US2003144209A1PendingUtilityA1

Amino -terminal modified parathyroid hormone (PTH) analogs

Assignee: MASSACHUSETTS GERNERAL HOSPITAPriority: Nov 25, 1998Filed: Feb 11, 2003Published: Jul 31, 2003

Est. expiryNov 25, 2018(expired)· nominal 20-yr term from priority

Inventors:F. Richard Bringhurst Hisashi Takasu Thomas J. Gardella

A61P 3/14A61P 43/00A61P 35/00A61P 19/10A61K 38/00A61P 19/08C07K 14/635

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Claims

Abstract

PTH derivatives having one or more amino acid substitutions that confer PTH-1/PTH-2 receptor agonist properties comprising a biologically active peptide at least 90% identical to a peptide consisting essentially of the formula: (a) X 01 ValSerGluIleGlnLeuMetHisAsnLeuGlyLysHisLeuAs nSerMetGluArgValGluTrpLeuArgLysLysLeuGlnAspValHisAsnPhe (SEQ ID NO:1); (b) fragments thereof containing amino acids 1-29, 1-30, 1-31, 1-32, or 1-33; (c) pharmaceutically acceptable salts thereof; or (d) N- or C-derivatives thereof; wherein: X 01 is desamino Ser, desamino Ala or desamino Gly, provided that said peptide is not desamino Ser 1 hPTH(1-31)NH 2 or desamino Ser 1 hPTH(1-34)NH 2 .

Claims

exact text as granted — not AI-modified

What is claimed is:  
     
         1 . A biologically active peptide at least 90% identical to a peptide consisting essentially of the formula: 
 (a) X 01  ValSerGluIleGlnLeuMetHisAsnLeuGlyLysHisLeuAs nSerMetGluArgValGluTrpLeuArgLysLysLeuGlnAspValHisAsnPhe (SEQ ID NO:1);    (b) fragments thereof containing amino acids 1-29, 1-30, 1-31, 1-32, or 1-33;    (c) pharmaceutically acceptable salts thereof; or    (d) N- or C-derivatives thereof;    wherein: 
 X 01  is desamino Ser, desamino Ala or desamino Gly, provided that said peptide is not desamino Ser 1  hPTH(1-31)NH 2  or desamino Ser 1  hPTH(1-34)NH 2 .  
   
     
     
         2 . A biologically active peptide consisting essentially of the formula: 
 (a) X 01  ValSerGluIleGlnLeuMetHisAsnLeuGlyLysHisLeuAs nSerMetGluArgValGluTrpLeuArgLysLysLeuGlnAspValHisAsnPhe (SEQ ID NO:1);    (b) fragments thereof containing amino acids 1-29, 1-30, 1-31, 1-32, or 1-33;    (c) pharmaceutically acceptable salts thereof; or    (d) N- or C-derivatives thereof;    wherein: 
 X 01  is desamino Ser, desamino Ala or desamino Gly, provided that said peptide is not desamino Ser 1  hPTH(1-31 )NH 2  or desamino Ser 1  hPTH(1-34)NH 2 .  
   
     
     
         3 . The peptide of  claim 1  which is: 
 Desamino-AlaValSerGluIleGlnLeuMetHisAsnLeuGlyLysHisLeuAsnSer MetGluArgValGluTrpLeuArgLysLysLeuGlnAspValHisAsnPhe(SEQ ID NO:5).  
 
     
     
         4 . The peptide of  claim 1  which is: 
 Desamino-GlyValSerGluIleGlnLeuMetHisAsnLeuGlyLysHisLeuAsnSer MetGluArgValGluTrpLeuArgLysLysLeuGlnAspValHisAsnPhe(SEQ ID NO:2).  
 
     
     
         5 . The peptide of  claim 1  wherein the peptide is labeled with a label selected from the group consisting of: radiolabel, flourescent label, bioluminescent label, or chemiluminescent label.  
     
     
         6 . The peptide of  claim 5 , wherein said radiolabel is  99m Tc.  
     
     
         7 . A pharmaceutical composition comprising 
 (a) a biologically active peptide at least 90% identical to a peptide consisting essentially of the formula: 
 X 01  ValSerGluIleGlnLeuMetHisAsnLeuGlyLysHisLeuAsnSerMet GluArgValGluTrpLeuArgLysLysLeuGlnAspValHisAsnPhe(SEQ ID NO:1);  
   (b) fragments thereof containing amino acids 1-29, 1-30, 1-31, 1-32, or 1-33;    (c) pharmaceutically acceptable salts thereof; or    (d) N- or C-derivatives thereof;    wherein: 
 X 01  is desamino Ser, desamino Ala or desamino Gly; and a pharmaceutically acceptable carrier.  
   
     
     
         8 . A pharmaceutical composition comprising 
 (a) a biologically active peptide consisting essentially of the formula: 
 X 01  ValSerGluIleGlnLeuMetHisAsnLeuGlyLysHisLeuAsnSerMet GluArgValGluTrpLeuArgLysLysLeuGlnAspValHisAsnPhe(SEQ ID NO:1);  
   (b) fragments thereof containing amino acids 1-29, 1-30, 1-31, 1-32, or 1-33;    (c) pharmaceutically acceptable salts thereof; or    (d) N- or C-derivatives thereof;    wherein: 
 X 01  is desamino Ser, desamino Ala or desamino Gly; and a pharmaceutically acceptable carrier.  
   
     
     
         9 . A nucleic acid molecule consisting essentially of a polynucleotide encoding a biologically active peptide which has an amino acid sequence selected from the group consisting of: 
 (a) X 01  ValSerGluIleGlnLeuMetHisAsnLeuGlyLysHisLeuAsn SerMetGluArgValGluTrpLeuArgLysLysLeuGlnAspValHisAsnPhe (SEQ ID NO:1);    (b) fragments thereof containing amino acids 1-29, 1-30, 1-31, 1-32, or 1-33;    wherein: 
 X 01  is desamino Ser, desamino Ala or desamino Gly, provided that said peptide is not desamino Ser 1  hPTH(1-31)NH 2  or desamino Ser 1  hPTH(1-34)NH 2 .  
   
     
     
         10 . A recombinant DNA molecule comprising: (1) an expression control region, said region in operable linkage with (2) a polynucleotide sequence coding for a biologically active peptide, wherein said peptide is selected from the group consisting of: 
 (a) X 01  ValSerGluIleGInLeuMetHisAsnLeuGlyLysHisLeuAsn SerMetGluArgValGluTrpLeuArgLysLysLeuGlnAspValHisAsnPhe (SEQ ID NO:1);    (b) fragments thereof containing amino acids 1-29, 1-30, 1-31, 1-32, or 1-33;    wherein: 
 X 01  is desamino Ser, desamino Ala or desamino Gly, provided that said peptide is not desamino Ser 1  hPTH(1-31)NH 2  or desamino Ser 1  hPTH(1-34)NH 2 .  
   
     
     
         11 . A method of preparing a biologically active peptide comprising introducing into a host the recombinant DNA molecule of  claim 9 , and causing expression of said molecule.  
     
     
         12 . A method for making a recombinant vector comprising inserting a nucleic acid molecule of  claim 8  into a vector.  
     
     
         13 . The recombinant DNA molecule of  claim 9 , wherein said control region includes a bacterial, viral, fungal or mammalian promoter.  
     
     
         14 . A host cell containing the recombinant DNA molecule of  claim 9 .  
     
     
         15 . The cell of  claim 13  which is prokaryotic.  
     
     
         16 . The cell of  claim 14  which is bacterial.  
     
     
         17 . The cell of  claim 13  which is eukaryotic.  
     
     
         18 . The cell of  claim 16  which is a yeast cell or a mammalian cell.  
     
     
         19 . A method for treating mammalian conditions characterized by decreases in bone mass, which method comprises administering to a subject in need thereof an effective bone mass-increasing amount of a biologically active peptide, wherein said peptide comprises an amino acid sequence at least 90% identical to a member selected from the group consisting essentially of: 
 (a) X 01  ValSerGluIleGlnLeuMetHisAsnLeuGlyLysHisLeuAsn SerMetGluArgValGluTrpLeuArgLysLysLeuGlnAspValHisAsnPhe (SEQ ID NO:1);    (b) fragments thereof containing amino acids 1-29, 1-30, 1-31, 1-32, or 1-33;    (c) pharmaceutically acceptable salts thereof; or    (d) N- or C-derivatives thereof;    wherein: 
 X 01  is desamino Ser, desamino Ala or desamino Gly, provided that said peptide is not desamino Ser 1  hPTH(1-31)NH 2  or desamino Ser 1  hPTH(1-34)NH 2 ; and a pharmaceutically acceptable carrier.  
   
     
     
         20 . A method for treating mammalian conditions characterized by decreases in bone mass, which method comprises administering to a subject in need thereof an effective bone mass-increasing amount of a biologically active peptide consisting essentially of the formula: 
 (a) X 01  ValSerGluIleGlnLeuMetHisAsnLeuGlyLysHisLeuAsn SerMetGluArgValGluTrpLeuArgLysLysLeuGlnAspValHisAsnPhe (SEQ ID NO:1);    (b) fragments thereof containing amino acids 1-29, 1-30, 1-31, 1-32, or 1-33;    (c) pharmaceutically acceptable salts thereof; or (d) N- or C-derivatives thereof;    wherein: 
 X 01  is desamino Ser, desamino Ala or desamino Gly, provided that said peptide is not desamino Ser 1  hPTH(1-31)NH 2  or desamino Ser 1  hPTH(1-34)NH 2 ; and a pharmaceutically acceptable carrier.  
   
     
     
         21 . A method for determining rates of bone reformation, bone resorption and/or bone remodeling comprising administering to a patient an effective amount of a peptide of  claim 4  and determining the uptake of said peptide into the bone of said patient.  
     
     
         22 . The method of  claim 19 , wherein said effective bone mass-increasing amount of said peptide is administered by providing to the patient DNA encoding said peptide and expressing said peptide in vivo.  
     
     
         23 . A method of  claim 19 , wherein the condition to be treated is osteoporosis.  
     
     
         24 . A method of  claim 19 , wherein said osteoporosis is old age osteoporosis.  
     
     
         25 . A method of  claim 19 , wherein said osteoporosis is post-menopausal osteoporosis.  
     
     
         26 . A method of  claim 19 , wherein the effective amount of said peptide for increasing bone mass is from about 0.01 μg/kg/day to about 1.0 μg/kg/day.  
     
     
         27 . The method of  claim 19 , wherein the method of administration is parenteral.  
     
     
         28 . The method of  claim 19 , wherein the method of administration is subcutaneous.  
     
     
         29 . The method of  claim 19 , wherein the method of administration is nasal insufflation.

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