Afucosylated anti-fgfr2iiib antibodies

Abstract

The present invention provides antibodies that bind FGFR2IIIb, wherein the antibodies are afucosylated. The present invention provides compositions comprising antibodies that bind FGFR2IIIb, wherein at least 95% of the antibodies in the composition are afucosylated. In some embodiments, methods of treating cancer comprising administering afucosylated anti-FGFR2IIIb antibodies are provided.

1 . A composition comprising a plurality of anti-FGFR2IIIb antibodies, wherein each anti-FGFR2IIIb antibody comprises heavy chain and light chain variable regions, wherein the heavy chain variable region comprises:
 (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 6;   (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 7; and   (iii) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 8;   and the light chain variable region comprises:   (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 9;   (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 10; and   (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 11;   wherein at least 95% of the anti-FGFR2IIIb antibodies in the composition are afucosylated.   
     
     
         2 . (canceled) 
     
     
         3 . (canceled) 
     
     
         4 . The composition of  claim 1 , wherein the heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 4 and the light chain variable domain comprises the amino acid sequence of SEQ ID NO: 5. 
     
     
         5 . (canceled) 
     
     
         6 . (canceled) 
     
     
         7 . The composition of  claim 1 , wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 2 and the light chain comprises the amino acid sequence of SEQ ID NO: 3. 
     
     
         8 . A composition comprising a plurality of afucosylated anti-FGFR2IIIb antibodies, wherein the anti-FGFR2IIIb antibodies compete for binding to FGFR2IIIb with an antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 4 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 5. 
     
     
         9 . The composition of  claim 1 , wherein the antibodies are monoclonal antibodies. 
     
     
         10 . The composition of  claim 1 , wherein the antibodies are chimeric antibodies or humanized antibodies. 
     
     
         11 . (canceled) 
     
     
         12 . The composition of  claim 1 , wherein the antibodies lack fucose at Asn297. 
     
     
         13 . The composition of  claim 1 , wherein the antibodies comprise a κ light chain constant region, an IgG1 heavy chain constant region, or a κ light chain constant region and an IgG1 heavy chain constant region. 
     
     
         14 . (canceled) 
     
     
         15 . The composition of  claim 1 , wherein the afucosylated antibodies have enhanced ADCC activity in vitro compared to a fucosylated anti-FGFR2IIIb antibody having the same amino acid sequence. 
     
     
         16 . The composition of  claim 15 , wherein the afucosylated anti-FGFR2IIIb antibodies cause specific lysis that is at least 30 percentage points greater than specific lysis with the fucosylated anti-FGFR2IIIb antibody. 
     
     
         17 . The composition of  claim 16 , wherein ADCC activity is determined using Ba/F3 cells expressing FGFR2IIIb as target cells and isolated human PBMCs as effector cells. 
     
     
         18 . The composition of  claim 1 , wherein the afucosylated antibodies have enhanced affinity for Fc gamma RIIIA compared to a fucosylated anti-FGFR2IIIb antibody having the same amino acid sequence. 
     
     
         19 . The composition of  claim 18 , wherein the afucosylated anti-FGFR2IIIb antibodies bind to Fc gamma RIIIA with at least 3-fold greater affinity than the fucosylated anti-FGFR2IIIb antibody. 
     
     
         20 . The composition of  claim 19 , wherein affinity for Fc gamma RIIIA is determined using surface plasmon resonance. 
     
     
         21 . The composition of  claim 20 , wherein Fc gamma RIIIA is selected from Fc gamma RIIIA(V158) and Fc gamma RIIIA(F158). 
     
     
         22 . (canceled) 
     
     
         23 . The composition of  claim 1 , wherein the afucosylated anti-FGFR2IIIb antibodies bind FGFR2IIIb but do not bind to FGFR2IIIc. 
     
     
         24 . A host cell comprising nucleic acid encoding the anti-FGFR2IIIb antibody of  claim 1 , wherein the host cell lacks a functional alpha-1,6-fucosyltransferase gene (FUT8) gene. 
     
     
         25 . (canceled) 
     
     
         26 . (canceled) 
     
     
         27 . A method for making afucosylated anti-FGFR2IIIb antibodies, comprising culturing the host cell of  claim 24  under conditions suitable for producing afucosylated anti-FGFR2IIIb antibodies. 
     
     
         28 . (canceled) 
     
     
         29 . (canceled) 
     
     
         30 . (canceled) 
     
     
         31 . (canceled) 
     
     
         32 . A pharmaceutical composition comprising the composition of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         33 . A method of treating cancer in an individual comprising administering to an individual with cancer an effective amount of a pharmaceutical composition of  claim 32 . 
     
     
         34 - 57 . (canceled)