ANTI-TREM2 ANTIBODIES AND METHODS OF USE THEREOF
In one aspect, antibodies that specifically bind to a human triggering receptor expressed on myeloid cells 2 (TREM2) protein are provided. In some embodiments, the antibody decreases levels of soluble TREM2 (sTREM2). In some embodiments, the antibody enhances TREM2 activity.
1 . An isolated antibody or antigen-binding fragment thereof that specifically binds to a human TREM2, wherein the antibody or antigen-binding fragment thereof comprises:
(a) a CDR-H1 sequence comprising the sequence of GFSIEDFYIH (SEQ ID NO:29);
(b) a CDR-H2 sequence comprising the sequence of W-I-D-P-E-β 6 -G-β 8 -S—K-Y-A-P—K-F-Q-G (SEQ ID NO:47), wherein β 6 is N or Q and β 8 is D or E;
(c) a CDR-H3 sequence comprising the sequence of HADHGNYGSTMDY (SEQ ID NO:31);
(d) a CDR-L1 sequence comprising the sequence of HASQHINVWLS (SEQ ID NO:32);
(e) a CDR-L2 sequence comprising the sequence of KASNLHT (SEQ ID NO:33); and
(f) a CDR-L3 sequence comprising the sequence of QQGQTYPRT (SEQ ID NO:34).
2 . The isolated antibody or antigen-binding fragment of claim 1 ,
wherein the CDR-H2 sequence is selected from SEQ ID NOS:30, 39, 41, and 43.
3 . The isolated antibody or antigen-binding fragment of claim 1 , wherein the antibody or antigen-binding fragment comprises:
(a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO:29, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:30, a CDR-H3 comprising the amino acid sequence of SEQ ID NO:31, a CDR-L1 comprising the amino acid sequence of SEQ ID NO:32, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:33, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:34; or
(b) a CDR-H1 comprising the amino acid sequence of SEQ ID NO:29, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:39, a CDR-H3 comprising the amino acid sequence of SEQ ID NO:31, a CDR-L1 comprising the amino acid sequence of SEQ ID NO:32, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:33, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:34; or
(c) a CDR-H1 comprising the amino acid sequence of SEQ ID NO:29, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:41, a CDR-H3 comprising the amino acid sequence of SEQ ID NO:31, a CDR-L1 comprising the amino acid sequence of SEQ ID NO:32, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:33, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:34; or
(d) a CDR-H1 comprising the amino acid sequence of SEQ ID NO:29, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:43, a CDR-H3 comprising the amino acid sequence of SEQ ID NO:31, a CDR-L1 comprising the amino acid sequence of SEQ ID NO:32, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:33, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:34.
4 . The isolated antibody or antigen-binding fragment of claim 1 , comprising a V H sequence that has at least 85% sequence identity to any one of SEQ ID NOS:27, 35, 37, 38, 40, 42, 44, 45, and 46.
5 . The isolated antibody or antigen-binding fragment of claim 4 , wherein the V H sequence has at least 90% sequence identity to SEQ ID NO:27.
6 . The isolated antibody or antigen-binding fragment of claim 5 , wherein the V H sequence has at least 95% sequence identity to SEQ ID NO:27.
7 . The isolated antibody or antigen-binding fragment of claim 6 , wherein the V H sequence comprises SEQ ID NO:27.
8 . The isolated antibody or antigen-binding fragment of claim 1 , comprising a V L sequence that has at least 85% sequence identity to SEQ ID NO:28 or SEQ ID NO:36.
9 . The isolated antibody or antigen-binding fragment of claim 8 , wherein the V L sequence has at least 90% sequence identity to SEQ ID NO:28.
10 . The isolated antibody or antigen-binding fragment of claim 9 , wherein the V L sequence has at least 95% sequence identity to SEQ ID NO:28.
11 . The isolated antibody or antigen-binding fragment of claim 10 , wherein the V L sequence comprises SEQ ID NO:28.
12 . The isolated antibody or antigen binding fragment of claim 8 , wherein the antibody or antigen-binding fragment comprises:
(a) a V H sequence comprising SEQ ID NO:27 and a V L sequence comprising SEQ ID NO:28; or
(b) a V H sequence comprising SEQ ID NO:35 and a V L sequence comprising SEQ ID NO:36; or
(c) a V H sequence comprising SEQ ID NO:37 and a V L sequence comprising SEQ ID NO:36; or
(d) a V H sequence comprising SEQ ID NO:38 and a V L sequence comprising SEQ ID NO:36; or
(e) a V H sequence comprising SEQ ID NO:40 and a V L sequence comprising SEQ ID NO:36; or
(f) a V H sequence comprising SEQ ID NO:42 and a V L sequence comprising SEQ ID NO:36; or
(g) a V H sequence comprising SEQ ID NO:44 and a V L sequence comprising SEQ ID NO:36; or
(h) a V H sequence comprising SEQ ID NO:45 and a V L sequence comprising SEQ ID NO:36; or
(i) a V H sequence comprising SEQ ID NO:46 and a V L sequence comprising SEQ ID NO:36.
13 . The isolated antibody or antigen-binding fragment thereof of claim 1 , wherein the antigen-binding fragment is a Fab, a F(ab′) 2 , a scFv, or a bivalent scFv.
14 . A pharmaceutical composition comprising the isolated antibody or antigen-binding fragment thereof of claim 1 and a pharmaceutically acceptable carrier.
15 . An isolated polynucleotide comprising a nucleotide sequence encoding the isolated antibody or antigen-binding fragment thereof of claim 1 .
16 . A method of treating a neurodegenerative disease in a subject, comprising administering to the subject the isolated antibody or antigen-binding fragment thereof of claim 1 .
17 . The method of claim 16 , wherein the neurodegenerative disease is selected from the group consisting of: Alzheimer's disease, primary age-related tauopathy, progressive supranuclear palsy (PSP), frontotemporal dementia, frontotemporal dementia with parkinsonism linked to chromosome 17, argyrophilic grain dementia, amyotrophic lateral sclerosis, amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam (ALS-PDC), corticobasal degeneration, chronic traumatic encephalopathy, Creutzfeldt-Jakob disease, dementia pugilistica, diffuse neurofibrillary tangles with calcification, Down's syndrome, familial British dementia, familial Danish dementia, Gerstmann-Straussler-Scheinker disease, globular glial tauopathy, Guadeloupean parkinsonism with dementia, Guadelopean PSP, Hallevorden-Spatz disease, hereditary diffuse leukoencephalopathy with spheroids (HDLS), Huntington's disease, inclusion-body myositis, multiple system atrophy, myotonic dystrophy, Nasu-Hakola disease, neurofibrillary tangle-predominant dementia, Niemann-Pick disease type C, pallido-ponto-nigral degeneration, Parkinson's disease, Pick's disease, postencephalitic parkinsonism, prion protein cerebral amyloid angiopathy, progressive subcortical gliosis, subacute sclerosing panencephalitis, and tangle only dementia.
18 . A method of decreasing levels of sTREM2 in a subject having a neurodegenerative disease, comprising administering to the subject the isolated antibody or antigen-binding fragment thereof of claim 1 .
19 . A method of enhancing TREM2 activity in a subject having a neurodegenerative disease, comprising administering to the subject the isolated antibody or antigen-binding fragment thereof of claim 1 .