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-Flt-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 .- 32 . (canceled) 
     
     
         33 . A method of treating bronchopulmonary dysplasia (BPD) in an infant comprising
 administering to an infant in need of treatment an effective amount of an anti-Flt-1 antibody or antigen binding fragment thereof, wherein the administration of the anti-Flt-1 antibody or antigen binding fragment thereof results in improved lung development relative to a control.   
     
     
         34 . The method of  claim 33 , wherein the anti-Flt-1 antibody or antigen binding fragment thereof has binding affinity to human Flt-1 greater than 10 −12  M in a surface plasmon resonance binding assay. 
     
     
         35 . The method of  claim 33 , wherein the anti-Flt-1 antibody or antigen binding fragment thereof is characterized with an IC 50  below 1 pM in a competition assay with human Flt-I. 
     
     
         36 . The method of  claim 33 , wherein the anti-Flt-1 antibody or antigen binding fragment thereof does not bind to VEGFR2 and/or VEGFR3. 
     
     
         37 . The method of  claim 33 , 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. 
     
     
         38 . The method of  claim 37 , wherein the anti-Flt-1 antibody or antigen binding fragment thereof is IgG. 
     
     
         39 . The method of  claim 38 , wherein the anti-Flt-1 antibody or antigen binding fragment thereof is IgG1. 
     
     
         40 . The method of  claim 38  or  39 , wherein the anti-Flt-1 antibody or antigen binding fragment thereof is a monoclonal antibody, wherein the monoclonal antibody contains a human Fc region. 
     
     
         41 . The method of  claim 40 , 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. 
     
     
         42 . The method of  claim 41 , 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. 
     
     
         43 . The method of  claim 33 , wherein the anti-Flt-1 antibody or antigen binding fragment thereof is administered parenterally. 
     
     
         44 . The method of  claim 43 , wherein the parenteral administration is selected from intravenous, intradermal, intrathecal, inhalation, transdermal (topical), intraocular, intramuscular, subcutaneous, pulmonary delivery, and/or transmucosal administration. 
     
     
         45 . The method of  claim 33 , wherein the effective amount of anti-Flt-1 antibody or antigen-binding fragment thereof ranges from 0.5 mg/kg body weight to about 20 mg/kg body weight per dose. 
     
     
         46 . The method of  claim 33 , wherein the anti-Flt-1 antibody or antigen binding fragment thereof is administered bimonthly, monthly, triweekly, biweekly, weekly, daily, or at variable intervals. 
     
     
         47 . The method of  claim 33 , wherein the anti-Flt-1 antibody or antigen binding fragment thereof is delivered to one or more target tissues selected from lungs and heart. 
     
     
         48 . The method of  claim 33 , 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. 
     
     
         49 . The method of  claim 33 , 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. 
     
     
         50 . The method of  claim 33 , wherein the infant is an unborn infant and the anti-Flt-1 antibody or antigen binding fragment thereof is administered to the infant via intra-amniotic injection. 
     
     
         51 . The method of  claim 33 , wherein the method comprises parental administration to the infant after birth.