US2017240631A1PendingUtilityA1
Anti-trem2 antibodies and methods of use thereof
Est. expiryAug 8, 2034(~8.1 yrs left)· nominal 20-yr term from priority
A61P 25/28A61P 25/00C07K 2317/31C07K 2317/55C07K 2317/75A61K 2039/505C07K 2317/34C07K 2317/21C07K 16/283C07K 16/2803C07K 2317/92C07K 2317/76C07K 16/28C07K 2317/33C07K 2317/56C07K 2317/52
51
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Claims
Abstract
The invention is generally directed to methods and compositions that include antibodies, e.g., monoclonal, chimeric, humanized antibodies, antibody fragments, etc., that specifically bind a TREM2 protein, e.g., a mammalian TREM2 and/or human TREM2. The methods provided herein find use in preventing, reducing risk, or treating an individual having dementia, frontotemporal dementia, Alzheimer's disease, Nasu-Hakola disease, or multiple sclerosis.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . An isolated antibody that binds to a TREM2 protein, wherein the isolated antibody induces one or more TREM2 activities, and wherein the isolated antibody promotes survival of one or more innate immune cells or increases expression of IL-6.
2 . An isolated antibody that binds to a TREM2 protein, wherein the isolated antibody inhibits one or more TREM2 activities, and wherein the isolated antibody decreases survival of one or more innate immune cells.
3 . The isolated antibody of claim 1 or claim 2 , wherein the one or more innate immune cells are selected from the group consisting of macrophages, microglial cells, M1 microglial cells, activated M1 microglial cells, M2 microglial cells, dendritic cells, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, monocytes, osteoclasts, Langerhans cells of skin, Kupffer cells, and any combination thereof.
4 . An isolated antibody that binds to a TREM2 protein, wherein the isolated antibody binds to one or more amino acids within amino acid residues selected from the group consisting of:
i. amino acid residues 29-112 of SEQ ID NO: 1, or amino acid residues on a TREM2 protein corresponding to amino acid residues 29-112 of SEQ ID NO: 1; ii. amino acid residues 29-41 of SEQ ID NO: 1, or amino acid residues on a TREM2 protein corresponding to amino acid residues 29-41 of SEQ ID NO: 1; iii. amino acid residues 40-44 of SEQ ID NO: 1, or amino acid residues on a TREM2 protein corresponding to amino acid residues 40-44 of SEQ ID NO: 1; iv. amino acid residues 43-50 of SEQ ID NO: 1, or amino acid residues on a TREM2 protein corresponding to amino acid residues 43-50 of SEQ ID NO: 1; v. amino acid residues 49-57 of SEQ ID NO: 1, or amino acid residues on a TREM2 protein corresponding to amino acid residues 49-57 of SEQ ID NO: 1; vi. amino acid residues 47-69 of SEQ ID NO: 1, or amino acid residues on a TREM2 protein corresponding to amino acid residues 47-69 of SEQ ID NO: 1; vii. amino acid residues 67-76 of SEQ ID NO: 1, or amino acid residues on a TREM2 protein corresponding to amino acid residues 67-76 of SEQ ID NO: 1; viii. amino acid residues 76-86 of SEQ ID NO: 1, or amino acid residues on a TREM2 protein corresponding to amino acid residues 76-86 of SEQ ID NO: 1; ix. amino acid residues 91-100 of SEQ ID NO: 1, or amino acid residues on a TREM2 protein corresponding to amino acid residues 91-100 of SEQ ID NO: 1; x. amino acid residues 99-115 of SEQ ID NO: 1, or amino acid residues on a TREM2 protein corresponding to amino acid residues 99-115 of SEQ ID NO: 1; xi. amino acid residues 104-112 of SEQ ID NO: 1, or amino acid residues on a TREM2 protein corresponding to amino acid residues 104-112 of SEQ ID NO: 1; xii. amino acid residues 114-118 of SEQ ID NO: 1, or amino acid residues on a TREM2 protein corresponding to amino acid residues 114-118 of SEQ ID NO: 1; xiii. amino acid residues 130-171 of SEQ ID NO: 1, or amino acid residues on a TREM2 protein corresponding to amino acid residues 130-171 of SEQ ID NO: 1; xiv. amino acid residues 139-146 of SEQ ID NO: 1, or amino acid residues on a TREM2 protein corresponding to amino acid residues 139-146 of SEQ ID NO: 1; xv. amino acid residues 140-153 of SEQ ID NO: 1, or amino acid residues on a TREM2 protein corresponding to amino acid residues 140-153 of SEQ ID NO: 1; xvi. amino acid residues 130-144 of SEQ ID NO: 1, or amino acid residues on a TREM2 protein corresponding to amino acid residues 130-144 of SEQ ID NO: 1; and xvii. amino acid residues 158-171 of SEQ ID NO: 1, or amino acid residues on a TREM2 protein corresponding to amino acid residues 158-171 of SEQ ID NO: 1.
5 . The isolated antibody of claim 4 , wherein the isolated antibody binds to one or more amino acids within amino acid residues 43-50 of SEQ ID NO: 1, or amino acid residues on a TREM2 protein corresponding to amino acid residues 43-50 of SEQ ID NO: 1.
6 . The isolated antibody of claim 4 , wherein the isolated antibody binds to one or more amino acids within amino acid residues 49-57 of SEQ ID NO: 1, or amino acid residues on a TREM2 protein corresponding to amino acid residues 49-57 of SEQ ID NO: 1.
7 . The isolated antibody of claim 4 , wherein the isolated antibody binds to one or more amino acids within amino acid residues 139-146 of SEQ ID NO: 1, or amino acid residues on a TREM2 protein corresponding to amino acid residues 139-146 of SEQ ID NO: 1.
8 . The isolated antibody of claim 4 , wherein the isolated antibody binds to one or more amino acids within amino acid residues 140-153 of SEQ ID NO: 1, or amino acid residues on a TREM2 protein corresponding to amino acid residues 140-153 of SEQ ID NO: 1.
9 . The isolated antibody of claim 4 , wherein the isolated antibody binds to an epitope comprising one or more amino acids within amino acid residues 43-50 of SEQ ID NO: 1.
10 . The isolated antibody of claim 4 , wherein the isolated antibody binds to an epitope comprising one or more amino acids within amino acid residues 49-57 of SEQ ID NO: 1.
11 . The isolated antibody of claim 4 , wherein the isolated antibody binds to an epitope comprising one or more amino acids within amino acid residues 139-146 of SEQ ID NO: 1.
12 . The isolated antibody of claim 4 , wherein the isolated antibody binds to an epitope comprising one or more amino acids within amino acid residues 140-153 of SEQ ID NO: 1.
13 . The isolated antibody of any one of claims 1 - 12 , wherein the TREM2 protein is a mammalian protein or a human protein.
14 . The isolated antibody of claim 13 , wherein the TREM2 protein is a wild-type protein.
15 . The isolated antibody of claim 13 , wherein the TREM2 protein is a naturally occurring variant.
16 . The isolated antibody of any one of claims 1 - 15 , wherein the antibody is an agonist antibody, and wherein the antibody induces one or more TREM2 activities.
17 . The isolated antibody of any one of claims 1 - 16 , wherein the isolated antibody induces or retains TREM2 clustering on a cell surface.
18 . The isolated antibody of any one of claims 1 - 17 , wherein the one or more TREM2 activities are selected from the group consisting of:
i. TREM2 binding to DAP12; ii. DAP12 phosphorylation; iii. increasing the survival of macrophages, microglial cells, M1 microglial cells, activated M1 microglial cells, M2 microglial cells, dendritic cells, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, monocytes, osteoclasts, Langerhans cells of skin, and/or Kupffer cells; iv. Syk phosphorylation; v. increased expression of CD83 and/or CD86 on dendritic cells; vi. increasing phagocytosis by macrophages, dendritic cells, monocytes, and/or microglia; vii. increasing activity of one or more TREM2-dependent genes, optionally wherein the one or more TREM2-dependent genes comprise one or more nuclear factor of activated T-cells (NFAT) transcription factors; and viii. increasing expression of one or more mediators selected from the group consisting of IL-12p70, IL-6, and IL-10.
19 . The isolated antibody of any one of claims 1 - 18 , wherein the antibody is of the IgG class, the IgM class, or the IgA class.
20 . The isolated antibody of claim 19 , wherein the antibody is of the IgG class and has an IgG1, IgG2, IgG3, or IgG4 isotype.
21 . The isolated antibody of claim 19 , wherein the antibody has an IgG2 isotype.
22 . The isolated antibody of claim 21 , wherein the antibody comprises a human IgG2 constant region.
23 . The isolated antibody of claim 22 , wherein the human IgG2 constant region comprises an Fc region.
24 . The isolated antibody of any one of claims 21 - 23 , wherein the antibody induces the one or more TREM2 activities independently of binding to an Fc receptor.
25 . The isolated antibody of any one of claims 21 - 23 , wherein the antibody binds an inhibitory Fc receptor.
26 . The isolated antibody of claim 25 , wherein the inhibitory Fc receptor is inhibitory Fc-gamma receptor IIB (FcγIIB).
27 . The isolated antibody of claim 26 , wherein:
i. the isolated antibody has a human IgG2 isotype and comprises one or more amino acid substitutions in the Fc region at a residue position selected from the group consisting of V234A, G237A, H268Q, V309L, A330S, P331S, C232S, C233S, S267E, L328F, M252Y, S254T, T256E, and any combination thereof, wherein the numbering of the residues is according to EU or Kabat numbering; ii. the isolated antibody has a human IgG2 isotype, wherein the human IgG2 comprises a constant region, and wherein the human IgG2 constant region comprises a light chain constant region comprising a C214S amino acid substitution, wherein the numbering of the residues is according to EU or Kabat numbering; iii. the isolated antibody has a human or mouse IgG1 isotype and comprises one or more amino acid substitutions in the Fc region at a residue position selected from the group consisting of N297A, D265A, L234A, L235A, G237A, C226S, C229S, E233P, L234V, L234F, L235E, P331S, S267E, L328F, A330L, M252Y, S254T, T256E, and any combination thereof, wherein the numbering of the residues is according to EU or Kabat numbering; iv. the isolated antibody has an IgG1 isotype and comprises an IgG2 isotype heavy chain constant domain 1(CH1) and hinge region, optionally wherein the IgG2 isotype CH1 and hinge region comprise the amino acid sequence of ASTKGPSVFP LAPCSRSTSE STAALGCLVK DYFPEPVTVS WNSGALTSGVHTFPAVLQSS GLYSLSSVVT VPSSNFGTQT YTCNVDHKPS NTKVDKTVERKCCVECPPCP (SEQ ID NO: 397), and optionally wherein the antibody Fc region comprises a S267E amino acid substitution, a L328F amino acid substitution, or both, and/or a N297A or N297Q amino acid substitution, wherein the numbering of the residues is according to EU or Kabat numbering; v. the isolated antibody has a human or mouse IgG4 isotype and comprises one or more amino acid substitutions in the Fc region at a residue position selected from the group consisting of L235A, G237A, S228P, L236E, S267E, E318A, L328F, M252Y, S254T, T256E, and any combination thereof, wherein the numbering of the residues is according to EU or Kabat numbering; or vi. the isolated antibody has a hybrid IgG2/4 isotype, optionally wherein the antibody comprises an amino acid sequence comprising amino acids 118 to 260 of human IgG2 and amino acids 261 to 447 of human IgG4, wherein the numbering of the residues is according to EU or, Kabat numbering.
28 . The isolated antibody of any one of claims 1 - 15 , wherein the isolated antibody is an inert antibody.
29 . The isolated antibody of any one of claims 1 - 15 , wherein the isolated antibody is an antagonist antibody.
30 . The isolated antibody of claim 28 or claim 29 , wherein the isolated antibody inhibits one or more TREM2 activities.
31 . The isolated antibody of claim 30 , wherein the inhibited one or more TREM2 activities are selected from the group consisting of decreasing activity of one or more TREM2-dependent genes; decreasing activity of one or more nuclear factor of activated T-cells (NFAT) transcription factors; decreasing the survival of macrophages, microglial cells, M1 macrophages, M1microglial cells, M2 macrophages, M2 microglial cells, osteoclasts, Langerhans cells of skin, Kupffer cells, and/or dendritic cells; decreased expression of one or more mediators selected from the group consisting of IL-12p70, IL-6, and IL-10; and any combination thereof.
32 . The isolated antibody of any one of claims 29 - 31 , wherein the isolated antibody inhibits interaction between TREM2 and one or more TREM2 ligands, inhibits TREM2 signal transduction, or both.
33 . The isolated antibody of any one of claims 28 - 32 , wherein the antibody is incapable of binding an Fc-gamma receptor (FcγR).
34 . The isolated antibody of claim 33 , wherein:
i. the isolated antibody has a human or mouse IgG1 isotype and comprises one or more amino acid substitutions in the Fc region are at a residue position selected from the group consisting of N297A, N297Q, D265A, L234A, L235A, C226S, C229S, P238S, E233P, L234V, P238A, A327Q, A327G, P329A, K322A, L234F, L235E, P331S, T394D, A330L, M252Y, S254T, T256E, and any combination thereof, wherein the numbering of the residues is according to EU or Kabat numbering, optionally wherein the Fc region further comprises an amino acid deletion at a position corresponding to glycine 236 according to EU or Kabat numbering; ii. the isolated antibody has a human IgG2 isotype and comprises one or more amino acid substitutions in the Fc region are at a residue position selected from the group consisting of V234A, G237A, H268E, V309L, N297A, N297Q, A330S, P331S, C232S, C233S, M252Y, S254T, T256E, and any combination thereof, wherein the numbering of the residues is according to EU or Kabat numbering; or iii. the isolated antibody has a human or mouse IgG4 isotype and comprises one or more amino acid substitutions in the Fc region are at a residue position selected from the group consisting of E233P, F234V, L235A, G237A, E318A, S228P, L236E, S241P, L248E, T394D, M252Y, S254T, T256E, N297A, N297Q, and any combination thereof, wherein the numbering of the residues is according to EU or Kabat numbering.
35 . The isolated antibody of claim 27 (iii.) or 34 (i.), wherein the Fc region further comprises one or more additional amino acid substitutions at a position selected from the group consisting of A330L, L234F; L235E, P331S, and any combination thereof, wherein the numbering of the residues is according to EU or Kabat numbering.
36 . The isolated antibody of claim 27 (v.) or 34 (iii.), wherein the Fc region further comprises a S228P amino acid substitution according to EU or Kabat numbering.
37 . The isolated antibody of any one of claims 27 - 36 , wherein the Fc region further comprises one or more additional amino acid substitutions at a position selected from the group consisting of M252Y, S254T, T256E, and any combination thereof, wherein the numbering of the residues is according to EU or Kabat numbering.
38 . The isolated antibody of any one of claims 1 - 37 , wherein the isolated antibody is an antibody fragment that binds to one or more human proteins selected from the group consisting of human TREM2, and a naturally occurring variant of human TREM2, and wherein the antibody fragment is cross-linked to a second antibody fragment that binds to one or more human proteins selected from the group consisting of human TREM2, a naturally occurring variant of human TREM2, human DAP12, and naturally occurring variant of human DAP12.
39 . The isolated antibody of any one of claims 1 - 38 , wherein the isolated antibody is an antibody fragment, and wherein the antibody fragment is an Fab, Fab′, Fab′-SH, F(ab′)2, Fv or scFv fragment.
40 . The isolated antibody of any one of claims 1 - 39 , wherein the isolated antibody competes for binding of TREM2 with one or more TREM2 ligands.
41 . The isolated antibody of claim 40 , wherein the one or more TREM2 ligands are selected from the group consisting of E. coli cells, apoptotic cells, nucleic acids, anionic lipids, zwitterionic lipids, negatively charged phospholipids, phosphatidylserine, sulfatides, phosphatidylcholin, sphingomyelin, membrane phospholipids, lipidated proteins, proteolipids, lipidated peptides, and lipidated amyloid beta peptide.
42 . The isolated antibody of any one of claims 1 - 39 , wherein the isolated antibody competes for binding of TREM2 with one or more TREM2 ligands.
43 . The isolated antibody of any one of claims 1 - 42 , wherein the isolated antibody is a human antibody, a humanized antibody, a bispecific antibody, a multivalent antibody, or a chimeric antibody.
44 . The isolated antibody of any one of claims 1 - 43 , wherein the isolated antibody is a bispecific antibody recognizing a first antigen and a second antigen.
45 . The isolated antibody of claim 44 , wherein the first antigen is human TREM2 or a naturally occurring variant thereof, and the second antigen is a disease-causing protein selected from the group consisting of amyloid beta or fragments thereof, Tau, IAPP, alpha-synuclein, TDP-43, FUS protein, prion protein, PrPSc, huntingtin, calcitonin, superoxide dismutase, ataxin, Lewy body, atrial natriuretic factor, islet amyloid polypeptide, insulin, apolipoprotein AI, serum amyloid A, medin, prolactin, transthyretin, lysozyme, beta 2 microglobulin, gelsolin, keratoepithelin, cystatin, immunoglobulin light chain AL, S-IBM protein, Repeat-associated non-ATG (RAN) translation products, DiPeptide repeat (DPR) peptides, glycine-alanine (GA) repeat peptides, glycine-proline (GP) repeat peptides, glycine-arginine (GR) repeat peptides, proline-alanine (PA) repeat peptides, and proline-arginine (PR) repeat peptides; or a blood brain barrier targeting protein selected from the group consisting of: trasnferin receptor, insulin receptor, insulin like growth factor receptor, LRP-1, and LRP1.
46 . The isolated antibody of any one of claims 1 - 41 , wherein the isolated antibody is an antibody fragment that binds to one or more human proteins selected from the group consisting of human TREM2, and a naturally occurring variant of human TREM2; and wherein the antibody is used in combination with one or more antibodies that specifically bind a disease-causing protein selected from the group consisting of: amyloid beta or fragments thereof, Tau, IAPP, alpha-synuclein, TDP-43, FUS protein, prion protein, PrPSc, huntingtin, calcitonin, superoxide dismutase, ataxin, Lewy body, atrial natriuretic factor, islet amyloid polypeptide, insulin, apolipoprotein AI, serum amyloid A, medin, prolactin, transthyretin, lysozyme, beta 2 microglobulin, gelsolin, keratoepithelin, cystatin, immunoglobulin light chain AL, S-IBM protein, Repeat-associated non-ATG (RAN) translation products, DiPeptide repeat (DPR) peptides, glycine-alanine (GA) repeat peptides, glycine-proline (GP) repeat peptides, glycine-arginine (GR) repeat peptides, proline-alanine (PA) repeat peptides, and proline-arginine (PR) repeat peptides, and any combination thereof.
47 . The isolated antibody of any one of claims 1 - 44 , wherein the antibody is a monoclonal antibody.
48 . The isolated antibody of any one of claims 1 - 47 , wherein the isolated antibody is a bispecific antibody that binds to TREM2 and DAP12.
49 . The isolated antibody of any one of claims 1 - 48 , wherein the isolated antibody comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises:
(d) an HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:3-24, 398, and 404; (e) an HVR-H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:25-49, 399, and 405; and (f) an HVR-H3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:50-119, 400, and 406; and/or
wherein the light chain variable domain comprises:
(d) an HVR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:120-137, 401, and 407;
(e) an HVR-L2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:138-152, 402, and 408; and
(f) an HVR-L3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:153-236, 403, and 409.
50 . An isolated anti-human TREM2 antibody, wherein the isolated antibody comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises:
(a) an HVR-H1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:3-24, 398, and 404; (b) an HVR-H2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:25-49, 399, and 405; and (c) an HVR-H3 an amino acid sequence selected from the group consisting of SEQ ID NOs:50-119, 400, and 406; and/or
wherein the light chain variable domain comprises:
(a) an HVR-L1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:120-137, 401, and 407;
(b) an HVR-L2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:138-152, 402, and 408; and
(c) an HVR-L3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs:153-236, 403, and 409.
51 . An isolated anti-human TREM2 antibody which binds essentially the same TREM2 epitope as a monoclonal antibody selected from the group consisting of: Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, Ab21, Ab22, Ab23, Ab24, Ab25, Ab26, Ab27, Ab28, Ab29, Ab30, Ab31, Ab32, Ab33, Ab34, Ab35, Ab36, Ab37, Ab38, Ab39, Ab40, Ab41, Ab42, Ab43, Ab44, Ab45, Ab46, Ab47, Ab48, Ab49, Ab50, Ab51, Ab52, Ab53, Ab54, Ab55, Ab56, Ab57, Ab58, Ab59, Ab60, Ab61, Ab62, Ab63, Ab64, Ab65, Ab66, Ab67, Ab68, Ab69, Ab70, Ab71, Ab72, Ab73, Ab74, Ab75, Ab76, Ab77, Ab78, Ab79, Ab80, Ab81, Ab82, Ab83, Ab84, Ab85, Ab86, and Ab87.
52 . An isolated anti-human TREM2 antibody which competes with a monoclonal antibody selected from the group consisting of: Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, Ab21, Ab22, Ab23, Ab24, Ab25, Ab26, Ab27, Ab28, Ab29, Ab30, Ab31, Ab32, Ab33, Ab34, Ab35, Ab36, Ab37, Ab38, Ab39, Ab40, Ab41, Ab42, Ab43, Ab44, Ab45, Ab46, Ab47, Ab48, Ab49, Ab50, Ab51, Ab52, Ab53, Ab54, Ab55, Ab56, Ab57, Ab58, Ab59, Ab60, Ab61, Ab62, Ab63, Ab64, Ab65, Ab66, Ab67, Ab68, Ab69, Ab70, Ab71, Ab72, Ab73, Ab74, Ab75, Ab76, Ab77, Ab78, Ab79, Ab80, Ab81, Ab82, Ab83, Ab84, Ab85, Ab86, and Ab87 for binding to TREM2.
53 . The isolated antibody of any one of claims 50 - 52 , wherein the antibody is an agonist antibody, and wherein the antibody induces one or more TREM2 activities.
54 . The isolated antibody of claim 53 , wherein the isolated antibody induces or retains TREM2 clustering on a cell surface.
55 . The isolated antibody of claim 53 or claim 54 , wherein the one or more TREM2 activities are selected from the group consisting of TREM2 binding to DAP12; DAP12 phosphorylation; increasing the survival of macrophages, microglial cells, M1 microglial cells, activated M1 microglial cells, M2 microglial cells, dendritic cells, macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages, monocytes, osteoclasts, Langerhans cells of skin, and/or Kupffer cells; increased expression of IL-6; increased Syk phosphorylation; increased expression of CD83 and/or CD86 on dendritic cells; increasing phagocytosis by macrophages, dendritic cells, monocytes, and/or microglia; increasing activity of one or more TREM2-dependent genes, optionally wherein the one or more TREM2-dependent genes comprise one or more nuclear factor of activated T-cells (NFAT) transcription factors; and any combination thereof.
56 . The isolated antibody of any one of claims 53 - 55 , wherein the antibody is of the IgG class, the IgM class, or the IgA class.
57 . The isolated antibody of claim 56 , wherein the antibody is of the IgG class and has an IgG1, IgG2, IgG3, or IgG4 isotype.
58 . The isolated antibody of claim 57 , wherein the antibody has an IgG2 isotype.
59 . The isolated antibody of claim 58 , wherein the antibody comprises a human IgG2 constant region.
60 . The isolated antibody of claim 59 , wherein the human IgG2 constant region comprises an Fc region.
61 . The isolated antibody of any one of claims 58 - 60 , wherein the antibody induces the one or more TREM2 activities independently of binding to an Fc receptor.
62 . The isolated antibody of any one of claims 58 - 60 , wherein the antibody binds an inhibitory Fc receptor.
63 . The isolated antibody of claim 62 , wherein the inhibitory Fc receptor is inhibitory Fc-gamma receptor IIB (FcγIIB).
64 . The isolated antibody of claim 63 , wherein:
i. the isolated antibody has a human IgG2 isotype and comprises one or more amino acid substitutions in the Fc region at a residue position selected from the group consisting of V234A, G237A, H268Q, V309L, A330S, P331S, C232S, C233S, S267E, L328F, M252Y, S254T, T256E, and any combination thereof, wherein the numbering of the residues is according to EU or Kabat numbering; ii. the isolated antibody has a human IgG2 isotype, wherein the human IgG2 comprises a constant region, and wherein the human IgG2 constant region comprises a light chain constant region comprising a C214S amino acid substitution, wherein the numbering of the residues is according to EU or Kabat numbering; iii. the isolated antibody has a human or mouse IgG1 isotype and comprises one or more amino acid substitutions in the Fc region at a residue position selected from the group consisting of N297A, D265A, L234A, L235A, G237A, C226S, C229S, E233P, L234V, L234F, L235E, P331S, S267E, L328F, A330L, M252Y, S254T, T256E, and any combination thereof, wherein the numbering of the residues is according to EU or Kabat numbering; iv. the isolated antibody has an IgG1 isotype and comprises an IgG2 isotype heavy chain constant domain 1(CH1) and hinge region, optionally wherein the IgG2 isotype CH1 and hinge region comprise the amino acid sequence of ASTKGPSVFP LAPCSRSTSE STAALGCLVK DYFPEPVTVS WNSGALTSGVHTFPAVLQSS GLYSLSSVVT VPSSNFGTQT YTCNVDHKPS NTKVDKTVERKCCVECPPCP (SEQ ID NO: 397), and optionally wherein the antibody Fc region comprises a S267E amino acid substitution, a L328F amino acid substitution, or both, and/or a N297A or N297Q amino acid substitution, wherein the numbering of the residues is according to EU or Kabat numbering; v. the isolated antibody has a human or mouse IgG1 isotype and comprises one or more amino acid substitutions in the Fc region at a residue position selected from the group consisting of L235A, G237A, S228P, L236E, S267E, E318A, L328F, M252Y, S254T, T256E, and any combination thereof, wherein the numbering of the residues is according to EU or Kabat numbering; or vi. the isolated antibody has a hybrid IgG2/4 isotype, optionally wherein the antibody comprises an amino acid sequence comprising amino acids 118 to 260 of human IgG2 and amino acids 261 to 447 of human IgG4, wherein the numbering of the residues is according to EU or, Kabat numbering.
65 . The isolated antibody of any one of claims 50 - 64 , wherein the isolated antibody is an antibody fragment that binds to one or more human proteins selected from the group consisting of human TREM2, and a naturally occurring variant of human TREM2, and wherein the antibody fragment is cross-linked to a second antibody fragment that binds to one or more human proteins selected from the group consisting of human TREM2, a naturally occurring variant of human TREM2, human DAP12, and naturally occurring variant of human DAP12.
66 . The isolated antibody of any one of claims 50 - 65 , wherein the isolated antibody is an antibody fragment, and wherein the antibody fragment is an Fab, Fab′, Fab′-SH, F(ab′)2, Fv or scFv fragment.
67 . The isolated antibody of any one of claims 50 - 52 , wherein the isolated antibody is an inert antibody.
68 . The isolated antibody of any one of claims 50 - 52 , wherein the isolated antibody is an antagonist antibody.
69 . The isolated antibody of claim 67 or claim 68 , wherein the isolated antibody inhibits one or more TREM2 activities.
70 . The isolated antibody of claim 69 , wherein the inhibited one or more TREM2 activities are selected from the group consisting of decreasing activity of one or more TREM2-dependent genes; decreasing activity of one or more nuclear factor of activated T-cells (NFAT) transcription factors; decreasing the survival of macrophages, microglial cells, monocytes, osteoclasts, Langerhans cells of skin, Kupffer cells, and/or dendritic cells; decreased expression of one or more mediators selected from the group consisting of IL-12p70, IL-6, and IL-10; and any combination thereof.
71 . The isolated antibody of any one of claims 68 - 70 , wherein the isolated antibody inhibits interaction between TREM2 and one or more TREM2 ligands, inhibits TREM2 signal transduction, or both.
72 . The isolated antibody of any one of claims 67 - 71 , wherein the antibody is incapable of binding an Fc-gamma receptor (FcγR).
73 . The isolated antibody of claim 72 , wherein:
i. the isolated antibody has a human or mouse IgG1 isotype and comprises one or more amino acid substitutions in the Fc region are at a residue position selected from the group consisting of N297A, N297Q, D265A, L234A, L235A, C226S, C229S, P238S, E233P, L234V, P238A, A327Q, A327G, P329A, K322A, L234F, L235E, P331S, T394D, A330L, M252Y, S254T, T256E, and any combination thereof, wherein the numbering of the residues is according to EU or Kabat numbering, optionally wherein the Fc region further comprises an amino acid deletion at a position corresponding to glycine 236 according to EU or Kabat numbering; ii. the isolated antibody has a human IgG2 isotype and comprises one or more amino acid substitutions in the Fc region are at a residue position selected from the group consisting of V234A, G237A, H268E, V309L, N297A, N297Q, A330S, P331S, C232S, C233S, M252Y, S254T, T256E, and any combination thereof, wherein the numbering of the residues is according to EU or Kabat numbering; or iii. the isolated antibody has a human or mouse IgG4 isotype and comprises one or more amino acid substitutions in the Fc region are at a residue position selected from the group consisting of E233P, F234V, L235A, G237A, E318A, S228P, L236E, S241P, L248E, T394D, M252Y, S254T, T256E, N297A, N297Q, and any combination thereof, wherein the numbering of the residues is according to EU or Kabat numbering.
74 . The isolated antibody of any one of claims 67 - 73 , wherein the isolated antibody is an antibody fragment that binds to one or more human proteins selected from the group consisting of human TREM2, and a naturally occurring variant of human TREM2.
75 . The isolated antibody of any one of claims 67 - 74 , wherein the isolated antibody is an antibody fragment, and wherein the antibody fragment is an Fab, Fab′, Fab′-SH, F(ab′)2, Fv or scFv fragment.
76 . The isolated antibody of claim 64 (iii.) or 73 (i), wherein the Fc region further comprises one or more additional amino acid substitutions at a position selected from the group consisting of A330L, L234F; L235E, P331S, and any combination thereof, wherein the numbering of the residues is according to EU or Kabat numbering.
77 . The isolated antibody of claim 64 (v.) or 73 (iii.), wherein the Fc region further comprises a S228P amino acid substitution according to EU or Kabat numbering.
78 . The isolated antibody of any one of claims 64 - 77 , wherein the Fc region further comprises one or more additional amino acid substitutions at a position selected from the group consisting of M252Y, S254T, T256E, and any combination thereof, wherein the numbering of the residues is according to EU or Kabat numbering.
79 . The isolated antibody of any one of claims 50 - 78 , wherein the antibody is a human antibody, a humanized antibody, a bispecific antibody, a multivalent antibody, or a chimeric antibody.
80 . The isolated antibody of any one of claims 50 - 79 , wherein the antibody is a bispecific antibody recognizing a first antigen and a second antigen.
81 . The isolated antibody of any one of claims 50 - 80 , wherein the antibody is a monoclonal antibody.
82 . The isolated antibody of any one of the preceding claims, wherein the isolated antibody binds specifically to both human TREM2 and mouse TREM2.
83 . The isolated antibody of any one of the preceding claims, wherein the isolated antibody has dissociation constant (K D ) for human TREM2 and mouse TREM2 that ranges from less than about 5.75 nM to less than about 0.09 nM.
84 . The isolated antibody of any one of the preceding claims, wherein the isolated antibody has dissociation constant (K D ) for human TREM2-Fc fusion protein that ranges from less than about 1.51 nM to less than about 0.35 nM.
85 . The isolated antibody of any one of the preceding claims, wherein the isolated antibody has dissociation constant (K D ) for human monomeric TREM2 protein that ranges from less than about 5.75 nM to less than about 1.15 nm.
86 . The isolated antibody of any one of the preceding claims, wherein the isolated antibody has dissociation constant (K D ) for mouse TREM2-Fc fusion protein that ranges from less than about 0.23 nM to less than about 0.09 nM.
87 . An isolated nucleic acid encoding the antibody of any one of the preceding claims.
88 . A vector comprising the nucleic acid of claim 87 .
89 . An isolated host cell comprising the vector of claim 88 .
90 . A method of producing an antibody, comprising culturing the host cell of claim 89 so that the antibody is produced.
91 . The method of claim 90 , further comprising recovering the antibody produced by the cell.
92 . An isolated antibody produced by the method of claim 90 or claim 91 .
93 . A pharmaceutical composition comprising the antibody of any one of claims 1 - 86 and a pharmaceutically acceptable carrier.
94 . A method of preventing, reducing risk, or treating an individual having a disease, disorder, or injury selected from the group consisting of dementia, frontotemporal dementia, Alzheimer's disease, Nasu-Hakola disease, and multiple sclerosis, comprising administering to the individual a therapeutically effective amount of an isolated antibody that binds to a TREM2 protein.
95 . The method of claim 94 , wherein the isolated antibody is the isolated antibody of any one of claims 1 - 86 .
96 . The method of claim 94 or claim 95 , wherein the individual has a heterozygous variant of TREM2, wherein the variant comprises one or more substitutions selected from the group consisting of:
i. a glutamic acid to stop codon substitution in the nucleic acid sequence encoding amino acid residue Glu14 of SEQ ID NO: 1;
ii. a glutamine to stop codon substitution in the nucleic acid sequence encoding amino acid residue Gln33 of SEQ ID NO: 1;
iii. a tryptophan to stop codon substitution in the nucleic acid sequence encoding amino acid residue Trp44 of SEQ ID NO: 1;
iv. an arginine to histidine amino acid substitution at an amino acid corresponding to amino acid residue Arg47 of SEQ ID NO: 1;
v. a tryptophan to stop codon substitution in the nucleic acid sequence encoding amino acid residue Trp78 of SEQ ID NO: 1;
vi. a valine to glycine amino acid substitution at an amino acid corresponding to amino acid residue Val126 of SEQ ID NO: 1;
vii. an aspartic acid to glycine amino acid substitution at an amino acid corresponding to amino acid residue Asp134 of SEQ ID NO: 1; and
viii. a lysine to asparagine amino acid substitution at an amino acid corresponding to amino acid residue Lys186 of SEQ ID NO: 1.
97 . The method of claim 94 , wherein the individual has a heterozygous variant of TREM2, wherein the variant comprises a guanine nucleotide deletion at a nucleotide corresponding to nucleotide residue G313 of the nucleic acid sequence encoding SEQ ID NO: 1; a guanine nucleotide deletion at a nucleotide corresponding to nucleotide residue G267 of the nucleic acid sequence encoding SEQ ID NO: 1; or both.
98 . The method of claim 94 , wherein the individual has a heterozygous variant of DAP12, wherein the variant comprises one or more variants selected from the group consisting of:
i. a methionine to threonine substitution at an amino acid corresponding to amino acid residue Met1 of SEQ ID NO: 2; ii. a glycine to arginine amino acid substitution at an amino acid corresponding to amino acid residue Gly49 of SEQ ID NO: 2; iii. a deletion within exons 1-4 of the nucleic acid sequence encoding SEQ ID NO: 2; iv. an insertion of 14 amino acid residues at exon 3 of the nucleic acid sequence encoding SEQ ID NO: 2; and v. a guanine nucleotide deletion at a nucleotide corresponding to nucleotide residue G141 of the nucleic acid sequence encoding SEQ ID NO: 2.
99 . A method of inducing or promoting innate immune cell survival in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of an isolated agonist antibody that binds to a TREM2 protein.
100 . The method of claim 99 , wherein the isolated agonist antibody is the isolated antibody of any one of claims 1 , 3 , 4 - 27 , 38 - 66 , and 76 - 86 .
101 . A method of decreasing innate immune cell survival in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of an isolated antagonist antibody that binds to a TREM2 protein.
102 . The method of claim 101 , wherein the isolated antagonist antibody is the isolated antibody of any one of claims 2 - 15 , 28 - 52 , and 67 - 86 .Cited by (0)
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