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: 
       
         
           
                 
               
                   (SEQ ID NO: 22) 
                 
                   DVVMTQSPLSLPVTPGEPASISCRSSQSLLHSNGNNYLDWYLQKPGQSPQ 
                 
                     
                 
                   LLIYLGSNRASGVPDRFSGSGSDTDFTLQISRVEAEDVGVYYCMQGTHPA 
                 
                     
                 
                   ISFGQGTRLEIK, 
                 
             
                
                
                
                
                
                
               
            
           
         
       
       and a VH comprising the amino acid sequence: 
       
         
           
                 
               
                   (SEQ ID NO: 19) 
                 
                   EVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMHWVRQAPGQGLEWMGI 
                 
                     
                 
                   INPSGGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARGV 
                 
                     
                 
                   GAHDAFDIWGQGTTVTVSS. 
                 
             
                
                
                
                
                
                
               
            
           
         
       
     
     
         4 . The antibody or fragment of  claim 3 , comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:25 and a light chain comprising the amino acid sequence of SEQ ID NO:28. 
     
     
         5 . The antibody or fragment of  claim 4  comprising two heavy chains, each comprising the amino acid sequence of SEQ ID NO:25 and two light chains, each comprising the amino acid sequence of SEQ ID NO:28. 
     
     
         6 . The antibody or fragment of  claim 18 , comprising a VL comprising the amino acid sequence: 
       
         
           
                 
               
                   (SEQ ID NO: 24) 
                 
                   DVVMTQSPLSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSPQ 
                 
                     
                 
                   LLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQSLQTP 
                 
                     
                 
                   FTFGPGTKVDIK, 
                 
             
                
                
                
                
                
                
               
            
           
         
       
       and a VH comprising the amino acid sequence: 
       
         
           
                 
               
                   (SEQ ID NO: 21) 
                 
                   EVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMHWARQAPGQGLEWMGI 
                 
                     
                 
                   INPSGGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARVV 
                 
                     
                 
                   AAAVADYWGQGTLVTVSS. 
                 
             
                
                
                
                
                
                
               
            
           
         
       
     
     
         7 .- 11 . (canceled) 
     
     
         12 . A pharmaceutical composition comprising an antibody or fragment of  claim 4  together with a pharmaceutically acceptable carrier, diluent or excipient. 
     
     
         13 .- 17 . (canceled) 
     
     
         18 . 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). 
     
     
         19 . The antibody or fragment of  claim 6 , comprising a light chain comprising the amino acid sequence of SEQ ID NO: 30, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 27. 
     
     
         20 . The antibody or fragment of  claim 19 , comprising two light chains, each comprising the amino acid sequence of SEQ ID NO:30 and two heavy chains, each comprising the amino acid sequence of SEQ ID NO: 27. 
     
     
         21 . 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). 
     
     
         22 . The antibody or fragment of  claim 21 , comprising a VL comprising the amino acid sequence: 
       
         
           
                 
               
                   (SEQ ID NO: 23) 
                 
                   DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYA 
                 
                     
                 
                   ASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDLATYYCQQSYSTPFTFGP 
                 
                     
                 
                   GTKVDIK, 
                 
             
                
                
                
                
                
                
               
            
           
         
       
       and a VH comprising the amino acid sequence: 
       
         
           
                 
               
                   (SEQ ID NO: 20) 
                 
                   EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGG 
                 
                     
                 
                   IIPIFGTANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCATFA 
                 
                     
                 
                   LFGFREQAFDIWGQGTTVTVSS. 
                 
             
                
                
                
                
                
                
               
            
           
         
       
     
     
         23 . The antibody or fragment of  claim 22 , comprising a light chain comprising the amino acid sequence of SEQ ID NO: 29, and a heavy chain comprising the amino acid sequence of SEQ ID NO: 26. 
     
     
         24 . The antibody or fragment of  claim 23 , comprising two light chains, each comprising the amino acid sequence of SEQ ID NO: 29 and two heavy chains, each comprising the amino acid sequence of SEQ ID NO: 26. 
     
     
         25 . A method of treating cancer in a patient comprising administering to the patient an effective amount of the antibody or fragment of  claim 4 . 
     
     
         26 . The method of  claim 26 , wherein the cancer is leukemia. 
     
     
         27 . The method of  claim 26 , further comprising administering an effective amount of another anti-neoplastic agent or providing another anti-neoplastic treatment to the patient. 
     
     
         28 . The method of  claim 27 , wherein the anti-neoplastic treatment is methotrexate. 
     
     
         29 . An antibody of  claim 4  chemically or biosynthetically linked to an anti-neoplastic agent, an anti-angiogenic agent or a detectable signal-producing agent. 
     
     
         30 . An antibody of  claim 4  conjugated to an anti-tumor agent, wherein said agent can destroy or damage a tumor to which the antibody has bound or which is in the environment of the cell to which the antibody has bound.