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

• US 20100310560A1
• Filed: 06/10/2009
• Published: 12/09/2010
• Est. Priority Date: 03/20/2001
• Status: Active Grant

• Current Assignee: Cosmo Technologies Limited (Cosmo Pharmaceuticals NV)
• Original Assignee: BioXell S.p.A. (Cosmo Pharmaceuticals NV)
• Inventors: Bouchon, Axel, Colonna, Marco
• Granted Patent: US 8,231,878 B2
• Time in Patent Office: Days
• US Class Current: 424/134.1
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: C07K 14/70503 Immunoglobulin superfamily
• CPC Class Codes: C07K 16/2803 against the immunoglobulin superfamily
• CPC Class Codes: C07K 2317/54 F(ab')2
• CPC Class Codes: C07K 2317/55 Fab or Fab'
• CPC Class Codes: C07K 2317/77 Internalization into the cell
• CPC Class Codes: C07K 2319/30 Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
• CPC Class Codes: C07K 2319/32 fusions with soluble part of a cell surface receptor, "decoy receptors"

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.

Claims

1. A method for treating a subject having inflammatory bowel disease, comprising administering to the subject a therapeutically effective amount of a modulator of TREM-2 polypeptide, wherein the TREM-2 polypeptide has the amino acid sequence of SEQ ID NO:

4.

2. The method of claim 1, wherein the modulator is administered in combination with at least one other prophylactic or therapeutic agent.

3. The method of claim 1, wherein the modulator is a TREM-2 antagonist.

4. The method of claim 1, wherein the modulator is an anti-TREM-2 antibody.

5. The method of claim 1, wherein the modulator is a TREM-2 agonist.

6. The method of claim 1, wherein the modulator comprises DNA encoding TREM-2 so that TREM-2 polypeptide is expressed in vivo.

7. The method of claim 1, wherein the modulator comprises a fragment of TREM-2 polypeptide, wherein the TREM-2 polypeptide fragment comprises an amino acid sequence of SEQ ID NO. 4.

8. The method of claim 7, wherein the TREM-2 polypeptide fragment comprises an extracellular domain of the TREM-2 polypeptide having the amino acid sequence of SEQ ID NO. 4.

9. The method of claim 1, wherein the modulator is a fusion protein comprising a TREM-2 polypeptide having the amino acid sequence of SEQ ID NO:

4, or a fragment thereof, and a second polypeptide.

10. The method of claim 9, wherein the fusion protein comprises a fragment of TREM-2 polypeptide and a second polypeptide.

11. The method of claim 10 wherein the TREM-2 polypeptide fragment comprises an extracellular domain of the TREM-2 polypeptide having the amino acid sequence of SEQ ID NO:

4.

12. The method of claim 9, wherein the second polypeptide is an immunoglobulin, or a fragment thereof.

13. The method of claim 12, wherein the immunoglobulin is huIgG or huIgM, or a fragment thereof.