Anti-flt-1 antibodies in treating bronchopulmonary dysplasia

Abstract

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

1 . An anti-Flt-1 antibody or antigen binding fragment thereof,
 wherein the anti-Flt-1 antibody or antigen-binding fragment thereof comprises one or more complementarity determining regions (CDR) selected from the group consisting of
 a variable light (VL) chain CDR1 defined by an amino acid sequence having at least 80% identity to any one of SEQ ID NO:19 to SEQ ID NO:21, 
 a VL CDR2 defined by an amino acid sequence having at least 80% identity to any one of SEQ ID NO:22 to SEQ ID NO:24, 
 a VL CDR3 defined by an amino acid sequence having at least 80% identity to any one of SEQ ID NO:25 to SEQ ID NO:34, 
 a variable heavy (VH) chain CDR1 defined by an amino acid sequence having at least 80% identity to any one of SEQ ID NO:1 to SEQ ID NO:4, 
 a VH CDR2 defined by an amino acid sequence having at least 80% identity to any one of SEQ ID NO:5 to SEQ ID NO:14, and 
 a VH CDR3 defined by an amino acid sequence having at least 80% identity to any one of SEQ ID NO:15 to SEQ ID NO:18. 
   
     
     
         2 .- 15 . (canceled) 
     
     
         16 . An anti-Flt-1 antibody or antigen binding fragment thereof,
 wherein the anti-Flt-1 antibody or antigen-binding fragment thereof comprises: (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 anti-Flt-1 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 .- 20 . (canceled) 
     
     
         21 . The anti-Flt-1 antibody or antigen binding fragment thereof of  claim 1 , wherein the anti-Flt-1 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 anti-Flt-1 antibody or antigen binding fragment thereof of  claim 21 , wherein the anti-Flt-1 antibody or antigen-binding fragment thereof is IgG. 
     
     
         23 . (canceled) 
     
     
         24 . The anti-Flt-1 antibody or antigen binding fragment thereof of  claim 1 , wherein the anti-Flt-1 antibody or antigen-binding fragment thereof is a monoclonal antibody. 
     
     
         25 . The anti-Flt-1 antibody or antigen binding fragment thereof of  claim 24 , wherein the anti-Flt-1 antibody or antigen-binding fragment thereof is a humanized monoclonal antibody. 
     
     
         26 . The humanized monoclonal antibody of  claim 25 , wherein the humanized monoclonal antibody contains a human Fc region. 
     
     
         27 . The anti-Flt-1 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 . The anti-Flt-1 antibody or antigen binding fragment thereof of  claim 27 , wherein the Fc region contains one or more mutations at positions corresponding to Leu 234, Leu 235 and/or Gly 237 of human IgG1. 
     
     
         29 . The anti-Flt-1 antibody or antigen binding fragment thereof of  claim 1 , wherein the anti-Flt-1 antibody or antigen-binding fragment thereof does not bind to VEGFR2 and/or VEGFR3. 
     
     
         30 . The anti-Flt-1 antibody or antigen binding fragment thereof of  claim 1 , wherein the anti-Flt-1 antibody or antigen-binding fragment thereof does not bind to a mouse or monkey Flt-1. 
     
     
         31 .- 32 . (canceled) 
     
     
         33 . The anti-Flt-1 antibody or antigen binding fragment thereof of  claim 1  for treatment of Bronchopulmonary Dysplasia (BPD) in an individual, wherein the individual is an infant who is suffering from or susceptible to BPD. 
     
     
         34 . The anti-Flt-1 antibody or antigen binding fragment thereof of  claim 1  for treatment of Bronchopulmonary Dysplasia (BPD) in an individual, wherein the individual is pregnant with a fetus who is suffering from or susceptible to BPD. 
     
     
         35 . The anti-Flt-1 antibody or antigen binding fragment thereof of  claim 1 , wherein the anti-Flt-1 antibody or antigen binding fragment thereof is administered parenterally. 
     
     
         36 . The anti-Flt-1 antibody or antigen binding fragment thereof of  claim 1 , wherein the parenteral administration is selected from intravenous, intradermal, intrathecal, inhalation, transdermal (topical), intraocular, intramuscular, subcutaneous, pulmonary delivery, and/or transmucosal administration. 
     
     
         37 .- 38 . (canceled) 
     
     
         39 . The anti-Flt-1 antibody or antigen binding fragment thereof of  claim 1 , wherein the anti-Flt-1 antibody or antigen binding fragment thereof is administered bimonthly, monthly, triweekly, biweekly, weekly, daily, or at variable intervals. 
     
     
         40 . The anti-Flt-1 antibody or antigen binding fragment thereof of  claim 1 , wherein the anti-Flt-1 antibody or antigen binding fragment thereof is delivered to one or more target tissues selected from lungs and heart. 
     
     
         41 .- 42 . (canceled) 
     
     
         43 . The anti-Flt-1 antibody or antigen binding fragment thereof of  claim 1 , wherein the administration of the anti-Flt-1 antibody or antigen binding fragment thereof results in growth of healthy lung tissue, decreased lung inflammation, increased alveologenesis, increased angiogenesis, improved structure of pulmonary vascular bed, reduced lung scarring, improved lung growth, reduced respiratory insufficiency, improved exercise tolerance, reduced adverse neurological outcome, and/or improved pulmonary function relative to a control. 
     
     
         44 . The anti-Flt-1 antibody or antigen binding fragment thereof of  claim 1 , further comprising co-administering at least one additional agent or therapy selected from a surfactant, oxygen therapy, ventilator therapy, a steroid, vitamin A, inhaled nitric oxide, high calorie nutritional formulation, a diuretic, and/or a bronchodilator.