Compositions and methods for treating antiphospholipid syndrome

Abstract

The invention features compositions and methods of using a dimeric inhibitor, e.g., A1-A1, to selectively target β2GPI in β2GPI/antibody complexes. The compositions can be administered to subjects (e.g., a mammal, such as a human) having or likely to develop APS, or one or more symptoms of APS, in order to treat or inhibit the disease or treat or reduce its symptoms. The inhibitors of the invention include two ligand-binding A1 modules, e.g., from ApoER2, connected by a flexible linker.

What is claimed is: 
     
         1 - 32 . (canceled) 
     
     
         33 . A polypeptide comprising a first A1 domain of apolipoprotein E receptor 2 (ApoER2), wherein said A1 domain is the first low density lipoprotein (LDL) receptor-type A (LA) module of said ApoER2, a second A1 domain of said ApoER2, and a linker that joins said first A1 domain to said second A1 domain. 
     
     
         34 . The polypeptide of  claim 33 , wherein said ApoER2 is human ApoER2. 
     
     
         35 . A polypeptide comprising a first low density lipoprotein (LDL) receptor-type A (LA) module, a second LA module, and a linker that joins said first LA module to said second LA module;
 wherein said first LA module comprises a first A1 domain comprising an amino acid sequence with 85% or more sequence identity to the amino acid sequence of SEQ ID NO: 2, 3, 14, or 15;   said second LA module comprises a second A1 domain comprising an amino acid sequence with 85% or more sequence identity to the amino acid sequence of SEQ ID NO: 2, 3, 14, or 15; and   said polypeptide specifically binds to first and second β2GPI monomers in a dimeric β2GPI/antibody complex.   
     
     
         36 . The polypeptide of  claim 35 , wherein the amino acid sequence of said first LA module is the same as the amino acid sequence of said second LA module. 
     
     
         37 . The polypeptide of  claim 35 , wherein said first A1 domain comprises an amino acid sequence with 85% or more sequence identity to the amino acid sequence of SEQ ID NO: 2 or 14 and said second A1 domain comprises an amino acid sequence with 85% or more sequence identity to the amino acid sequence of SEQ ID NO: 3 or 15. 
     
     
         38 . The polypeptide of  claim 37 , wherein said linker comprises the amino acid sequence of any one of SEQ ID NOs: 4-12. 
     
     
         39 . The polypeptide of  claim 38 , wherein said linker comprises the amino acid sequence of SEQ ID NO: 4. 
     
     
         40 . The polypeptide of  claim 35 , wherein said polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 1. 
     
     
         41 . The polypeptide of  claim 40 , wherein said polypeptide comprises the amino acid sequence of SEQ ID NO: 1. 
     
     
         42 . The polypeptide of  claim 35 , wherein said polypeptide comprises an amino acid sequence having at least 85% sequence identity to SEQ ID NO: 13. 
     
     
         43 . The polypeptide of  claim 42 , wherein said polypeptide comprises the amino acid sequence of SEQ ID NO: 13. 
     
     
         44 . The polypeptide of  claim 35 , wherein the amino acid sequence of said first LA module is different from the amino acid sequence of said second LA module. 
     
     
         45 . The polypeptide of  claim 35 , wherein said first A1 domain comprises an amino acid sequence with 90% or more sequence identity to the amino acid sequence of SEQ ID NO: 2, 3, 14, or 15, and said second A1 domain comprises an amino acid sequence with 90% or more sequence identity to the amino acid sequence of SEQ ID NO: 2, 3, 14, or 15. 
     
     
         46 . The polypeptide of  claim 45 , wherein said first A1 domain comprises an amino acid sequence with 90% or more sequence identity to the amino acid sequence of SEQ ID NO: 2 or 14 and said second A1 domain comprises an amino acid sequence with 90% or more sequence identity to the amino acid sequence of SEQ ID NO: 3 or 15. 
     
     
         47 . The polypeptide of  claim 35 , wherein said first A1 domain comprises an amino acid sequence with 95% or more sequence identity to the amino acid sequence of SEQ ID NO: 2, 3, 14, or 15, and said second A1 domain comprises an amino acid sequence with 95% or more sequence identity to the amino acid sequence of SEQ ID NO: 2, 3, 14, or 15. 
     
     
         48 . The polypeptide of  claim 47 , wherein said first A1 domain comprises an amino acid sequence with 95% or more sequence identity to the amino acid sequence of SEQ ID NO: 2 or 14 and said second A1 domain comprises an amino acid sequence with 95% or more sequence identity to the amino acid sequence of SEQ ID NO: 3 or 15. 
     
     
         49 . The polypeptide of  claim 35 , wherein said first A1 domain comprises the amino acid sequence of SEQ ID NO: 2, 3, 14, or 15, and said second A1 domain comprises the amino acid sequence of SEQ ID NO: 2, 3, 14, or 15. 
     
     
         50 . The polypeptide of  claim 49 , wherein said first A1 domain comprises the amino acid sequence of SEQ ID NO: 2 or 14 and said second A1 domain comprises the amino acid sequence of SEQ ID NO: 3 or 15. 
     
     
         51 . A composition comprising the polypeptide of  claim 33 . 
     
     
         52 . A composition comprising the polypeptide of  claim 35 .