Modulation of t cells with bispecific antibodies and fc fusions

Abstract

The present invention relates to methods and compositions for modulating T cells. The modulation includes suppressing or inducing regulatory T cells or cytotoxic T cells.

1 .- 69 . (canceled) 
     
     
         70 . A heterodimeric protein comprising:
 (a) a first monomer comprising:
 (i) a first Fc domain; 
 (ii) an IL-2 protein; and 
   (b) a second monomer comprising:
 (i) a second Fc domain. 
   
     
     
         71 . The heterodimeric protein according to  claim 70 , wherein the first and second Fc domains are variant Fc domains comprising amino acid variants selected from the group consisting of: L368D/K370S and S364K; L368D/K370S and S364K/E357L; L368D/K370S and S364K/E357Q; T411E/K360E/Q362E and D401K; L368E/K370S and S364K; and K370S and S364K/E357Q, wherein numbering is according to EU index as in Kabat. 
     
     
         72 . The heterodimeric protein according to  claim 71 , wherein the first and/or second variant Fc domain further comprises an amino acid variant independently selected from the group consisting of: 236R, 328R, 330L, 236R/328R, 239D/332E, E233P/L234V/L235A/G236del/S239K, E233P/L234V/L235A/G236del/S239K/A327G, E233P/L234V/L235A/G236del/S267K/A327G, E233P/L234V/L235A/G236del, and E233P/L234V/L235A/G236del/S267K, wherein numbering is according to EU index as in Kabat. 
     
     
         73 . The heterodimeric protein according to  claim 70 ,
 wherein the first Fc domain is a variant Fc domain comprising amino acid variants E233P/L234V/L235A/G236del/S267K and S364K/E357Q, and   wherein the second Fc domain is a variant Fc domain comprising amino acid variants E233P/L234V/L235A/G236del/S267K and L368D/K370S, wherein numbering is according to EU index as in Kabat.   
     
     
         74 . The heterodimeric protein according to  claim 70 , wherein the IL-2 protein is an IL-2 variant having reduced ability to bind to IL-2Rβ, IL-2Rγ, and/or IL-2Rα. 
     
     
         75 . The heterodimeric protein according to  claim 70 , wherein the IL-2 protein is an IL-2 variant having increased ability to bind to IL-2Rα. 
     
     
         76 . The heterodimeric protein according to  claim 70 , wherein the IL-2 protein is an IL-2 variant having reduced ability to bind to IL-2Rβ and/or IL-2Rγ and increased ability to bind to IL-2Rα. 
     
     
         77 . A method of inducing T cells, the method comprising contacting the T cells with a composition comprising a heterodimeric protein according to  claim 70 . 
     
     
         78 . The method according to  claim 77 , wherein the T cells are regulatory T cells (Tregs). 
     
     
         79 . A method of suppressing T cells, the method comprising contacting the T cells with a composition comprising a heterodimeric protein according to  claim 70 . 
     
     
         80 . A method A method of treating an autoimmune disease in a subject, the method comprising administering to the subject a composition comprising a heterodimeric protein according to  claim 70 . 
     
     
         81 . A method A method of treating a cancer in a subject, the method comprising administering to the subject a composition comprising a heterodimeric protein according to  claim 70 . 
     
     
         82 . A nucleic acid composition encoding a heterodimeric protein, the nucleic acid composition comprising:
 a) a first nucleic acid encoding the first monomer of  claim 70 ; and   b) a second nucleic acid encoding the second monomer of  claim 70 .   
     
     
         83 . A host cell comprising the nucleic acid composition of  claim 82 . 
     
     
         84 . A method of making a heterodimeric protein comprising culturing a host cell according to  claim 83  under conditions whereby the heterodimeric protein is produced. 
     
     
         85 . A method of purifying a heterodimeric protein according to  claim 70 , the method comprising:
 (a) providing a composition comprising the heterodimeric protein;   (b) loading the composition onto an ion exchange column; and   (c) collecting a fraction containing the heterodimeric protein.   
     
     
         86 . An IL-2 Fc fusion comprising:
 (a) a first monomer comprising:
 (i) a first Fc domain; 
 (ii) a first IL-2 protein; and 
   (b) a second monomer comprising
 (i) a second Fc domain; and 
 (ii) a second IL-2 protein. 
   
     
     
         87 . The IL-2 Fc fusion according to  claim 86 , wherein the first and/or second IL-2 protein is an IL-2 variant engineered to have reduced ability to bind to IL-2Rβ, IL-2Rγ, and/or IL-2Rα. 
     
     
         88 . A method of inducing T cells, the method comprising contacting the T cells with an IL-2 Fc fusion according to  claim 86 . 
     
     
         89 . The method according to  claim 88 , wherein the T cells are regulatory T cells (Tregs). 
     
     
         90 . A method of suppressing T cells, the method comprising contacting the T cells with an IL-2 Fc fusion according to  claim 86 . 
     
     
         91 . A method A method of treating an autoimmune disease in a subject, the method comprising administering to the subject an IL-2 Fc fusion according to  claim 86 . 
     
     
         92 . A method A method of treating a cancer in a subject, the method comprising administering to the subject an IL-2 Fc fusion according to  claim 86 . 
     
     
         93 . A nucleic acid composition encoding an IL-2 fusion, the nucleic acid composition comprising:
 a) a first nucleic acid encoding the first monomer of  claim 86 ; and   b) a second nucleic acid encoding the second monomer of  claim 86 .   
     
     
         94 . A host cell comprising the one or more nucleic acids of  claim 86 . 
     
     
         95 . A method of making an IL-2 Fc fusion, the method comprising culturing a host cell according to  claim 94  under conditions whereby the IL-2 Fc fusion is produced. 
     
     
         96 . A method of purifying an IL-2 Fc fusion according to  claim 86 , the method comprising:
 (a) providing a composition comprising the IL-2 Fc fusion;   (b) loading the composition onto an ion exchange column; and   (c) collecting a fraction containing the IL-2 Fc fusion.