Anti-trem2 antibodies and methods of use thereof

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.

1 .- 50 . (canceled) 
     
     
         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: Ab 1, 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  claim 51 , 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 , 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  claim 53 , 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  claim 58 , wherein the antibody induces the one or more TREM2 activities independently of binding to an Fc receptor. 
     
     
         62 . The isolated antibody of  claim 58 , 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 . (canceled) 
     
     
         66 . The isolated antibody of  claim 51 , 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  claim 51 , wherein the isolated antibody is an inert antibody. 
     
     
         68 . The isolated antibody of  claim 51 , wherein the isolated antibody is an antagonist antibody. 
     
     
         69 .- 78 . (canceled) 
     
     
         79 . The isolated antibody of  claim 51 , wherein the antibody is a human antibody, a humanized antibody, a bispecific antibody, a multivalent antibody, or a chimeric antibody. 
     
     
         80 . (canceled) 
     
     
         81 . The isolated antibody of  claim 51 , wherein the antibody is a monoclonal antibody. 
     
     
         82 . The isolated antibody of  claim 51 , wherein the isolated antibody binds specifically to both human TREM2 and mouse TREM2. 
     
     
         83 .- 102 . (canceled)