Phospholipid ether (ple) car t cell tumor targeting (ctct) agents

Abstract

Aspects of the invention described herein relate to synthetic compounds that are useful for targeting and labeling tumor cells so as to facilitate recognition by binding agents including Chimeric Antigen Receptor T cells (CAR T cells), which are administered to a subject by intravenous or locoregional administration. Several compositions and methods of making and using these compositions to treat or inhibit a disease in a subject are contemplated.

What is claimed is: 
     
         1 . A complex comprising: a chimeric antigen receptor (CAR) or a T cell receptor (TCR); and a compound comprising a lipid, wherein the lipid comprises a hydrophobic group, a polar head group, and a target moiety; wherein the CAR or TCR is specifically bound to the target moiety. 
     
     
         2 . The complex of  claim 1 , wherein the hydrophobic group comprises a fatty acid. 
     
     
         3 . The complex of  claim 1 , wherein the hydrophobic group comprises a C 8-22  alkyl group. 
     
     
         4 . The complex of  claim 1 , wherein the hydrophobic group comprises a terpenoid lipid. 
     
     
         5 . The complex of  claim 1 , wherein the lipid comprises an ether linkage, wherein the ether linkage is between the polar head group and the hydrophobic group. 
     
     
         6 . The complex of  claim 5 , wherein the lipid is a phospholipid ether. 
     
     
         7 . The complex of  claim 1 , wherein the polar head comprises a group selected from choline, phosphatidylcholine, sphingomyelin, phosphoethanolamine, an oligosaccharide residue, a sugar residue, glycerol, phosphatidyl serine, phosphatidyl inositol, phosphocholine, piperidine moiety, or a trimethylarseno-ethyl-phosphate. 
     
     
         8 . The complex of  claim 1 , wherein the target moiety is selected from the group consisting of a hapten, a poly(his) tag, a strep-tag, a FLAG-tag, a V5-tag, a myc-tag, an HA-tag, an NE-tag, a biotin, a digoxigenin, a dinitrophenol, a fluorescein, and a derivative thereof. 
     
     
         9 . The complex of  claim 8 , wherein the target moiety comprises a fluorescein or a derivative thereof. 
     
     
         10 . The complex of  claim 1 , wherein the lipid further comprises a spacer between the target moiety and the polar head group, wherein the spacer is selected from the group consisting of poly(carboxybetaine), peptide, polyglycidol, polyethylene, polyanhydride, polyphosphoester, polycaprolactone, polyethylene glycol (PEG), a hapten (2x), and an alkane chain. 
     
     
         11 . The complex of  claim 10 , wherein the PEG spacer comprises from 1 to 21 PEG subunits. 
     
     
         12 . The complex of  claim 1 , wherein the compound has the structure of formula (I):
                       wherein:   n is 0 to 21; and   x is 8 to 22.   
     
     
         13 . A cell comprising the complex of  claim 1 , wherein the CAR or TCR is expressed on the surface of the cell, or the lipid is intercalated in a lipid bilayer of the cell. 
     
     
         14 . The cell of  claim 13 , wherein the cell is selected from a precursor T cell, a hematopoietic stem cell, a CD8+ T cell, or a CD4+ T cell, a tumor cell, an immune cell, a T cell, or a B cell. 
     
     
         15 . A compound of formula (I) or (II):
                                             wherein:   n is 0 to 21;   x is 8 to 22; and   Y is O or NH.   
     
     
         16 . A complex comprising an antibody or an antigen binding fragment thereof comprising a target moiety, a chimeric antigen receptor (CAR) or a T cell receptor (TCR) specifically bound to the target moiety, wherein an antibody or an antigen binding fragment thereof is specific for an antigen present on a cancer cell, virus, or bacterial cell. 
     
     
         17 . The complex of  claim 16 , wherein the target moiety is selected from the group consisting of a hapten, a poly(his) tag, a strep-tag, a FLAG-tag, a V5-tag, a myc-tag, an HA-tag, an NE-tag, a biotin, a digoxigenin, a dinitrophenol, a fluorescein, and a derivative thereof; and wherein the CAR or TCR is expressed on the surface of a cell selected from a precursor T cell, a hematopoietic stem cell, a CD8+ T cell, or a CD4+ T cell, a tumor cell, an immune cell, a T cell, or a B cell. 
     
     
         18 . A method of treating, ameliorating, or inhibiting a cancer in a subject comprising:
 a) administering to the subject a composition comprising an antibody or antigen binding fragment thereof comprising a target moiety; and   b) administering to the subject a cell comprising a chimeric antigen receptor (CAR) or a T cell receptor (TCR) capable of specifically binding to the target moiety.   
     
     
         19 . The method of  claim 18 , wherein the target moiety is selected from the group consisting of a hapten, a poly(his) tag, a strep-tag, a FLAG-tag, a V5-tag, a myc-tag, an HA-tag, an NE-tag, a biotin, a digoxigenin, a dinitrophenol, a fluorescein, and a derivative thereof; and wherein the cell is selected from a precursor T cell, a hematopoietic stem cell, a CD8+ T cell, or a CD4+ T cell, a tumor cell, an immune cell, a T cell, or a B cell.