Anti-flt3 antibodies

Abstract

The present invention provides fully human antibodies that specifically bind to human FLT3 within extracellular domains 4 or 5 with high affinity. The invention further provides methods of treating leukemia by administering an effective amount of an antibody either alone or in combination with an anti-cancer agent or treatment including methotrexate.

1 . An antibody that specifically binds human FLT3 (SEQ ID NO. 43) or a FLT3-binding fragment of the antibody, comprising a CDRH1 having the sequence SYYMH (SEQ ID NO:2), a CDRH2 having the sequence IINPSGGSTSYAQKFQG (SEQ ID NO:3), a CDRH3 having the sequence GVGAHDAFDI (SEQ ID NO:4) or VVAAAVADY (SEQ ID NO:5), a CDRL1 having the sequence RSSQSLLHSNGNNYLD (SEQ ID NO:6) or RSSQSLLHSNGYNYLD (SEQ ID NO:7), a CDRL2 having the sequence LGSNRAS (SEQ ID NO:8), and a CDRL3 having the sequence MQGTHPAIS (SEQ ID NO:9) or MQSLQTPFT (SEQ ID NO:11). 
     
     
         2 . The antibody or fragment of  claim 1  comprising a CDRH1 having the sequence SYYMH (SEQ ID NO:2), a CDRH2 having the sequence IINPSGGSTSYAQKFQG (SEQ ID NO:3), a CDRH3 having the sequence GVGAHDAFDI (SEQ ID NO:4), a CDRL1 having the sequence RSSQSLLHSNGNNYLD (SEQ ID NO:6), a CDRL2 having the sequence LGSNRAS (SEQ ID NO:8), and a CDRL3 having the sequence MQGTHPAIS (SEQ ID NO:9). 
     
     
         3 . The antibody or fragment of  claim 2 , comprising a VL comprising the amino acid sequence:
 DVVMTQSPLSLPVTPGEPASISCRSSQSLLHSNGNNYLDWYLQKPGQSPQLLIYLG SNRASGVPDRFSGSGSDTDFTLQISRVEAEDVGVYYCMQGTHPAISFGQGTRLEI K (SEQ ID NO:22), and a VH comprising the amino acid sequence:   
       
         
           
                 
               
                   (SEQ ID NO: 19) 
                 
                 
               
                   EVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMHWVRQAPGQGLEWM 
                 
                     
                 
                   GIINPSGGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYC 
                 
                     
                 
                   ARGVGAHDAFDIWGQGTTVTVSS. 
                 
             
                
               
            
             
                
                
                
                
                
               
            
           
         
       
     
     
         4 . The antibody of  claim 3 , comprising a light chain of SEQ ID NO: 28, and a heavy chain of SEQ ID NO: 25, or a FLT3-binding fragment of the antibody. 
     
     
         5 . The antibody of  claim 4 , comprising two light chains of SEQ ID NO: 28 and two heavy chains of SEQ ID NO: 25, or a FLT3-binding fragment of the antibody. 
     
     
         6 . The antibody or fragment of  claim 1 , comprising a CDRH1 having the sequence SYYMH (SEQ ID NO:2), a CDRH2 having the sequence IINPSGGSTSYAQKFQG (SEQ ID NO:3), a CDRH3 having the sequence VVAAAVADY (SEQ ID NO:5), a CDRL1 having the sequence RSSQSLLHSNGYNYLD (SEQ ID NO:7), a CDRL2 having the sequence LGSNRAS (SEQ ID NO:8), and a CDRL3 having the sequence MQSLQTPFT (SEQ ID NO:11). 
     
     
         7 . The antibody or fragment of  claim 6 , comprising a VL comprising the amino acid sequence:
 DVVMTQSPLSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSPQLLIYLG SNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQSLQTPFTFGPGTKVDI K (SEQ ID NO:24), and a VH comprising the amino acid sequence:   
       
         
           
                 
               
                   (SEQ ID NO: 21) 
                 
                 
               
                   EVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMHWARQAPGQGLEWM 
                 
                     
                 
                   GIINPSGGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYC 
                 
                     
                 
                   ARVVAAAVADYWGQGTLVTVSS. 
                 
             
                
               
            
             
                
                
                
                
                
               
            
           
         
       
     
     
         8 . The antibody of  claim 7 , comprising a light chain of SEQ ID NO: 30, and a heavy chain of SEQ ID NO: 27, or a FLT3-binding fragment of the antibody. 
     
     
         9 . The antibody of  claim 8 , comprising two light chains of SEQ ID NO:30 and two heavy chains of SEQ ID NO: 27, or a FLT3-binding fragment of the antibody. 
     
     
         10 . An antibody that specifically binds human FLT3 (SEQ ID NO:43) or a FLT3-binding fragment of the antibody, comprising a CDRH1 having the sequence SYAIS (SEQ ID NO:13), a CDRH2 having the sequence GIIPIFGTANYAQKFQG (SEQ ID NO:14), a CDRH3 having the sequence FALFGFREQAFDI (SEQ ID NO:15), a CDRL1 having the sequence RASQSISSYLN (SEQ ID NO:16), a CDRL2 having the sequence AASSLQS (SEQ ID NO:17), and a CDRL3 having the sequence QQSYSTPFT (SEQ ID NO:18). 
     
     
         11 . The antibody or fragment of  claim 10 , comprising a VL comprising the amino acid sequence:
 DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQS GVPSRFSGSGSGTDFTLTISSLQPEDLATYYCQQSYSTPFTFGPGTKVDIK (SEQ ID NO:23), and a VH comprising the amino acid sequence:   
       
         
           
                 
               
                   (SEQ ID NO: 20) 
                 
                 
               
                   EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWM 
                 
                     
                 
                   GGIIPIFGTANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYC 
                 
                     
                 
                   ATFALFGFREQAFDIWGQGTTVTVSS. 
                 
             
                
               
            
             
                
                
                
                
                
               
            
           
         
       
     
     
         12 . The antibody of  claim 11 , comprising a light chain of SEQ ID NO: 29, and a heavy chain of SEQ ID NO: 26, or a FLT3-binding fragment of the antibody. 
     
     
         13 . The antibody of  claim 12 , comprising two light chains of SEQ ID NO: 29 and two heavy chains of SEQ ID NO: 26, or a FLT3-binding fragment of the antibody. 
     
     
         14 . An isolated polynucleotide comprising a sequence encoding a light chain of SEQ ID NO: 28 or a heavy chain of SEQ ID NO: 25. 
     
     
         15 . An expression vector comprising the polynucleotide of  claim 14  operably linked to expression control elements such that an antibody comprising a light chain of SEQ ID NO: 28, and a heavy chain of SEQ ID NO: 25 may be expressed. 
     
     
         16 . A recombinant mammalian cell comprising the expression vector of  claim 15 , which recombinant cell is capable of producing an antibody comprising a light chain of SEQ ID NO: 28, and a heavy chain of SEQ ID NO: 25. 
     
     
         17 . A process for producing an antibody comprising a light chain of SEQ ID NO: 28, and a heavy chain of SEQ ID NO: 25, comprising culturing the cell of  claim 16  under conditions such that the antibody is expressed, and isolating the antibody. 
     
     
         18 . An antibody or fragment produced by the process of  claim 17 . 
     
     
         19 . A pharmaceutical composition comprising the antibody of  claim 18  and a pharmaceutically acceptable carrier, diluent or excipient. 
     
     
         20 . A pharmaceutical composition comprising the antibody of  claim 4  and a pharmaceutically acceptable carrier, diluent or excipient. 
     
     
         21 . A method of treating cancer in a patient comprising administering to the patient an effective amount of the antibody or fragment of  claim 4 . 
     
     
         22 . The method of  claim 21 , wherein the cancer is leukemia. 
     
     
         23 . The method of  claim 21 , further comprising administering an effective amount of another anti-neoplastic agent or providing another anti-neoplastic treatment to the patient. 
     
     
         24 . The method of  claim 23 , wherein the anti-neoplastic treatment comprises administering an effective amount of methotrexate.