Anti-trem2 antibodies and methods of use thereof

Abstract

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 - 88 . (canceled) 
     
     
         89 . A method of treating a neurodegenerative disease in a subject, comprising administering to the subject an isolated antibody that specifically binds to a human triggering receptor expressed on myeloid cells 2 (TREM2), wherein the antibody comprises:
 (a) a variable region comprising:
 i. a CDR-H1 sequence comprising the sequence of G-F-T-F-T-α 6 -F-Y-M-S (SEQ ID NO:28), wherein α 6  is D or N; 
 ii. a CDR-H2 sequence comprising the sequence of V-I-R-N-β 5 -β 6 -N-β 8 -Y-T-β 11 -β 12 -Y-N-P-S-V-K-G (SEQ ID NO:29), wherein β 5  is K or R; β 6  is A or P; β 8  is G or A; β 11  is A or T; and β 12  is G or D; 
 iii. a CDR-H3 sequence comprising the sequence of γ 1 -R-L-γ 4 -Y-G-F-D-Y (SEQ ID NO:30), wherein γ 1  is A or T; and γ 4  is T or S; 
 iv. a CDR-L1 sequence comprising the sequence of Q-S-S-K-S-L-L-H-S-δ 10 -G-K-T-Y-L-N (SEQ ID NO:31), wherein δ 10  is N or T; 
 v. a CDR-L2 sequence comprising the sequence WMSTRAS (SEQ ID NO:8); and 
 vi. a CDR-L3 sequence comprising the sequence of Q-Q-F-L-E-ϕ 6 -P-F-T (SEQ ID NO:32), wherein ϕ 6  is Y or F: 
   (b) a first Fc polypeptide that specifically binds to human transferrin receptor 1 and comprises a sequence having at least 90% sequence identity to SEQ ID NO:49; and   (c) a second Fc polypeptide.   
     
     
         90 . The method of  claim 89 , 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. 
     
     
         91 . A method of decreasing levels of sTREM2 in a subject having a neurodegenerative disease, comprising administering to the subject an isolated antibody that specifically binds to a human triggering receptor expressed on myeloid cells 2 (TREM2), wherein the antibody comprises:
 (a) a variable region comprising:
 i. a CDR-H1 sequence comprising the sequence of G-F-T-F-T-α 6 -F-Y-M-S (SEQ ID NO:28), wherein α 6  is D or N; 
 ii. a CDR-H2 sequence comprising the sequence of V-I-R-N-β 5 -β 6 -N-β 8 -Y-T-β 11 -β 12 -Y-N-P-S-V-K-G (SEQ ID NO:29), wherein β 5  is K or R; β 6  is A or P; β 8  is G or A; β 11  is A or T; and β 12  is G or D; 
 iii. a CDR-H3 sequence comprising the sequence of γ 1 -R-L-γ 4 -Y-G-F-D-Y (SEQ ID NO:30), wherein γ 1  is A or T; and γ 4  is T or S; 
 iv. a CDR-L1 sequence comprising the sequence of Q-S-S-K-S-L-L-H-S-δ 10 -G-K-T-Y-L-N (SEQ ID NO:31), wherein δ 10  is N or T; 
 v. a CDR-L2 sequence comprising the sequence WMSTRAS (SEQ ID NO:8); and 
 vi. a CDR-L3 sequence comprising the sequence of Q-Q-F-L-E-ϕ 6 -P-F-T (SEQ ID NO:32), wherein ϕ 6  is Y or F: 
   (b) a first Fc polypeptide that specifically binds to human transferrin receptor 1 and comprises a sequence having at least 90% sequence identity to SEQ ID NO:49; and   (c) a second Fc polypeptide.   
     
     
         92 . A method of enhancing TREM2 activity in a subject having a neurodegenerative disease, comprising administering to the subject an isolated antibody that specifically binds to a human triggering receptor expressed on myeloid cells 2 (TREM2), wherein the antibody comprises:
 (a) a variable region comprising:
 i. a CDR-H1 sequence comprising the sequence of G-F-T-F-T-α 6 -F-Y-M-S (SEQ ID NO:28), wherein α 6  is D or N; 
 ii. a CDR-H2 sequence comprising the sequence of V-I-R-N-β 5 -β 6 -N-β 8 -Y-T-β 11 -β 12 -Y-N-P-S-V-K-G (SEQ ID NO:29), wherein β 5  is K or R; β 6  is A or P; β 8  is G or A; β 11  is A or T; and β 12  is G or D; 
 iii. a CDR-H3 sequence comprising the sequence of γ 1 -R-L-γ 4 -Y-G-F-D-Y (SEQ ID NO:30), wherein γ 1  is A or T; and γ 4  is T or S; 
 iv. a CDR-L1 sequence comprising the sequence of Q-S-S-K-S-L-L-H-S-δ 10 -G-K-T-Y-L-N (SEQ ID NO:31), wherein δ 10  is N or T; 
 v. a CDR-L2 sequence comprising the sequence WMSTRAS (SEQ ID NO:8); and 
 vi. a CDR-L3 sequence comprising the sequence of Q-Q-F-L-E-ϕ 6 -P-F-T (SEQ ID NO:32), wherein ϕ 6  is Y or F; 
   (b) a first Fc polypeptide that specifically binds to human transferrin receptor 1 and comprises a sequence having at least 90% sequence identity to SEQ ID NO:49; and   (c) a second Fc polypeptide.   
     
     
         93 - 102 . (canceled) 
     
     
         103 . The method of  claim 89 , wherein:
 i. the CDR-H1 sequence is selected from the group consisting of SEQ ID NOS:4 and 12;   ii. the CDR-H2 sequence is selected from the group consisting of SEQ ID NOS:5, 13, and 25;   iii. the CDR-H3 sequence is selected from the group consisting of SEQ ID NOS:6, 14, and 17;   iv. the CDR-L1 sequence is selected from the group consisting of SEQ ID NOS:7 and 23;   v. the CDR-L2 sequence comprises the sequence WMSTRAS (SEQ ID NO:8); and   vi. the CDR-L3 sequence is selected from the group consisting of SEQ ID NOS:9 and 18.   
     
     
         104 . The method of  claim 89 , wherein the variable region comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO:4, a CDR-H2 comprising the amino acid sequence of SEQ ID NO:25, a CDR-H3 comprising the amino acid sequence of SEQ ID NO:17, a CDR-L1 comprising the amino acid sequence of SEQ ID NO:23, a CDR-L2 comprising the amino acid sequence of SEQ ID NO:8, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO:18. 
     
     
         105 . The method of  claim 89 , wherein the variable region comprises a V H  sequence that has at least 85% sequence identity to SEQ ID NO:24 and a V L  sequence has at least 85% sequence identity to SEQ ID NO:22. 
     
     
         106 . The method of  claim 89 , wherein the first Fc polypeptide comprises: Trp, Leu, or Glu at position 380; Tyr or Phe at position 384; Thr at position 386; Glu at position 387; Trp at position 388; Ser, Ala, or Val at position 389; Ser or Asn at position 390; Thr or Ser at position 413; Glu or Ser at position 415; Glu at position 416; and Phe at position 421, according to EU numbering. 
     
     
         107 . The method of  claim 106 , wherein:
 (a) the first Fc polypeptide has a T366W substitution and the second Fc polypeptide has T366S, L368A, and Y407V substitutions, according to EU numbering;   (b) the first Fc polypeptide and/or the second Fc polypeptide comprises amino acid substitutions of Ala at position 234 and Ala at position 235, according to EU numbering; and/or   (c) the first Fc polypeptide and/or the second Fc polypeptide comprises amino acid substitutions of Leu at position 428 and Ser at position 434, according to EU numbering.   
     
     
         108 . The method of  claim 89 , wherein the first Fc polypeptide comprises the sequence of SEQ ID NO:41 or 64, and the second Fc polypeptide comprises the sequence of SEQ ID NO:39 or 63. 
     
     
         109 . The method of  claim 108 , comprising:
 (i) a first heavy chain (HC) comprising a V H  comprising SEQ ID NO:24 and the first Fc polypeptide comprising SEQ ID NO:41 or 64;   (ii) a second heavy chain (HC) comprising a V H  comprising SEQ ID NO:24 and the second Fc polypeptide comprising SEQ ID NO:39 or 63; and   (iii) two light chains each comprising a V L  comprising SEQ ID NO:22.   
     
     
         110 . The method of  claim 109 , comprising:
 (i) a first heavy chain (HC) that comprises or consists of the amino acid sequence set forth in SEQ ID NO:42 or 65;   (ii) a second HC that comprises or consists of the amino acid sequence set forth in SEQ ID NO:53 or 73; and   (iii) a first and a second light chain (LC) that each comprises or consists of the amino acid sequence set forth in SEQ ID NO:54.   
     
     
         111 . The method of  claim 89 , wherein the first Fc polypeptide comprises the sequence of SEQ ID NO:44 or 66, and the second Fc polypeptide comprises the sequence of SEQ ID NO:39 or 63. 
     
     
         112 . The method of  claim 111 , comprising:
 (i) a first heavy chain (HC) comprising a V H  comprising SEQ ID NO:24 and the first Fc polypeptide comprising SEQ ID NO:44 or 66;   (ii) a second heavy chain (HC) comprising a V H  comprising SEQ ID NO:24 and the second Fc polypeptide comprising SEQ ID NO:39 or 63; and   (iii) two light chains each comprising a V L  comprising SEQ ID NO:22.   
     
     
         113 . The method of  claim 112 , comprising:
 (i) a first heavy chain (HC) that comprises or consists of the amino acid sequence set forth in SEQ ID NO:45 or 67;   (ii) a second HC that comprises or consists of the amino acid sequence set forth in SEQ ID NO:53 or 73; and   (iii) a first and a second light chain (LC) that each comprises or consists of the amino acid sequence set forth in SEQ ID NO:54.   
     
     
         114 . The method of  claim 89 , wherein the first Fc polypeptide comprises the sequence of SEQ ID NO:47 or 68, and the second Fc polypeptide comprises the sequence of SEQ ID NO:39 or 63. 
     
     
         115 . The method of  claim 114 , comprising:
 (i) a first heavy chain (HC) comprising a V H  comprising SEQ ID NO:24 and the first Fc polypeptide comprising SEQ ID NO:47 or 68;   (ii) a second heavy chain (HC) comprising a V H  comprising SEQ ID NO:24 and the second Fc polypeptide comprising SEQ ID NO:39 or 63; and   (iii) two light chains each comprising a V L  comprising SEQ ID NO:22.   
     
     
         116 . The method of  claim 115 , comprising:
 (i) a first heavy chain (HC) that comprises or consists of the amino acid sequence set forth in SEQ ID NO:48 or 69;   (ii) a second HC that comprises or consists of the amino acid sequence set forth in SEQ ID NO:53 or 73; and   (iii) a first and a second light chain (LC) that each comprises or consists of the amino acid sequence set forth in SEQ ID NO:54.   
     
     
         117 . The method of  claim 89 , wherein the first Fc polypeptide comprises the sequence of SEQ ID NO:47 or 68, and the second Fc polypeptide comprises the sequence of SEQ ID NO:61 or 84. 
     
     
         118 . The method of  claim 117 , comprising:
 (i) a first heavy chain (HC) comprising a V H  comprising SEQ ID NO:24 and the first Fc polypeptide comprising SEQ ID NO:47 or 68;   (ii) a second heavy chain (HC) comprising a V H  comprising SEQ ID NO:24 and the second Fc polypeptide comprising SEQ ID NO:61 or 84; and   (iii) two light chains each comprising a V L  comprising SEQ ID NO:22.   
     
     
         119 . The method of  claim 118 , comprising:
 (i) a first heavy chain (HC) that comprises or consists of the amino acid sequence set forth in SEQ ID NO:48 or 69;   (ii) a second HC that comprises or consists of the amino acid sequence set forth in SEQ ID NO:52 or 72; and   (iii) a first and a second light chain (LC) that each comprises or consists of the amino acid sequence set forth in SEQ ID NO:54.   
     
     
         120 . The method of  claim 89 , wherein the first Fc polypeptide comprises the sequence of SEQ ID NO:50 or 70, and the second Fc polypeptide comprises the sequence of SEQ ID NO:39 or 63. 
     
     
         121 . The method of  claim 120 , comprising:
 (i) a first heavy chain (HC) comprising a V H  comprising SEQ ID NO:24 and the first Fc polypeptide comprising SEQ ID NO:50 or 70;   (ii) a second heavy chain (HC) comprising a V H  comprising SEQ ID NO:24 and the second Fc polypeptide comprising SEQ ID NO:39 or 63; and   (iii) two light chains each comprising a V L  comprising SEQ ID NO:22.   
     
     
         122 . The method of  claim 121 , comprising:
 (i) a first heavy chain (HC) that comprises or consists of the amino acid sequence set forth in SEQ ID NO:51 or 71;   (ii) a second HC that comprises or consists of the amino acid sequence set forth in SEQ ID NO:53 or 73; and   (iii) a first and a second light chain (LC) that each comprises or consists of the amino acid sequence set forth in SEQ ID NO:54.   
     
     
         123 . A method of treating a neurodegenerative disease in a subject, comprising administering to the subject an isolated antibody that specifically binds to a human triggering receptor expressed on myeloid cells 2 (TREM2), wherein the antibody comprises:
 (i) a first heavy chain (HC) comprising a V H  comprising SEQ ID NO:24 and a first Fc polypeptide comprising SEQ ID NO:47;   (ii) a second heavy chain (HC) comprising a V H  comprising SEQ ID NO:24 and a second Fc polypeptide comprising SEQ ID NO:39; and   (iii) two light chains each comprising a V L  comprising SEQ ID NO:22.   
     
     
         124 . The method of  claim 123 , comprising:
 (i) a first heavy chain (HC) that consists of the amino acid sequence set forth in SEQ ID NO:48;   (ii) a second HC that consists of the amino acid sequence set forth in SEQ ID NO:53; and   (iii) a first and a second light chain (LC) that each consists of the amino acid sequence set forth in SEQ ID NO:54.   
     
     
         125 . A method of treating a neurodegenerative disease in a subject, comprising administering to the subject an isolated antibody that specifically binds to a human triggering receptor expressed on myeloid cells 2 (TREM2), wherein the antibody comprises:
 (i) a first heavy chain (HC) comprising a V H  comprising SEQ ID NO:24 and a first Fc polypeptide comprising SEQ ID NO:68;   (ii) a second heavy chain (HC) comprising a V H  comprising SEQ ID NO:24 and a second Fc polypeptide comprising SEQ ID NO:63; and   (iii) two light chains each comprising a V L  comprising SEQ ID NO:22.   
     
     
         126 . The method of  claim 125 , comprising:
 (i) a first heavy chain (HC) that consists of the amino acid sequence set forth in SEQ ID NO:69;   (ii) a second HC that consists of the amino acid sequence set forth in SEQ ID NO:73; and   (iii) a first and a second light chain (LC) that each consists of the amino acid sequence set forth in SEQ ID NO:54.   
     
     
         127 . A method of treating a neurodegenerative disease in a subject, comprising administering to the subject an isolated antibody that specifically binds to a human triggering receptor expressed on myeloid cells 2 (TREM2), wherein the antibody comprises:
 (a) a variable region comprising:
 i. a CDR-H1 sequence comprising the sequence of G-F-T-F-T-α 6 -F-Y-M-S (SEQ ID NO:28), wherein α 6  is D or N; 
 ii. a CDR-H2 sequence comprising the sequence of V-I-R-N-β 5 -β 6 -N-β 8 -Y-T-β 11 -β 12 -Y-N-P-S-V-K-G (SEQ ID NO:29), wherein β 5  is K or R; β 6  is A or P; β 8  is G or A; Δ 11  is A or T; and β 12  is G or D; 
 iii. a CDR-H3 sequence comprising the sequence of γ 1 -R-L-γ 4 -Y-G-F-D-Y (SEQ ID NO:30), wherein γ 1  is A or T; and γ 4  is T or S; 
 iv. a CDR-L1 sequence comprising the sequence of Q-S-S-K-S-L-L-H-S-δ 10 -G-K-T-Y-L-N (SEQ ID NO:31), wherein δ 10  is N or T; 
 v. a CDR-L2 sequence comprising the sequence WMSTRAS (SEQ ID NO:8); and 
 vi. a CDR-L3 sequence comprising the sequence of Q-Q-F-L-E-ϕ 6 -P-F-T (SEQ ID NO:32), wherein ϕ 6  is Y or F; 
   (b) a first Fc polypeptide that specifically binds to human transferrin receptor 1 and comprises: Trp, Leu, or Glu at position 380; Tyr or Phe at position 384; Thr at position 386; Glu at position 387; Trp at position 388; Ser, Ala, or Val at position 389; Ser or Asn at position 390; Thr or Ser at position 413; Glu or Ser at position 415; Glu at position 416; and Phe at position 421, according to EU numbering; and   (c) a second Fc polypeptide.   
     
     
         128 . The method of  claim 127 , wherein:
 (a) the first Fc polypeptide has a T366W substitution and the second Fc polypeptide has T366S, L368A, and Y407V substitutions, according to EU numbering;   (b) the first Fc polypeptide and/or the second Fc polypeptide comprises amino acid substitutions of Ala at position 234 and Ala at position 235, according to EU numbering; and/or   (c) the first Fc polypeptide and/or the second Fc polypeptide comprises amino acid substitutions of Leu at position 428 and Ser at position 434, according to EU numbering.   
     
     
         129 . The method of  claim 89 , wherein the neurodegenerative disease is Alzheimer's disease. 
     
     
         130 . A method of treating Alzheimer's disease in a subject, comprising administering to the subject an isolated antibody that specifically binds to a human triggering receptor expressed on myeloid cells 2 (TREM2), wherein the antibody comprises:
 (i) a first heavy chain (HC) comprising a V H  comprising SEQ ID NO:24 and a first Fc polypeptide comprising SEQ ID NO:47;   (ii) a second heavy chain (HC) comprising a V H  comprising SEQ ID NO:24 and a second Fc polypeptide comprising SEQ ID NO:39; and   (iii) two light chains each comprising a V L  comprising SEQ ID NO:22.   
     
     
         131 . The method of  claim 130 , comprising:
 (i) a first heavy chain (HC) that consists of the amino acid sequence set forth in SEQ ID NO:48;   (ii) a second HC that consists of the amino acid sequence set forth in SEQ ID NO:53; and   (iii) a first and a second light chain (LC) that each consists of the amino acid sequence set forth in SEQ ID NO:54.