Receptor trem (triggering receptor expressed on myeloid cells) and uses thereof

Abstract

Novel activating receptors of the Ig super-family expressed on human myeloid cells, called TREM(s) (triggering receptor expressed on myeloid cells) are provided. Specifically, two (2) members of TREMs, TREM-1 and TREM-2 are disclosed. TREM-1 is a transmembrane glycoprotein expressed selectively on blood neutrophils and a subset of monocytes but not on lymphocytes and other cell types and is upregulated by bacterial and fungal products. Use of TREM-1 in treatment and diagnosis of various inflammatory diseases is also provided. TREM-2 is also a transmembrane glycoprotein expressed selectively on mast cells and peripheral dendritic cells (DCs) but not on granulocytes or monocytes. DC stimulation via TREM-2 leads to DC maturation and resistance to apoptosis, and induces strong upregulation of CCR7 and subsequent chemotaxis toward macrophage inflammatory protein 3-β. TREM-2 has utility in modulating host immune responses in various immune disorders, including autoimmune diseases and allergic disorders.

1 . An isolated antibody or a fragment thereof that specifically binds to human triggering receptor expressed on myeloid cells-1 (TREM-1) having a sequence as set forth in SEQ ID NO: 3, wherein the antibody or a fragment thereof binds to an epitope comprising amino acids E46, K47, F48, K75, V80 and Q81. 
     
     
         2 - 4 . (canceled) 
     
     
         5 . A pharmaceutical composition comprising the antibody or a fragment thereof of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         6 . An isolated nucleic acid encoding the antibody or a fragment thereof of  claim 1 . 
     
     
         7 . A host cell comprising the nucleic acid of  claim 6 . 
     
     
         8 . A method of treating an autoimmune disease or chronic inflammation in a subject in need thereof comprising administering to the subject the antibody or a fragment thereof of  claim 1 . 
     
     
         9 . The method of  claim 8 , wherein the autoimmune disease is selected from rheumatoid arthritis, juvenile idiopathic arthritis, psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis and systemic lupus erythematosus. 
     
     
         10 . A method of treating a cancer in a subject in need thereof comprising administering to the subject the antibody or a fragment thereof of  claim 1 . 
     
     
         11 . An isolated antibody or a fragment thereof that specifically binds to human TREM-1 having a sequence as set forth in SEQ ID NO: 3,
 (i) wherein the antibody or the fragment thereof binds to an epitope comprising amino acid residues D38, K40, K75, Y90, H91, and R97 or   (ii) wherein the antibody or a fragment thereof binds to an epitope comprising the amino acid residues D38, K40, Y90, H91, and R97.   
     
     
         12 . The antibody or a fragment thereof of  claim 11 ,
 (i) wherein the antibody or a fragment thereof binds to an epitope comprising D38, K40, D42, S74, K75, P79, V80, Q81, V82, G83, Y90, H91, H93 and R97;   (ii) wherein the antibody or a fragment thereof binds to an epitope comprising D38, K40, D42, K75, V80, Q81, Y90, H91, H93 and R97; or   (iii) wherein the antibody or a fragment thereof binds to an epitope comprising D38, K40, D42, K75, Y90, H91, H93 and R97.   
     
     
         13 . An isolated nucleic acid encoding the antibody or a fragment thereof of  claim 11 . 
     
     
         14 . A host cell comprising the nucleic acid of  claim 13 . 
     
     
         15 . A method of treating an autoimmune disease or chronic inflammation in a subject in need thereof comprising administering to the subject the antibody or a fragment thereof of  claim 11 . 
     
     
         16 . The method of  claim 15 , wherein the autoimmune disease is selected from rheumatoid arthritis, juvenile idiopathic arthritis, psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis and systemic lupus erythematosus. 
     
     
         17 . A method of treating a cancer in a subject in need thereof comprising administering to the subject the antibody or a fragment thereof of  claim 11 . 
     
     
         18 . An isolated antibody or a fragment thereof that binds to a wild type human TREM-1 (SEQ ID NO: 3), wherein the antibody or a fragment thereof binds to an epitope comprising amino acid residues D38-F48. 
     
     
         19 . The antibody or a fragment thereof according to  claim 18 , wherein the epitope further comprises amino acids T70-R84 of wild type human TREM-1 (SEQ ID NO: 3). 
     
     
         20 . An isolated nucleic acid encoding the antibody or a fragment thereof of  claim 18 . 
     
     
         21 . A host cell comprising the nucleic acid of  claim 20 . 
     
     
         22 . A method of treating an autoimmune disease or chronic inflammation in a subject in need thereof comprising administering to the subject the antibody or a fragment thereof of  claim 18 . 
     
     
         23 . The method of  claim 22 , wherein the autoimmune disease is selected from rheumatoid arthritis, juvenile idiopathic arthritis, psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis and systemic lupus erythematosus. 
     
     
         24 . A method of treating a cancer in a subject in need thereof comprising administering to the subject the antibody or a fragment thereof of  claim 18 .