Antibody-cytokine engrafted proteins and methods of use for immune related disorders

Abstract

The present disclosure provides antibody cytokine engrafted proteins that bind to and stimulate intracellular signaling through a high affinity interleukin receptor. The antibody cytokine engrafted proteins find use in enhancing anti-inflammatory cell responses, and reducing pro-inflammatory effects in the treatment, amelioration and prevention of immune related disorders such as Type 1 Diabetes.

What is claimed is: 
     
         1 . An antibody cytokine engrafted protein that comprises a heavy chain that comprises SEQ ID NO:22 and a light chain that comprises SEQ ID NO: 35. 
     
     
         2 . The antibody cytokine engrafted protein of  claim 1 , wherein the heavy chain comprises a heavy chain variable region (VH) that comprises SEQ ID NO: 20, and the light chain comprises a light chain variable region (VL) that comprises SEQ ID NO: 33. 
     
     
         3 . The antibody cytokine engrafted protein of  claim 1 , wherein the antibody cytokine engrafted protein stimulates Treg cell proliferation greater than native IL2 or aldesleukin. 
     
     
         4 . The antibody cytokine engrafted protein of  claim 1 , wherein the antibody cytokine engrafted protein stimulates CD8 T effector cell proliferation less than IL2 or aldesleukin. 
     
     
         5 . A nucleic acid encoding an antibody cytokine engrafted protein that comprises a polynucleotide encoding a heavy chain of SEQ ID NO:23 and a polynucleotide encoding a light chain of SEQ ID NO:36. 
     
     
         6 . A recombinant host cell comprising the nucleic acid of  claim 5 . 
     
     
         7 . The recombinant host cell of  claim 6 , which is a mammalian cell. 
     
     
         8 . The recombinant host cell of  claim 7 , wherein the mammalian cell is a CHO cell. 
     
     
         9 . A pharmaceutical composition comprising the antibody cytokine engrafted protein of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         10 . An antibody cytokine engrafted protein comprising a heavy chain variable region (VH) that comprises SEQ ID NO: 20 and a light chain variable region (VL) that comprises SEQ ID NO: 33. 
     
     
         11 . The antibody cytokine engrafted protein of  claim 10 , wherein the VH consists of SEQ ID NO: 20 and the VL consists of SEQ ID NO: 33. 
     
     
         12 . The antibody cytokine engrafted protein of  claim 10 , which comprises a heavy chain that comprises SEQ ID NO:22 and a light chain that comprises SEQ ID NO: 35. 
     
     
         13 . The antibody cytokine engrafted protein of  claim 10 , wherein the antibody cytokine engrafted protein stimulates Treg cell proliferation greater than native IL2 or aldesleukin. 
     
     
         14 . The antibody cytokine engrafted protein of  claim 10 , wherein the antibody cytokine engrafted protein stimulates CD8 T effector cell proliferation less than IL2 or aldesleukin. 
     
     
         15 . The antibody cytokine engrafted protein of  claim 10 , further comprising an IgG class antibody Fc region. 
     
     
         16 . The antibody cytokine engrafted protein of  claim 15 , wherein the IgG class is selected from IgG1, IgG2, or IgG4. 
     
     
         17 . The antibody cytokine engrafted protein of  claim 10 , further comprising a modified Fc region having reduced effector function. 
     
     
         18 . The antibody cytokine engrafted protein of  claim 17 , wherein the modified Fc region comprises at least one mutation selected from D265A, P329A, P329G, N297A, L234A, and L235A. 
     
     
         19 . The antibody cytokine engrafted protein of  claim 17 , wherein the modified Fc region comprises a combination of mutations selected from D265A/P329A, D265A/N297A, L234A/L235A, and P329G/L234A/L235A. 
     
     
         20 . The antibody cytokine engrafted protein of  claim 10 , comprising a modified Fc region comprising the mutation D265A/P329A, wherein the antibody cytokine engrafted protein simulates less expansion of NK cells when compared to aldesleukin. 
     
     
         21 . An antibody cytokine engrafted protein comprising:
 (i) a heavy chain variable region (VH) that comprises a HCDR1 of SEQ ID NO: 17, a HCDR2 of SEQ ID NO: 18, a HCDR3 of SEQ ID NO: 19; and   (ii) a light chain variable region (VL) that comprises a LCDR1 of SEQ ID NO: 30, a LCDR2 of SEQ ID NO: 31, and a LCDR3 of SEQ ID NO: 32;   wherein the VH comprises at least 90% sequence identity to SEQ ID NO: 20; and   wherein the VL comprises at least 90% sequence identity to SEQ ID NO: 33.   
     
     
         22 . The antibody cytokine engrafted protein of  claim 21 , further comprising a modified Fc region having reduced effector function. 
     
     
         23 . The antibody cytokine engrafted protein of  claim 21 , wherein the modified Fc region comprises at least one mutation selected from D265A, P329A, P329G, N297A, L234A, and L235A. 
     
     
         24 . The antibody cytokine engrafted protein of  claim 21 , wherein the modified Fc region comprises a combination of mutations selected from D265A/P329A, D265A/N297A, L234A/L235A, and P329G/L234A/L235A.