Anti-fgfr3 antibodies and methods using same

Abstract

The invention provides FGFR3 antibodies, and compositions comprising and methods of using these antibodies.

1 . An isolated anti-FGFR3 antagonist antibody, where the antibody binds human FGFR3 with a Kd of 1×10 −8  or stronger, wherein the antibody binds a polypeptide consisting essentially of amino acid sequence LAVPAANTVRFRCPA (SEQ ID NO: 179) or SDVEFHCKVYSDAQP (SEQ ID NO:180), and wherein the antibody inhibits dimerization of FGFR3 receptor with another unit of the receptor, whereby activation of the receptor is inhibited. 
     
     
         2 . The anti-FGFR3 antagonist antibody of  claim 1 , wherein the antibody binds FGFR3-IIIb and FGFR3-IIIc. 
     
     
         3 . The anti-FGFR3 antagonist antibody of  claim 1 , wherein a bivalent form of the antibody does not possess substantial agonist function. 
     
     
         4 - 9 . (canceled) 
     
     
         10 . The anti-FGFR3 antagonist antibody of  claim 1 , wherein the antibody does not induce substantial FGFR3 down-regulation. 
     
     
         12 - 13 . (canceled) 
     
     
         14 . The anti-FGFR3 antagonist antibody of  claim 1 , wherein the antibody inhibits constitutive FGFR3 activity. 
     
     
         15 . The anti-FGFR3 antagonist antibody of  claim 14 , wherein constitutive FGFR3 activity is ligand-dependent constitutive FGFR3 activity. 
     
     
         16 . The anti-FGFR3 antagonist antibody of  claim 14 , wherein constitutive FGFR3 activity is ligand-independent constitutive FGFR3 activity. 
     
     
         17 . The anti-FGFR3 antagonist antibody of  claim 1 , wherein the anti-FGFR3 antibody inhibits FGFR3 comprising one or more mutations, wherein the mutation corresponds to FGFR3-IIIb R248C , FGFR3-IIIb K652E , FGFR3-IIIb S249C , FGFR3-IIIb G372C , and FGFR3-IIIb Y375C . 
     
     
         18 - 31 . (canceled) 
     
     
         32 . The anti-FGFR3 antagonist antibody of  claim 1 , wherein at least a portion of the framework sequence is a human consensus framework sequence. 
     
     
         33 . The anti-FGFR3 antagonist antibody of  claim 1 , wherein the antibody comprises human κ subgroup consensus framework sequence. 
     
     
         34 . The anti-FGFR3 antagonist antibody of  claim 1 , wherein the antibody comprises heavy chain human subgroup III consensus framework sequence. 
     
     
         35 . The anti-FGFR3 antagonist antibody of  claim 1 , wherein the antibody is a monoclonal antibody. 
     
     
         36 . The anti-FGFR3 antagonist antibody of  claim 1 , wherein the antibody is selected from the group consisting of a chimeric antibody, a humanized antibody, an affinity matured antibody, a human antibody, and a bispecific antibody. 
     
     
         37 . The anti-FGFR3 antagonist antibody of  claim 1 , wherein the antibody is an antibody fragment. 
     
     
         38 - 59 . (canceled) 
     
     
         60 . An isolated anti-FGFR3 antagonist antibody, where the antibody binds human FGFR3 with a Kd of 1×10 −8  or stronger, wherein the antibody binds to an epitope, wherein the epitope comprises residues 158, 170, 171, 173, 175, and 315 of FGFR3 IIIb polypeptide, and wherein the antibody inhibits dimerization of FGFR3 receptor with another unit of the receptor, whereby activation of the receptor is inhibited. 
     
     
         61 . The anti-FGFR3 antagonist antibody of  claim 60 , wherein the epitope comprises residues 158, 159, 159, 169, 170, 171, 173, 175, 205, 207, and 315 of FGFR3 IIIb. 
     
     
         62 . The anti-FGFR3 antagonist antibody of  claim 60 , wherein the epitope comprises residues 154, 155, 158, 159, 161, 162, 163, 164, 175, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 177, 202, 205, 207, 210, 212, 214, 216, 217, 241, 246, 247, 248, 278, 279, 280, 281, 282, 283, 314, 315, 316, 317 and 318 of FGFR3 IIIb. 
     
     
         63 . The anti-FGFR3 antagonist antibody of  claim 60 , wherein the antibody binds FGFR3-IIIb and FGFR3-IIIc. 
     
     
         64 . The anti-FGFR3 antagonist antibody of  claim 60 , wherein a bivalent form of the antibody does not possess substantial agonist function. 
     
     
         65 . The anti-FGFR3 antagonist antibody of  claim 60 , wherein the antibody does not induce substantial FGFR3 down-regulation. 
     
     
         66 . The anti-FGFR3 antagonist antibody of  claim 60 , wherein the antibody inhibits constitutive FGFR3 activity. 
     
     
         67 . The anti-FGFR3 antagonist antibody of  claim 66 , wherein constitutive FGFR3 activity is ligand-dependent constitutive FGFR3 activity. 
     
     
         68 . The anti-FGFR3 antagonist antibody of  claim 66 , wherein constitutive FGFR3 activity is ligand-independent constitutive FGFR3 activity. 
     
     
         69 . The anti-FGFR3 antagonist antibody of  claim 60 , wherein the anti-FGFR3 antibody inhibits FGFR3 comprising one or more mutations, wherein the mutation corresponds to FGFR3-IIIb R248C , FGFR3-IIIb K652E , FGFR3-IIIb S249C , FGFR3-IIIb G372C , and FGFR3-IIIb Y375C . 
     
     
         70 . The anti-FGFR3 antagonist antibody of  claim 60 , wherein at least a portion of the framework sequence is a human consensus framework sequence. 
     
     
         71 . The anti-FGFR3 antagonist antibody of  claim 60 , wherein the antibody comprises human κ subgroup consensus framework sequence. 
     
     
         72 . The anti-FGFR3 antagonist antibody of  claim 60 , wherein the antibody comprises heavy chain human subgroup III consensus framework sequence. 
     
     
         73 . The anti-FGFR3 antagonist antibody of  claim 60 , wherein the antibody is a monoclonal antibody. 
     
     
         74 . The anti-FGFR3 antagonist antibody of  claim 60 , wherein the antibody is selected from the group consisting of a chimeric antibody, a humanized antibody, an affinity matured antibody, a human antibody, and a bispecific antibody. 
     
     
         75 . The anti-FGFR3 antagonist antibody of  claim 60 , wherein the antibody is an antibody fragment.