Humanized axl antibodies

Abstract

The present invention refers to monoclonal humanized antibodies, which bind to the extracellular domain of the AXL receptor tyrosine kinase and which at least partially inhibit AXL activity.

1 . A monoclonal humanized antibody that binds to the extracellular domain of AXL and at least partially inhibits AXL activity, comprising a heavy chain amino acid sequence selected from the group consisting of SEQ ID NO:40 to SEQ ID NO:48, or at least the variable domain thereof, or an amino acid sequence having a sequence identity of at least 90% thereto,
 or a variable domain of a heavy chain amino acid sequence selected from the group consisting of SEQ ID NO:80 to SEQ ID NO:82, or an amino acid sequence having a sequence identity of at least 90% thereto and/or a light chain amino acid sequence selected from the group consisting of SEQ ID NO: 18 to SEQ ID NO:30, or at least the variable domain thereof or an amino acid sequence having a sequence identity of at least 90% thereto,   or a variable domain of a light chain amino acid sequence selected from the group consisting of SEQ ID NO: 73 to SEQ ID NO:79, or an amino acid sequence having a sequence identity of at least 90% thereto,   or a fragment thereof recognizing the same epitope on the extracellular domain of AXL.   
     
     
         2 . The monoclonal humanized antibody of  claim 1 , selected from the group of humanized h#11B7 antibodies selected from the group consisting of h#11B7-T1, h#11B7-T2, h#11B7-T3, h#11B7-T4, h#11B7-T5, h#11B7-T6, h#11B7-T7, h#11B7-T8, h#11B7-T9, h#11B7-T10, h#11B7-T11, h#11B7-T12, h#11B7-T13, h#11B7-T14, h#11B7-T15, h#11B7-T16, h#11B7-T17, h#11B7-T18, h#11B7-T19, h#11B7-T20, h#11B7-T21, h#11B7-T22, h#11B7-T23, h#11B7-T24, h#11B7-T25, h#11B7-T26, h#11B7-T27 or h#11B7-T28. 
     
     
         3 . The monoclonal humanized antibody according to  claim 1 , which is coupled to a labeling group. 
     
     
         4 . The monoclonal humanized antibody according to  claim 1 , which is coupled to an effector-group. 
     
     
         5 . An isolated nucleic acid molecule selected from the group consisting of:
 (a) a nucleic acid sequence encoding an monoclonal antibody, antibody fragment or a derivative thereof of  claim 1 ,   (b) a nucleic acid sequence as shown in one of the SEQ ID NOs. selected from the group consisting of SEQ ID NO:5 to SEQ ID NO:17, SEQ ID NO:31 to SEQ ID NO:39, SEQ ID NO:49 to SEQ ID NO: 54 and SEQ ID NO:61 to SEQ ID NO:66   (c) a nucleic acid sequence encoding a polypeptide selected from the group consisting of SEQ ID NO:18 to SEQ ID NO:30, SEQ ID NO:40 to SEQ ID NO:48, SEQ ID NO:55 to SEQ ID NO:60, SEQ ID NO:66 to SEQ ID NO:73, SEQ ID NO:73 to SEQ ID NO:120 and SEQ ID NO:121 to SEQ ID NO:132.   (d) a nucleic acid complementary to any of the sequences in (a) to (c), or   (e) a nucleic acid sequence capable of hybridizing to (a), (b), (c) or (d) under stringent conditions and encoding a polypeptide, wherein an antibody or functional fragment thereof comprising said polypeptide binds to the extracellular domain of AXL.   
     
     
         6 . A vector comprising a nucleic acid sequence of  claim 5 . 
     
     
         7 . The vector according to  claim 6 , which is an expression vector and the nucleic acid sequence is operably linked to a control sequence. 
     
     
         8 . A host comprising the vector of  claim 6 . 
     
     
         9 . The host of  claim 8  which is a human, bacteria, animal, fungal, amphibian or plant cell. 
     
     
         10 . The host of  claim 8  which is a non-human transgenic animal. 
     
     
         11 . A pharmaceutical composition comprising a humanized anti-AXL-antibody, the nucleic acid molecule of  claim 5 , the vector of  claim 6 , the host of  claim 8 , or a polypeptide obtained from the host of  claim 8 , in combination with a further active agent 
     
     
         12 . A process of manufacturing a monoclonal humanized antibody according to  claim 1 , comprising the step of obtaining said polypeptide from the host of  claim 14 . 
     
     
         13 . A method for diagnosing a condition associated with the expression of AXL, comprising contacting a sample with a monoclonal humanized antibody according to  claim 1 , and detecting the presence of AXL. 
     
     
         14 . The method according to  claim 13 , wherein the condition is a hyperproliferative disease associated with AXL expression, overexpression and/or hyperactivity. 
     
     
         15 . A method for preventing or treating a condition associated with the expression of AXL in a patient, comprising administering to a patient in need thereof an effective amount of at least the monoclonal humanized antibody according to  claim 1 . 
     
     
         16 . The method according to  claim 15 , wherein the condition is a hyperproliferative disease associated with AXL expression, overexpression and/or hyperactivity. 
     
     
         17 . The method according to  claim 15 , wherein the patient is a mammalian patient. 
     
     
         18 . A method for treating drug resistant cancer, comprising administering to a patient in need thereof an effective amount of the monoclonal humanized antibody according to  claim 1 . 
     
     
         19 . A method for the treatment of a hyperproliferative disease, comprising administering to a patient in need thereof an effective amount of the monoclonal humanized antibody according to  claim 1  in combination with an antineoplastic agent.