Anti-flt-1 antibodies in treating duchenne muscular dystrophy

Abstract

The present invention provides, among other things, methods and compositions for treating muscular dystrophy, in particular. Duchenne muscular dystrophy (DMD). In some embodiments, a method according to the present invention includes administering to an individual who is suffering from or susceptible to DMD an effective amount of an anti-Flt-1 antibody, or antigen binding fragment thereof, such that at least one symptom or feature of DMD is reduced in intensity, severity, or frequency, or has delayed onset.

1 . A method of treating Duchenne Muscular Dystrophy (DMD) comprising
 administering to an individual who is suffering from or susceptible to DMD an effective amount of an anti-Flt-1 antibody, or an antigen binding fragment thereof, such that at least one symptom or feature of DMD is reduced in intensity, severity, or frequency, or has delayed onset.   
     
     
         2 . The method of  claim 1 , wherein the anti-Flt-1 antibody, or an antigen binding fragment thereof, is characterized with an ability to bind human Flt-1 at an affinity greater than 10 −9 M in a surface plasmon resonance binding assay. 
     
     
         3 .- 9 . (canceled) 
     
     
         10 . The method of  claim 1 , wherein the anti-Flt-1 antibody, or an antigen binding fragment thereof, does not bind to VEGFR2 and/or VEGFR3. 
     
     
         11 .- 12 . (canceled) 
     
     
         13 . The method of  claim 1 , wherein the anti-Flt-1 antibody, or an 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. 
     
     
         14 .- 15 . (canceled) 
     
     
         16 . The method of  claim 1 , wherein the anti-Flt-1 antibody, or an antigen binding fragment thereof, is a monoclonal antibody. 
     
     
         17 . The method of  claim 16 , wherein the monoclonal antibody is a humanized monoclonal antibody. 
     
     
         18 . The method of  claim 17 , wherein the humanized monoclonal antibody contains a human Fc region. 
     
     
         19 . The method of  claim 18 , 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. 
     
     
         20 . The method of  claim 19 , wherein the Fc region contains one or more mutations at one or more positions corresponding to Thr 250, Met 252, Ser 254, Thr 256, Thr 307, Glu 380, Met 428, His 433, and/or Asn 434 of human IgG1. 
     
     
         21 .- 31 . (canceled) 
     
     
         32 . The method of  claim 1 , wherein the at least one symptom or feature of DMD is selected from the group consisting of muscle wasting, muscle weakness, muscle fragility, muscle hypertrophy, muscle pseudohypertrophy, joint contracture, skeletal deformation, cardiomyopathy, impaired swallowing, impaired bowel and bladder function, muscle ischemia, cognitive impairment, behavioral dysfunction, socialization impairment, scoliosis, and impaired respiratory function. 
     
     
         33 . An anti-Flt-1 antibody, or an antigen binding fragment thereof, having a binding affinity to human Flt-1 greater than 10 −9 M in a surface plasmon resonance binding assay. 
     
     
         34 . The anti-Flt-1 antibody, or an antigen binding fragment thereof, of  claim 33 , wherein the binding affinity to human Flt-1 is greater than 10 −10  M in a surface plasmon resonance binding assay. 
     
     
         35 . The anti-Flt-1 antibody, or an antigen binding fragment thereof, of  claim 33 , wherein the binding affinity to human Flt-1 is greater than 10 −12  Mina surface plasmon resonance binding assay. 
     
     
         36 . The anti-Flt-1 antibody, or an antigen binding fragment thereof, of  claim 33 , wherein the anti-Fit-1 antibody, or an antigen binding fragment thereof, is further characterized with an IC 50  below 100 μM for inhibition of binding of VEGF and/or PLGF to human Flt-1 in a competition assay. 
     
     
         37 . The anti-Fit-1 antibody, or an antigen binding fragment thereof, of  claim 33 , wherein the IC50 is below 10 μM. 
     
     
         38 . The anti-Flt-1 antibody, or an antigen binding fragment thereof, of  claim 33 , wherein the IC50 is below 1 μM. 
     
     
         39 . The anti-Flt-1 antibody, or an antigen binding fragment thereof, of  claim 33 , wherein the anti-Flt-1 antibody, or an antigen binding fragment thereof, does not bind to VEGFR2 and/or VEGFR3. 
     
     
         40 . The anti-Flt-1 antibody, or an antigen binding fragment thereof, of  claim 33 , wherein the anti-Flt-1 antibody, or an antigen binding fragment thereof, does not bind a mouse or monkey Flt-1. 
     
     
         41 . The anti-Flt-1 antibody, or an antigen binding fragment thereof, of  claim 33 , wherein the anti-Flt-1 antibody, or an antigen binding fragment thereof, binds to a mouse and/or monkey Flt-1. 
     
     
         42 . A pharmaceutical composition comprising an anti-Flt-1 antibody, or an antigen binding fragment thereof, of  claim 33 , and a pharmaceutically acceptable carrier.