Methods of treating pre-eclampsia or eclampsia

Abstract

Disclosed herein are methods for treating pre-eclampsia and eclampsia using compounds that increase VEGF or PlGF levels or compounds that decrease sFlt-1 levels. Compounds that inhibit the binding of VEGF or PlGF to sFlt1—are also disclosed herein for the treatment of pre-eclampsia or eclampsia.

1 . A method for inhibiting the binding of VEGF or PlGF, or fragments or derivatives thereof, to an sFlt-1 polypeptide in a subject having pre-eclampsia or eclampsia or a propensity to develop pre-eclampsia or eclampsia, said method comprising contacting the sFlt-1 polypeptide with a polypeptide that binds sFlt-1, wherein said polypeptide is selected from the group consisting of an anti-sFlt-1 antibody, or an antigen-binding fragment thereof, VEGF, or PlGF. 
     
     
         2 . The method of  claim 1 , wherein said polypeptide that binds sFlt-1 competitively inhibits the binding of VEGF or PlGF to sFlt-1, 
     
     
         3 . The method of  claim 1 , wherein said polypeptide that binds sFlt-1 is an anti-sFlt-1 antibody, or an antigen binding fragment thereof. 
     
     
         4 . The method of  claim 3 , wherein said anti-sFlt-1 antibody, or antigen binding fragment thereof, specifically binds sFlt-1. 
     
     
         5 . The method of  claim 4 , wherein said anti-sFlt-1 antibody, or antigen binding fragment thereof, binds sFlt-1 and does not bind Flt-1. 
     
     
         6 . The method of  claim 3 , wherein said antibody, or antigen binding fragment thereof, reduces the levels of sFlt-1 in said subject. 
     
     
         7 . The method of  claim 3 , wherein said antibody is a monoclonal antibody, a chimeric antibody, a human antibody, or a humanized antibody. 
     
     
         8 . The method of  claim 3 , wherein said antibody, or antigen-binding fragment thereof, is an Fv, Fab, Fab′, F(ab′) 2  fragment, or scFv. 
     
     
         9 . The method of  claim 3 , wherein said antibody, or antigen-binding fragment thereof, is an IgG. 
     
     
         10 . The method of  claim 9 , wherein said antibody, or antigen-binding fragment thereof, is an IgG 1 , IgG 2 , IgG 3 , or IgG 4 . 
     
     
         11 . The method of  claim 1 , further comprising administering an anti-hypertensive drug to said subject. 
     
     
         12 . The method of  claim 11 , wherein said anti-hypertensive drug is selected from the group consisting of methyldopa, hydralazine, hydrochloride, or labetalol. 
     
     
         13 . The method of  claim 1 , wherein said polypeptide is PlGF, or an isoform or fragment of PlGF that binds sFlt-1. 
     
     
         14 . The method of  claim 1 , wherein said sFlt-1 is an isoform of sFlt-1 or an sFlt-1 polypeptide resulting from degradation or enzymatic cleavage. 
     
     
         15 . The method of  claim 1 , wherein said polypeptide is VEGF, or an isoform or fragment of VEGF that binds sFlt-1. 
     
     
         16 . The method of  claim 15 , wherein said VEGF is VEGF121, VEGF 165, or VEGF 189. 
     
     
         17 . The method of  claim 1 , wherein said subject is a pregnant human or a post-partum human. 
     
     
         18 . The method of  claim 1 , wherein said method further comprises monitoring said pre-eclampsia or eclampsia in said subject, wherein said monitoring comprises measuring the level of sFlt-1, free VEGF, or free PlGF polypeptide in a sample from said subject, wherein a decrease in the level of sFlt-1 or an increase in the level of free VEGF or free PlGF relative to a reference that is indicative of pre-eclampsia or eclampsia indicates an improvement in said pre-eclampsia or eclampsia in said subject. 
     
     
         19 . The method of  claim 18 , wherein the level of sFlt-1 is measured and a decrease in the level of sFlt-1 relative to said reference indicates an improvement in said pre-eclampsia or eclampsia in said subject. 
     
     
         20 . The method of  claim 18 , wherein the level of sFlt-1 is the level of free or bound sFlt-1. 
     
     
         21 . The method of  claim 18 , wherein the level of sFlt-1 is the level of total sFlt-1. 
     
     
         22 . The method of  claim 18 , wherein the level of sFlt-1 is the level of an isoform of sFlt-1 or an sFlt-1 polypeptide resulting from degradation or enzymatic cleavage. 
     
     
         23 . The method of  claim 18 , wherein the level of free VEGF or free PlGF is measured and an increase in the level of free VEGF or free PlGF relative to a reference indicates an improvement in said pre-eclampsia or eclampsia in said subject. 
     
     
         24 . The method of  claim 18 , wherein said measuring of levels is done on two or more occasions and a change in said levels between measurements indicates an improvement in said pre-eclampsia or eclampsia. 
     
     
         25 . The method of  claim 1 , wherein said pre-eclampsia or eclampsia is characterized by increased sFlt-1 polypeptide or nucleic acid expression levels relative to a normal reference sample of level. 
     
     
         26 . The method of  claim 25 , wherein said normal reference sample or level is a prior sample or level from said subject. 
     
     
         27 . A method for reducing the level or biological activity of sFlt-1 polypeptide in a subject having pre-eclampsia or eclampsia or a propensity to develop pre-eclampsia or eclampsia, said method comprising contacting the sFlt-1 polypeptide with an anti-sFlt-1 antibody or an antigen-binding fragment thereof. 
     
     
         28 . The method of  claim 27 , wherein the anti-sFlt-1 antibody specifically binds sFlt-1. 
     
     
         29 . The method of  claim 28 , wherein the anti-sFlt-1 antibody binds sFlt-1 and does not bind to Flt-1. 
     
     
         30 . The method of  claim 27 , wherein said antibody is a monoclonal antibody, a chimeric antibody, a human antibody, or a humanized antibody. 
     
     
         31 . The method of  claim 27 , wherein said antibody or antigen-binding fragment is an Fv, Fab, Fab′, F(ab′) 2  fragment, or scFv. 
     
     
         32 . The method of  claim 27 , wherein said subject is a pregnant human or a post-partum human. 
     
     
         33 . The method of  claim 27 , wherein said sFlt-1 is an isoform of sFlt-1 or an sFlt-1 polypeptide resulting from degradation or enzymatic cleavage. 
     
     
         34 . The method of  claim 27 , wherein said method further comprises monitoring said pre-eclampsia or eclampsia in said subject, wherein said monitoring comprises measuring the level of sFlt-1, free VEGF, or free PlGF polypeptide in a sample from said subject, wherein a decrease in the level of sFlt-1 or an increase in the level of free VEGF or free PlGF relative to a reference that is indicative of pre-eclampsia or eclampsia indicates an improvement in said pre-eclampsia or eclampsia in said subject. 
     
     
         35 . The method of  claim 34 , wherein the level of sFlt-1 is measured and a decrease in the level of sFlt-1 relative to said reference indicates an improvement in said pre-eclampsia or eclampsia in said subject. 
     
     
         36 . The method of  claim 34 , wherein the level of sFlt-1 is the level of free or bound sFlt-1. 
     
     
         37 . The method of  claim 34 , wherein the level of sFlt-1 is the level of total sFlt-1. 
     
     
         38 . The method of  claim 34 , wherein said sFlt-1 is an isoform of sFlt-1 or an sFlt-1 polypeptide resulting from degradation or enzymatic cleavage.