Methods of impairing osteoclast differentiation using antibodies that bind siglec-15

Abstract

This invention relates, in part, to unique and newly identified genetic polynucleotides involved in the process of bone remodeling; variants and derivatives of the polynucleotides and corresponding polypeptides; uses of the polynucleotides, polypeptides, variants and derivatives; and methods and compositions for the amelioration of symptoms caused by bone remodeling disorders. Disclosed in particular are, the isolation and identification of polynucleotides, polypeptides, variants and derivatives involved in osteoclast activity, validation of the identified polynucleotides for their potential as therapeutic targets and use of the polynucleotides, polypeptides, variants and derivatives for the amelioration of disease states and research purposes.

What is claimed is: 
     
       1. A method of impairing osteoclast differentiation in a mammal in need thereof, the method comprising administering an antibody or antigen binding fragment which specifically binds to human Siglec-15 (SEQ ID NO.:2) or murine Siglec-15 (SEQ ID NO.:108) to said mammal. 
     
     
       2. The method of  claim 1 , wherein the antibody or antigen binding fragment impairs an osteoclast differentiation activity of human Siglec-15 or murine Siglec 15. 
     
     
       3. The method of  claim 2 , wherein the osteoclast differentiation activity is characterized by differentiation of osteoclast precursor cells into differentiated osteoclasts. 
     
     
       4. The method of  claim 2 , wherein the antibody is a polyclonal antibody. 
     
     
       5. The method of  claim 2 , wherein the antibody or antigen binding fragment is a monoclonal antibody or an antigen binding fragment thereof. 
     
     
       6. The method of  claim 5 , wherein the monoclonal antibody or antigen binding fragment is produced from an isolated mammalian cell. 
     
     
       7. The method of  claim 6 , wherein the isolated mammalian cell is a human cell. 
     
     
       8. The method of  claim 6 , wherein the antibody or antigen binding fragment comprises a constant region of a human antibody or a fragment thereof. 
     
     
       9. The method of  claim 8 , wherein the antibody or antigen binding fragment comprises a framework region of a human antibody. 
     
     
       10. The method of  claim 2 , wherein the antibody or antigen binding fragment is a FV, a Fab, a Fab′ or a (Fab′) 2 . 
     
     
       11. The method of  claim 3 , wherein the osteoclast precursor cells are human osteoclast precursor cells. 
     
     
       12. The method of  claim 11 , wherein the human osteoclast precursor cells are primary human osteoclast precursor cells. 
     
     
       13. The method of  claim 2 , wherein the antibody or antigen binding fragment binds to human Siglec-15 with a greater affinity than to murine Siglec-15. 
     
     
       14. The method of  claim 2 , wherein the antibody or antigen binding fragment binds to human Siglec-15 and does not bind murine Siglec-15. 
     
     
       15. A method for inhibiting bone resorption comprising administering to a subject in need thereof, an antibody or antigen binding fragment which specifically binds to human Siglec-15 (SEQ ID NO.:2) or murine Siglec-15 (SEQ ID NO.:108). 
     
     
       16. The method of  claim 15 , wherein the antibody or antigen binding fragment impairs an activity of human Siglec-15 or murine Siglec-15 in osteoclast precursor cells or in osteoclasts. 
     
     
       17. The method of  claim 16 , wherein the activity is osteoclastogenesis. 
     
     
       18. The method of  claim 15 , wherein the antibody or antigen binding fragment inhibits osteoclast differentiation. 
     
     
       19. The method of  claim 15 , wherein the antibody or antigen binding fragment is administered in combination with a drug or an hormone. 
     
     
       20. The method of  claim 19 , wherein the drug is an antiresorptive drug or a drug increasing bone mineral density. 
     
     
       21. The method of  claim 15 , wherein the subject in need thereof, suffers from a bone remodelling disorder. 
     
     
       22. The method of  claim 21 , wherein the bone remodelling disorder is associated with a decrease in bone mass. 
     
     
       23. The method of  claim 21 , wherein the bone remodelling disorder is selected from the group consisting of osteoporosis, osteopenia, osteomalacia, hyperparathyroidism, hyperthyroidism, hypogonadism, thyrotoxicosis, systemic mastocytosis, adult hypophosphatasia, hyperadrenocorticism, osteogenesis imperfecta, Paget's disease, Cushing's disease/syndrome, Turner syndrome, Gaucher disease, Ehlers-Danlos syndrome, Marfan's syndrome, Menkes' syndrome, Fanconi's syndrome, multiple myeloma, hypercalcemia, hypocalcemia, arthritides, periodontal disease, rickets, fibrogenesis imperfecta ossium, osteosclerotic disorders, pycnodysostosis, and damage caused by macrophage-mediated inflammatory processes. 
     
     
       24. The method of  claim 15 , wherein the antibody or antigen binding fragment binds to human Siglec-15 with a greater affinity than to murine Siglec-15. 
     
     
       25. The method of  claim 15 , wherein the antibody or antigen binding fragment binds to human Siglec-15 and does not bind murine Siglec-15. 
     
     
       26. A method of impairing osteoclast differentiation in a human in need thereof, the method comprising administering an antibody or antigen binding fragment thereof which specifically binds to human Siglec-15 (SEQ ID NO: 2) or murine Siglec-15 (SEQ ID NO: 108), the antibody or antigen binding fragment comprising:
 (a) a light chain variable sequence comprising an amino sequence of SEQ ID NO: 61 and a heavy chain variable sequence comprising an amino acid sequence of SEQ ID NO: 63;   (b) a light chain variable sequence comprising an amino sequence of SEQ ID NO: 69 and a heavy chain variable sequence comprising an amino acid sequence of SEQ ID NO: 71; or   (c) a light chain variable sequence comprising an amino sequence of SEQ ID NO: 77 and a heavy chain variable sequence comprising an amino acid sequence of SEQ ID NO: 79.