Inhibition of bone resorption with rankl binding peptides

Abstract

Methods are provided for inhibiting bone resorption and/or osteoclast activity. More specifically, methods are provided wherein polypeptides against RANK-L are administered to a subject less frequently and/or at lower dose, while still maintaining effective inhibition of bone resorption and/or osteoclast activity in the subject at unexpectedly prolonged periods of time, particularly in view of the doses administered.

1 . A method for prevention and/or treatment of bone diseases and/or disorders by inhibiting bone resorption or osteoclast activity comprising administering a polypeptide that specifically binds Receptor Activator of Nuclear Factor kappa B Ligand (RANKL) to a subject, wherein the amount of the polypeptide administered is effective to change one or more markers of bone metabolism and/or bone homeostasis selected from cross-linking telopeptide of type I collagen (CTX-1), N-terminal telopeptide of type I collagen (NTX-1), tartrate-resistant acid phosphatase isoform 5b (TRACP5b), N-terminal propeptide of type I procollagen (P1NP) and bone-specific alkaline phosphatase (BAP), for at least 30 days after administration,
 wherein the polypeptide comprises two or more immunoglobulin single variable domains that specifically bind RANKL and that essentially consist of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which CDR1 is chosen from SEQ ID NO: 1, CDR2 is chosen from SEQ ID NO: 2, and CDR3 is chosen from SEQ ID NO: 3, and   wherein   the polypeptide is administered in an amount from about 0.003 mg/kg to about 0.03 mg/kg and the serum levels of CTX-1 are reduced by 30% for at least about 30 days after administration;   the polypeptide is administered in an amount from about 0.01 mg/kg to about 0.1 mg/kg and the serum levels of CTX-1 are reduced by 30% for at least about 120 days after administration;   the polypeptide is administered in an amount from about 0.1 mg/kg to about 1 mg/kg and the serum levels of CTX-1 are reduced by 30% for at least about 270 days after administration;   the polypeptide is administered in an amount of less than or equal to 0.03 mg/kg and the serum levels of CTX-1 are reduced by at least 45% for at least about 30 days after administration;   the polypeptide is administered in an amount from about 0.01 mg/kg to about 3 mg/kg, preferably in an amount from about 0.01 mg/kg to about 0.1 mg/kg and the serum levels of CTX-1 are reduced by at least 45% for at least about 60 days after administration;   the polypeptide is administered in an amount from about 0.01 mg/kg to about 0.3 mg/kg, preferably 0.03 mg/kg to about 0.3 mg/kg and the serum levels of CTX-1 are reduced by at least 45% for about 30 days to 3 months, preferably for at least about 90 days after administration;   the polypeptide is administered in an amount from about 0.1 mg/kg to about 1 mg/kg and the serum levels of CTX-1 are reduced by at least 45% for at least about 120 days after administration;   the polypeptide is administered in an amount from about 0.3 mg/kg to about 1 mg/kg and the CTX-1 is reduced by at least 45% for about 3 months to 6 months after administration;   the polypeptide is administered in an amount of less than or equal to 0.3 mg/kg and the CTX-1 is reduced by at least 45% for about 3 months to 6 months after administration;   the polypeptide is administered in an amount of less than or equal to 1 mg/kg and the serum levels of CTX-1 are reduced by at least 45% for about 6 months after administration;   the polypeptide is administered in an amount from about 0.03 mg/kg to about 0.3 mg/kg and the serum levels of CTX-1 are reduced by at least 70% for at least about 30 days after administration;   the polypeptide is administered in an amount from about 0.1 mg/kg to about 1 mg/kg and the serum levels of CTX-1 are reduced by at least 70% for at least about 120 days after administration;   the polypeptide is administered in an amount from about 0.01 mg/kg to about 0.1 mg/kg and the levels of NTX-1 are reduced by at least 30% for at least 60 days after administration;   the polypeptide is administered in an amount from about 0.03 mg/kg to about 0.3 mg/kg and the levels of NTX-1 are reduced by at least 30% for at least about 90 days after administration;   the polypeptide is administered in an amount from about 0.1 mg/kg to about 1 mg/kg and the levels of NTX-1 are reduced by at least 30% for at least about 120 days after administration;   the polypeptide is administered in an amount from about 1 mg/kg to about 10 mg/kg and the levels of NTX-1 are reduced by at least 30% for at least about 180 days (or 6 months), preferably at least 10 months, or even at least 12 months after administration;   the polypeptide is administered in an amount from about 0.01 mg/kg to about 3 mg/kg, preferably in an amount from about 0.01 mg/kg to about 0.1 mg/kg and the levels of NTX-1 are reduced by at least 45% for at least about 30 days after administration;   the polypeptide is administered in an amount from about 0.03 mg/kg to about 0.3 mg/kg and the levels of NTX-1 are reduced by at least 45% for at least about 60 days after administration;   the polypeptide is administered in an amount from about 0.01 mg/kg to about 3 mg/kg, preferably, 0.01 mg/kg to about 0.3 mg/kg, or 0.03 mg/kg to about 0.3 mg/kg and the levels of NTX-1 are reduced by at least 45% for at least about 30 days to 3 months after administration;   the polypeptide is administered in an amount of less than or equal to 0.03 mg/kg and the levels of NTX-1 are reduced by at least 45% for at least about 30 days to 3 months after administration;   the polypeptide is administered in an amount from about 0.1 mg/kg to about 1 mg/kg and the levels of NTX-1 are reduced by at least 45%, compared to pre-treatment or normal levels, for at least about 150 days after administration;   the polypeptide is administered in an amount from about 0.3 mg/kg to about 1 mg/kg and the levels of NTX-1 are reduced by at least 45% for about 3 months to 6 months after administration;   the polypeptide is administered in an amount of less than or equal to 0.3 mg/kg and the levels of NTX-1 are reduced by at least 45% for about 3 months to 6 months after administration;   the polypeptide is administered in an amount from about 1 mg/kg to about 10 mg/kg, preferably in an amount from about 1 mg/kg to about 3 mg/kg the levels of NTX-1 are reduced by at least 45% for at least 6 months to 1 year after administration;   the polypeptide is administered in an amount of less than or equal to 1 mg/kg and the levels of NTX-1 are reduced by at least 45% for at least about 180 days (or 6 months) after administration;   the polypeptide is administered in an amount from about 0.1 mg/kg to about 1 mg/kg and the levels of NTX-1 are reduced by at least 70% for at least about 30 days after administration;   the polypeptide is administered in an amount from about 0.3 mg/kg to about 3 mg/kg and the levels of NTX-1 are reduced by at least 70% for at least about 90 days after administration;   the polypeptide is administered in an amount from about 1 mg/kg to about 10 mg/kg and the levels of NTX-1 are reduced by at least 70% for at least about 120 days after administration;   the polypeptide is administered in an amount from about 0.1 mg/kg to about 1 mg/kg, preferably in an amount from about 0.3 mg/kg to about 3 mg/kg, more preferably in an amount from about 0.3 mg/kg to about 1 mg/kg and the levels of NTX-1 are reduced by at least 80% for at least about 30 days (to 3 months) after administration;   the polypeptide is administered in an amount from about 1 mg/kg to about 10 mg/kg and the levels of NTX-1 are reduced by at least 80%, compared to pre-treatment or normal levels, for at least about 90 days after administration;   the polypeptide is administered in an amount from about 0.03 mg/kg to about 0.3 mg/kg and the serum levels of TRACP5b are reduced by at least 30% for at least about 60 days after administration;   the polypeptide is administered in an amount from about 0.1 mg/kg to about 1 mg/kg and the serum levels of TRACP5b are reduced by at least 30% for at least about 90 days after administration;   the polypeptide is administered in an amount from about 0.3 mg/kg to about 3 mg/kg and the serum levels of TRACP5b are reduced by at least 30% for at least about 120 days after administration;   the polypeptide is administered in an amount from about 0.1 mg/kg to about 1 mg/kg and the serum levels of TRACP5b are reduced by at least 45% for at least about 30 days after administration;   the polypeptide is administered in an amount from about 0.3 mg/kg to about 3 mg/kg and the serum levels of TRACP5b are reduced by at least 45%, compared to pre-treatment or normal levels, for at least about 90 days after administration;   the polypeptide is administered in an amount from about 0.003 mg/kg to about 0.03 mg/kg and the serum levels of P1NP are reduced by at least 30% for at least about 90 days after administration;   the polypeptide is administered in an amount from about 0.01 mg/kg to about 0.1 mg/kg and the serum levels of P1NP 1 are reduced by at least 30% for at least about 120 days after administration;   the polypeptide is administered in an amount from about 0.03 mg/kg to about 0.3 mg/kg and the serum levels of P1NP are reduced by at least 45% for at least about 90 days after administration; or   the polypeptide is administered in an amount from about 0.1 mg/kg to about 1 mg/kg and the serum levels of P1NP are reduced by at least 70% for at least about 90 days after administration.   
     
     
         2 . (canceled) 
     
     
         3 . The method according to  claim 1 , wherein the polypeptide comprises or consists of SEQ ID NO: 10 or SEQ ID NO: 12. 
     
     
         4 . The method according to  claim 1 , wherein the polypeptide is administered subcutaneously. 
     
     
         5 . The method according to  claim 1 , wherein the subject has osteoporosis. 
     
     
         6 .- 59 . (canceled) 
     
     
         60 . The method according to  claim 3 , wherein the polypeptide is administered subcutaneously. 
     
     
         61 . The method according to  claim 3 , wherein the subject has osteoporosis. 
     
     
         62 . The method according to  claim 4 , wherein the subject has osteoporosis. 
     
     
         63 . The method according to  claim 60 , wherein the subject has osteoporosis.