NO: 343 and the heavy chain consists of or consists essentially of the amino acid sequence of SEQ ID NO: 345; (c) the light chain consists of or consists essentially of the amino acid sequence of SEQ ID NO: 346 and the heavy chain consists of or consists essentially of the amino acid sequence of SEQ ID NO: 347; (d) the light chain consists of or consists essentially of the amino acid sequence of SEQ ID NO: 348 and the heavy chain consists of or consists essentially of the amino acid sequence of SEQ ID NO: 349; (e) the light chain consists of or consists essentially of the amino acid sequence of SEQ ID NO: 350 and the heavy chain consists of or consists essentially of the amino acid sequence of SEQ ID NO: 351; or (f) the light chain consists of or consists essentially of the amino acid sequence of SEQ ID NO: 352 and the heavy chain consists of or consists essentially of the amino acid sequence of SEQ ID NO: 353.

[0100] Unless otherwise indicated by reference to a particular sequence in Tables 1A, 1B, 3A, 3B, 3C, 3D, 3E, and in the related discussion, the numbering of amino acid residues in an immunoglobulin heavy or light chain is according to the Kabat-EU numbering scheme as set forth in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed., US Department of Health and Human Services, NIH publication No. 91-3242, pp. 662, 680, 689 (1991) and Edelman et al., Proc. Natl. Acad. USA, Vol. 63:78-85 (1969). The Kabat numbering scheme is typically used when referring to amino acid positions within variable regions, while the EU numbering scheme is generally used when referring to amino acid positions associated with immunoglobulin constant regions.

[0101] In some embodiments, the TREM2 antigen binding protein comprises an antibody that competes with an antibody comprising a CDRL1, CDRL2, CDRL3, or light chain variable region disclosed in Tables 1A, 3A, 3C, and 3E, and a heavy chain variable region disclosed in Tables 1B, 3B, 3D, and 3E. In some embodiments, a suitable assay for detecting competitive binding employs a kinetic sensor used in the Octet® system (Pall ForteBio), which uses biolayer interferometry to measure binding interactions. One group of antibodies, antibodies 10E3, 13E7, 24F4, 4C5, 4G10, 32E3, and 6E7, compete with each other for binding to human TREM2, indicating that they share the same or similar epitopes on human TREM2. Antibodies 16B8, 26A10, 26C10, 26F2, 33B12, and 5E3 compete with each other for TREM2 binding but not with the antibodies in the first group or with antibodies 24A10, 24G6, or 25F12, indicating that this second group of antibodies binds to distinct epitopes on human TREM2. Antibodies 24A10 and 24G6 share a similar epitope on human TREM2, as these two antibodies compete with each other for human TREM2 binding but not with any other antibodies. Antibody 25F12 did not compete with any of the other tested antibodies for human TREM2 binding, indicating that this antibody binds to an additional epitope.

[0102] In some embodiments, the TREM2 agonist antigen binding protein competes with a reference antibody for binding to human TREM2, wherein the reference antibody comprises a light chain variable region comprising a sequence selected from SEQ ID NOs: 46-63, and a heavy chain variable region comprising a sequence selected from SEQ ID NOs: 110-126. In other embodiments, the TREM2 agonist antigen binding protein of the invention competes with a reference antibody for binding to human TREM2, wherein the reference antibody comprises a light chain variable region comprising a sequence selected from SEQ ID NOs: 153-162, and a heavy chain variable region comprising a sequence selected from SEQ ID NOs: 180-190. In yet other embodiments, the TREM2 agonist antigen binding protein of the invention competes with a reference antibody for binding to human TREM2, wherein the reference antibody comprises a light chain variable region comprising a sequence selected from SEQ ID NOs: 61 and 295-300, and a heavy chain variable region comprising a sequence selected from SEQ ID NOs: 124 and 307-312. In certain embodiments, the TREM2 agonist antigen binding proteins of the invention compete for binding to human TREM2 with one or more of the anti-TREM2 antibodies described herein, including 12G10, 26A10, 26C10, 26F2, 33B12, 24C12, 24G6, 24A10, 10E3, 13E7, 14C12, 25F12, 32E3, 24F4, 16B8, 4C5, 6E7, 5E3, 4G10, V3, V9, V10, V23, V24, V27, V30, V33, V40, V44, V48, V49, V52, V57, V60, V68, V70, V73, V76, V83, V84, and V90.

[0103] In some embodiments, the TREM2 agonist antigen binding protein competes with a reference antibody for binding to human TREM2, where the reference antibody comprises a light chain variable region comprising the sequence of SEQ ID NO: 61 and a heavy chain variable region comprising the sequence of SEQ ID NO: 124. In such embodiments, the antigen binding protein that competes with this reference antibody for binding to human TREM2 may bind to the same or a similar epitope as antibody 6E7 or other antibodies 10E3, 13E7, 24F4, 4C5, 4G10, and 32E3.

[0104] In some embodiments, the TREM2 agonist antigen binding protein competes with a reference antibody for binding to human TREM2, where the reference antibody comprises a light chain variable region comprising the sequence of SEQ ID NO: 62 and a heavy chain variable region comprising the sequence of SEQ ID NO: 125. In such embodiments, the antigen binding protein that competes with this reference antibody for binding to human TREM2 may bind to the same or a similar epitope as antibody 5E3 or other antibodies 16B8, 26A10, 26C10, 26F2, and 33B12.

[0105] In some embodiments, the TREM2 agonist antigen binding protein competes with a reference antibody for binding to human TREM2, where the reference antibody comprises a light chain variable region comprising the sequence of SEQ ID NO: 52 and a heavy chain variable region comprising the sequence of SEQ ID NO: 115. In such embodiments, the antigen binding protein that competes with this reference antibody for binding to human TREM2 may bind to the same or a similar epitope as antibody 24G6 or antibody 24A10.

[0106] In some embodiments, the TREM2 agonist antigen binding protein competes with a reference antibody for binding to human TREM2, where the reference antibody comprises a light chain variable region comprising the sequence of SEQ ID NO: 56 and a heavy chain variable region comprising the sequence of SEQ ID NO: 119. In such embodiments, the antigen binding protein that competes with this reference antibody for binding to human TREM2 may bind to the same or a similar epitope as antibody 25F12.

[0107] In some embodiments, isolated nucleic acids encoding the anti-TREM2 binding domain of an antigen binding protein of the invention may be used to synthesize the antigen binding protein or to generate variants. In some embodiments, a polynucleotide may comprise a nucleotide sequence that is at least 80% identical, at least 90% identical, at least 95% identical, or at least 98% identical to any of the nucleotide sequences listed in Table 3G. [Table 18-1] [Table 18-2] [Table 18-3] [Table 18-4] [Table 18-5] [Table 18-6] [Table 18-7] [Table 18-8] [Table 18-9]

[0108] In some embodiments, the isolated nucleic acid encoding the anti-TREM2 antibody light chain variable region comprises a sequence that is at least 80% identical, at least 90% identical, at least 95% identical, or at least 98% identical to a sequence selected from SEQ ID NOs: 208-236 and 313-318. In particular embodiments, the isolated nucleic acid encoding the anti-TREM2 antibody light chain variable region comprises a sequence selected from SEQ ID NOs: 208-236 and 313-318. In related embodiments, the isolated nucleic acid encoding the anti-TREM2 antibody heavy chain variable region comprises a sequence that is at least 80% identical, at least 90% identical, at least 95% identical, or at least 98% identical to a sequence selected from SEQ ID NOs: 237-264 and 319-325. In other related embodiments, the isolated nucleic acid encoding the anti-TREM2 antibody heavy chain variable region comprises a sequence selected from SEQ ID NOs: 237-264 and 319-325.

[0109] In some embodiments, the polynucleotides encode a full-length light chain and a full-length heavy chain. Exemplary polynucleotide sequences are provided in Table 3F.

[0110] In some embodiments, the present invention provides methods for treating adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a human patient, comprising administering to the patient anti-TREM2 antibody "Ab-1." In some embodiments, the methods of the present invention comprise administering to the human patient a liquid formulation described herein.

[0111] As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of, a disease or disorder described herein, or one or more symptoms thereof. In some embodiments, treatment may be administered after one or more symptoms have occurred. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, e.g., to prevent or delay their recurrence.

[0112] As used herein, a patient or subject "in need of prevention," "in need of treatment," or "in need thereof" refers to a patient or subject who has a confirmed mutation in the CSF1R gene and therefore has ALSP. Such a patient would reasonably benefit from a given treatment or therapy, as determined by a suitable medical professional (e.g., in the case of a human, a physician, nurse, or nurse practitioner; in the case of a non-human mammal, a veterinarian).

[0113] As used herein, an "asymptomatic" patient or subject refers to a person who has a confirmed mutation in the CSF1R gene and is therefore susceptible to ALSP, but does not have symptoms consistent with ALSP. Symptoms of ALSP include cognitive impairment, frontal lobe dysfunction, psychiatric symptoms, extrapyramidal symptoms, pyramidal symptoms, involuntary movements, gait disturbances, convulsions, pathological reflexes, speech disorders, dysphagia, apraxia, sensory disturbances, autonomic symptoms, headache, stroke, dementia, encephalitis, memory loss, depression, loss of executive function, bradykinesia, rigidity, and / or cerebellar symptoms. In one embodiment, the patient or subject has elevated neurofilament light chain protein (NfL). In another embodiment, the patient or subject lacks elevated neurofilament light chain protein (NfL). In one embodiment, the patient or subject has reduced levels of soluble colony-stimulating factor 1 receptor (sCSF1R). In another embodiment, the patient or subject lacks suppressed levels of soluble colony-stimulating factor 1 receptor (sCSF1R). In a further embodiment, the patient or subject has bilateral cerebral white matter lesions with or without thinning of the corpus callosum as measured by magnetic resonance imaging (MRI).

[0114] As used herein, a "prodromal" patient or subject refers to one who has a confirmed mutation in the CSF1R gene and MRI findings, but who is asymptomatic for ALSP.

[0115] A "therapeutically effective amount" or "therapeutically effective dose" of a drug or therapeutic agent, e.g., the anti-TREM2 antibody "Ab-1," is any quantity of the agent that, when used alone or in combination with another therapeutic agent, protects a patient or subject from developing a disease, e.g., ALSP, or promotes disease regression as evidenced by a reduction in the severity of disease symptoms, an increase in the frequency and duration of disease symptom-free periods, or prevention of a disability or impairment due to disease morbidity. The ability of a therapeutic agent to promote disease regression can be assessed using a variety of methods known to those skilled in the art, such as, for example, by assaying the activity of the agent in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or in in vitro assays.

[0116] In a preferred embodiment, a therapeutically effective amount of an agent, such as the anti-TREM2 antibody "Ab-1," alone or in combination with another agent, results in a reduction in the severity of at least one disease symptom, an increase in the frequency and duration of disease symptom-free periods, or prevention of a disease-related disorder or defect. Additionally, the terms "effective" and "efficacy" with respect to treatment include both pharmacological effectiveness and physiological safety. Pharmacological effectiveness refers to the ability of an agent to reduce the severity of at least one disease symptom, increase the frequency and duration of disease symptom-free periods, or prevent a disease-related disorder or defect in a patient. Physiological safety refers to the level of toxicity or other adverse physiological effects (adverse effects) at the cellular, organ, and / or organismal level resulting from administration of the agent.

[0117] As used herein, the term "therapeutic benefit" or "benefit from therapy" refers to a reduction in the severity of disease symptoms, an increase in the frequency and duration of disease symptom-free periods, or prevention of impairment or disability due to disease morbidity.

[0118] In some embodiments, the anti-TREM2 antibody "Ab-1" is administered to a human patient via IV infusion. In some embodiments, the IV infusion of the anti-TREM2 antibody "Ab-1" is for up to about 5 hours, up to about 4 hours, up to about 3 hours, up to about 2 hours, or up to about 60 minutes. In some embodiments, the IV infusion of the anti-TREM2 antibody "Ab-1" is for about 5 minutes to about 5 hours, about 5 minutes to about 4 hours, about 5 minutes to about 3 hours, about 5 minutes to about 2 hours, or about 5 minutes to about 60 minutes. In some embodiments, the IV infusion of the anti-TREM2 antibody "Ab-1" is for about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, about 30 minutes, about 35 minutes, about 40 minutes, about 45 minutes, about 50 minutes, about 55 minutes, about 60 minutes, about 70 minutes, about 80 minutes, or about 90 minutes.

[0119] In some embodiments, the anti-TREM2 antibody "Ab-1" is administered to a human patient at a dose of up to about 200 mg / kg. In some embodiments, the anti-TREM2 antibody "Ab-1" is administered to a human patient at a dose of up to about 150 mg / kg. In some embodiments, the anti-TREM2 antibody "Ab-1" is administered to a human patient at a dose of up to about 100 mg / kg. In some embodiments, the anti-TREM2 antibody "Ab-1" is administered to a human patient at a dose of about 1 mg / kg to about 100 mg / kg, about 1 mg / kg to about 90 mg / kg, about 1 mg / kg to about 80 mg / kg, about 1 mg / kg to about 70 mg / kg, or about 1 mg / kg to about 60 mg / kg. In some embodiments, the anti-TREM2 antibody "Ab-1" is administered to a human patient at a dose of about 1 mg / kg, about 2 mg / kg, about 3 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.

[0120] In some embodiments, the anti-TREM2 antibody "Ab-1" is administered to a human patient once daily. In some embodiments, the anti-TREM2 antibody "Ab-1" is administered to a human patient once, twice, three times, or four times weekly. In some embodiments, the anti-TREM2 antibody "Ab-1" is administered to a human patient once, twice, three times, or four times monthly. In some embodiments, the anti-TREM2 antibody "Ab-1" is administered to a human patient once every 1, 2, 3, or 4 weeks. In some embodiments, the anti-TREM2 antibody "Ab-1" is administered to a human patient once every 2, 3, 4, 5, 6, 7, 8, 9, 10, or 14 days. In some embodiments, the anti-TREM2 antibody "Ab-1" is administered to a human patient once weekly.

[0121] In some embodiments, the invention provides liquid formulations comprising anti-TREM2 antibody "Ab-1" at a concentration of up to about 300 mg / mL. In some embodiments, the invention provides liquid formulations comprising anti-TREM2 antibody "Ab-1" at a concentration of up to about 250 mg / mL. In some embodiments, the invention provides liquid formulations comprising anti-TREM2 antibody "Ab-1" at a concentration of up to about 200 mg / mL. In some embodiments, the invention provides liquid formulations comprising anti-TREM2 antibody "Ab-1" at a concentration of up to about 150 mg / mL. In some embodiments, the present invention provides a liquid formulation comprising anti-TREM2 antibody "Ab-1" at a concentration of about 300 mg / mL, about 250 mg / mL, about 200 mg / mL, about 180 mg / mL, about 170 mg / mL, about 160 mg / mL, about 150 mg / mL, about 140 mg / mL, about 130 mg / mL, about 120 mg / mL, about 110 mg / mL, or about 100 mg / mL. In some embodiments, the present invention provides a liquid formulation comprising anti-TREM2 antibody "Ab-1" at a concentration of about 140 mg / mL. In some embodiments, the methods of the present invention comprise administering to a human patient a liquid formulation described herein. In some embodiments, the methods of the present invention comprise administering to a human patient a liquid formulation comprising anti-TREM2 antibody "Ab-1" at a concentration of about 140 mg / mL.

[0122] In some embodiments, the patient is between 18 and 55 years of age (inclusive). In some embodiments, the patient is between 18 and 42 years of age. In some embodiments, the patient is between 42 and 55 years of age. In some embodiments, the patient is 42 years of age or younger. In some embodiments, the patient is 42 years of age or older.

[0123] In some embodiments, the patient is not a WOCBP (Woman of Childbearing Potential), hi some embodiments, the patient is a WOCBP who is using effective contraception during the course of treatment with an anti-TREM2 antibody and for at least 10 weeks after treatment.

[0124] In some embodiments, the patient is a non-smoker (or other nicotine / tobacco user, including vaping), as determined by history (no nicotine use over the past year). In some embodiments, the patient has a negative urine cotinine test immediately prior to or at the time of administration of the anti-TREM2 antibody "Ab-1."

[0125] In some embodiments, the patient has a body mass index (BMI) of 18.5 to 30.0 kg / m, inclusive. In some embodiments, the patient is assessed for vital signs (systolic and diastolic blood pressure and pulse rate) immediately prior to or at the time of administration of the anti-TREM2 antibody "Ab-1."

[0126] In some embodiments, the patient is of first-generation Japanese ethnic origin. In some embodiments, the patient was born in Japan. In some embodiments, the patient has parents and grandparents who are ethnically Japanese and were born in Japan. In some embodiments, the patient has not made any significant changes in lifestyle since leaving Japan. In some embodiments, the patient has been outside of Japan for less than 10 years.

[0127] In some embodiments, the patient has no clinically significant history or evidence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, neurological, immunological, or psychiatric disorder(s). In some embodiments, the patient has not received monoclonal antibody therapy within 120 days prior to receiving anti-TREM2 antibody "Ab-1". In some embodiments, the patient has no history of alcohol and / or illicit drug abuse within 2 years prior to receiving anti-TREM2 antibody "Ab-1".

[0128] In some embodiments, the patient does not have a positive test for hepatitis B surface antigen (HBsAg), hepatitis C antibodies, or human immunodeficiency virus (HIV) antibodies.

[0129] In some embodiments, the patient does not have a positive urine test for ethanol immediately prior to or at the time of administration of the anti-TREM2 antibody "Ab-1."

[0130] In some embodiments, the patient does not have a positive urine drug (e.g., cocaine, amphetamine, barbiturate, opiate, benzodiazepine, and cannabinoid) or cotinine test immediately prior to or at the time of administration of anti-TREM2 antibody "Ab-1."

[0131] In some embodiments, the patient is not a lactating female patient immediately prior to or at the time of administration of the anti-TREM2 antibody "Ab-1."

[0132] In some embodiments, the patient is not a female patient with a positive serum pregnancy test immediately prior to or at the time of administration of the anti-TREM2 antibody "Ab-1."

[0133] In some embodiments, the patient has not donated blood (>500 mL) or blood products within 2 months (56 days) prior to receiving the anti-TREM2 antibody "Ab-1."

[0134] In some embodiments, the patient has not received any investigational drug within 30 days or 5 half-lives, whichever is longer, prior to receiving the anti-TREM2 antibody "Ab-1."

[0135] In some embodiments, the patient has no history of hypersensitivity to any of the therapeutic monoclonal antibodies, or any of the excipients, or pharmaceutical agents with similar chemical structures.

[0136] In some embodiments, the patient does not have a positive reverse transcription polymerase chain reaction (RT-PCR) test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immediately prior to or at the time of administration of the anti-TREM2 antibody "Ab-1."

[0137] In some embodiments, the patient does not have clinical signs and symptoms consistent with SARS-CoV-2 infection, such as fever, dry cough, difficulty breathing, sore throat, fatigue, or laboratory-confirmed acute infection with SARS-CoV-2, immediately prior to or at the time of administration of the anti-TREM2 antibody "Ab-1."

[0138] In some embodiments, the patient does not have a severe course of coronavirus disease 2019 (COVID-19; extracorporeal membrane oxygenation, mechanically ventilated intensive care unit stay).

[0139] In some embodiments, the patient has not been recently exposed (within 14 days prior to receiving the anti-TREM2 antibody "Ab-1") to someone with COVID-19 symptoms or a positive test for SARS-CoV-2.

[0140] In some embodiments, the patient has not received any COVID-19 treatment immediately prior to or at the time of administration of the anti-TREM2 antibody "Ab-1."

[0141] In some embodiments, the patient has not received their last dose of a COVID-19 vaccine within 14 days prior to receiving the anti-TREM2 antibody "Ab-1" (i.e., the patient must complete vaccination at least 14 days prior to hospitalization).

[0142] In some embodiments, the patient undergoes genetic testing prior to administration of anti-TREM2 antibody "Ab-1." In some embodiments, the patient does not have an alanyl-tRNA synthetase 2 (AARS2) gene mutation, e.g., as confirmed by genetic testing. In some embodiments, the patient has a colony-stimulating factor 1 receptor (CSF1R) gene mutation, e.g., as confirmed by genetic testing. In some embodiments, the patient has a mutation in an exon in the CSF1R gene, e.g., exons 1-21. In some embodiments, the patient has a mutation in an exon in the CSF1R gene, e.g., exons 2-17 or 18-21. In some embodiments, the patient has signs or symptoms of ALSP. Exemplary signs or symptoms of ALSP include cognitive impairment, frontal lobe dysfunction, psychiatric symptoms, extrapyramidal symptoms, pyramidal symptoms, involuntary movements, gait disturbances, seizures, pathological reflexes, speech disturbances, swallowing disturbances, apraxia, sensory disturbances, autonomic symptoms, headache, stroke, dementia, encephalitis, memory loss, depression, loss of executive function, bradykinesia, rigidity, and cerebellar symptoms.

[0143] In some embodiments, the anti-TREM2 antibody "Ab-1" is administered to an asymptomatic patient or subject. In some embodiments, the asymptomatic patient is a prodromal stage patient. In some embodiments, the asymptomatic patient or subject is susceptible to ALSP. In some embodiments, the susceptible patient or subject has a colony-stimulating factor 1 receptor (CSF1R) gene mutation, e.g., as confirmed by genetic testing. In some embodiments, the CSF1R gene mutation is a loss-of-function mutation. In some embodiments, the susceptible patient or subject has a mutation in an exon in the CSF1R gene, e.g., exons 1-21. In some embodiments, the susceptible patient or subject has a mutation in an exon in the CSF1R gene, e.g., exons 2-17 or 18-21. In some embodiments, the susceptible patient or subject with a CSF1R gene mutation does not have signs or symptoms of ALSP. In some embodiments, the anti-TREM2 antibody "Ab-1" is administered to an asymptomatic patient or subject before the onset of ALSP symptoms. In some embodiments, susceptible patients or subjects with CSF1R gene mutations do not have magnetic resonance imaging (MRI) findings consistent with ALSP. Exemplary MRI findings consistent with ALSP include bilateral cerebral white matter lesions with or without thinning of the corpus callosum. In some embodiments, susceptible patients or subjects with CSF1R gene mutations have MRI findings consistent with ALSP. In some embodiments, susceptible patients or subjects with CSF1R gene mutations have biomarkers for ALSP. In some embodiments, susceptible patients or subjects with CSF1R gene mutations have elevated levels of neurofilament light chain (NfL) detected in cerebrospinal fluid (CSF) and / or blood. In some embodiments, susceptible patients or subjects with CSF1R gene mutations have reduced levels of soluble colony-stimulating factor 1 receptor (sCSF1R) detected in CSF.

[0144] In some embodiments, the patient exhibits a reduction in the severity of ALSP symptoms upon administration of the anti-TREM2 antibody "Ab-1." In some embodiments, the patient exhibits a reduction in the severity of ALSP symptoms upon administration of the anti-TREM2 antibody "Ab-1," e.g., by about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, e.g., compared to the severity of symptoms in the absence of administration of the anti-TREM2 antibody "Ab-1."

[0145] In some embodiments, the patient undergoes CSF collection via lumbar puncture immediately before, at the time of, or after administration of anti-TREM2 antibody "Ab-1." In some embodiments, the patient undergoes CSF collection via lumbar puncture immediately before, at, or after receiving a first dose of anti-TREM2 antibody "Ab-1." In some embodiments, the patient undergoes CSF collection via lumbar puncture immediately before, at, or after receiving a second dose of anti-TREM2 antibody "Ab-1." In some embodiments, the patient undergoes CSF collection via lumbar puncture immediately before, at, or after receiving a third dose of anti-TREM2 antibody "Ab-1." In some embodiments, the patient does not undergo CSF ​​collection via lumbar puncture, and the patient is sensitive to anesthetics or derivatives used during CSF collection, or any agents used to prepare the area for lumbar puncture. In some embodiments, the patient did not undergo CSF ​​collection via lumbar puncture, and the patient had a previous CSF collection within 30 days prior to receiving anti-TREM2 antibody "Ab-1."

[0146] In some embodiments, the patient does not undergo CSF ​​collection via lumbar puncture, and the patient has a history of spinal deformity, major lumbar back surgery, clinically significant back pain, clinically significant abnormal x-rays, and / or injury.

[0147] In some embodiments, the patient does not undergo CSF ​​collection via lumbar puncture and the patient has an ongoing skin infection at the lumbar puncture injection site.

[0148] In some embodiments, the patient does not undergo CSF ​​collection via lumbar puncture, and the patient has clinically significant coagulation test values ​​(prothrombin time / international normalized ratio, partial thromboplastin time) outside the normal reference range immediately prior to or at the time of administration of the anti-TREM2 antibody "Ab-1."

[0149] In some embodiments, the present invention provides a method for treating adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a human patient, comprising administering to the patient an anti-TREM2 antibody "Ab-1" via IV infusion at a dose of about 60 mg / kg, about 50 mg / kg, about 40 mg / kg, about 30 mg / kg, about 20 mg / kg, about 10 mg / kg, about 5 mg / kg, about 3 mg / kg, about 2 mg / kg, or about 1 mg / kg, wherein the IV infusion is about 60 minutes in length.

[0150] In some embodiments, the present invention provides a method for treating adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a human patient, comprising administering to the patient an anti-TREM2 antibody "Ab-1" via IV infusion at a dose of about 60 mg / kg, about 50 mg / kg, about 40 mg / kg, about 30 mg / kg, about 20 mg / kg, about 10 mg / kg, about 5 mg / kg, about 3 mg / kg, about 2 mg / kg, or about 1 mg / kg, wherein the IV infusion is about 50 minutes in length.

[0151] In some embodiments, the present invention provides a method for treating adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a human patient, comprising administering to the patient anti-TREM2 antibody "Ab-1" via IV infusion at a dose of about 60 mg / kg, about 50 mg / kg, about 40 mg / kg, about 30 mg / kg, about 20 mg / kg, about 10 mg / kg, about 5 mg / kg, about 3 mg / kg, about 2 mg / kg, or about 1 mg / kg, wherein the IV infusion is about 45 minutes in length.

[0152] In some embodiments, the present invention provides a method for treating adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a human patient, comprising administering to the patient an anti-TREM2 antibody "Ab-1" via IV infusion at a dose of about 60 mg / kg, about 50 mg / kg, about 40 mg / kg, about 30 mg / kg, about 20 mg / kg, about 10 mg / kg, about 5 mg / kg, about 3 mg / kg, about 2 mg / kg, or about 1 mg / kg, wherein the IV infusion is about 40 minutes in length.

[0153] In some embodiments, the present invention provides a method for treating adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a human patient, comprising administering to the patient an anti-TREM2 antibody "Ab-1" via IV infusion at a dose of about 60 mg / kg, about 50 mg / kg, about 40 mg / kg, about 30 mg / kg, about 20 mg / kg, about 10 mg / kg, about 5 mg / kg, about 3 mg / kg, about 2 mg / kg, or about 1 mg / kg, wherein the IV infusion is about 35 minutes in length.

[0154] In some embodiments, the present invention provides a method for treating adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a human patient, comprising administering to the patient an anti-TREM2 antibody "Ab-1" via IV infusion at a dose of about 60 mg / kg, about 50 mg / kg, about 40 mg / kg, about 30 mg / kg, about 20 mg / kg, about 10 mg / kg, about 5 mg / kg, about 3 mg / kg, about 2 mg / kg, or about 1 mg / kg, wherein the IV infusion is about 30 minutes in length.

[0155] In some embodiments, the present invention provides a method for treating adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a human patient, comprising administering to the patient an anti-TREM2 antibody "Ab-1" via IV infusion at a dose of about 60 mg / kg, about 50 mg / kg, about 40 mg / kg, about 30 mg / kg, about 20 mg / kg, about 10 mg / kg, about 5 mg / kg, about 3 mg / kg, about 2 mg / kg, or about 1 mg / kg, wherein the IV infusion is about 25 minutes in length.

[0156] In some embodiments, the present invention provides a method for treating adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a human patient, comprising administering to the patient an anti-TREM2 antibody "Ab-1" via IV infusion at a dose of about 60 mg / kg, about 50 mg / kg, about 40 mg / kg, about 30 mg / kg, about 20 mg / kg, about 10 mg / kg, about 5 mg / kg, about 3 mg / kg, about 2 mg / kg, or about 1 mg / kg, wherein the IV infusion is about 20 minutes in length.

[0157] In some embodiments, the present invention provides a method for treating adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a human patient, comprising administering to the patient an anti-TREM2 antibody "Ab-1" via IV infusion at a dose of about 60 mg / kg, about 50 mg / kg, about 40 mg / kg, about 30 mg / kg, about 20 mg / kg, about 10 mg / kg, about 5 mg / kg, about 3 mg / kg, about 2 mg / kg, or about 1 mg / kg, wherein the IV infusion is about 15 minutes in length.

[0158] In some embodiments, the present invention provides a method for treating adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a human patient, comprising administering to the patient an anti-TREM2 antibody "Ab-1" via IV infusion at a dose of about 60 mg / kg, about 50 mg / kg, about 40 mg / kg, about 30 mg / kg, about 20 mg / kg, about 10 mg / kg, about 5 mg / kg, about 3 mg / kg, about 2 mg / kg, or about 1 mg / kg, wherein the IV infusion is about 10 minutes in length.

[0159] In some embodiments, the present invention provides a method for treating adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a human patient, comprising administering to the patient an anti-TREM2 antibody "Ab-1" via IV infusion at a dose of about 60 mg / kg, about 50 mg / kg, about 40 mg / kg, about 30 mg / kg, about 20 mg / kg, about 10 mg / kg, about 5 mg / kg, about 3 mg / kg, about 2 mg / kg, or about 1 mg / kg, wherein the IV infusion is about 5 minutes in length.

[0160] In some embodiments, the present invention provides a method for treating adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a human patient, comprising administering to the patient anti-TREM2 antibody "Ab-1" via IV infusion at a dose of about 4.2 grams, about 3.5 grams, about 2.8 grams, about 2.1 grams, about 1.4 grams, about 700 mg, about 350 mg, about 210 mg, about 140 mg, or about 70 mg, wherein the IV infusion is about 60 minutes in length.

[0161] In some embodiments, the present invention provides a method for treating adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a human patient, comprising administering to the patient anti-TREM2 antibody "Ab-1" via IV infusion at a dose of about 4.2 grams, about 3.5 grams, about 2.8 grams, about 2.1 grams, about 1.4 grams, about 700 mg, about 350 mg, about 210 mg, about 140 mg, or about 70 mg, wherein the IV infusion is about 50 minutes in length.

[0162] In some embodiments, the present invention provides a method for treating adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a human patient, comprising administering to the patient anti-TREM2 antibody "Ab-1" via IV infusion at a dose of about 4.2 grams, about 3.5 grams, about 2.8 grams, about 2.1 grams, about 1.4 grams, about 700 mg, about 350 mg, about 210 mg, about 140 mg, or about 70 mg, wherein the IV infusion is about 45 minutes in length.

[0163] In some embodiments, the present invention provides a method for treating adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a human patient, comprising administering to the patient anti-TREM2 antibody "Ab-1" via IV infusion at a dose of about 4.2 grams, about 3.5 grams, about 2.8 grams, about 2.1 grams, about 1.4 grams, about 700 mg, about 350 mg, about 210 mg, about 140 mg, or about 70 mg, wherein the IV infusion is about 40 minutes in length.

[0164] In some embodiments, the present invention provides a method for treating adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a human patient, comprising administering to the patient anti-TREM2 antibody "Ab-1" via IV infusion at a dose of about 4.2 grams, about 3.5 grams, about 2.8 grams, about 2.1 grams, about 1.4 grams, about 700 mg, about 350 mg, about 210 mg, about 140 mg, or about 70 mg, wherein the IV infusion is about 35 minutes in length.

[0165] In some embodiments, the present invention provides a method for treating adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a human patient, comprising administering to the patient anti-TREM2 antibody "Ab-1" via IV infusion at a dose of about 4.2 grams, about 3.5 grams, about 2.8 grams, about 2.1 grams, about 1.4 grams, about 700 mg, about 350 mg, about 210 mg, about 140 mg, or about 70 mg, wherein the IV infusion is about 30 minutes in length.

[0166] In some embodiments, the present invention provides a method for treating adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a human patient, comprising administering to the patient anti-TREM2 antibody "Ab-1" via IV infusion at a dose of about 4.2 grams, about 3.5 grams, about 2.8 grams, about 2.1 grams, about 1.4 grams, about 700 mg, about 350 mg, about 210 mg, about 140 mg, or about 70 mg, wherein the IV infusion is about 25 minutes in length.

[0167] In some embodiments, the present invention provides a method for treating adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a human patient, comprising administering to the patient anti-TREM2 antibody "Ab-1" via IV infusion at a dose of about 4.2 grams, about 3.5 grams, about 2.8 grams, about 2.1 grams, about 1.4 grams, about 700 mg, about 350 mg, about 210 mg, about 140 mg, or about 70 mg, wherein the IV infusion is about 20 minutes in length.

[0168] In some embodiments, the present invention provides a method for treating adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a human patient, comprising administering to the patient anti-TREM2 antibody "Ab-1" via IV infusion at a dose of about 4.2 grams, about 3.5 grams, about 2.8 grams, about 2.1 grams, about 1.4 grams, about 700 mg, about 350 mg, about 210 mg, about 140 mg, or about 70 mg, wherein the IV infusion is about 15 minutes in length.

[0169] In some embodiments, the present invention provides a method for treating adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a human patient, comprising administering to the patient anti-TREM2 antibody "Ab-1" via IV infusion at a dose of about 4.2 grams, about 3.5 grams, about 2.8 grams, about 2.1 grams, about 1.4 grams, about 700 mg, about 350 mg, about 210 mg, about 140 mg, or about 70 mg, wherein the IV infusion is about 10 minutes in length.

[0170] In some embodiments, the present invention provides a method for treating adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a human patient, comprising administering to the patient anti-TREM2 antibody "Ab-1" via IV infusion at a dose of about 4.2 grams, about 3.5 grams, about 2.8 grams, about 2.1 grams, about 1.4 grams, about 700 mg, about 350 mg, about 210 mg, about 140 mg, or about 70 mg, wherein the IV infusion is about 5 minutes in length.

[0171] In some embodiments, the present invention provides a method for treating adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a subject, comprising administering VGL101 to a subject in need thereof by intravenous infusion at a dose of 10-75 mg / kg every 2-6 weeks, wherein after administration of VGL101, the subject is evaluated for one or more of the following: i) safety and tolerability of VGL101, ii) effect of VGL101 on imaging and biomarkers, iii) efficacy of VGL101, or iv) pharmacokinetics of VGL101. In some embodiments, the dose of VGL101 administered to the subject is 10-50 mg / kg. In some embodiments, VGL101 is administered to the subject every 3-5 weeks. In some embodiments, VGL101 is administered to the subject every 3 weeks. In some embodiments, VGL101 is administered to the subject every 4 weeks. In some embodiments, VGL101 is administered to the subject every 5 weeks.

[0172] In some embodiments, the present invention provides methods for assessing the safety and tolerability of VGL101 by one or more of the following: ia) the nature and frequency of adverse events, serious adverse events, and discontinuations due to adverse events, ib) safety clinical trials, ic) immunogenicity studies, id) vital sign measurements, ie) electrocardiograms, and if) the Columbia-Suicide Severity Rating Scale (C-SSRS).

[0173] In some embodiments, the present invention provides methods for assessing the effect of VGL101 on imaging and biomarkers by change from baseline. In some embodiments, the change from baseline is measured by one or more of the following: ii-ai) neurofilament light chain (NfL) in cerebrospinal fluid (CSF) and blood, ii-a-ii) structural and volumetric magnetic resonance imaging (MRI), ii-a-iii) MRI-based ALSP severity score, and ii-a-iv) soluble colony-stimulating factor 1 receptor (sCSF1R) in CSF. In some embodiments, the change from baseline is measured by one or more of the following: ii-ci) cytokine panel and soluble TREM2 (sTREM2) in CSF, and ii-c-ii) blood biomarkers of disease progression.

[0174] In some embodiments, the present invention provides methods for assessing the efficacy of VGL101 by one or more of the following: iii-a) change from baseline; iii-b) response to the Clinical Global Impression Index-Change (CGI-C), defined as a much / very improved response; iii-c) response to the Patient Global Impression Index-Change (PGI-C), defined as a much / very improved response. In some embodiments, the change from baseline is measured by one or more of the following: Montreal Cognitive Assessment (MoCA), Clinical Dementia Rating Scale + National Center for Alzheimer's Disease - Frontotemporal Dementia (CDR® + NACC-FTD), Brief Assessment of Cognition (BAC) Battery, Corticobasal Ganglionic Function Scale (CBFS), 2-Minute Walk Test (2MWT), Timed Up and Go (TUG) Test, Gait and Balance Assessment in Ambulatory Subjects, Functional Activities Questionnaire (FAQ), Neuropsychiatric Symptom Inventory-12-Item Version (NPI-12), Zarit Burden Interview.

[0175] In some embodiments, the present invention provides methods for assessing the pharmacokinetics of VGL101 by serum and CSF concentrations of VGL101.

[0176] In some embodiments, the invention provides a method for treating adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a subject, comprising administering VGL101 to the subject at a dose of 10-75 mg / kg by intravenous infusion every 2-6 weeks, wherein the subject does not have one or more, two or more, three or more, four or more, or all of the following: (i) a neurological disease that produces cognitive, motor, or behavioral impairment, optionally wherein the neurological disease is brain tumor, hydrocephalus, Alzheimer's disease, frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), stroke, Huntington's disease, multiple sclerosis (MS), Parkinson's disease, or Down's syndrome; (ii) Axis I psychiatric disorders, unless the psychiatric disorder is mild or treated depression; (iii) alcohol or substance use disorder; (iv) a concurrent diagnosis that may confound neuropsychological testing, optionally the diagnosis being a hearing or visual impairment; (v) concurrent diagnoses that may confound gait measurements; (vi) hypersensitivity to anesthetic agents or derivatives used during CSF collection, history of spinal deformity, major lumbar back surgery, clinically significant back pain, clinically significant abnormal x-rays, ongoing skin infection or injury at the lumbar puncture injection site, radiological evidence of elevated intracranial pressure, or bleeding disorder; (vii) inability to undergo magnetic resonance imaging (MRI), optionally where the subject has an implant that is not MRI compatible, or is claustrophobic or unable to remain motionless for the procedure; (viii) brain MRI findings of acute or subacute hemorrhage, macrohemorrhage, more than four microhemorrhages, or one or more superficial siderosis, or other clinically significant imaging abnormalities, optionally wherein the imaging abnormality is an arteriovenous abnormality, an aneurysm, or a subdural hematoma; (ix) are pregnant, planning to become pregnant within the next 12 months, or breastfeeding; (x) at significant risk for suicidal or violent behavior; (xi) a current history of any serious or unstable medical illness, optionally, the illness being renal failure, congestive heart failure, uncontrolled diabetes mellitus, or progressive pulmonary disease; (xii) clinically significant abnormalities in vital signs, ECG, or laboratory parameters; (xiii) a history of cancer requiring active treatment within the past 5 years, except for cervical cancer (primary) or basal cell carcinoma of the skin; (xiv) history or known infection with human immunodeficiency virus (HIV) or hepatitis B or C; (xv) a history of hypersensitivity to anti-human TREM2 antibodies, other therapeutic monoclonal antibodies, or any of the excipients, or to pharmaceuticals with similar chemical structures; (xvi) have undergone hematopoietic stem cell transplantation (HSCT) or are planning to undergo HSCT during treatment, or (xvii) Previous participation in a gene therapy study.

[0177] In some embodiments, the present invention provides a method for preventing or delaying the onset or recurrence of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a subject, comprising administering VGL101 to a subject in need thereof by intravenous infusion at a dose of 10-75 mg / kg every 2-6 weeks, wherein after administration of VGL101, the subject is evaluated for one or more of the following: i) safety and tolerability of VGL101, ii) effect of VGL101 on imaging and biomarkers, iii) efficacy of VGL101, or iv) pharmacokinetics of VGL101. In some embodiments, the dose of VGL101 administered to the subject is 10-50 mg / kg. In some embodiments, VGL101 is administered to the subject every 3-5 weeks. In some embodiments, VGL101 is administered to the subject every 3 weeks. In some embodiments, VGL101 is administered to the subject every 4 weeks. In some embodiments, VGL101 is administered to the subject every 5 weeks.

[0178] In some embodiments, the present invention provides a method for preventing or delaying the onset or recurrence of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a subject, the method comprising administering VGL101 to a subject in need thereof by intravenous infusion at a dose of 10-75 mg / kg every 2-6 weeks, wherein the subject has a colony-stimulating factor 1 receptor (CSF1R) gene mutation that can cause ALSP. In some embodiments, the CSF1R gene mutation is a loss-of-function mutation.

[0179] In some embodiments, the present invention provides a method for preventing or delaying the onset or recurrence of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a subject, the method comprising administering VGL101 to a subject in need thereof at a dose of 10-75 mg / kg by intravenous infusion every 2-6 weeks, wherein the subject is asymptomatic for ALSP. In some embodiments, the subject has bilateral cerebral white matter lesions with or without thinning of the corpus callosum as measured by magnetic resonance imaging (MRI).

[0180] In some embodiments, the present invention provides a method of preventing or delaying the onset or recurrence of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a subject, the method comprising administering VGL101 to a subject in need thereof by intravenous infusion at a dose of 10-75 mg / kg every 2-6 weeks, wherein the subject has elevated levels of neurofilament light chain (NfL) detected in cerebrospinal fluid (CSF) and / or blood. In some embodiments, the subject lacks elevated levels of neurofilament light chain (NfL) detected in cerebrospinal fluid (CSF) and / or blood.

[0181] In some embodiments, the present invention provides a method of preventing or delaying the onset or recurrence of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a subject, the method comprising administering VGL101 to a subject in need thereof by intravenous infusion at a dose of 10-75 mg / kg every 2-6 weeks, wherein the subject has suppressed levels of soluble colony-stimulating factor 1 receptor (sCSF1R) detected in cerebrospinal fluid (CSF). In some embodiments, the subject lacks suppressed levels of soluble colony-stimulating factor 1 receptor (sCSF1R) detected in cerebrospinal fluid (CSF).

[0182] In some embodiments, the present invention provides a method for preventing or delaying the onset or recurrence of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a human patient, comprising administering to the patient via IV infusion an anti-TREM2 antibody "Ab-1" at a dose of about 60 mg / kg, about 50 mg / kg, about 40 mg / kg, about 30 mg / kg, about 20 mg / kg, about 10 mg / kg, about 5 mg / kg, about 3 mg / kg, about 2 mg / kg, or about 1 mg / kg, wherein the IV infusion is about 60 minutes in length.

[0183] In some embodiments, the invention provides a method for preventing or delaying the onset or recurrence of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a human patient, comprising administering to the patient via IV infusion an anti-TREM2 antibody "Ab-1" at a dose of about 60 mg / kg, about 50 mg / kg, about 40 mg / kg, about 30 mg / kg, about 20 mg / kg, about 10 mg / kg, about 5 mg / kg, about 3 mg / kg, about 2 mg / kg, or about 1 mg / kg, wherein the IV infusion is about 50 minutes in length.

[0184] In some embodiments, the invention provides a method for preventing or delaying the onset or recurrence of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a human patient, comprising administering to the patient via IV infusion an anti-TREM2 antibody "Ab-1" at a dose of about 60 mg / kg, about 50 mg / kg, about 40 mg / kg, about 30 mg / kg, about 20 mg / kg, about 10 mg / kg, about 5 mg / kg, about 3 mg / kg, about 2 mg / kg, or about 1 mg / kg, wherein the IV infusion is about 45 minutes in length.

[0185] In some embodiments, the invention provides a method for preventing or delaying the onset or recurrence of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a human patient, comprising administering to the patient via IV infusion an anti-TREM2 antibody "Ab-1" at a dose of about 60 mg / kg, about 50 mg / kg, about 40 mg / kg, about 30 mg / kg, about 20 mg / kg, about 10 mg / kg, about 5 mg / kg, about 3 mg / kg, about 2 mg / kg, or about 1 mg / kg, wherein the IV infusion is about 40 minutes in length.

[0186] In some embodiments, the present invention provides a method for preventing or delaying the onset or recurrence of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a human patient, comprising administering to the patient via IV infusion an anti-TREM2 antibody "Ab-1" at a dose of about 60 mg / kg, about 50 mg / kg, about 40 mg / kg, about 30 mg / kg, about 20 mg / kg, about 10 mg / kg, about 5 mg / kg, about 3 mg / kg, about 2 mg / kg, or about 1 mg / kg, wherein the IV infusion is about 35 minutes in length.

[0187] In some embodiments, the invention provides a method for preventing or delaying the onset or recurrence of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a human patient, comprising administering to the patient via IV infusion an anti-TREM2 antibody "Ab-1" at a dose of about 60 mg / kg, about 50 mg / kg, about 40 mg / kg, about 30 mg / kg, about 20 mg / kg, about 10 mg / kg, about 5 mg / kg, about 3 mg / kg, about 2 mg / kg, or about 1 mg / kg, wherein the IV infusion is about 30 minutes in length.

[0188] In some embodiments, the present invention provides a method for preventing or delaying the onset or recurrence of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a human patient, comprising administering to the patient via IV infusion an anti-TREM2 antibody "Ab-1" at a dose of about 60 mg / kg, about 50 mg / kg, about 40 mg / kg, about 30 mg / kg, about 20 mg / kg, about 10 mg / kg, about 5 mg / kg, about 3 mg / kg, about 2 mg / kg, or about 1 mg / kg, wherein the IV infusion is about 25 minutes in length.

[0189] In some embodiments, the present invention provides a method for preventing or delaying the onset or recurrence of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a human patient, comprising administering to the patient via IV infusion an anti-TREM2 antibody "Ab-1" at a dose of about 60 mg / kg, about 50 mg / kg, about 40 mg / kg, about 30 mg / kg, about 20 mg / kg, about 10 mg / kg, about 5 mg / kg, about 3 mg / kg, about 2 mg / kg, or about 1 mg / kg, wherein the IV infusion is about 20 minutes in length.

[0190] In some embodiments, the present invention provides a method for preventing or delaying the onset or recurrence of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a human patient, comprising administering to the patient via IV infusion an anti-TREM2 antibody "Ab-1" at a dose of about 60 mg / kg, about 50 mg / kg, about 40 mg / kg, about 30 mg / kg, about 20 mg / kg, about 10 mg / kg, about 5 mg / kg, about 3 mg / kg, about 2 mg / kg, or about 1 mg / kg, wherein the IV infusion is about 15 minutes in length.

[0191] In some embodiments, the invention provides a method for preventing or delaying the onset or recurrence of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a human patient, comprising administering to the patient via IV infusion an anti-TREM2 antibody "Ab-1" at a dose of about 60 mg / kg, about 50 mg / kg, about 40 mg / kg, about 30 mg / kg, about 20 mg / kg, about 10 mg / kg, about 5 mg / kg, about 3 mg / kg, about 2 mg / kg, or about 1 mg / kg, wherein the IV infusion is about 10 minutes in length.

[0192] In some embodiments, the invention provides a method for preventing or delaying the onset or recurrence of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a human patient, comprising administering to the patient via IV infusion an anti-TREM2 antibody "Ab-1" at a dose of about 60 mg / kg, about 50 mg / kg, about 40 mg / kg, about 30 mg / kg, about 20 mg / kg, about 10 mg / kg, about 5 mg / kg, about 3 mg / kg, about 2 mg / kg, or about 1 mg / kg, wherein the IV infusion is about 5 minutes in length.

[0193] In some embodiments, the present invention provides a method for preventing or delaying the onset or recurrence of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a human patient, comprising administering to the patient via IV infusion an anti-TREM2 antibody "Ab-1" at a dose of about 4.2 grams, about 3.5 grams, about 2.8 grams, about 2.1 grams, about 1.4 grams, about 700 mg, about 350 mg, about 210 mg, about 140 mg, or about 70 mg, wherein the IV infusion is about 60 minutes in length.

[0194] In some embodiments, the present invention provides a method for preventing or delaying the onset or recurrence of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a human patient, comprising administering to the patient via IV infusion an anti-TREM2 antibody "Ab-1" at a dose of about 4.2 grams, about 3.5 grams, about 2.8 grams, about 2.1 grams, about 1.4 grams, about 700 mg, about 350 mg, about 210 mg, about 140 mg, or about 70 mg, wherein the IV infusion is about 50 minutes in length.

[0195] In some embodiments, the present invention provides a method for preventing or delaying the onset or recurrence of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a human patient, comprising administering to the patient via IV infusion an anti-TREM2 antibody "Ab-1" at a dose of about 4.2 grams, about 3.5 grams, about 2.8 grams, about 2.1 grams, about 1.4 grams, about 700 mg, about 350 mg, about 210 mg, about 140 mg, or about 70 mg, wherein the IV infusion is about 45 minutes in length.

[0196] In some embodiments, the present invention provides a method for preventing or delaying the onset or recurrence of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a human patient, comprising administering to the patient via IV infusion an anti-TREM2 antibody "Ab-1" at a dose of about 4.2 grams, about 3.5 grams, about 2.8 grams, about 2.1 grams, about 1.4 grams, about 700 mg, about 350 mg, about 210 mg, about 140 mg, or about 70 mg, wherein the IV infusion is about 40 minutes in length.

[0197] In some embodiments, the present invention provides a method for preventing or delaying the onset or recurrence of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a human patient, comprising administering to the patient via IV infusion an anti-TREM2 antibody "Ab-1" at a dose of about 4.2 grams, about 3.5 grams, about 2.8 grams, about 2.1 grams, about 1.4 grams, about 700 mg, about 350 mg, about 210 mg, about 140 mg, or about 70 mg, wherein the IV infusion is about 35 minutes in length.

[0198] In some embodiments, the present invention provides a method for preventing or delaying the onset or recurrence of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a human patient, comprising administering to the patient via IV infusion an anti-TREM2 antibody "Ab-1" at a dose of about 4.2 grams, about 3.5 grams, about 2.8 grams, about 2.1 grams, about 1.4 grams, about 700 mg, about 350 mg, about 210 mg, about 140 mg, or about 70 mg, wherein the IV infusion is about 30 minutes in length.

[0199] In some embodiments, the present invention provides a method for preventing or delaying the onset or recurrence of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a human patient, comprising administering to the patient via IV infusion an anti-TREM2 antibody "Ab-1" at a dose of about 4.2 grams, about 3.5 grams, about 2.8 grams, about 2.1 grams, about 1.4 grams, about 700 mg, about 350 mg, about 210 mg, about 140 mg, or about 70 mg, wherein the IV infusion is about 25 minutes in length.

[0200] In some embodiments, the present invention provides a method for preventing or delaying the onset or recurrence of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a human patient, comprising administering to the patient via IV infusion an anti-TREM2 antibody "Ab-1" at a dose of about 4.2 grams, about 3.5 grams, about 2.8 grams, about 2.1 grams, about 1.4 grams, about 700 mg, about 350 mg, about 210 mg, about 140 mg, or about 70 mg, wherein the IV infusion is about 20 minutes in length.

[0201] In some embodiments, the present invention provides a method for preventing or delaying the onset or recurrence of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a human patient, comprising administering to the patient via IV infusion an anti-TREM2 antibody "Ab-1" at a dose of about 4.2 grams, about 3.5 grams, about 2.8 grams, about 2.1 grams, about 1.4 grams, about 700 mg, about 350 mg, about 210 mg, about 140 mg, or about 70 mg, wherein the IV infusion is about 15 minutes in length.

[0202] In some embodiments, the present invention provides a method for preventing or delaying the onset or recurrence of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a human patient, comprising administering to the patient via IV infusion an anti-TREM2 antibody "Ab-1" at a dose of about 4.2 grams, about 3.5 grams, about 2.8 grams, about 2.1 grams, about 1.4 grams, about 700 mg, about 350 mg, about 210 mg, about 140 mg, or about 70 mg, wherein the IV infusion is about 10 minutes in length.

[0203] In some embodiments, the present invention provides a method for preventing or delaying the onset or recurrence of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a human patient, comprising administering to the patient via IV infusion an anti-TREM2 antibody "Ab-1" at a dose of about 4.2 grams, about 3.5 grams, about 2.8 grams, about 2.1 grams, about 1.4 grams, about 700 mg, about 350 mg, about 210 mg, about 140 mg, or about 70 mg, wherein the IV infusion is about 5 minutes in length.

[0204] Liquid formulations In some embodiments, the present invention provides a liquid formulation comprising an anti-TREM2 antibody "Ab-1" and a pharmaceutically acceptable excipient (e.g., a buffer) and / or carrier (e.g., water). The amount of anti-TREM2 antibody "Ab-1" in the liquid formulation of the present invention is such that it is effective to measurably inhibit TREM2 or a variant thereof in a patient. In certain embodiments, the liquid formulation of the present invention is formulated for administration to a patient in need of such a composition. In some embodiments, the composition of the present invention is formulated for parenteral (e.g., intravenous) administration to a patient.

[0205] In some embodiments, the liquid formulations of the present invention contain the anti-TREM2 antibody "Ab-1" at a concentration of about 50 mg / mL to about 250 mg / mL. In some embodiments, the liquid formulations of the present invention contain the anti-TREM2 antibody "Ab-1" at a concentration of about 70 mg / mL to about 230 mg / mL, about 90 mg / mL to about 210 mg / mL, about 100 mg / mL to about 200 mg / mL, about 120 mg / mL to about 180 mg / mL, about 120 mg / mL to about 160 mg / mL, or about 130 mg / mL to about 150 mg / mL. In some embodiments, the liquid formulations of the invention contain the anti-TREM2 antibody "Ab-1" at a concentration of about 80 mg / mL, about 90 mg / mL, about 100 mg / mL, about 110 mg / mL, about 120 mg / mL, about 130 mg / mL, about 140 mg / mL, about 150 mg / mL, about 160 mg / mL, about 170 mg / mL, about 180 mg / mL, about 190 mg / mL, or about 200 mg / mL. In some embodiments, the liquid formulations of the invention contain the anti-TREM2 antibody "Ab-1" at a concentration of about 135 mg / mL, about 136 mg / mL, about 137 mg / mL, about 138 mg / mL, about 139 mg / mL, about 140 mg / mL, about 141 mg / mL, about 142 mg / mL, about 143 mg / mL, about 144 mg / mL, or about 145 mg / mL.

[0206] In some embodiments, the liquid formulations of the present invention comprise sodium acetate. In some embodiments, the liquid formulations of the present invention comprise sodium acetate at a concentration of about 5 mM to about 25 mM. In some embodiments, the liquid formulations of the present invention comprise sodium acetate at a concentration of about 6 mM to about 24 mM, about 7 mM to about 23 mM, about 8 mM to about 22 mM, about 9 mM to about 21 mM, about 10 mM to about 20 mM, about 11 mM to about 19 mM, about 12 mM to about 18 mM, about 13 mM to about 17 mM, or about 14 mM to about 16 mM. In some embodiments, the liquid formulations of the present invention comprise sodium acetate at a concentration of about 10 mM, about 11 mM, about 12 mM, about 13 mM, about 14 mM, about 15 mM, about 16 mM, about 17 mM, about 18 mM, about 19 mM, or about 20 mM. In some embodiments, the liquid formulations of the present invention comprise sodium acetate at a concentration of about 14.5 mM, about 14.6 mM, about 14.7 mM, about 14.8 mM, about 14.9 mM, about 15 mM, about 15.1 mM, about 15.2 mM, about 15.3 mM, about 15.4 mM, or about 15.5 mM.

[0207] In some embodiments, the liquid formulations of the present invention comprise sucrose. In some embodiments, the liquid formulations of the present invention comprise sucrose at a concentration of about 4% to about 14% (w / v) of the total liquid formulation volume. In some embodiments, the liquid formulations of the present invention comprise sucrose at a concentration of about 5% to about 13%, about 6% to about 12%, about 7% to about 11%, or about 8% to about 10% (w / v) of the total liquid formulation volume. In some embodiments, the liquid formulations of the present invention comprise sucrose at a concentration of about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, or about 12% (w / v) of the total liquid formulation volume. In some embodiments, the liquid formulations of the present invention comprise sucrose at a concentration of about 8.5%, about 8.6%, about 8.7%, about 8.8%, about 8.9%, about 9%, about 9.1%, about 9.2%, about 9.3%, about 9.4%, or about 9.5% (w / v) of the total liquid formulation volume.

[0208] In some embodiments, the liquid formulations of the present invention comprise polysorbate 80. In some embodiments, the liquid formulations of the present invention comprise polysorbate 80 at a concentration of about 0.005% to about 0.015% (w / v) of the total liquid formulation volume. In some embodiments, the liquid formulations of the present invention comprise polysorbate 80 at a concentration of about 0.006% to about 0.014%, about 0.007% to about 0.013%, about 0.008% to about 0.012%, or about 0.009% to about 0.011% (w / v) of the total liquid formulation volume. In some embodiments, the liquid formulations of the present invention comprise polysorbate 80 at a concentration of about 0.005%, about 0.006%, about 0.007%, about 0.008%, about 0.009%, about 0.01%, about 0.011%, about 0.012%, about 0.013%, about 0.014%, or about 0.015% (w / v) of the total liquid formulation volume.

[0209] In some embodiments, the liquid formulations of the present invention have a pH of about 4.4 to about 6.0. In some embodiments, the liquid formulations of the present invention have a pH of about 4.4 to about 6.0, about 4.5 to about 5.9, about 4.6 to about 5.8, about 4.7 to about 5.7, about 4.8 to about 5.6, about 4.9 to about 5.5, about 5.0 to about 5.4, or about 5.1 to about 5.3. In some embodiments, the liquid formulations of the present invention have a pH of about 4.8, about 4.9, about 5.0, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, or about 5.6. In some embodiments, the liquid formulations of the present invention have a pH of about 5.16, about pH 5.17, about pH 5.18, about pH 5.19, about pH 5.20, about pH 5.21, about pH 5.22, about pH 5.23, or about pH 5.24.

[0210] In certain embodiments, liquid formulations of the invention comprise anti-TREM2 antibody "Ab-1" at a concentration of about 140 mg / mL. In some embodiments, liquid formulations of the invention comprise sodium acetate at a concentration of about 15 mM. In some embodiments, liquid formulations of the invention comprise sucrose at a concentration of about 9% (w / v) of the total liquid formulation volume. In some embodiments, liquid formulations of the invention comprise polysorbate 80 at a concentration of about 0.01% (w / v) of the total liquid formulation volume. In some embodiments, liquid formulations of the invention have a pH of about 5.2.

[0211] In certain embodiments, the present invention provides a liquid formulation, comprising: Anti-TREM2 antibody "Ab-1" at a concentration of approximately 140 mg / mL, Sodium acetate at a concentration of about 15 mM; Sucrose at a concentration of about 9% (w / v) of the total liquid formulation volume; and polysorbate 80 at a concentration of about 0.01% (w / v) of the total liquid formulation volume; The pH is approximately 5.2.

[0212] The liquid formulations of the present invention may be administered parenterally by injection, infusion, or implantation (intravenous, intramuscular, subcutaneous, etc.) as a liquid formulation or via a suitable delivery device or implant containing conventional non-toxic pharmaceutically acceptable carriers and adjuvants.

[0213] If necessary, liquid formulations may also contain solubilizers.The components of the formulation can be mixed separately or together in unit dosage form, for example, as a dry lyophilized powder (which can be reconstituted before use with a carrier such as physiological saline) or as a concentrated solution in a sealed container such as an ampoule or sachet indicating the amount of active ingredient.When the composition is administered by infusion, it can be dispensed in an infusion bottle or bag containing sterile pharmaceutical-grade water or physiological saline.When the formulation is administered by injection, an ampoule of sterile water or physiological saline can be provided so that the components can be mixed before injection.

[0214] The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, one or more polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), oils such as vegetable oils (e.g., peanut oil, corn oil, sesame oil, etc.), and combinations thereof. Suitable fluidity can be maintained, for example, by using a coating such as lecithin, by maintaining the required particle size in the case of dispersions, and / or by using surfactants. In many cases, it is preferable to include an isotonic agent, for example, sugar or sodium chloride. In a preferred embodiment, water is added to the liquid formulation of the present invention.

[0215] Solutions and dispersions of the active compound as a free acid or base or a pharmacologically acceptable salt thereof can be prepared in water or other solvent or dispersion medium, the dispersion medium suitably mixed with one or more pharmaceutically acceptable excipients, including, but not limited to, buffers, surfactants, dispersing agents, emulsifiers, viscosity modifiers, and combinations thereof.

[0216] Suitable surfactants may be anionic, cationic, amphoteric, or nonionic surfactants. Suitable anionic surfactants include, but are not limited to, those containing carboxylate, sulfonate, and sulfate ions. Examples of anionic surfactants include sodium, potassium, and ammonium long-chain alkyl and alkylaryl sulfonates, such as sodium dodecylbenzenesulfonate; dialkylsulfosuccinates, such as sodium dodecylbenzenesulfonate; dialkylsulfosuccinates, such as sodium bis-(2-ethylthiol)-sulfosuccinate; and alkyl sulfates, such as sodium lauryl sulfate. Cationic surfactants include, but are not limited to, quaternary ammonium compounds, such as benzalkonium chloride, benzethonium chloride, cetrimonium bromide, stearyldimethylbenzylammonium chloride, polyoxyethylene, and coconut amine. Examples of nonionic surfactants include ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stearate, polyglyceryl-4-oleate, sorbitan acylate, sucrose acylate, PEG-150 laurate, PEG-400 monolaurate, polyoxyethylene monolaurate, polysorbate, polyoxyethylene octylphenyl ether, PEG-1000 cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, Poloxamer® 401, stearoyl monoisopropanolamide, and polyoxyethylene hydrogenated tallowamide. Examples of amphoteric surfactants include sodium N-dodecyl beta-alanine, sodium N-lauryl beta-iminodipropionate, myristoamphoacetate, lauryl betaine, and lauryl sulfobetaine. The formulation may contain a preservative to prevent microbial growth. Suitable preservatives include, but are not limited to, parabens, chlorobutanol, phenol, sorbic acid, and thimerosal. The formulation may also contain an antioxidant to prevent the degradation of the active agent(s).

[0217] Water-soluble polymers are often used in formulations for parenteral administration. Suitable water-soluble polymers include, but are not limited to, polyvinylpyrrolidone, dextran, carboxymethylcellulose, and polyethylene glycol.

[0218] Sterile injectable solution can be prepared by incorporating the active compound into a suitable solvent or dispersion medium in the required amount, optionally with one or more of the excipients listed above, followed by filtration sterilization.Generally, dispersion is prepared by incorporating various sterilized active ingredients into a sterile vehicle, which contains a basic dispersion medium and other ingredients required from the above-listed list.For the preparation of sterile powder for sterile injectable solution, the preferred preparation method is vacuum drying and freeze-drying technology, which obtains the powder of active ingredient plus any additional desired ingredients from the solution previously sterile-filtered.Powder can be prepared so that the particles are inherently porous, which can increase the dissolution of particles.The method for producing porous particles is well known in the art.

[0219] In some embodiments, the liquid formulations of the present invention are mixed with an IV infusion vehicle. In some embodiments, the liquid formulations are mixed with an injectable medium such as normal saline (0.9% sodium chloride), 5% dextrose (D5W), and lactated Ringer's injection. In some embodiments, the present invention provides liquid pharmaceutical compositions prepared by mixing the liquid formulations of the present invention with water and subsequently diluting with saline or 5% dextrose. In some embodiments, the liquid pharmaceutical composition is diluted into a saline or 5% dextrose IV bag for IV administration. In some embodiments, the liquid pharmaceutical composition in the saline or 5% dextrose IV bag is stored at room temperature (about 20-25°C) for up to about 4 hours before IV administration. In some embodiments, the liquid pharmaceutical composition in the saline or 5% dextrose IV bag is stored under refrigerated (about 2-8°C) conditions for up to about 20 hours before IV administration. In some embodiments, the liquid pharmaceutical composition in the saline or 5% dextrose IV bag is stored under refrigerated (about 2-8°C) conditions for up to about 20 hours, followed by storage at room temperature (about 20-25°C) for up to about 4 hours prior to IV administration.

[0220] It should also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, excretion rate, drug combination, and the judgment of the treating physician, as well as the severity of the particular disease being treated.

[0221] The disclosure herein is further presented as a non-limiting list of numbered embodiments.

[0222] E1. A method of treating adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a subject, the method comprising administering VGL101 to the subject in need thereof at a dose of 10-75 mg / kg by intravenous infusion every 2-6 weeks, wherein after administration of VGL101, the subject is evaluated for one or more of the following: i) the safety and tolerability of VGL101; ii) the effect of VGL101 on imaging and biomarkers; iii) the efficacy of VGL101, and iv) Pharmacokinetics of VGL101.

[0223] E2. A method for preventing or delaying the onset or recurrence of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a subject, the method comprising administering VGL101 to the subject in need thereof by intravenous infusion at a dose of 10-75 mg / kg every 2-6 weeks, wherein after administration of VGL101, the subject is evaluated for one or more of the following: i) the safety and tolerability of VGL101; ii) the effect of VGL101 on imaging and biomarkers; iii) the efficacy of VGL101, and iv) Pharmacokinetics of VGL101.

[0224] E3. The method of E2, wherein the subject has a colony-stimulating factor 1 receptor (CSF1R) gene mutation that can cause ALSP.

[0225] E4. The method according to E3, wherein the CSF1R gene mutation is a loss-of-function mutation.

[0226] E5. The method of any one of E2-E4, wherein the subject is asymptomatic for ALSP.

[0227] E6. The method according to any one of E2 to E5, wherein the subject is a prodromal stage patient.

[0228] E7. The method of any one of E2 to E6, wherein the VGL101 is administered to the subject before the onset of signs or symptoms of ALSP.

[0229] E8. The method of any one of E2 to E7, wherein the subject has bilateral cerebral white matter lesions with or without thinning of the corpus callosum as measured by magnetic resonance imaging (MRI).

[0230] E9. The method of any one of E2-E8, wherein the subject has elevated levels of neurofilament light chain (NfL) detected in cerebrospinal fluid (CSF) and / or blood.

[0231] E10. The method of any one of E2-E8, wherein the subject lacks elevated levels of neurofilament light chain (NfL) detected in cerebrospinal fluid (CSF) and / or blood.

[0232] E11. The method of any one of E2 to E10, wherein the subject has suppressed levels of soluble colony-stimulating factor 1 receptor (sCSF1R) detected in cerebrospinal fluid (CSF).

[0233] E12. The method of any one of E2 to E10, wherein the subject lacks suppressed levels of soluble colony-stimulating factor 1 receptor (sCSF1R) detected in cerebrospinal fluid (CSF).

[0234] E13. The method of any one of E1 to E12, wherein the VGL101 is administered to the subject every 3 to 5 weeks.

[0235] E14. The method of any one of E1 to E13, wherein the VGL101 is administered to the subject every three weeks.

[0236] E15. The method of any one of E1 to E14, wherein the VGL101 is administered to the subject every four weeks.

[0237] E16. The method of any one of E1 to E15, wherein the VGL101 is administered to the subject every 28 days.

[0238] E17. The method of any one of E1 to E16, wherein the VGL101 is administered to the subject every 5 weeks.

[0239] E18. The method according to any one of E1 to E17, wherein the dose of VGL101 administered to the subject is between 10 and 60 mg / kg.

[0240] E19. The method of any one of E1 to E18, wherein the dose of VGL101 administered to the subject is 20 mg / kg.

[0241] E20. The method of any one of E1 to E19, wherein the dose of VGL101 administered to the subject is 30 mg / kg.

[0242] E21. The method of any one of E1 to E20, wherein the dose of VGL101 administered to the subject is 40 mg / kg.

[0243] E22. The method of any one of E1 to E21, wherein the dose of VGL101 administered to the subject is 50 mg / kg.

[0244] E23. The method of any one of E1 to E22, wherein the dose of VGL101 administered to the subject is 60 mg / kg.

[0245] E24. The method according to any one of E1 to E23, wherein the intravenous infusion is carried out for 30 to 90 minutes.

[0246] E25. The method according to any one of E1 to E24, wherein the intravenous infusion is carried out for 50 to 70 minutes.

[0247] E26. The method of any one of E1-E25, wherein two or more injections are administered.

[0248] E27. The method of any one of E1 to E26, wherein three infusions are administered.

[0249] E28. The method of E27, wherein said injection is administered every 28 days.

[0250] E29. The method of any one of E1-E28, wherein VGL101 is formulated in 500 mL of 0.9% saline.

[0251] E30. The method according to any one of E1 to E29, comprising i).

[0252] E31. The method of any one of E1 to E30, comprising ii).

[0253] E32. The method according to any one of E1 to E31, comprising iii).

[0254] E33. The method according to any one of E1 to E32, comprising iv).

[0255] E34. For i), the method of any one of the preceding claims, wherein the safety and tolerability of VGL101 is assessed by one or more of the following: ia) the nature and frequency of adverse events, serious adverse events, and discontinuations due to adverse events; ib) safety clinical trials; ic) immunogenicity test, id) vital sign measurements, i.e.) electrocardiogram, and if) Columbia-Suicide Severity Rating Scale (C-SSRS).

[0256] E35. The method according to E34, including ia).

[0257] E36. The method according to any one of E34 to E35, including ib).

[0258] E37. The method according to any one of E34 to E36, comprising (i) administering to the subject a dose of 100 mg / kg of ethanol.

[0259] E38. The method according to any one of E34 to E37, including (i) the method according to any one of E34 to E37.

[0260] The method of any one of E34 to E38, including E39. ie).

[0261] The method of any one of E34 to E39, including E40. if).

[0262] E41. The method of any one of E1 to E40, wherein for ii), the effect of VGL101 on imaging and biomarkers is assessed by change from baseline.

[0263] E42. The method of E41, wherein said change from baseline is measured by one or more of the following: ii-ai) neurofilament light chains (NfL) in cerebrospinal fluid (CSF) and blood; ii-a-ii) structural and volumetric magnetic resonance imaging (MRI); ii-a-iii) MRI-based ALSP severity score, and ii-a-iv) Soluble colony-stimulating factor 1 receptor (sCSF1R) in CSF.

[0264] E43. The method of E41, wherein said change from baseline is measured by one or more of the following: ii-ci) cytokine panel and soluble TREM2 (sTREM2) in CSF, and ii-c-ii) Blood biomarkers of disease progression.

[0265] E44. Regarding iii), the method of any one of E1 to E43, wherein the efficacy of VGL101 is assessed by one or more of the following: iii-a) change from baseline, iii-b) Response to Clinical Global Impression-Change (CGI-C), defined as a much / very improved response, and iii-c) Response to Patient Global Impression-Change (PGI-C), defined as a much / very improved response.

[0266] E45. For iii-a), the method of E44, wherein said change from baseline is measured by one or more of the following: Montreal Cognitive Assessment (MoCA), Clinical Dementia Rating Scale + National Coordinating Center for Alzheimer's Disease - Frontotemporal Dementia (CDR® + NACC-FTD), Brief Assessment of Cognitive Function (BAC) Battery, Corticobasal Ganglionic Function Scale (CBFS), · 2-minute walk test (2MWT), Timed Up and Go (TUG) test, Gait and balance assessment in ambulatory subjects, Functional Activity Questionnaire (FAQ), Neuropsychiatric Inventory-12-item version (NPI-12), ·Zarit Burden Interview.

[0267] E46. The method of any one of E1 to E45, wherein the pharmacokinetics of VGL101 is assessed by serum and CSF concentrations of VGL101.

[0268] E47. The method of any one of E1-E46, wherein VGL101 is formulated as a liquid formulation, said liquid formulation further comprising a pharmaceutically acceptable excipient and / or carrier.

[0269] E48. The method of E47, wherein VGL101 is present at a concentration of about 140 mg / mL.

[0270] E49. The method of any one of E47-E48, wherein the liquid formulation further comprises sodium acetate, for example, at a concentration of about 15 mM.

[0271] E50. The method of any one of E47-E49, wherein said liquid formulation further comprises sucrose at a concentration of about 9% (w / v) of the total liquid formulation volume.

[0272] E51. The method of any one of E47 to E50, wherein the liquid formulation further comprises polysorbate 80, for example, at a concentration of about 0.01% (w / v) of the total liquid formulation volume.

[0273] E52. The method of any one of E47 to E51, wherein the liquid formulation has a pH of about 5.2.

[0274] E53. The method of any one of E47-E52, wherein the liquid formulation has a pH of about 5.2 and comprises: Anti-TREM2 antibody "Ab-1" at a concentration of approximately 140 mg / mL, Sodium acetate at a concentration of about 15 mM; Sucrose at a concentration of about 9% (w / v) of the total liquid formulation volume; Polysorbate 80 at a concentration of approximately 0.01% (w / v) of the total liquid formulation volume.

[0275] Examples Anti-TREM2 antibodies such as VGL101 can be prepared by methods known to those skilled in the art, for example, as described in WO2018 / 195506A1, the contents of which are incorporated herein by reference in their entirety.

[0276] [Table 19-1] [Table 19-2] [Example]

[0277] Example 1 Pharmacokinetic analysis of VGL101 regarding the basis for first-in-human dose Observed systemic concentration versus time data for VGL101 in non-human primates (NHPs), cynomolgus monkeys, were modeled using a standard two-compartment pharmacokinetic (PK) model. PK model parameters were allometrically scaled based on body weight. Simulations of human exposure in the systemic circulation and cerebrospinal fluid (CSF) were performed using dose levels of 1, 3, 10, 20, 40, and 60 mg / kg and compared with in vitro measurements of binding activity in a human macrophage assay. A margin of safety was calculated by comparing predicted human exposure to predicted NHP exposure at the 200 mg / kg dose.

[0278] IV VGL101 single doses of 1, 3, 10, 20, 40, and 60 mg / kg, and multiple q28d doses of 20, 40, and 60 mg / kg were input into the simulation model to generate serum concentration time profiles. For the multiple ascending dose portion of the study, three doses are expected to be administered every 28 days. C after the third dose for the single and q28d doses max , AUC after single dose inf , and AUC after the third dose for the q28d dose 28日 Human serum exposure parameters of C were predicted. The mean VGL101 potency number is the predicted mean potency as a percentage of maximum value over 28 days after the single and third q28d doses, based on the predicted mean serum concentrations over the interval. max VGL101 efficacy in numbers is C max The predicted efficacy as a percentage of maximum after the single and third q28d doses based on the q28d dose.

[0279] VGL101 concentrations increased proportionally within this dose range, with t 1 / 2 The simulated dose range is predicted to produce in vitro EC values ​​in serum and the central nervous system (CNS) in a dose-dependent manner. 50 These appear to result in predicted concentrations that would exceed the values ​​and may reflect pharmacologically active doses. [Table 20]

[0280] Example 2 Phase II Safety, Tolerability, and Proof-of-Concept Study of VGL101 in Patients with Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP) Experience 1.Purpose: Main purpose: To evaluate the safety and tolerability of the anti-TREM2 antibody VGL101 for the treatment of ALSP. Secondary purpose: To evaluate the effect of VGL101 on imaging and biomarkers of disease progression in subjects with ALSP. Exploratory purpose: To evaluate the clinical efficacy of VGL101 for the treatment of ALSP. Pharmacokinetics: To evaluate the pharmacokinetics of VGL101 in subjects with ALSP. 2.Design:

[0281] This is a Phase II, multicenter, open-label study of VGL101 in subjects with documented genetic mutations in the CSF1R gene and who meet the study inclusion criteria described below. The study includes a screening period, a treatment period, an extension period, and a safety follow-up period.

[0282] Subjects who meet the study inclusion / exclusion criteria will be enrolled in the study and receive intravenous (IV) infusions of VGL101 every 28±7 days for a total of 13 doses. Subjects in the study will be dosed at either 20 mg / kg or 40 mg / kg.

[0283] Clinic visits will be conducted at screening, baseline, and specific pre-specified time points. At each visit, clinical assessments (clinician, subject, and study partner rating scales, as well as gait and balance performance assessments) will be performed; blood will be collected for biomarker analysis, VGL101 serum concentrations, and safety laboratory assessments; vital signs, adverse events (AEs), and concomitant medications and treatments will be recorded; and the Columbia-Suicide Severity Rating Scale (C-SSRS) will be completed. MRI will be performed at screening and specific pre-specified time points. Cerebrospinal fluid (CSF) for PK and biomarker analysis will be collected at baseline and specific pre-specified time points.

[0284] Treatment group and duration All subjects will receive VGL101 via IV infusion every 28±7 days for a total of 13 doses. Subjects in this study will be dosed at either 20 mg / kg or 40 mg / kg.

[0285] Selection criteria: Subjects who meet at least the following criteria are eligible for the study: 1. Subjects must be 18 years of age or older and of either sex on the date the Informed Consent Form (ICF) is signed. 2. The subject has evidence of a genetic mutation in the CSF1R gene. 3. Subject meets both of the following criteria (Parts A and B): A. The subject has evidence of two or more of the following categories of clinical signs or symptoms: Cognitive or psychiatric disorder b. Pyramidal signs on neurological examination c. Extrapyramidal signs such as stiffness. d. epilepsy B. Screening MRI reveals MRI findings consistent with ALSP, particularly bilateral cerebral white matter lesions with or without thinning of the corpus callosum. 4. The subject must have a study partner (i.e., caregiver, family member, friend, etc.) who, in the investigator's judgment, is in frequent and sufficient contact with the subject to provide accurate information about the subject's health, cognition, and functional ability. The study partner must be willing to sign the Study Partner ICF.

[0286] Exclusion criteria Subjects who meet any of the following criteria are not eligible for this study: 1. The subject has any neurological disease that poses a risk to the subject or that can result in cognitive, motor, or behavioral disorders similar to ALSP, including, but not limited to, brain tumor, hydrocephalus, Alzheimer's disease, frontotemporal dementia (FTD), ALS, stroke, Huntington's disease, multiple sclerosis, Parkinson's disease, and Down's syndrome. 2. Subject with any condition or situation that, in the opinion of the investigator or sponsor's medical personnel, could place the subject at significant risk, confound the study results, or significantly interfere with the subject's participation in the study.

[0287] Screening failure A screen failure is defined as a subject who consents to participate in a clinical trial but is not subsequently enrolled. To ensure transparent reporting of screen failures to meet the Consolidated Standards for Reporting Clinical Trials (CONSORT) publication requirements and to answer inquiries from regulatory authorities, a minimum set of screen failure information is required. The minimum information includes demographic information, details of the screen failure, eligibility criteria, and any SAEs.

[0288] Individuals who do not meet the criteria for inclusion in the study (screening failures) may be rescreened after consultation with the sponsor's medical monitor and resolution of the issues that led to the initial screening failure, unless the reason for screening failure is related to the subject not having a CSF1R gene mutation.

[0289] 3.Evaluation criteria: Primary endpoint: Safety and tolerability as assessed by: - The nature and frequency of adverse events, serious adverse events, and discontinuations due to adverse events -Safety clinical trials -Immunogenicity studies -Vital sign measurements -electro-cardiogram -Columbia-Suicide Severity Rating Scale (C-SSRS).

[0290] Secondary endpoints: Change from baseline in neurofilament light chain (NfL) levels in cerebrospinal fluid (CSF) and blood Changes from baseline in structural and volumetric magnetic resonance imaging (MRI) Change from baseline in MRI-based ALSP severity score Change from baseline in soluble colony-stimulating factor 1 receptor (sCSF1R) in CSF

[0291] Secondary Objectives - Exploratory Endpoints: Changes from baseline in CSF and blood NfL Changes from baseline in structural and volumetric MRI Change from baseline in MRI-based ALSP severity score Change from baseline in sCSF1R in CSF Change from baseline in cytokine panel and change from baseline in soluble TREM2 (sTREM2) in CSF Changes from baseline in blood biomarkers of disease progression

[0292] Exploratory Objectives - Exploratory Endpoints: Change from baseline in the following clinical outcome measures: -Montreal Cognitive Assessment (MoCA) - Clinical Dementia Rating Scale + National Coordinating Center for Alzheimer's Disease - Frontotemporal Dementia (CDR® + NACC-FTD) -Brief Assessment of Cognitive Function (BAC) Battery - Corticobasal Ganglionic Function Scale (CBFS) -2-minute walk test (2MWT) -Timed Up and Go (TUG) test -Gait and balance assessment in ambulatory subjects -Functional Activity Questionnaire (FAQ) - Neuropsychiatric Inventory-12-item version (NPI-12) -Zarit Burden Interview Response to Clinical Global Impression-Change (CGI-C), defined as a much / very improved response Patient Global Impression Response-Change (PGI-C), defined as a much / very improved response

[0293] Pharmacokinetic endpoints: Serum and CSF concentrations of VGL101

[0294] Cognitive assessment Montreal Cognitive Assessment (MoCA): The MoCA is a short 30-question test used to assess cognitive ability and dementia (Smith T, et. al., Can J Psychiatry. 2007;52(5):329-32; Chou KL, et. al., Mov Disord. 2010;25(15):2501-7). The MoCA assesses different types of cognitive domains, including orientation, short-term memory, delayed recall, abstraction, visuospatial, and executive function, language, and attention. Available in 35 languages, the scale takes 10-12 minutes to complete. Scores range from zero to 30, with a score of 26 or higher generally considered normal. MoCA completion.

[0295] Clinical Dementia Rating Scale + National Coordinating Center for Alzheimer's Disease - Frontotemporal Dementia (CDR® + NACC-FTD): The CDR® + NACC-FTD (Mheniargic T, et. al., Alzheimer's Dement. 2020;16(1):79-90) is a semi-structured global rating scale developed to measure the severity of dementia symptoms in Alzheimer's disease and related dementias. The scale measures six domains: memory, orientation, judgment and problem-solving, community affairs engagement, home and hobbies, and personal care. The first five domains are rated on a 5-point scale (0 = normal, 0.5 = problematic or minimal impairment, 1 = mild but definitely impaired, 2 = moderate impairment, and 3 = most severe impairment). The sixth domain, personal care, does not have a 0.5 rating and is therefore rated on a 4-point scale.

[0296] The ratings of the six individual domains are summed to generate the Clinical Dementia Rating (CDR) Sum of Boxes (CDR-SB) score. The global CDR score is calculated from the six domains and rated on a 5-point scale (0 / 0.5 / 1 / 2 / 3). The global CDR and CDR-SB are widely used in clinical research and therapeutic trials. Because the CDR focuses primarily on Alzheimer's disease, it gives more weight to memory and orientation problems and less weight to behavioral and language problems.

[0297] To extend the utility of the CDR to FTD spectrum disorders, behavioral and language domains were added to the CDR to form the 8-domain Frontotemporal Dementia and Cortical Atrophy (FTLD)-CDR scale. Following adoption by the National Alzheimer's Disease Coordinating Center (NACC), the scale name was changed to CDR®+NACC-FTLD (CDR®+NACC-FTLD). The additional behavioral and language domains are rated on a 5-point scale ranging from 0 to 3. The CDR®+NACC-FTLD box sum score (CDR®+NACC-FTLD-SB) is defined as the sum of the CDR-SB, behavioral domain assessment, and language domain assessment. The CDR®+NACC-FTLD-SB correlates well with frontotemporal cerebral blood perfusion insufficiency in FTLD patients and is useful for characterizing non-memory symptoms in patients with dementia. The CDR®+NACC-FTLD was chosen as the outcome measure for this study because the frontal lobe is often affected by the ALSP disease process and behavioral symptoms are common in patients with ALSP. The CDR®+NACC-FTLD will be administered by trained site staff.

[0298] Brief Assessment of Cognition (BAC): The BAC (https: / / littlegreensoftware.com / work / bacbacs) is a tablet-based version of the paper-based BAC tool, developed for use in schizophrenia and other conditions affecting cognition. The BAC can be administered as a full battery or as a customized selection of smaller test subsets. The following test subsets are included: verbal memory, digit sequencing, token motor tasks, verbal fluency, symbol coding, and the Tower of London test, which tests executive function, reasoning, and problem solving. All BAC tests are completed under the supervision of a trained assessor. The BAC is a composite T-score that averages the standardized scale scores from each of the six tests.

[0299] Corticobasal Ganglionic Function Scale (CBFS): The CBFS (Lang AE, et. al., Parkinsonism Relat Disord. 2020;79:121-6) is a novel rating scale that assesses experiences in activities of daily living (EDL) and behavioral, language, and cognitive impairments in patients with four recurrent tauopathies. The CBFS consists of 14 questions regarding motor EDL and 17 questions regarding non-motor EDL, each rated on a 5-point Likert scale ranging from 0 to 4, with 0 = normal or no problems and 4 = severe problems. Questions are patient-directed but require a collaborative response from the patient and caregiver. Responses should be based on usual or average functioning over the past two weeks. Complete the CBFS.

[0300] Exercise assessment (ambulatory subjects) The 2-Minute Walk Test (2MWT): The 2MWT (Witherspoon JW, et. al., Eur J Paediatr Neurol. 2019;23(1):165-70) is a measure of self-paced walking ability and functional capacity, particularly for individuals unable to manage long walking periods. The 2MWT has been used as an outcome measure in various health conditions, including neuromuscular disorders, in adult and pediatric populations. The test measures the distance a person can walk in 2 minutes. Individuals are encouraged to walk as fast and safely as possible for 2 minutes, covering as much ground as possible without running. Breaks are permitted as needed, but the timer is not stopped. Walking aids may be used if necessary but should be consistent across trials. Breaks and aid use should be recorded. Healthy subjects under the age of 59 can walk a maximum of 200 meters in 2 minutes; therefore, a testing area that allows for a minimum number of turns should be available. Administer the 2MWT.

[0301] Timed Up and Go (TUG) Test: The TUG (Ibrahim A, et. al., J Multidiscip Healthc. 2017;10:409-16) is used to determine the time required to sit, stand, and walk. Additionally, the test helps assess the likelihood of falls. While initially designed for older adults, the TUG is also used in populations with conditions that may affect gait and balance. This tool has been validated for Parkinson's disease, multiple sclerosis, hip fracture, Alzheimer's disease, cerebrovascular accident (CVA), Huntington's disease, and post-CVA populations. Individuals begin in a seated position in a chair with armrests and, upon command, stand, walk 3 meters, turn around, return to the chair, and sit down. The time is stopped when the patient is seated. Use of walking aids should be recorded and consistent across tests. The TUG is administered.

[0302] Disease severity assessment Clinical Global Impression-Change (CGI-C): The CGI-C (Guy W (Ed.), ECDEU Assessment Manual for Psychopharmacology, 1976) is a 7-point scale that requires clinicians to rate how much a patient's illness has improved or worsened compared to their baseline condition at the start of the intervention. Raters choose one answer based on the question: "Compared to the patient's condition at the start of the study, how much has the patient changed?" Scores are as follows: 1 = very improved, 2 = greatly improved, 3 = minimally improved, 4 = no change, 5 = minimally worsened, 6 = much worse, and 7 = very worse. Complete the CGI-C.

[0303] Patient Global Impression-Change (PGI-C): The PGI-C is the patient-reported outcome counterpart to the CGI-C (Guy W (Ed.), ECDEU Assessment Manual for Psychopharmacology, 1976). A qualitative assessment of meaningful change is determined by the patient in response to the question, "Compared to your condition at the start of the trial, how much has your condition changed?" Scores are as follows: 1 = very improved, 2 = greatly improved, 3 = minimally improved, 4 = no change, 5 = minimally worsened, 6 = much worse, and 7 = very worse. Complete the PGI-C. Functional, psychological, and other evaluations

[0304] Functional Assessment Questionnaire (FAQ): The FAQ (Pfeffer RI, et. al., J Gerontol. 1982;37(3):323-9) measures instrumental activities of daily living, such as preparing a balanced meal or managing personal finances. Thus, functional changes in instrumental activities of daily living, which require high cognitive abilities, are seen earlier in the dementia process than changes in basic activities of daily living. Therefore, the FAQ is useful for monitoring these functional changes over time in patients with mild dementia and has been used in clinical trials of patients with mild cognitive impairment, as well as mild to moderate and severe dementia.

[0305] The FAQ assesses 10 functions related to personal finances, shopping, playing games, preparing meals, watching television, following the news, taking medications, and traveling. Each function is rated from 0 to 3 (0 = normal, 1 = able to do it independently with difficulty, 2 = needs assistance, 3 = completely dependent on others). The FAQ correlates highly with cognitive measures and is sensitive to change over time. Complete the FAQ.

[0306] Neuropsychiatric Symptom Inventory-12-Item Version (NPI-12): The NPI-12 (Cummings JL, et. al., Neurol. 1994;44(12):2308-14) is an abbreviated inventory that provides a brief assessment of neuropsychiatric symptomatology in clinical practice and clinical trials. The NPI-12 assesses 12 behavioral domains that are common in dementia: hallucinations, delusions, agitation / aggression, vocalization / depression, anxiety, irritability, inhibition, fever, lethargy, abnormal motor behavior, changes in sleep and nighttime behavior, and changes in appetite and feeding.

[0307] The NPI-12 is provided by the clinician to the study partner. The study partner is typically a family member involved in the patient's daily care, but may also be a professional caregiver or other relevant party as long as they have detailed knowledge of the patient's behavior. The clinician reads each question to the caregiver as written. After reading each screening question, the caregiver is asked whether the described behavior is present. If the answer is "no," the clinician proceeds to the next section and reads the next screening question. If the answer is "yes," the assessor then assesses the frequency (rarely, often, very often), severity (mild, moderate, or severe) of symptoms present in the past month, and the associated impact of symptom occurrence on them (i.e., caregiver distress: none, minimal, mild, moderate, severe, or very severe or extreme). The total score can be used to monitor the worsening or improvement of neuropsychiatric symptoms. Complete the NPI-12.

[0308] Zarit Burden Interview: The Zarit Burden Interview (Knight BG, et. al., J Clin Geropsychology. 2000;6:249-58) is a caregiver self-report measure used to assess the burden of illness on the primary caregiver. The revised version contains 22 items, with each interview item being described that the caregiver is asked to rate on a 5-point scale from 0 ("never") to 4 ("almost always"). Complete the Zarit Burden Interview.

[0309] Safety evaluation Vital signs: Systolic and diastolic blood pressure, heart rate, and oral temperature will be recorded at each visit. Vital signs will be measured in the sitting or supine position after at least 5 minutes of rest. The same arm and position should be used for all measurements during the study.

[0310] Weight and Height: Height will be measured at screening. Weight will be determined at screening, before administration of any VGL101 dose, and at each visit. Subjects should be minimally clothed (no shoes or heavy clothing) and fasted before being weighed.

[0311] Physical and Neurological Examination: A complete physical examination includes a general appearance and examination of the skin, neck (including the thyroid gland), eyes, ears, nose, throat, heart, lungs, abdomen, lymph nodes, and extremities. Genital, rectal, and breast examinations may be omitted if not clinically indicated. The neurological examination includes assessment of mental status (e.g., level of consciousness, orientation, speech, memory), examination of cranial nerves II through XII, motor examination (muscle appearance, tone, strength, reflexes), sensory examination, coordination, stance, gait, and balance. Physical and neurological examinations are performed at screening, baseline, and certain pre-specified time points.

[0312] Electrocardiogram (ECG): A single 12-lead ECG will be obtained at screening, baseline, and certain pre-specified time points. The ECG should be obtained with the subject in the supine position and after at least 5 minutes of rest.

[0313] Columbia-Suicide Severity Rating Scale (C-SSRS): The C-SSRS (Posner K, et al., Am J Psych. 2011;168(12):1266-77) is a semi-structured interview designed to quantify the severity of suicidal ideation and behavior. The C-SSRS is available in over 100 languages ​​and takes approximately 5 minutes to complete. Interviewers are not required to have mental health training, but if they have no previous experience, they can receive training in administering the questionnaire. Two versions of the scale are used: a "baseline / screening" (lifetime and last 6 months) version and a "since last visit" version.

[0314] A "Baseline / Screening" (Lifetime and Last 6 Months) version, which assesses the subject's lifetime experience of suicidal events and suicidal ideation, as well as the occurrence of suicidal events or suicidal ideation within a specified period prior to study enrollment, will be completed for all subjects at screening to determine eligibility. For subjects who respond positively to questions 4 or 5 of the C-SSRS at screening / baseline, a risk assessment will be required by a qualified health care professional to assess whether the subject is safe to participate in the study.

[0315] The "Since Last Visit" C-SSRS form will be completed at baseline and at certain pre-specified study visits (safety follow-up visits). If a subject exhibits possible suicidal ideation related to their actual intent or method or plan, as indicated by a "yes" response to questions 4 or 5 of the C-SSRS, the investigator will assess whether a risk assessment by a licensed mental health professional (or only the investigator if the investigator is a licensed mental health professional) is necessary and whether the subject should continue or discontinue the study.

[0316] Pharmacokinetics / Pharmacodynamics Blood Samples: Blood samples for determination of serum concentrations of VGL101 will be obtained prior to the start of the IV infusion and 1 hour after the end of the IV infusion at baseline and certain pre-specified time points. Samples will also be obtained for analysis of blood biomarkers of disease progression. Instructions for blood sample collection, processing, and handling will be provided by the sponsor.

[0317] Cerebrospinal fluid samples: Cerebrospinal fluid samples for determination of VGL101 concentrations, as well as biomarker analysis (including but not limited to NfL protein, sCSF1R, sTREM2, and cytokines) and basal CSF analysis will be obtained via lumbar puncture at baseline and certain pre-specified time points.

[0318] Magnetic Resonance Imaging: T1 (with and without contrast), T2, fluid-suppressed inversion recovery (FLAIR), T2*, and diffusion-weighted MRI scans will be obtained at screening and at certain pre-specified time points. MRI scans will be obtained 7 days before or 7 days after the scheduled visit, although additional flexibility in scheduling visits is possible after consultation with the sponsor.

[0319] Genetics: A blood sample is taken at baseline to confirm that the subject has the CSF1R gene mutation.

[0320] Immunogenicity Assessment: Serum samples for determination of anti-VGL101 antibodies will be obtained prior to the start of IV infusion at baseline and at certain pre-specified time points.

[0321] Based on preclinical data, VGL101 administered according to the study protocol should demonstrate a favorable safety and tolerability profile in patients with ALSP, as measured by one or more of the primary endpoints. VGL101 administered according to the study protocol should also demonstrate favorable effects on imaging and biomarkers of disease progression in subjects with ALSP, as measured by one or more of the "Secondary Objectives - Exploratory Endpoints." VGL101 administered according to the study protocol should also demonstrate signs of clinical efficacy for the treatment of ALSP in patients with ALSP, as measured by one or more of the "Exploratory Objectives - Exploratory Endpoints." VGL101 administered according to the study protocol should also demonstrate favorable pharmacokinetics in subjects with ALSP, as measured by pharmacokinetic endpoints.

[0322] While the inventors have described several embodiments of the invention, it will be apparent that the inventors' basic examples may be modified to provide other embodiments that utilize the compounds and methods of the invention. It will therefore be understood that the scope of the invention is defined by this application and the claims, rather than by the specific embodiments that have been represented by way of example.

Claims

1. 1. A method of treating adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a subject, the method comprising administering VGL101 to the subject in need thereof by intravenous infusion every 2 to 6 weeks at a dose of 10 to 75 mg / kg, wherein after administration of VGL101, the subject is evaluated for one or more of the following: i) the safety and tolerability of VGL101; ii) the effect of VGL101 on imaging and biomarkers; iii) the efficacy of VGL101, and iv) Pharmacokinetics of VGL101.

2. 1. A method of preventing or delaying the onset or recurrence of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) in a subject, the method comprising administering VGL101 to the subject in need thereof by intravenous infusion every 2 to 6 weeks at a dose of 10 to 75 mg / kg, wherein after administration of VGL101, the subject is evaluated by one or more of the following: i) the safety and tolerability of VGL101; ii) the effect of VGL101 on imaging and biomarkers; iii) the efficacy of VGL101, and iv) Pharmacokinetics of VGL101.

3. 3. The method of claim 2, wherein the subject has a colony-stimulating factor 1 receptor (CSF1R) gene mutation that can cause ALSP.

4. The method of claim 3, wherein the CSF1R gene mutation is a loss-of-function mutation.

5. The method of any one of claims 2 to 4, wherein the subject is asymptomatic for ALSP.

6. The method according to any one of claims 2 to 5, wherein the subject is a prodromal stage patient.

7. The method of any one of claims 2 to 6, wherein the VGL101 is administered to the subject prior to the onset of signs or symptoms of ALSP.

8. 8. The method of any one of claims 2 to 7, wherein the subject has bilateral cerebral white matter lesions with or without thinning of the corpus callosum as measured by magnetic resonance imaging (MRI).

9. 9. The method of any one of claims 2 to 8, wherein the subject has elevated levels of neurofilament light chain (NfL) detected in cerebrospinal fluid (CSF) and / or blood.

10. 9. The method of any one of claims 2 to 8, wherein the subject lacks elevated levels of neurofilament light chain (NfL) detected in cerebrospinal fluid (CSF) and / or blood.

11. 11. The method of any one of claims 2 to 10, wherein the subject has suppressed levels of soluble colony-stimulating factor 1 receptor (sCSF1R) detected in cerebrospinal fluid (CSF).

12. 11. The method of any one of claims 2 to 10, wherein the subject lacks suppressed levels of soluble colony-stimulating factor 1 receptor (sCSF1R) detected in cerebrospinal fluid (CSF).

13. The method of any one of claims 1 to 12, wherein the VGL101 is administered to the subject every 3 to 5 weeks.

14. The method of any one of claims 1 to 13, wherein the dose of VGL101 administered to the subject is between 10 and 60 mg / kg.

15. 15. The method of any one of claims 1 to 14, wherein the intravenous infusion is performed over a period of 30 to 90 minutes.

16. 16. The method of any one of claims 1-15, wherein VGL101 is formulated in 500 mL of 0.9% saline.

17. The method of any one of claims 1 to 16, wherein for i) the safety and tolerability of VGL101 is assessed by one or more of the following: ia) the nature and frequency of adverse events, serious adverse events, and discontinuations due to adverse events; ib) safety clinical trials; ic) immunogenicity test, id) vital sign measurements; i-e) electrocardiogram, and i-f) Columbia-Suicide Severity Rating Scale (C-SSRS).

18. 18. The method of any one of claims 1 to 17, wherein for ii), the effect of VGL101 on imaging and biomarkers is assessed by change from baseline.

19. 38. The method of claim 37, wherein the change from baseline is measured in one or more of the following: ii-a-i) neurofilament light chain (NfL) in cerebrospinal fluid (CSF) and blood; ii-a-ii) structural and volumetric magnetic resonance imaging (MRI); ii-a-iii) MRI-based ALSP severity score; ii-a-iv) soluble colony-stimulating factor 1 receptor in CSF (sCSF1R); ii-ci) cytokine panel and soluble TREM2 (sTREM2) in CSF, and ii-c-ii) Blood biomarkers of disease progression.

20. 20. The method of any one of claims 1 to 19, wherein for iii) the efficacy of VGL101 is assessed by one or more of the following: iii-a) Change from baseline as measured by one or more of the following: Montreal Cognitive Assessment (MoCA), Clinical Dementia Rating Scale + National Alzheimer's Disease Coordinating Center - Frontotemporal Dementia (CDR® + NACC-FTD), Brief Assessment of Cognitive Function (BAC) Battery, Corticobasal Ganglionic Function Scale (CBFS), - 2-minute walk test (2MWT), - Timed Up and Go (TUG) test, Gait and balance assessment in ambulatory subjects, -Functional Activities Questionnaire (FAQ), Neuropsychiatric Symptom Inventory-12 item version (NPI-12), ・Zarit Burden Interview, iii-b) Response to Clinical Global Impression-Change (CGI-C), defined as a much / very improved response; and iii-c) Patient Global Impression Response-Change (PGI-C), response defined as much / very improved response.

21. The method of any one of claims 1 to 20, wherein the pharmacokinetics of VGL101 is assessed by serum and CSF concentrations of VGL101.

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