TCR Mimic Antibodies as Vascular Targeting Tools

Abstract

The present invention includes a method of delivering a therapeutic agent into and across an endothelial cell (EC) in a subject in need thereof, comprising: identifying a subject in need for treatment of a cancer in the brain; attaching to a TCR mimic an active agent to form a therapeutic agent; and administering to the subject the therapeutic agent in a pharmaceutically acceptable carrier, wherein the therapeutic agent effectively crosses the blood-central nervous system microvascular barrier.

What is claimed is: 
     
         1 . A method of delivering a therapeutic agent into and across an endothelial cell (EC) in a subject in need thereof, comprising:
 identifying a subject in need for treatment of a cancer in the brain;   attaching to a TCR mimic an active agent to form a therapeutic agent; and   administering to the subject the therapeutic agent in a pharmaceutically acceptable carrier, wherein the therapeutic agent effectively crosses the blood-central nervous system microvascular barrier.   
     
     
         2 . The method of  claim 1 , wherein the barrier being crossed is the blood-brain barrier (BBB), blood-retina barrier, blood-nerve barrier or blood-spinal cord barrier. 
     
     
         3 . The method of  claim 1 , wherein the disease or disorder is a cancer other than a brain cancer that has metastasized to the brain. 
     
     
         4 . The method of  claim 1 , wherein the disease or disorder is a breast cancer that has metastasized to the brain. 
     
     
         5 . The method of  claim 1 , wherein the TCR mimic is an antibody or fragment thereof and is selected from RL6A or RL21A. 
     
     
         6 . The method of  claim 1 , wherein the therapeutic agent or carrier is directly conjugated to a targeting molecule by: (a) non-specific or specific protein-protein interaction; (b) covalent bonding; (c) non-covalent bonding; or (d) coordinating chemical bonding; which conjugation is optionally effected via a spacer or linker that bridges between the therapeutic agent or carrier and the targeting molecule, or (e) a recombinant fusion or hybrid polypeptide. 
     
     
         7 . The method of  claim 1 , wherein the step of administering is (a) by continuous intravenous or intraarterial infusion; or (b) by bolus injection by an intravenous, intramuscular, intraarterial, or intralesional route. 
     
     
         8 . The method of  claim 1 , wherein the active agent is an antineoplastic agent, a cytotoxic agent, anti-inflammatory, a hormone, an enzyme, a neurotransmitter, a neurotrophic factor, antibiotics, a cytokine, or a neuropeptide. 
     
     
         9 . A method of delivering a therapeutic agent into and across a microvascular blood-central nervous system (CNS) barrier in a subject, comprising:
 identifying a subject in need for treatment of a cancer in the brain; and   administering to a subject with at least one of a CNS disease or disorder or a peripheral disease or disorder with CNS involvement, a composition comprising:   a TCR mimic and active agent that together form a therapeutic agent; and   a pharmaceutically acceptable carrier, wherein the therapeutic agent is encapsulated in a nanocontainer to which is linked the targeting molecule, wherein an effective barrier-entering and barrier crossing amount of the therapeutic agent enters and crosses the microvascular blood CNS barrier.   
     
     
         10 . The method of  claim 9 , wherein the barrier being crossed is the blood-brain barrier (BBB), blood-retina barrier, blood-nerve barrier or blood-spinal cord barrier. 
     
     
         11 . The method of  claim 9 , wherein the disease or disorder is a cancer other than a brain cancer that has metastasized to the brain. 
     
     
         12 . The method of  claim 9 , wherein the disease or disorder is a breast cancer that has metastasized to the brain. 
     
     
         13 . The method of  claim 9 , wherein the TCR mimic is an antibody or fragment thereof and is selected from RL6A or RL21A. 
     
     
         14 . The method of  claim 9 , wherein the therapeutic agent or carrier is directly conjugated to a targeting molecule by: (a) non-specific or specific protein-protein interaction; (b) covalent bonding; (c) non-covalent bonding; or (d) coordinating chemical bonding; which conjugation is optionally effected via a spacer or linker that bridges between the therapeutic agent or carrier and the targeting molecule, or (e) a recombinant fusion or hybrid polypeptide. 
     
     
         15 . The method of  claim 9 , wherein the step of administering is at least one of: (a) by continuous intravenous or intraarterial infusion; or (b) by bolus injection by an intravenous, intramuscular, intraarterial, or intralesional route. 
     
     
         16 . The method of  claim 9 , wherein the active agent is an antineoplastic agent, a cytotoxic agent, anti-inflammatory, a hormone, an enzyme, a neurotransmitter, a neurotrophic factor, antibiotics, a cytokine, or a neuropeptide. 
     
     
         17 . A method for treating a neuronal disease or condition comprising:
 identifying a subject in need of such treatment for a cancer in the brain;   administering to the subject in need of such treatment a neuroprotective and/or neurorestorative agent in an amount effective to treat the disorder in the subject, wherein the agent comprises:   a TCR mimic that targets an MHC-peptide combination found on the surface of an endothelial cells of the neuronal vasculature that is conjugated to an active agent to form a therapeutic agent and that crosses at least one of the blood-brain barrier, blood-retina barrier, blood-nerve barrier, or blood-spinal cord barrier.   
     
     
         18 . The method of  claim 17 , wherein the disease or disorder is a cancer other than a brain cancer that has metastasized to the brain. 
     
     
         19 . The method of  claim 17 , wherein the disease or disorder is a breast cancer that has metastasized to the brain. 
     
     
         20 . The method of  claim 17 , wherein the TCR mimic is an antibody or fragment thereof and is selected from RL6A or RL21A. 
     
     
         21 . The method of  claim 17 , wherein the therapeutic agent or carrier is directly conjugated to a targeting molecule by: (a) non-specific or specific protein-protein interaction; (b) covalent bonding; (c) non-covalent bonding; or (d) coordinating chemical bonding; which conjugation is optionally effected via a spacer or linker that bridges between the therapeutic agent or carrier and the targeting molecule, or (e) a recombinant fusion or hybrid polypeptide. 
     
     
         22 . The method of  claim 17 , wherein the step of administering is at least one of (a) by continuous intravenous or intraarterial infusion; or (b) by bolus injection by an intravenous, intramuscular, intraarterial, or intralesional route. 
     
     
         23 . The method of  claim 17 , wherein the active agent is an antineoplastic agent, a cytotoxic agent, anti-inflammatory, a hormone, an enzyme, a neurotransmitter, a neurotrophic factor, antibiotics, a cytokine, or a neuropeptide.