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 . A method of treating sepsis in a subject, the method comprising administering a population of enucleated erythroid cells to the subject, wherein the enucleated erythroid cells of the population comprise two or more exogenous polypeptides present on the surface of the enucleated erythroid cells, wherein at least two of the two or more exogenous polypeptides comprise a binding domain that binds specifically to an inflammatory cytokine. 
     
     
         2 . The method of  claim 1 , wherein the binding domain is an antibody or an antibody fragment. 
     
     
         3 . The method of  claim 2 , wherein the antibody fragment is an scFv. 
     
     
         4 . The method of  claim 1 , wherein the binding domain is a receptor of an inflammatory cytokine. 
     
     
         5 . The method of  claim 1 , wherein a first exogenous polypeptide of the at least two exogenous polypeptides comprises a binding domain that binds to a first inflammatory cytokine, and a second exogenous polypeptide of the at least two exogenous polypeptides comprises a binding domain that binds to a second inflammatory cytokine, wherein the first and the second inflammatory cytokines are different. 
     
     
         6 . The method of  claim 5 , wherein the first inflammatory cytokine and the second inflammatory cytokine are independently selected from the group consisting of: tumor necrosis factor-alpha, IL-6, interferon-gamma, IL-12, IL-1, G-CSF, IL-8, IL-11, IL-17, IL-18, interferon-alpha, interferon-beta, and tumor necrosis factor beta. 
     
     
         7 . The method of  claim 5 , wherein the enucleated erythroid cells of the population comprise a third exogenous polypeptide present on the surface of the enucleated erythroid cells, wherein the third exogenous polypeptide comprises a binding domain that binds specifically to a third inflammatory cytokine. 
     
     
         8 . The method of  claim 7 , wherein the first, the second, and the third inflammatory cytokines are different. 
     
     
         9 . The method of  claim 8 , wherein the first inflammatory cytokine, the second inflammatory cytokine, and the third inflammatory cytokine are independently selected from the group consisting of: tumor necrosis factor-alpha, IL-6, interferon-gamma, IL-12, IL-1, G-CSF, IL-8, IL-11, IL-17, IL-18, interferon-alpha, interferon-beta, and tumor necrosis factor beta. 
     
     
         10 . The method of  claim 7 , wherein the enucleated erythroid cells of the population comprise a fourth exogenous polypeptide present on the surface of the enucleated erythroid cells, wherein the fourth exogenous polypeptide comprises a binding domain that binds specifically to a fourth inflammatory cytokine. 
     
     
         11 . The method of  claim 10 , wherein the first, the second, the third, and the fourth inflammatory cytokines are different. 
     
     
         12 . The method of  claim 11 , wherein the first inflammatory cytokine, the second inflammatory cytokine, the third inflammatory cytokine, and the fourth inflammatory cytokine are independently selected from the group consisting of: tumor necrosis factor-alpha, IL-6, interferon-gamma, IL-12, IL-1, G-CSF, IL-8, IL-11, IL-17, IL-18, interferon-alpha, interferon-beta, and tumor necrosis factor beta. 
     
     
         13 . The method of  claim 1 , wherein the population of enucleated erythroid cells are reticulocytes. 
     
     
         14 . The method of  claim 1 , wherein the population of enucleated erythroid cells are erythrocytes. 
     
     
         15 . The method of  claim 1 , wherein the enucleated erythroid cells are not hypotonically loaded cells. 
     
     
         16 . The method of  claim 1 , wherein the enucleated erythroid cells exhibit substantially the same osmotic membrane fragility as an isolated, unmodified, uncultured erythroid cell that does not comprise the at least two exogenous polypeptides. 
     
     
         17 . The method of  claim 1 , wherein the enucleated erythroid cells are human enucleated erythroid cells. 
     
     
         18 . The method of  claim 1 , wherein the enucleated erythroid cells were produced by a process comprising:
 providing a nucleated erythroid cell precursor comprising exogenous nucleic acid encoding the two or more exogenous polypeptides; and   culturing the nucleated erythroid cell precursor under conditions suitable for enucleation of the nucleated erythroid cell precursor and for the production of the two or more exogenous polypeptides.   
     
     
         19 . The method of  claim 18 , wherein the process further comprises introducing the exogenous nucleic acid into the nucleated erythroid cell precursor. 
     
     
         20 . The method of  claim 18 , wherein the nucleated erythroid cell precursor is a CD34 +  hematopoietic stem cell.