Erythropoietin receptor binding antibodies

Abstract

The present invention relates to antibodies and antibody fragments thereof that bind to and activate an erythropoietin receptor. The present invention also relates to methods of modulating the endogenous activity of an erythropoietin receptor in a mammal using said antibodies as well as pharmaceutical compositions containing said antibodies.

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         5 . An antibody or antibody fragment thereof that activates an endogenous activity of a human erythropoietin receptor in a mammal, comprising: 
 at least one heavy chain variable region having the amino acid sequence of SEQ ID NO: 3 or antibody fragment thereof; and    at least one light chain variable region having the amino acid sequence of SEQ ID NO: 5 or antibody fragment thereof,    wherein said antibody or antibody fragment thereof does not interact with a peptide having an amino acid sequence of SEQ ID NO:1.    
     
     
         6 . An antibody or antibody fragment thereof that activates an endogenous activity of a human erythropoietin receptor in a mammal, comprising 
 at least one heavy chain variable region having the amino acid sequence of SEQ ID NO: 7 or antibody fragment thereof; wherein said antibody or antibody fragment thereof does not interact with a peptide having an amino acid sequence of SEQ ID NO:1.    
     
     
         7 . An antibody or antibody fragment thereof that activates an endogenous activity of a human erythropoietin receptor in a mammal, comprising 
 at least one light chain variable region having the amino acid sequence of SEQ ID NO: 9 or antibody fragment thereof; wherein said antibody or antibody fragment thereof does not interact with a peptide having an amino acid sequence of SEQ ID NO:1.    
     
     
         8 . An antibody or antibody fragment thereof that activates an endogenous activity of a human erythropoietin receptor in a mammal, said antibody comprising: 
 at least one heavy chain variable region having the amino acid sequence of SEQ ID NO: 7 or antibody fragment thereof; and    at least one light chain variable region having the amino acid sequence of SEQ ID NO: 9 or antibody fragment thereof,    wherein said antibody or antibody fragment thereof does not interact with a peptide having an amino acid sequence of SEQ ID NO:1.    
     
     
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         11 . An antibody or antibody fragment thereof that activates an endogenous activity of a human erythropoietin receptor in a mammal, said antibody comprising: 
 the amino acid sequences of at least one heavy chain variable region and at least one light chain variable region selected from the group consisting of SEQ ID NO:11/SEQ ID NO:13, SEQ ID NO:15/SEQ ID NO:17, SEQ ID NO:19/SEQ ID NO:21, SEQ ID NO:11/SEQ ID NO:23, SEQ ID NO:11/SEQ ID NO:25, SEQ ID NO:11/SEQ ID NO:27, SEQ ID NO:11/SEQ ID NO:29, SEQ ID NO:31/SEQ ID NO:33, SEQ ID NO:35/SEQ ID NO:37, SEQ ID NO:39/SEQ ID NO:41, SEQ ID NO:43/SEQ ID NO:45, SEQ ID NO:47/SEQ ID NO:49, SEQ ID NO:51/SEQ ID NO:53 and SEQ ID NO:55/SEQ ID NO:57 or antibody fragment thereof, wherein said antibody or antibody fragment thereof does not interact with a peptide having an amino acid sequence of SEQ ID NO:1.    
     
     
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         40 . An isolated antibody capable of binding a human erythropoietin receptor in a mammal, said antibody comprising a heavy chain variable region comprising a continuous sequence from CDR1 through CDR3 having the amino acid sequence selected from the group consisting of: SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:60, and SEQ ID NO:61 and fragments thereof.  
     
     
         41 . An isolated antibody capable of binding a human erythropoietin receptor in a mammal, said antibody comprising a light chain variable region comprising a continuous sequence from CDR1 through CDR3 having the amino acid sequence selected from the group consisting of: SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65, SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:74, SEQ ID NO:75, SEQ ID NO:76, SEQ ID NO:77, SEQ ID NO:78 and fragments thereof.  
     
     
         42 . A method of activating an endogenous activity of a human erythropoietin receptor in a mammal, the method comprising the step of administering to said mammal a therapeutically effective amount of an antibody or antibody fragment thereof to activate said receptor, wherein said antibody or antibody fragment thereof does not interact with a peptide having an amino acid sequence of SEQ ID NO:1.  
     
     
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         44 . A method of treating a mammal suffering aplasia, the method comprising the step of administering to a mammal in need of treatment a therapeutically effective amount of an antibody or antibody fragment thereof to activate said receptor, wherein said antibody or antibody fragment thereof does not interact with a peptide having an amino acid sequence of SEQ ID NO:1.  
     
     
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         46 . A pharmaceutical composition comprising a therapeutically effective amount of an antibody or antibody fragment thereof and a pharmaceutically acceptable excipient, wherein said antibody or antibody fragment thereof does not interact with a peptide having an amino acid sequence of SEQ ID NO:1.  
     
     
         47 . An isolated and purified polynucleotide sequence selected from the group consisting of: SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:10, SEQ ID NO:12, SEQ ID NO:14, SEQ ID NO:16, SEQ ID NO:18, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:34, SEQ ID NO:36, SEQ ID NO:38, SEQ ID NO:40, SEQ ID NO:42, SEQ ID NO:44, SEQ ID NO:46, SEQ ID NO:48, SEQ ID NO:50, SEQ ID NO:52, SEQ ID NO:54, SEQ ID NO:56, fragments, complements, and degenerate codon equivalents thereof.  
     
     
         48 . An isolated and purified amino acid sequence selected from the group consisting of: SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:9, SEQ ID NO:11, SEQ ID NO:13, SEQ ID NO:15, SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:21, SEQ ID NO:23, SEQ ID NO:25, SEQ ID NO:27, SEQ ID NO:29, SEQ ID NO:31, SEQ ID NO:33, SEQ ID NO:35, SEQ ID NO:37, SEQ ID NO:39, SEQ ID NO:41, SEQ ID NO:43, SEQ ID NO:45, SEQ ID NO:47, SEQ ID NO:49, SEQ ID NO:51, SEQ ID NO:53, SEQ ID NO:55, SEQ ID NO:57, SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:60, SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65, SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68 and fragments thereof.  
     
     
         49 . An antibody or antibody fragment thereof that activates an endogenous activity of a human erythropoietin receptor in a mammal wherein said antibody or antibody fragment is a gamma-2 isotype.  
     
     
         50 . The antibody or antibody fragment of  claim 49  wherein said antibody or antibody fragment is a monoclonal antibody.  
     
     
         51 . The antibody or antibody fragment of  claim 50  wherein said antibody or antibody fragment is a humanized antibody.  
     
     
         52 . The antibody or antibody fragment of  claim 50  wherein said antibody or antibody fragment is a human antibody.  
     
     
         53 . The antibody or antibody fragment of  claim 50  wherein said antibody or antibody fragment does not interact with a peptide having an amino acid sequence of SEQ ID NO:1.  
     
     
         54 . The antibody or antibody fragment of  claim 50  wherein said antibody or antibody fragment is selected from the group consisting of Ab3, Ab12, Ab22, Ab54, Ab60, Ab102, Ab135, Ab145, Ab198, Ab254, Ab267, Ab390, Ab412, Ab430/432, Ab467 and Ab484.  
     
     
         55 . A method of activating an endogenous activity of a human erythropoietin receptor in a mammal, the method comprising the step of administering to a mammal a therapeutically effective amount of the antibody or antibody fragment of  claim 49  to activate said receptor.  
     
     
         56 . A method of modulating an endogenous activity of a human erythropoietin receptor in a mammal, the method comprising the step of administering to a mammal a therapeutically effective amount of the antibody or antibody fragment of  claim 49  to modulate the activity of the receptor.  
     
     
         57 . A method of treating a mammal suffering aplasia, the method comprising the step of administering to a mammal in need of treatment a therapeutically effective amount of the antibody or antibody fragment of  claim 49  to activate the receptor.  
     
     
         58 . A method of treating a mammal suffering aplasia, the method comprising the step of administering to a mammal in need of treatment a therapeutically effective amount of the antibody or antibody fragment of  claim 49  to modulate the activity of the receptor.  
     
     
         59 . A method of treating a mammal suffering anemia, the method comprising the steps of administering to a mammal in need of treatment a therapeutically effective amount of the antibody or antibody fragment of  claim 49  to modulate the activity of the receptor.  
     
     
         60 . A pharmaceutical composition comprising a therapeutically effective amount of the antibody or antibody fragment of  claim 49  and a pharmaceutically acceptable excipient.