Chimeric neuregulins and method of making and use thereof

Abstract

Composition containing a chimeric neuregulin polypeptides and method of making such polypeptides are disclosed. The chimeric neuregulin comprises a first moiety of at least 10 amino acids, wherein the first moiety is derived from a first polypeptide; and a second moiety of at least 5 amino acids, wherein the second moiety is derived from a second polypeptide; wherein the first polypeptide is a neuregulin and the chimeric neuregulin exhibits an enhanced binding affinity to integrin, Erb 3, or Erb 4 comparing to that of the first neuregulin.

What is claimed is: 
     
         1 . A chimeric neuregulin polypeptide having an integrin domain that binds to an integrin and an Erb3/4 binding domain that binds to Erb3 and/or Erb4, said chimeric neuregulin polypeptide comprising:
 a neuregulin backbone derived from a native neuregulin polypeptide; and   a donor fragment of at least one amino acid,   wherein said donor fragment (1) replaces a target fragment in said native neuregulin polypeptide, wherein said donor fragment differs from said target fragment by at least one amino acid, or (2) is inserted into an insertion site of said neuregulin polypeptide; and   wherein said donor fragment forms at least a portion of said integrin binding domain and/or at least a portion of said Erb3/4 binding domain of said chimeric neuregulin polypeptide.   
     
     
         2 . The chimeric neuregulin polypeptide of  claim 1 , wherein said chimeric neuregulin polypeptide has an enhanced binding affinity to integrin, Erb 3, or Erb 4, comparing to said native neuregulin peptide. 
     
     
         3 . The chimeric neuregulin polypeptide of  claim 1 , wherein said donor fragment comprises a polypeptide derived from another neuregulin that is different from said native neuregulin. 
     
     
         4 . The chimeric neuregulin polypeptide of  claim 1 , wherein said donor fragment comprises a polypeptide derived from a non-neuregulin. 
     
     
         5 . The chimeric neuregulin polypeptide of  claim 1 , wherein said donor fragment comprises polypeptides derived from two neuregulins that are different from said native neuregulin. 
     
     
         6 . The chimeric neuregulin polypeptide of  claim 1 , wherein said original neuregulin polypeptide is NRG2 or a fragment of NRG2, and wherein said donor fragment comprises a polypeptide derived from NRG1β. 
     
     
         7 . The chimeric neuregulin polypeptide of  claim 1 , wherein said native neuregulin polypeptide is NRG4 or a fragment of NRG4, and wherein said donor fragment comprises a polypeptide derived from NRG1, or a polypeptide derived from NRG2, or both a polypeptide derived from NRG1 and a polypeptide derived from NRG2. 
     
     
         8 . The chimeric neuregulin polypeptide of  claim 1 , further comprising a second donor fragment of at least one amino acid, wherein said second donor fragment (1) replaces a second target fragment in said native neuregulin polypeptide, wherein said second donor fragment differs from said second target fragment by at least one amino acid, or (2) is inserted into an insertion site of said native neuregulin polypeptide, 
     
     
         9 . The chimeric neuregulin polypeptide of  claim 1 , wherein said chimeric neuregulin polypeptide is a PEGylated. 
     
     
         10 . A pharmaceutical composition, comprising:
 an effective amount of the chimeric neuregulin polypeptide of  claim 1 , and   a pharmaceutically acceptable carrier.   
     
     
         11 . A chimeric neuregulin, comprising:
 a first moiety of at least 10 amino acids, wherein said first moiety is derived from a first polypeptide; and   a second moiety of at least 5 amino acids, wherein said second moiety is derived from a second polypeptide;   wherein said first polypeptide is a first neuregulin, and wherein said chimeric neuregulin exhibits an enhanced binding affinity to integrin, Erb 3, or Erb 4 comparing to that of said first neuregulin.   
     
     
         12 . The chimeric neuregulin of  claim 11 , wherein said second polypeptide is a neuregulin that is different from said first neuregulin. 
     
     
         13 . The chimeric neuregulin of  claim 11 , wherein said second polypeptide is a non-neuregulin polypeptide. 
     
     
         14 . The chimeric neuregulin of  claim 11 , further comprising a third moiety derived from a third polypeptide. 
     
     
         15 . The chimeric neuregulin of  claim 14 , wherein said third polypeptide is a neuregulin that is different from said native neuregulin. 
     
     
         16 . The chimeric neuregulin of  claim 14 , wherein said second polypeptide is a second neuregulin and said third polypeptide is a third neuregulin, wherein said first neuregulin, said second neuregulin and said third neuregulin are different from each other. 
     
     
         17 . The chimeric neuregulin polypeptide of  claim 11 , wherein said first neuregulin is NRG2, and wherein said second polypeptide is NRG1β. 
     
     
         18 . The chimeric neuregulin of  claim 11 , wherein said first neuregulin is NRG4, and wherein said second polypeptide is NRG1 or NRG2. 
     
     
         19 . The chimeric neuregulin of  claim 11 , wherein said first moiety comprises a NRG integrin binding domain or a NRG Erb3/4 binding domain. 
     
     
         20 . The chimeric neuregulin of  claim 11 , wherein said first moiety comprises a NRG integrin binding domain, and wherein said second moiety comprises a NRG Erb3/4 binding domain. 
     
     
         21 . The chimeric neuregulin of  claim 11 , wherein said first moiety comprises a NRG Erb3/4 binding domain, and wherein said second moiety comprises a NRG integrin binding domain. 
     
     
         22 . A pharmaceutical composition, comprising:
 an effective amount of the chimeric neuregulin polypeptide of  claim 11 , and   a pharmaceutically acceptable carrier.   
     
     
         23 . A method for ameliorating neuronal damage in a subject, comprising:
 administering to said subject an effective amount of the pharmaceutical composition of  claim 22 .   
     
     
         24 . The method of  claim 23 , wherein said neuronal damage is caused by an occlusive stroke and wherein said pharmaceutical composition is administered within 72 hours of said occlusive stroke. 
     
     
         25 . The method of  claim 24 , wherein said pharmaceutical composition is administered in conjunction with t-PA. 
     
     
         26 . The method of  claim 24 , wherein said pharmaceutical composition is administered in conjunction with a glutamate receptor inhibitor. 
     
     
         27 . The method of  claim 24 , wherein said pharmaceutical composition is administered after the initial inflammation due to the occlusive stroke has subsided to enhance migration of stem cells from a ventricle into an area of the brain damaged by the occlusive stroke. 
     
     
         28 . The method of  claim 23 , wherein said neuronal damage is caused by exposure to a neurotoxin and wherein said pharmaceutical composition is administered within 72 hours of said exposure. 
     
     
         29 . The method of  claim 28 , wherein said neurotoxin is an organophosphate. 
     
     
         30 . The method of  claim 28 , wherein the composition is administered in conjunction with an antidotes to neurotoxin or an anticonvulsant. 
     
     
         31 . The method of  claim 23 , wherein said neuronal damage is caused by acute CNS injuries, and wherein said composition is administered within 72 hours of the cause of CNS injury. 
     
     
         32 . The method of  claim 23 , wherein said neuronal damage is caused by a neurodegenerative disorder. 
     
     
         33 . The method of  claim 32 , wherein said neurodegenerative disorder is Alzheimer's disease, Parkinson's disease, Huntington's disease or amyotrophic lateral sclerosis. 
     
     
         34 . A method for preventing or ameliorating secondary neuronal injury and inflammation following traumatic brain injury (TBI), comprising:
 administering into a subject in need of such treatment an effective amount of the pharmaceutical composition of  claim 22 .   
     
     
         35 . A method for ameliorating blood vessel damage caused by acute mechanical or chemical assault in a subject, comprising:
 administering to said subject an effective amount of the pharmaceutical composition of  claim 22 .   
     
     
         36 . The method of  claim 35 , wherein said blood vessel damage is caused by placement of a balloon or stent in a blood vessel, diagnostic cardiac catheterization, or cardiac surgery.