Composition and method for delivery of BMP-2 amplifier/co-activator for enhancement of osteogenesis

Abstract

A composition comprising a synthetic growth factor analog comprising a non-growth factor heparin binding region, a linker and a sequence that binds specifically to a cell surface receptor and an osteoconductive material where the synthetic growth factor analog is attached to and can be released from the osteoconductive material and is an amplifier/co-activator of osteoinduction.

What is claimed is: 
     
       1. A compound of formula II:  
       
         
           
           
               
               
           
         
         wherein:
 X is selected from the group consisting of SEQ ID NO NOs: 7 15, 16, 18, and 19; 
 R 1  is hydrogen (H—), such that the terminal group is —NH 2 ; 
 R 6  is a lysine; 
 R 5  is a lysine an ornithine; 
 R 4  is —NH 2  at the carboxyl terminal group; 
 Y is Ahx-Ahx-Ahx wherein Ahx is 6-aminohexanoic acid; and 
 Z is SEQ ID NO: 5 2. 
 
       
     
     
       2. A composition comprising:
 a compound of formula II   
       
         
           
           
               
               
           
         
         wherein:
 X is SEQ ID NO: 7; 
 R 1  is hydrogen (H—), such that the terminal group is —NH 2 ; 
 R 6  is a lysine; 
 R 5  is a lysine; 
 R 4  is —NH 2  at the carboxyl terminal group; 
 Y is Ahx-Ahx-Ahx wherein Ahx is 6-aminohexanoic acid; 
 Z is SEQ ID NO: 5; and 
 
         an osteoconductive material comprising one or more of an inorganic material, a synthetic polymer, a natural polymer, or an allograft bone, 
         wherein the compound of formula II is attached to and can be released from the osteoconductive material. 
       
     
     
       3. The composition of  claim 2  wherein the osteoconductive material is selected from hydroxyapatite, tricalcium phosphate, collagen, hyaluronate, calcium sulfate, polyglycolic acid fibers, polylactic-co-glycolic acid, allograft, and any combination thereof. 
     
     
       4. The composition of  claim 2  wherein the osteoconductive material is formed into a granule, a putty, a powder, a gel, a block or a combination thereof. 
     
     
       5. A kit comprising:
 a lyophilized vial of, with or without excipients, a compound of formula II   
       
         
           
           
               
               
           
         
         wherein:
 X is SEQ ID NO: 7; 
 R 1  is hydrogen (H—), such that the terminal group is —NH 2 ; 
 R 6  is a lysine; 
 R 5  is a lysine; 
 R 4  is —NH 2  at the carboxyl terminal group; 
 Y is Ahx-Ahx-Ahx wherein Ahx is 6-aminohexanoic acid; 
 Z is SEQ ID NO: 5; and 
 
         a container of osteoconductive material. 
       
     
     
       6. A method for treating a bone lesion comprising:
 coating an osteoconductive material with a compound of formula II having the following structure   
       
         
           
           
               
               
           
         
         wherein:
 X is SEQ ID NO: 7; 
 R 1  is hydrogen (H—), such that the terminal group is —NH 2 ; 
 R 6  is a lysine; 
 R 5  is a lysine; 
 R 4  is —NH 2  at the carboxyl terminal group; 
 Y is Ahx-Ahx-Ahx wherein Ahx is 6-aminohexanoic acid; and 
 Z is SEQ ID NO: 5, 
 
         to generate a coated osteoconductive material with the compound of formula II releasably attached thereto; and 
         implanting the coated osteoconductive material in the bone lesion; wherein the osteoconductive material comprising one or more of an inorganic material, a synthetic polymer, or an allograft bone. 
       
     
     
       7. The method of  claim 6  wherein an exogenous or recombinant bone growth factor is added to the osteoconductive material. 
     
     
       8. The method of  claim 6  wherein the osteoconductive material is formed from granules, polymers, powders, gel, cement, putty or any combination thereof. 
     
     
       9. The method of  claim 6  wherein the method further comprises adding host bone chips or bone marrow aspirate to the osteoconductive material. 
     
     
       10. The method of  claim 6  wherein releasing the compound is rate-controlled by manipulating the composition of the osteoconductive material, the concentration of the compound attached to the osteoconductive material, or the physical properties of the osteoconductive material. 
     
     
       11. The method of  claim 6  wherein the osteoconductive material is used in combination with a load bearing device to treat the bone lesion. 
     
     
       12. The method of  claim 11  wherein the load bearing device is selected from cages, wedges, rods, pedicle screws, vertebral body replacement, intervertebral body fusion device, and rings for bone fusion. 
     
     
       13. The method of  claim 11  wherein the treatment of the bone lesion results in spine fusion. 
     
     
       14. A method for treating a bone lesion comprising:
 administering to a vertebrate subject in need of such treatment an effective amount of a compound of formula II   
       
         
           
           
               
               
           
         
         wherein:
 X is SEQ ID NO: 7; 
 R 1  is hydrogen (H—), such that the terminal group is —NH 2 ; 
 R 6  is a lysine; 
 R 5  is a lysine; 
 R 4  is —NH 2  at the carboxyl terminal group; 
 Y is Ahx-Ahx-Ahx wherein Ahx is 6-aminohexanoic acid; and 
 Z is SEQ ID NO: 5. 
 
       
     
     
       15. The compound of claim 1, wherein X is SEQ ID NO: 15. 
     
     
       16. The compound of claim 1, wherein X is SEQ ID NO: 16. 
     
     
       17. The compound of claim 1, wherein X is SEQ ID NO: 18. 
     
     
       18. The compound of claim 1, wherein X is SEQ ID NO: 19.