Humanized anti-factor d antibodies and uses thereof

Abstract

The invention relates to humanized anti-human Factor D monoclonal antibodies, their nucleic acid and amino acid sequences, the cells and vectors that harbor these antibodies and their use in the preparation of compositions and medicaments for treatment of diseases and disorders associated with excessive or uncontrolled complement activation. These antibodies are useful for diagnostics, prophylaxis and treatment of disease.

1 . A murine antibody comprising: (a) a heavy chain variable domain sequence of SEQ ID NO: 1; (b) a light chain variable domain sequence of SEQ ID NO: 2; or (c) a heavy chain variable domain sequence of SEQ ID NO: 1 and a light chain variable domain sequence of SEQ ID NO: 2. 
     
     
         2 .- 3 . (canceled) 
     
     
         4 . An antibody comprising SEQ ID NO: 13, 14, 15, 16, 17, and 18. 
     
     
         5 . A chimeric antibody comprising SEQ ID NO: 1 and SEQ ID NO: 2. 
     
     
         6 . A variable domain of a humanized antibody comprising a heavy chain variable domain amino acid sequence selected from the group consisting of: SEQ ID NO: 6; SEQ ID NO: 8; SEQ ID NO: 10; and SEQ ID NO: 12. 
     
     
         7 . A variable domain of a humanized antibody comprising a light chain variable domain amino acid sequence selected from the group consisting of SEQ ID NO: 5; SEQ ID NO: 7; SEQ ID NO: 9; and SEQ ID NO: 11. 
     
     
         8 . A humanized anti-Factor D antibody comprising: (a) the variable domain sequence of SEQ ID NO: 5 and the variable domain sequence in SEQ ID NO: 6; (b) the variable domain sequence of SEQ ID NO: 7 and the variable domain sequence in SEQ ID NO: 8; (c) the variable domain sequence of SEQ ID NO: 9 and the variable domain sequence in SEQ ID NO: 10; or (d) the variable domain sequence of SEQ ID NO: 11 and the variable domain sequence in SEQ ID NO: 12. 
     
     
         9 .- 11 . (canceled) 
     
     
         12 . A humanized anti-Factor D antibody having a variable light chain comprising a CDR-L1 having the sequence of SEQ ID NO: 16; a CDR-L2 having the sequence of SEQ ID NO: 17, 21, or 24, and a CDR-L3 having the sequence of SEQ ID NO: 18, 19, or 22. 
     
     
         13 . A humanized anti-Factor D antibody having a variable heavy chain comprising a CDR-H1 having the sequence of SEQ ID NO: 13 or 25; a CDR-H2 having the sequence of SEQ ID NO: 14; and a CDR-H3 having the sequence of SEQ ID NO: 15 or 20. 
     
     
         14 . A polypeptide comprising the following amino acid sequence: 
       QX 1 QLVQSGX 2 E LKKPGASVKV SCKASGYTFT SYGMNWVX 3 QA PGQGLEWMGW INTYTGETTYADDFKGRFVF SLDTSVSTAY LQISSLKAED TAX 4 YYCX 5 REG GVNNWGQGTL VTVSS (SEQ ID NO: 27), 
       wherein X 1  is I or V; X 2  is P or S; X 3  is K or R; X 4  is T or V; and X 5  is E or A. 
     
     
         15 . A polypeptide comprising the following amino acid sequence: 
       DIQX 6 TQSPSSLSX 7 SVGDRVTITCITSTDIDDDMNWYQQKPGKX 8 PKLLIX 9 DGNTLRPG VPSRFSX 10 GSGX 11 DFTLTISSLQPEDVATYYCLQSDSLPYTFGQ GTKLEIK (SEQ ID NO: 26), 
       wherein X 6  is V or M; X 7  is M or A; X 8  is P or V; X 9  is S or Y; X 10  is S or G; and X 11  is A or T. 
     
     
         16 . A polypeptide comprising the amino acid sequence of any one of SEQ ID NOS: 5-12. 
     
     
         17 . (canceled) 
     
     
         18 . A humanized antibody comprising the polypeptide of  claim 14 . 
     
     
         19 . The humanized antibody of  claim 18  further comprising:
 (a) a polypeptide comprising the following amino acid sequence: 
 
       DIQX 6 TQSPSSLSX 7 SVGDRVTITCITSTDIDDDMNWYQQKPGKX 8 PKLLIX 9 DGNTLRPG VPSRFSX 10 SGSGX 11 DFTLTISSLQPEDVATYYCLQSDSLPYTFGQ GTKLEIK (SEQ ID NO: 26), wherein X 6  is V or M; X 7  is M or A; X 8  is P or V; X 9  is S or Y; X 10  is S or G; and X 11  is A or T; or
 (b) a polypeptide comprising the following amino acid sequence: 
 
       DIQX 6 TQSPSSLSX 7 SVGDRVTITCITSTDIDDDMNWYQQKPGKX 8 PKLLIX 9 DGNTLRPG VPSRFSX 10 SGSGX 11 DFTLTISSLQPEDVATYYCLQSDSLPYTFGQ GTKLEIK (SEQ ID NO: 26), wherein X 6  is V or M; X 7  is M or A; X 8  is P or V; X 9  is S or Y; X 10  is S or G; X 11  is A or T; and the amino acid at position 104 of SEQ ID NO: 26 is a valine or a leucine. 
     
     
         20 . An antibody fragment of  claim 13 . 
     
     
         21 . An isolated nucleic acid comprising the sequence of SEQ ID NO: 3 or 4. 
     
     
         22 . (canceled) 
     
     
         23 . An isolated nucleic acid encoding an antibody of  claim 13 . 
     
     
         24 . An isolated nucleic acid encoding the polypeptide of  claim 16 . 
     
     
         25 . A vector comprising the nucleic acid of  claim 23 . 
     
     
         26 . A vector comprising the nucleic acid of  claim 24 . 
     
     
         27 . A cell line comprising the vector of  claim 25 . 
     
     
         28 . A composition comprising the antibody of  claim 13 . 
     
     
         29 . A method to treat a complement mediated disorder comprising administering the composition of  claim 28 . 
     
     
         30 . The method according to  claim 29 , wherein the disorder is an ocular disease such as age-related macular degeneration or diabetic retinopathy. 
     
     
         31 . A variable domain of  claim 7  wherein amino acid at position 104 of SEQ ID NO: 7 is a valine or a leucine. 
     
     
         32 . A humanized anti-Factor D antibody of  claim 8  comprising the variable domain sequence of SEQ ID NO: 7 wherein the amino acid at position 104 of SEQ ID NO: 7 is a valine or a leucine and the variable domain sequence of SEQ ID NO: 8. 
     
     
         33 . A polypeptide of  claim 15  wherein the amino acid at position 104 of SEQ ID NO: 26 is a valine or a leucine. 
     
     
         34 . A polypeptide of  claim 16  wherein the amino acid at position 104 of SEQ ID NO: 7 is a valine or a leucine. 
     
     
         35 . A method of making a humanized anti-Factor D antibody or fragment thereof of  claim 13 . 
     
     
         36 . An antibody which competes with murine antibody 166-32 and/or humanized anti-Factor D antibody clone #56, #111, #250 or #416 and/or an antibody comprising variable domain or HVR sequences of humanized anti-Factor D antibody clone #56, #111, #250 or #416. 
     
     
         37 . An antibody which binds to the same epitope as murine antibody 166-32 and/or humanized anti-Factor D antibody clone #56, #111, #250 or #416 and/or an antibody comprising variable domain or HVR sequences of humanized anti-Factor D antibody clone #56, #111, #250 or #416.