Fusion Proteins for Modulating Regulatory and Effector T Cells

Abstract

The present invention provides fusion proteins that act on the glucocorticoid-induced TNFR family-related gene (GITR) and OX40 signaling pathway. The proteins of the invention are useful in modulating both regulatory T (Treg) cells and effector T (Teff) cells.

What is claimed is: 
     
         1 . A fusion protein comprising a first domain and a second domain,
 wherein the first domain comprises a binding moiety that binds to a first member from the tumor necrosis family receptor (TNFR) superfamily, and   wherein the second domain comprises a binding moiety that binds to a second member from the TNFR superfamily.   
     
     
         2 . The fusion protein of  claim 1 , wherein the first member from the TNFR superfamily and the second member from the TNFR superfamily are co-expressed in a single cell. 
     
     
         3 . The fusion protein of  claim 1 , wherein the first member from the TNFR superfamily comprises GITR and the second member from the TNFR superfamily comprises OX40. 
     
     
         4 . The fusion protein of  claim 1 , wherein the first domain comprises an antibody, or fragment thereof, that binds GITR. 
     
     
         5 . The fusion protein of  claim 1 , wherein the first domain comprises at least a portion of a ligand that binds to GITR. 
     
     
         6 . The fusion protein of  claim 1 , wherein the second domain comprises an antibody, or fragment thereof, that binds OX40. 
     
     
         7 . The fusion protein of  claim 1 , wherein the second domain comprises at least a portion of the extracellular domain of OX40 ligand. 
     
     
         8 . The fusion protein of  claim 1 , wherein the first domain comprises an antibody, or fragment thereof, that binds GITR and the second domain comprises an antibody, or fragment thereof, that binds OX40. 
     
     
         9 . The fusion protein of  claim 1 , wherein the fusion protein is a type I-II protein fusion wherein the first domain comprises a component of a type I protein and the second domain comprises a component of a type II protein, further wherein the type I protein is a protein having its amino terminus orientated extracellularly in the native protein and the type II is a protein having its carboxyl terminus orientated extracellularly in the native protein. 
     
     
         10 . A method of regulating immune cells, the method comprising contacting a population of immune cells with a fusion protein comprising a first domain and a second domain,
 wherein the first domain comprises a binding moiety that binds to a first member from the TNFR superfamily, and   wherein the second domain comprises a binding moiety that binds to a second member from the TNFR superfamily.   
     
     
         11 . The method of  claim 10 , wherein the first member from the TNFR superfamily comprises GITR and the second member from the TNFR superfamily comprises OX40. 
     
     
         12 . The method of  claim 10 , wherein the population of immune cells comprises regulatory T (Treg) cells and effector T (Teff) cells. 
     
     
         13 . The method of  claim 12 , wherein the fusion protein attenuates Treg suppressive function. 
     
     
         14 . The method of  claim 12 , wherein the fusion protein inhibits Treg generation. 
     
     
         15 . The method of  claim 12 , wherein the fusion protein increases Teff cell proliferation, interleukin-2 production, and NF-κB signaling. 
     
     
         16 . A method of modulating an immune response in a mammal in need thereof, the method comprising administering to the mammal a therapeutically effective amount of a fusion protein comprising a first domain and a second domain,
 wherein the first domain comprises a binding moiety that binds to a first member from the TNFR superfamily, and   wherein the second domain comprises a binding moiety that binds to a second member from the TNFR superfamily.   
     
     
         17 . The method of  claim 16 , wherein the first member from the TNFR superfamily comprises GITR and the second member from the TNFR superfamily comprises OX40. 
     
     
         18 . The method of  claim 16 , wherein the fusion protein modulates Treg cells and Teff cells. 
     
     
         19 . The method of  claim 16 , wherein the mammal is human. 
     
     
         20 . A method of treating or ameliorating cancer in a mammal in need thereof, the method comprising administering to the mammal a therapeutically effective amount of a fusion protein comprising a first domain and a second domain,
 wherein the first domain comprises a binding moiety that binds to a first member from the TNFR superfamily, and   wherein the second domain comprises a binding moiety that binds to a second member from the TNFR superfamily.   
     
     
         21 . The method of  claim 20 , wherein the first member from the TNFR superfamily comprises GITR and the second member from the TNFR superfamily comprises OX40. 
     
     
         22 . The method of  claim 20 , wherein the fusion protein modulates Treg cells and Teff cells. 
     
     
         23 . The method of  claim 20 , wherein the mammal is human. 
     
     
         24 . A method of enhancing an immune response in a mammal in need thereof, the method comprising administering to the mammal a therapeutically effective amount of a fusion protein comprising a first domain and a second domain,
 wherein the first domain comprises a binding moiety that binds to a first member from the TNFR superfamily, and   wherein the second domain comprises a binding moiety that binds to a second member from the TNFR superfamily.   
     
     
         25 . The method of  claim 24 , wherein the first member from the TNFR superfamily comprises GITR and the second member from the TNFR superfamily comprises OX40. 
     
     
         26 . The method of  claim 24 , wherein the fusion protein modulates Treg cells and Teff cells. 
     
     
         27 . The method of  claim 24 , wherein the mammal is human.