Therapies and methods to treat tlr2-mediated diseases and disorders

Abstract

The disclosure provides for methods and treatments of TLR2-mediated diseases and disorders comprising administering an antibody, antibody fragment, or polypeptide that binds to and inhibits the biological activity of oxidized phospholipids.

What is claimed is: 
     
         1 - 15 . (canceled) 
     
     
         16 . A method of inhibiting one or more immunopotentiating agent selected from the group consisting of TNFα, CCL5, CCL2, CXCL1, IL-6 and IL12 comprising, administering a therapeutically effective amount of an antibody, antibody fragment, or polypeptide that binds specifically to an oxidative phospholipid (OxPL), wherein the antibody, antibody fragment or polypeptide inhibits the level of the immunopotentiating agent in the plasma of a subject. 
     
     
         17 . The method of  claim 16 , wherein the antibody, antibody fragment, or polypeptide is a single-chain variable fragment (ScFv). 
     
     
         18 . The method of  claim 16 , wherein the antibody or antibody fragment recognizes and binds to a phosphocholine headgroup of an oxidized phospholipid, wherein the antibody or antibody fragment comprises a variable heavy chain domain (V H ) and/or a variable light chain domain (V L ), and wherein (a) the V H  comprises an amino acid sequence that includes one, two or three complementarity determining regions (CDRs) selected from the group consisting of: SEQ ID NO:6 and sequence that are at least 95%, 96%, 97%, 98%, 99% or 99.9% identical to SEQ ID NO:6; SEQ ID NO:7 and sequence that are at least 95%, 96%, 97%, 98%, 99% or 99.9% identical to SEQ ID NO:7; and SEQ ID NO:8 and sequence that are at least 95%, 96%, 97%, 98%, 99% or 99.9% identical to SEQ ID NO:8; and (b) the V L  comprises an amino acid sequence that includes one, two or three complementarity determining regions (CDRs) selected from the group consisting of: SEQ ID NO:9 or 12 and sequence that are at least 95%, 96%, 97%, 98%, 99% or 99.9% identical to SEQ ID NO:9 or 12; SEQ ID NO:10 and sequence that are at least 95%, 96%, 97%, 98%, 99% or 99.9% identical to SEQ ID NO:10; and SEQ ID NO:11 and sequence that are at least 95%, 96%, 97%, 98%, 99% or 99.9% identical to SEQ ID NO:11. 
     
     
         19 . The method of  claim 16 , wherein the antibody, antibody fragment, or polypeptide is administered intravascularly. 
     
     
         20 . The method of  claim 18 , wherein the V H  comprises an amino acid sequence that includes CDRs comprising SEQ ID NO:6, 7 and 8, and/or the V L  comprises an amino acid sequence that includes CDRs comprising SEQ ID NO:9, 10 and 11, or SEQ ID NO:10, 11 and 12. 
     
     
         21 . The method of  claim 18 , wherein the antibody or antibody fragment is selected from the group consisting of: (a) an antibody or scFv with heavy and light chain domains comprising the complementarity determining regions of SEQ ID NO:6, 7, 8, 9, 10 and 11; and (b) an antibody or scFv with heavy and light chain domains comprising the complementarity determining regions of SEQ ID NO:6, 7, 8, 10, 11 and 12. 
     
     
         22 . The method of  claim 18 , wherein the heavy and light chain domains are linked to an Fc or FC2 region. 
     
     
         23 . The method of  claim 18 , wherein the antibody fragment comprises a single chain variable fragment (“scFv”) that recognizes a phosphocholine headgroup of an oxidized phospholipid. 
     
     
         24 . The method of  claim 23 , wherein the scFv is soluble under physiological conditions. 
     
     
         25 . The method of  claim 16 , wherein the antibody, antibody fragment, or polypeptide comprises: a variable heavy chain domain (V H ) comprising the complementarity determining regions (CDRs) of the V H  amino acid sequence set forth in SEQ ID NO:2; and a variable light chain domain (V L ) comprising the CDRs of the V L  amino acid sequence set forth in SEQ ID NO:2 or 4. 
     
     
         26 . The method of  claim 25 , wherein the antibody fragment is a single chain variable fragment (scFv). 
     
     
         27 . The method of  claim 25 , wherein the V H  and/or V L  are linked to an Fc or FC2 region. 
     
     
         28 . The method of  claim 25 , wherein the V H  comprises the CDR amino acid sequences set forth in SEQ ID NOs: 6, 7, and 8; and the V L  comprises the CDR amino acid sequences set forth in SEQ ID NOs: 9, 10, and 11. 
     
     
         29 . The method of  claim 28 , wherein: the V H  comprises an amino acid sequence that is at least 95% identical to the V H  amino acid sequence set forth in SEQ ID NO:2; and the V L  comprises an amino acid sequences that is at least 95% identical to the V L  amino acid sequence set forth in SEQ ID NO:2. 
     
     
         30 . The method of  claim 28 , wherein: the V H  comprises the V H  amino acid sequence set forth in SEQ ID NO:2; and the V L  comprises the V L  amino acid sequence set forth in SEQ ID NO:2. 
     
     
         31 . The method of  claim 25 , wherein the V H  comprises the CDR amino acid sequences set forth in SEQ ID NOs: 6, 7, and 8; and the V L  comprises the CDR amino acid sequences set forth in SEQ ID NOs: 12, 10, and 11. 
     
     
         32 . The method of  claim 31 , wherein: the V H  comprises an amino acid sequence that is at least 95% identical to the V H  amino acid sequence set forth in SEQ ID NO:4; and the V L  comprises an amino acid sequences that is at least 95% identical to the V L  amino acid sequence set forth in SEQ ID NO:4. 
     
     
         33 . The method of  claim 31 , wherein: the V H  comprises the V H  amino acid sequence set forth in SEQ ID NO:4; and the V L  comprises the V L  amino acid sequence set forth in SEQ ID NO:4.