Anti-flt-1 antibodies for treating duchenne muscular dystrophy

Abstract

The present invention provides, among other things, anti-Flt-I antibodies and methods for treating muscular dystrophy, in particular, Duchenne muscular dystrophy (DMD). In some embodiments, a method according to the present invention in-cludes administering to an individual who is suffering from or susceptible to DMD an effective amount of an anti-Flt-I antibody or antigen-binding protein thereof such that at least one symptom or feature of DMD is reduced in intensity, severity, or frequency, or has delayed onset.

1 . An antibody or antigen-binding fragment thereof that specifically binds to human Flt-I comprising one or more complementarity determining regions (CDR) selected from the group consisting of
 (a) a variable light (VL) chain CDR1 defined by an amino acid sequence having at least 90% identity to SEQ NO:21;   a VL CDR2 defined by an amino acid sequence having at least 90% identity to SEQ ID NO:24;   a VL CDR3 defined by an amino acid sequence having at east 90% identity to SEQ ID NO:26;   a variable heavy (VH) chain CDR1 defined by an amino acid sequence having at least 90% identity to SEQ ID NO:2;   a VH CDR2 defined by an amino acid sequence having at least 90% identity to any one of SEQ ID NO:6, and   a VH CDR3 defined by an amino acid sequence having at least 90% identity to any one of SEQ ID NO:16.   (b) a VL CDR1 defined by the amino acid sequence having at least 90% identity to SEQ ID NO:21, a VL CDR2 defined by the amino acid sequence having at least 90% identity to SEQ ID NO:24, a VL CDR3 defined by the amino acid sequence having at least 90% identity to SEQ ID NO: 27, a VH CDR1 defined by the amino acid sequence having at least 90% identity to SEQ ID NO: 2, a VH CDR2 defined by the amino acid sequence having at least 90% identity to SEQ ID NO: 7, and a VH CDR3 defined by the amino acid sequence having at least 90% identity to SEQ ID NO: 17;   (c) a VL CDR1 defined by the amino acid sequence having at least 90% identity to SEQ ID NO:21, a VL CDR2 defined by the amino acid sequence having at least 90% identity to SEQ ID NO:24, a VL CDR3 defined by the amino acid sequence having at least 90% identity to SEQ ID NO: 26, a VH CDR1 defined by the amino acid sequence having at least 90% identity to SEQ ID NO: 3, a VH CDR2 defined by the amino acid sequence having at least 90% identity to SEQ ID NO: 12, and a VH CDR3 defined by the amino acid sequence having at least 90% identity to SEQ ID NO: 17;   (d) a VL CDR1 defined by the amino acid sequence having at least 90% identity to SEQ ID NO:21, a VL CDR2 defined by the amino acid sequence having at least 90% identity to SEQ ID NO:24, a VL CDR3 defined by the amino acid sequence having at least 90% identity to SEQ ID NO: 28, a VH CDR1 defined by the amino acid sequence having at least 90% identity to SEQ ID NO: 2, a VH CDR2 defined by the amino acid sequence having at least 90% identity to SEQ ID NO: 8, and a VH CDR3 defined by the amino acid sequence having at least 90% identity to SEQ ID NO: 17; or   (e) a VL CDR1 defined by the amino acid sequence having at least 90% identity to SEQ ID NO:21, a VL CDR2 defined by the amino acid sequence having at least 90% identity to SEQ ID NO:24, a VL CDR3 defined by the amino acid sequence having at least 90% identity to SEQ ID NO: 32, a VH CDR1 defined by the amino acid sequence having at least 90% identity to SEQ ID NO: 3, a VH CDR2 defined by the amino acid sequence having at least 90% identity to SEQ ID NO: 12, and a VH CDR3 defined by the amino acid sequence having at least 90% identity to SEQ ID NO: 17.   
     
     
         2 .- 15 . (canceled) 
     
     
         16 . An antibody or antigen-binding fragment thereof of  claim 1  that specifically binds to human Flt-1, comprising: (i) a light chain variable (VL) region comprising an amino acid sequence having at least 80% identity to any one of SEQ ID NO:49 to SEQ ID NO:61, and/or (ii) a heavy chain variable (VH) region comprising an amino acid sequence having at least 80% identity to any one of SEQ ID NO:35 to SEQ ID NO:48. 
     
     
         17 . The antibody or antigen-binding fragment thereof of  claim 16 , wherein the VL region comprises the amino acid sequence of SEQ ID NO: 60 and the VH region comprises the amino acid sequence of SEQ ID NO:45. 
     
     
         18 . The antibody of  claim 1 , wherein the antibody further comprises a heavy chain constant region comprising an amino acid sequence having at least 80% identity to any one of SEQ ID NO:87 to SEQ ID NO:89. 
     
     
         19 . An antibody or antigen-binding fragment thereof that specifically binds to human Flt-I, comprising: (i) a light chain comprising an amino acid sequence having at least 80% identity to any one of SEQ II) N0:75 tot SEQ ID NO:86, and/or (ii) a heavy chain comprising an amino acid sequence having at least 80% identity to any one of SEQ ID NO:62 to SEQ ID NO:74. 
     
     
         20 . The antibody or antigen-binding fragment thereof of  claim 19 , wherein the light chain comprises the amino acid sequence of SEQ ID NO:76 and the heavy chain comprises the amino acid sequence of SEQ ID NO:71. 
     
     
         21 . The antibody or antigen-binding fragment thereof of  claim 1 , wherein the antibody or antigen-binding fragment thereof is selected from the group consisting of IgG, F(ab′)2, F(ab)2, Fab′, Fab, ScFvs, diabodies, triabodies and tetrabodies. 
     
     
         22 . The antibody or antigen-binding fragment thereof of  claim 21 , wherein the antibody or antigen-binding fragment thereof is IgG. 
     
     
         23 . (canceled) 
     
     
         24 . The antibody or antigen-binding fragment thereof of  claim 1 , wherein the antibody or antigen-binding fragment thereof is a monoclonal antibody. 
     
     
         25 . (canceled) 
     
     
         26 . The antibody or antigen-binding fragment thereof of  claim 24 , wherein the monoclonal antibody contains a human Fc region. 
     
     
         27 . The antibody or antigen-binding fragment thereof of  claim 26 , wherein the Fc region contains one or more mutations that enhance the binding affinity between the Fc region and the FcRn receptor such that the in vivo half-life of the antibody is prolonged. 
     
     
         28 . (canceled) 
     
     
         29 . The antibody or antigen-binding fragment thereof of  claim 1 , wherein the antibody or antigen-binding fragment thereof does not bind to VEGFR2 and/or VEGFR3. 
     
     
         30 . The antibody or antigen-binding fragment thereof of  claim 1 , wherein the antibody or antigen-binding fragment thereof does not bind to a mouse or monkey Flt-1. 
     
     
         31 .- 32 . (canceled) 
     
     
         33 . An isolated antibody or antigen-binding fragment thereof that competes with the antibody or antigen-binding fragment thereof of  claim 1 . 
     
     
         34 . A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         35 .- 39 . (canceled) 
     
     
         40 . A method for treating a Flt-1-mediated disease, disorder or condition comprising administering to a subject in need of treatment the antibody or antigen-binding fragment thereof of  claim 1 . 
     
     
         41 . The method of  claim 40 , wherein the Flt-1-mediated disease, disorder or condition is Duchenne muscular dystrophy, Becker muscular dystrophy, preeclampsia or chronic kidney disease. 
     
     
         42 . A method of treating Duchenne Muscular Dystrophy (DMD), the method comprising:
 administering to a subject who is suffering from or susceptible to DMD an effective amount of the antibody or antigen-binding fragment thereof of  claim 1 , such that at least one symptom or feature of DMD is reduced in intensity, severity, or frequency, or has delayed onset.   
     
     
         43 - 44 . (canceled) 
     
     
         45 . The method of  claim 42 , wherein the antibody or antigen-binding fragment thereof is administered parenterally. 
     
     
         46 . The method of  claim 45 , wherein the parenteral administration is selected from intravenous, intradermal, intrathecal, inhalation, transdermal (topical), intraocular, intramuscular, subcutaneous, and/or transmucosal administration. 
     
     
         47 .- 60 . (canceled)