Cancer Treatment Comprising Therapeutics That Bind to Phosphatidylserine

Abstract

Disclosed is the surprising discovery that aminophospholipids, such as phosphatidylserine and phosphatidylethanolamine, are specific, accessible and stable markers of the luminal surface of tumor blood vessels. The present invention thus provides aminophospholipid-targeted diagnostic and therapeutic constructs for use in tumor intervention. Antibody-therapeutic agent conjugates and constructs that bind to aminophospholipids are particularly provided, as are methods of specifically delivering therapeutic agents, including toxins and coagulants, to the stably-expressed aminophospholipids of tumor blood vessels, thereby inducing thrombosis, necrosis and tumor regression.

What is claimed is: 
     
         1 . A phosphatidylserine-targeted therapeutic agent comprising, in operative association, a selected therapeutic agent and a binding protein, or active fragment thereof, that binds to phosphatidylserine on tumor blood vessels; wherein said selected therapeutic agent is a phospholipid liposome or nanocapsule. 
     
     
         2 . A composition comprising a phosphatidylserine-targeted therapeutic agent, comprising a phosphatidylserine binding protein, or active fragment thereof, operatively associated with a phospholipid liposome or nanocapsule; wherein said phospholipid liposome or nanocapsule entraps said phosphatidylserine binding protein, or active fragment thereof, to form a construct that binds to phosphatidylserine and has an anti-tumor effect. 
     
     
         3 . A pharmaceutical composition comprising an amount of at least a first anti-cancer agent effective to treat cancer and a pharmaceutically acceptable carrier; wherein said at least a first anti-cancer agent is a phosphatidylserine-targeted therapeutic agent that comprises a phosphatidylserine binding protein, or active fragment thereof, in operative association with the lipid bilayer of a phospholipid liposome or nanocapsule. 
     
     
         4 . The composition of  claim 3 , further comprising at least a second anti-cancer agent. 
     
     
         5 . The composition of  claim 4 , wherein said at least a second anti-cancer agent is contained in the core of said phospholipid liposome or nanocapsule. 
     
     
         6 . A kit comprising, in at least one container, therapeutically effective amounts of:
 (a) at least a first anti-cancer agent; wherein said at least a first anti-cancer agent is a phosphatidylserine-targeted therapeutic agent that comprises a phosphatidylserine binding protein, or active fragment thereof, in operative association with the lipid bilayer of a phospholipid liposome or nanocapsule; and   (b) at least a second, distinct anti-cancer agent.   
     
     
         7 . The kit of  claim 6 , wherein said at least a first anti-cancer agent and said at least a second, distinct anti-cancer agent are comprised within distinct containers. 
     
     
         8 . The kit of  claim 6 , wherein said at least a second, distinct anti-cancer agent is a chemotherapeutic agent, radiotherapeutic agent, anti-angiogenic agent or apoptosis-inducing agent. 
     
     
         9 . The kit of  claim 6 , wherein said kit further comprises, in another container, a diagnostically effective amount of a detectably-labeled phosphatidylserine binding construct. 
     
     
         10 . A composition comprising:
 (a) a liposome or nanocapsule formed from phospholipids that comprises a lipid bilayer and a core;   (b) a phosphatidylserine binding protein, or active fragment thereof, that binds to phosphatidylserine on a target cell plasma membrane; and   (c) a pharmaceutically acceptable carrier;   
       wherein said liposome or nanocapsule entraps said phosphatidylserine binding protein, or active fragment thereof, in said lipid bilayer; and wherein said composition binds to phosphatidylserine and has an anti-tumor effect. 
     
     
         11 . The composition of  claim 10 , wherein said liposome or nanocapsule has a diameter of from 25 nm to 4 μm. 
     
     
         12 . The composition of  claim 10 , wherein the liposome or nanocapsule has a size of about 0.1 μm. 
     
     
         13 . The composition of  claim 10 , wherein said composition further comprises a supplementary active ingredient. 
     
     
         14 . The composition of  claim 13 , wherein said supplementary active ingredient is contained in said core of said phospholipid liposome or nanocapsule. 
     
     
         15 . A method for treating an animal having a vascularized tumor, comprising administering to said animal a therapeutically effective amount of a phosphatidylserine-targeted therapeutic agent that comprises a phosphatidylserine binding protein, or active fragment thereof, in operative association with a phospholipid liposome or nanocapsule; wherein said phospholipid liposome or nanocapsule entraps said phosphatidylserine binding protein, or active fragment thereof, to form a construct that binds to phosphatidylserine in said vascularized tumor and exerts an anti-tumor effect. 
     
     
         16 . The method of  claim 15 , wherein said method induces apoptosis, causes tumor cell death or induces necrosis in said vascularized tumor. 
     
     
         17 . The method of  claim 15 , wherein said phosphatidylserine-targeted therapeutic agent is administered to said animal intravenously. 
     
     
         18 . The method of  claim 15 , further comprising:
 (a) subjecting said animal to surgery or radiotherapy; or   (b) simultaneously or sequentially administering to said animal a therapeutically effective amount of another anti-cancer agent.   
     
     
         19 . The method of  claim 18 , wherein said another anti-cancer agent is a chemotherapeutic agent, radiotherapeutic agent, anti-angiogenic agent or apoptosis-inducing agent. 
     
     
         20 . The method of  claim 15 , wherein said animal is a human patient. 
     
     
         21 . A method for delivering a diagnostic or therapeutic agent to a vascularized tumor, comprising:
 (a) preparing a phosphatidylserine-targeted liposome or nanocapsule construct that contains said diagnostic or therapeutic agent; wherein said construct comprises a phosphatidylserine binding protein, or active fragment thereof, operatively associated with a phospholipid liposome or nanocapsule; and   (b) administering a biologically effective amount of said construct to an animal having a vascularized tumor, wherein said construct binds to phosphatidylserine in said vascularized tumor and thereby delivers said diagnostic or therapeutic agent thereto.   
     
     
         22 . The method of  claim 21 , wherein said phospholipid liposome or nanocapsule comprises a lipid bilayer and a core; wherein said phosphatidylserine binding protein, or active fragment thereof, is entrapped in said lipid bilayer; and wherein said diagnostic or therapeutic agent is contained within said core. 
     
     
         23 . A method for imaging a vascularized tumor, comprising:
 (a) preparing a phosphatidylserine-targeted liposome or nanocapsule construct that contains a detectable or imaging agent; wherein said construct comprises a phosphatidylserine binding protein, or active fragment thereof, operatively associated with a phospholipid liposome or nanocapsule;   (b) administering a diagnostically effective amount of said construct to an animal having a vascularized tumor, wherein said construct binds to phosphatidylserine in said vascularized tumor; and   (c) detecting the image of the tumor so formed.