Constructs Binding to Phosphatidylserine and Their Use in Disease Treatment and Imaging

Abstract

Disclosed are new phosphatidylserine binding constructs with surprising combinations of properties, and a range of diagnostic and therapeutic conjugates thereof. The new constructs effectively bind phosphatidylserine targets in disease and enhance their destruction, and can also specifically deliver attached imaging or therapeutic agents to the disease site. Also disclosed are methods of using the new construct compositions, therapeutic conjugates and combinations thereof in tumor vasculature targeting, cancer diagnosis and treatment, and fir treating viral infections and other diseases.

What is claimed is: 
     
         1 . A construct comprising an antibody Fc region operatively attached to two β2-glycoprotein 1 (β2GPI) polypeptides, wherein said β2GPI polypeptides each comprise at least an intact domain V of β2GPI, wherein said intact domain V binds to phosphatidylserine, wherein said β2GPI polypeptides form a dimer when attached to said antibody Fc region and wherein said construct retains the property of binding to phosphatidylserine. 
     
     
         2 . A method of inhibiting virus replication, infection or spread, comprising contacting a population of cells with a construct in accordance with  claim 1  in an amount effective to inhibit virus replication, infection or spread in said population of cells. 
     
     
         3 . The method of  claim 2 , wherein said population of cells is located within an animal and said construct is administered to said animal. 
     
     
         4 . A method for treating an animal with a viral infection, comprising administering to said animal a construct in accordance with  claim 1  in an amount effective to inhibit viral replication, infection or spread in said animal, thereby treating said viral infection. 
     
     
         5 . The method of  claim 4 , wherein said animal is a human patient. 
     
     
         6 . A method for treating an animal with cancer, comprising administering to said animal a construct in accordance with  claim 1  in an amount effective to treat said cancer in said animal. 
     
     
         7 . The method of  claim 6 , further comprising administering a second anti-cancer agent to said animal. 
     
     
         8 . The method of  claim 6 , wherein said animal is a human patient. 
     
     
         9 . A method for forming an image of a tumor in an animal having a tumor, comprising administering to said animal a diagnostically effective amount of a construct operatively attached to an in vivo detectable agent, thereby forming a detectable image of said tumor; wherein said construct comprises an antibody Fc region operatively attached to two β2-glycoprotein I (β2GPI) polypeptides, wherein said β2GPI polypeptides each comprise at least an intact domain V of β2GPI, wherein said intact domain V binds to phosphatidylserine, wherein said β2GPI polypeptides form a dimer when attached to said antibody Fc region and wherein said construct retains the property of binding to phosphatidylserine. 
     
     
         10 . The method of  claim 9 , wherein said β2GPI polypeptides each comprise at least an intact domain V of β2GPI and domain I of β2GPI. 
     
     
         11 . The method of  claim 9 , wherein said β2GPI polypeptides each comprise domain 1, domain II, domain III, domain IV and an intact domain V of β2GPI. 
     
     
         12 . The method of  claim 9 , wherein said β2GPI polypeptides each comprise at least an intact domain V of human β2GPI. 
     
     
         13 . The method of  claim 9 , wherein said antibody Fe region is a human antibody Fe region. 
     
     
         14 . The method of  claim 9 , wherein said antibody Fc region is operatively attached to said β2GPI polypeptides via a peptide cross-linker. 
     
     
         15 . The method of  claim 9 , wherein said construct is prepared by recombinant expression as a fusion protein. 
     
     
         16 . The method of  claim 9 , wherein said method further comprises subsequently administering to said animal a therapeutically effective amount of said construct, thereby causing an anti-tumor effect. 
     
     
         17 . The method of  claim 9 , wherein said animal is a human patient. 
     
     
         18 . A method for forming an image of a tumor in an animal having a tumor, comprising administering to said animal a diagnostically effective amount of a construct operatively attached to an in vivo detectable agent, thereby forming a detectable image of said tumor; wherein said construct comprises an antibody Fc region operatively attached to two β2-glycoprotein I (β2GPI) polypeptides, wherein said β2GPI polypeptides each comprise at least domain I of β2GPI and an intact domain V of β2GPI, wherein said intact domain V binds to phosphatidylserine, wherein said β2GPI polypeptides form a dimer when attached to said antibody Fc region and wherein said construct retains the property of binding to phosphatidylserine. 
     
     
         19 . A method for forming an image of a tumor in an animal having a tumor, comprising administering to said animal a diagnostically effective amount of a construct operatively attached to an in vivo detectable agent, thereby forming a detectable image of said tumor; wherein said construct comprises an antibody Fc region operatively attached to two β2-glycoprotein I (β2GPI) polypeptides, wherein said β2GPI polypeptides each comprise at least an intact domain V of β2GPI and one or more of the other four domains of β2GPI, wherein said intact domain V binds to phosphatidylserine, wherein said β2GPI polypeptides form a dimer when attached to said antibody Fc region and wherein said construct retains the property of binding to phosphatidylserine.