Compositions and methods related to multimodal therapeutic cell systems for autoimmune indications

Abstract

The invention includes compositions and methods related to multimodal therapies, e.g., for treating immune conditions. A multimodal therapy described herein provides and/or administers a plurality of agents that function in a coordinated manner to provide a therapeutic benefit to a subject in need thereof, e.g., a subject having an autoimmune disease or inflammatory disease.

1 . An enucleated erythroid cell comprising an exogenous polypeptide comprising desmoglein-1 or a functional fragment thereof, or desmoglein-3 or a functional fragment thereof. 
     
     
         2 . The enucleated erythroid cell of  claim 1 , wherein the exogenous polypeptide comprises desmoglein-1 or a functional fragment thereof. 
     
     
         3 . The enucleated erythroid cell of  claim 1 , wherein the exogenous polypeptide comprises desmoglein-3 or a functional fragment thereof. 
     
     
         4 . The enucleated erythroid cell of  claim 1 , wherein the exogenous polypeptide comprises desmoglein-1 or a functional fragment thereof, and the enucleated erythroid cell further comprises a second exogenous polypeptide comprising desmoglein-3 or a functional fragment thereof. 
     
     
         5 . The enucleated erythroid cell of  claim 4 , wherein the exogenous polypeptide and the second exogenous polypeptide have an abundance ratio of from about 2:1 to 1:2 by copy number. 
     
     
         6 . The enuncleated erythroid cell of  claim 5 , wherein the exogenous polypeptide and the second exogenous polypeptide have an abundance ratio of about 1:1 by copy number. 
     
     
         7 . The enucleated erythroid cell of  claim 1 , wherein the exogenous polypeptide is intracellular. 
     
     
         8 . The enucleated erythroid cell of  claim 1 , wherein the exogenous polypeptide is exposed on the surface of the enucleated erythroid cell. 
     
     
         9 . The enucleated erythroid cell of  claim 1 , wherein the exogenous polypeptide is a transmembrane polypeptide or a surface-anchored polypeptide. 
     
     
         10 . The enucleated erythroid cell of  claim 9 , wherein the exogenous polypeptide comprises a transmembrane domain. 
     
     
         11 . The enucleated erythroid cell of  claim 10 , wherein the transmembrane domain comprises a type I red blood cell transmembrane domain or a type II red blood cell transmembrane domain. 
     
     
         12 . The enucleated erythroid cell of  claim 11 , wherein the transmembrane domain comprises GPA. 
     
     
         13 . The enucleated erythroid cell of  claim 1 , which is a reticulocyte or erythrocyte. 
     
     
         14 . The enucleated erythroid cell of  claim 1 , wherein the enucleated erythroid cell exhibits substantially the same osmotic membrane fragility as an isolated, unmodified, uncultured erythroid cell that does not comprise the exogenous polypeptide, or wherein the enucleated erythroid cell is not a hypotonically loaded cell. 
     
     
         15 . The enucleated erythroid cell of  claim 1 , which was produced by a process comprising:
 providing a nucleated erythroid cell, or a precursor thereof, comprising an exogenous nucleic acid encoding the exogenous polypeptide; and   culturing the nucleated erythroid cell, or the precursor thereof, under conditions suitable for enucleation of the nucleated erythroid cell and for production of the exogenous polypeptide.   
     
     
         16 . The enucleated erythroid cell of  claim 15 , wherein the process of producing further comprises introducing the exogenous nucleic acid into the nucleated erythroid cell, or the precursor thereof. 
     
     
         17 . The enucleated erythroid cell of  claim 15 , wherein the exogenous nucleic acid is situated in a lentiviral vector. 
     
     
         18 . The enucleated erythroid cell of  claim 1 , which, when contacted with an inappropriately activated immune cell inactivates the inappropriately activated immune cell. 
     
     
         19 . The enucleated erythroid cell of  claim 18 , wherein the inappropriately activated immune cell is a T cell. 
     
     
         20 . A pharmaceutical preparation comprising a plurality of the enucleated erythroid cells of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         21 . The pharmaceutical preparation of  claim 20 , which comprises a population of erythroid cells that is greater than 50%, 60%, 70%, 80%, or 90% enucleated. 
     
     
         22 . A method of reducing an immune response in a subject, comprising administering to the subject the pharmaceutical composition of  claim 20 , thereby reducing an immune response in the subject. 
     
     
         23 . A method of treating pemphigus vulgaris, the method comprising administering to a subject in need thereof the pharmaceutical composition of  claim 20 , thereby treating said pemphigus vulgaris. 
     
     
         24 . A method of making an enucleated erythroid cell of  claim 1 , comprising:
 providing a nucleated erythroid cell, or a precursor thereof, comprising an exogenous nucleic acid encoding the exogenous polypeptide; and   culturing the nucleated erythroid cell, or the precursor thereof, under conditions suitable for enucleation of the nucleated erythroid cell and for production of the exogenous polypeptide.