IL15/IL15Ralpha HETERODIMERIC Fc-FUSION PROTEINS

Abstract

The present invention is directed to novel IL15/IL15Rα heterodimeric Fc fusion proteins.

What is claimed is: 
     
         1 . A heterodimeric protein comprising:
 a) a first fusion protein comprising a first protein domain and a first Fc domain, wherein said first protein domain is covalently attached to the N-terminus of said first Fc domain using a first domain linker;   b) a second fusion protein comprising a second protein domain and a second Fc domain, wherein said second protein domain is covalently attached to the N-terminus of said Fc domain using a second domain linker;   wherein said first and said second Fc domains have a set of amino acid substitutions selected from the group consisting of S267K/L368D/K370S:S267K/LS364K/E357Q; S364K/E357Q:L368D/K370S; L368D/K370S:S364K; L368E/K370S:S364K; T411T/E360E/Q362E:D401K; L368D/K370S:S364K/E357L and K370S:S364K/E357Q, according to EU numbering and wherein said first protein domain comprises an IL15 protein and said second protein domain comprises an IL15Rα protein.   
     
     
         2 . The heterodimeric protein according to  claim 1 , wherein said first and/or said second Fc domains have an additional set of amino acid substitutions comprising Q295E/N384D/Q418E/N421D, according to EU numbering. 
     
     
         3 . The heterodimeric protein according to  claim 1  or  2 , wherein said first and/or said second Fc domains have an additional set of amino acid substitutions consisting of G236R/L328R, E233P/L234V/L235A/G236del/S239K, E233P/L234V/L235A/G236del/S267K, E233P/L234V/L235A/G236del/S239K/A327G, E233P/L234V/L235A/G236del/S267K/A327G and E233P/L234V/L235A/G236del, according to EU numbering. 
     
     
         4 . The heterodimeric protein according to any one of  claims 1  to  3 , wherein said IL15 protein has a polypeptide sequence selected from the group consisting of SEQ ID NO:1 (full-length human IL15) and SEQ ID NO:2 (truncated human IL15), and said IL15Rα protein has a polypeptide sequence selected from the group consisting of SEQ ID NO:3 (full-length human IL15Rα) and SEQ ID NO:4 (sushi domain of human IL15Rα). 
     
     
         5 . The heterodimeric protein according to any one of  claims 1  to  4 , wherein said IL15 protein has one or more amino acid substitutions selected from the group consisting of N1D, N4D, D8N, D30N, D61N, E64Q, N65D, and Q108E. 
     
     
         6 . The heterodimeric protein according to any one of  claims 1  to  5 , wherein said IL15 protein and said IL15Rα protein have a set of amino acid substitutions or additions selected from the group consisting of E87C:D96/P97/C98; E87C:D96/C97/A98; V49C:S40C; L52C:S40C; E89C:K34C; Q48C:G38C; E53C:L42C; C42S:A37C; and L45C:A37C, respectively. 
     
     
         7 . The heterodimeric protein according to any one of  claims 1  to  6 , wherein said heterodimeric protein comprises:
 i) said first fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP15902) and said second fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP15908), 
 ii) said first fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP15902) and said second fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP15909), 
 iii) said first fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP16479) and said second fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP15908), 
 iv) said first fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP15902) and said second fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP16481), 
 v) said first fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP15902) and said second fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP16483), 
 vi) said first fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP16479) and said second fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP15909), 
 vii) said first fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP16479) and said second fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP16481), 
 viii) said first fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP16480) and said second fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP16482), 
 ix) said first fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP16480) and said second fusion protein h having as a polypeptide sequence of SEQ ID NO:XX (XENP15909), 
 x) said first fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP17064) and said second fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP17038), 
 xi) said first fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP17064) and said second fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP17040), or 
 xii) said first fusion protein having a polypeptide sequence of SEQ ID NO:XX (17062) and said second fusion protein having a polypeptide sequence of SEQ ID NO:XX (17044), 
 xiii) said first fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP17686) and said second fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP15908), 
 xiv) said first fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP17687) and said second fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP15908), 
 xv) said first fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP17688) and said second fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP15908), 
 xvi) said first fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP17689) and said second fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP15908), 
 xvii) said first fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP17690) and said second fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP15908), 
 xviii) said first fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP17691) and said second fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP15908), 
 xix) said first fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP17692) and said second fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP15908), 
 xx) said first fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP17693) and said second fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP15908), 
 xxi) said first fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP17694) and said second fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP15908), 
 xxii) said first fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP17695) and said second fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP15908), 
 xxiii) said first fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP17696) and said second fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP15908), 
 xxiv) said first fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP17697) and said second fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP15908), 
 xxv) said first fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP17698) and said second fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP15908), 
 xxvi) said first fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP17699) and said second fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP15908), 
 xxvii) said first fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP17701) and said second fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP15908), 
 xxviii) said first fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP17691) and said second fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP15908), 
 xxix) said first fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP17702) and said second fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP15908), 
 xxx) said first fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP17703) and said second fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP15908), 
 xxxi) said first fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP17704) and said second fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP15908), 
 xxxii) said first fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP17705) and said second fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP15908), 
 xxxiii) said first fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP18295) and said second fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP17761), 
 xxxiv) said first fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP18783) and said second fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP15908), 
 xxxv) said first fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP18784) and said second fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP15908), 
 xxxvi) said first fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP18786) and said second fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP15908), 
 xxxvii) said first fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP18788) and said second fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP15908), 
 xxxviii) said first fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP19242) and said second fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP16481), or 
 xxxix) said first fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP19243) and said second fusion protein having a polypeptide sequence of SEQ ID NO:XX (XENP16481). 
 
     
     
         8 . The heterodimeric protein according to any one of  claims 1  to  7 , wherein said first protein domain is covalently attached to the N-terminus of said first Fc domain directly and without using said first domain linker and/or said second protein domain is covalently attached to the N-terminus of said second Fc domain directly and without using said second domain linker. 
     
     
         9 . The heterodimeric protein according to any one of  claims 1  to  6 , wherein said heterodimeric protein is selected from the group consisting of XENP20818, XENP20819, XENP21471, XENP21472, XENP21473, XENP21474, XENP21475, XENP21476, XENP21477, XENP22013, XENP22815, XENP22816, XENP22817, XENP22818, XENP22819, XENP22820, XENP22821, XENP22822, XENP22823, XENP22824, XENP22825, XENP22826, XENP22827, XENP22828, XENP22829, XENP22830, XENP22831, XENP22832, XENP22833, XENP22834, XENP23343, XENP23504, XENP23554, XENP23555, XENP23557, XENP23559, XENP24019, XENP24020, XENP24045, XENP24051, XENP24052, XENP24113, XENP24301, XENP24306, and XENP24341. 
     
     
         10 . A nucleic acid composition encoding the first fusion protein of any one of  claims 1  to  9 . 
     
     
         11 . A nucleic acid composition encoding the second fusion protein of any one of  claims 1  to  10 . 
     
     
         12 . An expression vector comprising the nucleic acid composition of  claim 10 . 
     
     
         13 . An expression vector comprising the nucleic acid composition of  claim 11 . 
     
     
         14 . The expression vector of  claim 13  further comprising the nucleic acid composition of  claim 10 . 
     
     
         15 . A host cell comprising one or more expression vectors of any one of  claim 12  to  claim 14 . 
     
     
         16 . A heterodimeric protein comprising:
 a) a fusion protein comprising a first protein domain, a second protein domain, and a first Fc domain, wherein said first protein domain is covalently attached to the N-terminus of said second protein domain using a first domain linker, and wherein said second protein domain is covalently attached to the N-terminus of said first Fc domain using a second domain linker;   b) a second Fc domain;
 wherein said first and said second Fc domains have a set of amino acid substitutions selected from the group consisting of S267K/L368D/K370S:S267K/LS364K/E357Q; S364K/E357Q:L368D/K370S; L368D/K370S:S364K; L368E/K370S:S364K; T411T/E360E/Q362E:D401K; L368D/K370S:S364K/E357L and K370S:S364K/E357Q, according to EU numbering and wherein said first protein domain comprises an IL15Rα protein and said second protein domain comprises an IL15 protein. 
   
     
     
         17 . The heterodimeric protein according to  claim 16 , wherein said first and/or said second Fc domains have an additional set of amino acid substitutions comprising Q295E/N384D/Q418E/N421D, according to EU numbering. 
     
     
         18 . The heterodimeric protein according to  claim 16  or  17 , wherein said first and/or said second Fc domains have an additional set of amino acid substitutions consisting of G236R/L328R, E233P/L234V/L235A/G236del/S239K, E233P/L234V/L235A/G236del/S267K, E233P/L234V/L235A/G236del/S239K/A327G, E233P/L234V/L235A/G236del/S267K/A327G and E233P/L234V/L235A/G236del, according to EU numbering. 
     
     
         19 . The heterodimeric protein according to any one of  claims 16  to  18 , wherein said IL15 protein has a polypeptide sequence selected from the group consisting of SEQ ID NO:1 (full-length human IL15) and SEQ ID NO:2 (truncated human IL15), and said IL15Rα protein has a polypeptide sequence selected from the group consisting of SEQ ID NO:3 (full-length human IL15Rα) and SEQ ID NO:4 (sushi domain of human IL15Rα). 
     
     
         20 . The heterodimeric protein according to any one of  claims 16  to  19 , wherein said IL15 protein and said IL15Rα protein have a set of amino acid substitutions selected from the group consisting of E87C:D96/P97/C98; E87C:D96/C97/A98; V49C:S40C; L52C:S40C; E89C:K34C; Q48C:G38C; E53C:L42C; C42S:A37C; and L45C:A37C, respectively. 
     
     
         21 . The heterodimeric protein according to any one of  claims 16  to  20 , wherein said first fusion protein has a polypeptide sequence of SEQ ID NO:XX (16478) and said Fc domain has a polypeptide sequence of SEQ ID NO:XX (8924). 
     
     
         22 . The heterodimeric protein according to any one of  claims 16  to  21 , wherein said heterodimeric protein is XENP21478. 
     
     
         23 . A nucleic acid composition encoding the fusion protein of any one of  claim 16  to  claim 22 . 
     
     
         24 . A nucleic acid composition encoding the second Fc domain of any one of  claims 16  to  22 . 
     
     
         25 . An expression vector comprising the nucleic acid composition of  claim 23 . 
     
     
         26 . An expression vector comprising the nucleic acid composition of  claim 24 . 
     
     
         27 . The expression vector of  claim 26 , further comprising the nucleic acid composition of  claim 23 . 
     
     
         28 . A host cell comprising one or two expression vectors of any one of  claim 25  to  claim 27 . 
     
     
         29 . A heterodimeric protein comprising:
 a) a fusion protein comprising a first protein domain and a first Fc domain, wherein said first protein domain is covalently attached to the N-terminus of said first Fc domain using a domain linker;   b) a second Fc domain; and   c) a second protein domain noncovalently attached to said first protein domain;
 wherein said first and said second Fc domains have a set of amino acid substitutions selected from the group consisting of S267K/L368D/K370S:S267K/LS364K/E357Q; S364K/E357Q:L368D/K370S; L368D/K370S:S364K; L368E/K370S:S364K; T411T/E360E/Q362E:D401K; L368D/K370S:S364K/E357L and K370S:S364K/E357Q, according to EU numbering and wherein said first protein domain comprises an IL15Rα and said second protein domain comprises an IL15 protein. 
   
     
     
         30 . The heterodimeric protein according to  claim 29 , wherein said first and/or said second Fc domains have an additional set of amino acid substitutions comprising Q295E/N384D/Q418E/N421D, according to EU numbering. 
     
     
         31 . The heterodimeric protein according to  claim 29  or  30 , wherein said first and/or said second Fc domains have an additional set of amino acid substitutions consisting of G236R/L328R, E233P/L234V/L235A/G236del/S239K, E233P/L234V/L235A/G236del/S267K, E233P/L234V/L235A/G236del/S239K/A327G, E233P/L234V/L235A/G236del/S267K/A327G and E233P/L234V/L235A/G236del, according to EU numbering. 
     
     
         32 . The heterodimeric protein according to any one of  claims 29  to  31 , wherein said IL15 protein has a polypeptide sequence selected from the group consisting of SEQ ID NO:1 (full-length human IL15) and SEQ ID NO:2 (truncated human IL15), and said IL15Rα protein has a polypeptide sequence selected from the group consisting of SEQ ID NO:3 (full-length human IL15Rα) and SEQ ID NO:4 (sushi domain of human IL15Rα). 
     
     
         33 . The heterodimeric protein according to any one of  claims 29  to  32 , wherein said IL15 protein and said IL15Rα protein have a set of amino acid substitutions selected from the group consisting of E87C:D96/P97/C98; E87C:D96/C97/A98; V49C:S40C; L52C:S40C; E89C:K34C; Q48C:G38C; E53C:L42C; C42S:A37C; and L45C:A37C, respectively. 
     
     
         34 . The heterodimeric protein according to any one of  claims 29  to  33 , wherein said fusion protein has a polypeptide sequence selected from the group consisting of SEQ ID NO:XX (16481), SEQ ID NO:XX (17034), SEQ ID NO:XX (17038), SEQ ID NO:XX (17036), SEQ ID NO:XX (17039), SEQ ID NO:XX (17040), SEQ ID NO:XX (17044), SEQ ID NO:XX (17041), SEQ ID NO:XX (17043), SEQ ID NO:XX (17045), SEQ ID NO:XX (17042), SEQ ID NO:XX (15908), and SEQ ID NO:XX (17603). 
     
     
         35 . The heterodimeric protein according to any one of  claims 29  to  34 , wherein said second Fc domain has a polypeptide sequence of SEQ ID NO:XX (8793) or SEQ ID NO:XX (8927). 
     
     
         36 . The heterodimeric protein according to any one of  claims 29  to  35 , wherein said second protein domain has a polypeptide sequence selected from the group consisting of SEQ ID NO:XX (16484), SEQ ID NO:XX (17074), SEQ ID NO:XX (17071), SEQ ID NO:XX (17072), SEQ ID NO:XX (17075), SEQ ID NO:XX (17070), SEQ ID NO:XX (17073), and SEQ ID NO:XX (17083). 
     
     
         37 . The heterodimeric protein according to any one of  claims 29  to  36 , wherein said heterodimer protein comprises
 i) said fusion protein having a polypeptide sequence of SEQ ID NO:XX (16481), said second Fc domain having a polypeptide sequence of SEQ ID NO:XX (8793), and a second protein domain having a polypeptide sequence of SEQ ID NO:XX (16484); 
 ii) said fusion protein having a polypeptide sequence of SEQ ID NO:XX (17034), said second Fc domain having a polypeptide sequence of SEQ ID NO:XX (8793), and a second protein domain having a polypeptide sequence of SEQ ID NO:XX (16484); 
 iii) said fusion protein having a polypeptide sequence of SEQ ID NO:XX (17038), said second Fc domain having a polypeptide sequence of SEQ ID NO:XX (8793), and a second protein domain having a polypeptide sequence of SEQ ID NO:XX (16484); 
 iv) said fusion protein having a polypeptide sequence of SEQ ID NO:XX (17036), said second Fc domain having a polypeptide sequence of SEQ ID NO:XX (8793), and a second protein domain having a polypeptide sequence of SEQ ID NO:XX (16484); 
 v) said fusion protein having a polypeptide sequence of SEQ ID NO:XX (17038), said second Fc domain having a polypeptide sequence of SEQ ID NO:XX (8793), and a second protein domain having a polypeptide sequence of SEQ ID NO:XX (17074); 
 vi) said fusion protein having a polypeptide sequence of SEQ ID NO:XX (17039), said second Fc domain having a polypeptide sequence of SEQ ID NO:XX (8793), and a second protein domain having a polypeptide sequence of SEQ ID NO:XX (17074); 
 vii) said fusion protein having a polypeptide sequence of SEQ ID NO:XX (17040), said second Fc domain having a polypeptide sequence of SEQ ID NO:XX (8793), and a second protein domain having a polypeptide sequence of SEQ ID NO:XX (17074); 
 viii) said fusion protein having a polypeptide sequence of SEQ ID NO:XX (17044), said second Fc domain having a polypeptide sequence of SEQ ID NO:XX (8793), and a second protein domain having a polypeptide sequence of SEQ ID NO:XX (17071); 
 ix) said fusion protein having a polypeptide sequence of SEQ ID NO:XX (17044), said second Fc domain having a polypeptide sequence of SEQ ID NO:XX (8793), and a second protein domain having a polypeptide sequence of SEQ ID NO:XX (17072); 
 x) said fusion protein having a polypeptide sequence of SEQ ID NO:XX (17075), said second Fc domain having a polypeptide sequence of SEQ ID NO:XX (8793), and a second protein domain having a polypeptide sequence of SEQ ID NO:XX (17041); 
 xi) said fusion protein having a polypeptide sequence of SEQ ID NO:XX (17043), said second Fc domain having a polypeptide sequence of SEQ ID NO:XX (8793), and a second protein domain having a polypeptide sequence of SEQ ID NO:XX (17070); 
 xii) said fusion protein having a polypeptide sequence of SEQ ID NO:XX (17045), said second Fc domain having a polypeptide sequence of SEQ ID NO:XX (8793), and a second protein domain having a polypeptide sequence of SEQ ID NO:XX (17073); 
 xiii) said fusion protein having a polypeptide sequence of SEQ ID NO:XX (17042), said second Fc domain having a polypeptide sequence of SEQ ID NO:XX (8793), and a second protein domain having a polypeptide sequence of SEQ ID NO:XX (17083); or 
 xiv) said fusion protein having a polypeptide sequence of SEQ ID NO:XX (15908), said second Fc domain having a polypeptide sequence of SEQ ID NO:XX (8793), and a second protein domain having a polypeptide sequence of SEQ ID NO:XX (16484). 
 
     
     
         38 . The heterodimeric protein according to any one of  claims 29  to  37 , wherein said heterodimer protein is selected from the group consisting of XENP21479, XENP22357, XENP22354, XENP22355, XENP22356, XENP22357, XENP22358, XENP22359, XENP22360, XENP22361, XENP22362, XENP22363, XENP22364, XENP22365, XENP22366, XENP22637, XENP24349, and XENP24383. 
     
     
         39 . A nucleic acid composition encoding the fusion protein of any one of  claim 29  to  claim 38 . 
     
     
         40 . A nucleic acid composition encoding the second Fc domain of any one of  claims 29  to  37 . 
     
     
         41 . An expression vector comprising the nucleic acid composition of  claim 39 . 
     
     
         42 . An expression vector comprising the nucleic acid composition of  claim 40 . 
     
     
         43 . The expression vector of  claim 42 , further comprising the nucleic acid composition of  claim 39 . 
     
     
         44 . The expression vector of any one of  claims 41  to  43 , further comprising a nucleic acid composition encoding said second protein domain. 
     
     
         45 . A host cell comprising one or more expression vectors of any one of  claim 41  to  claim 44 . 
     
     
         46 . A heterodimeric protein comprising:
 a) a first fusion protein comprising a first protein domain and a first Fc domain, wherein said first protein domain is covalently attached to the N-terminus of said first Fc domain using a domain linker;   b) a second fusion protein comprising a second heavy chain comprising a second protein domain and a first second heavy chain comprising a second Fc domain, wherein said second protein domain is covalently attached to the C-terminus of said second Fc domain using a domain linker;   c) a third protein domain noncovalently attached to said first protein domain of said first fusion protein; and   d) a fourth protein domain noncovalently attached to said second protein domain of said second fusion protein,   wherein said first and said second Fc domains have a set of amino acid substitutions selected from the group consisting of S267K/L368D/K370S:S267K/LS364K/E357Q; S364K/E357Q:L368D/K370S; L368D/K370S:S364K; L368E/K370S:S364K; T411T/E360E/Q362E:D401K; L368D/K370S:S364K/E357L and K370S:S364K/E357Q, according to EU numbering and wherein said first protein domain and said second protein domain comprise an IL15Rα protein, and wherein said third protein domain and said fourth protein domain comprises an IL15 protein.   
     
     
         47 . The heterodimeric protein according to  claim 46 , wherein said first and/or said second Fc domains have an additional set of amino acid substitutions comprising Q295E/N384D/Q418E/N421D, according to EU numbering. 
     
     
         48 . The heterodimeric protein according to  claim 46  or  47 , wherein said first and/or said second Fc domains have an additional set of amino acid substitutions consisting of G236R/L328R, E233P/L234V/L235A/G236del/S239K, E233P/L234V/L235A/G236del/S267K, E233P/L234V/L235A/G236del/S239K/A327G, E233P/L234V/L235A/G236del/S267K/A327G and E233P/L234V/L235A/G236del, according to EU numbering. 
     
     
         49 . The heterodimeric protein according to any one of  claims 46  to  48 , wherein said IL15 protein has a polypeptide sequence selected from the group consisting of SEQ ID NO:1 (full-length human IL15) and SEQ ID NO:2 (truncated human IL15), and said IL15Rα protein has a polypeptide sequence selected from the group consisting of SEQ ID NO:3 (full-length human IL15Rα) and SEQ ID NO:4 (sushi domain of human IL15Rα). 
     
     
         50 . The heterodimeric protein according to any one of  claims 46  to  49 , wherein said IL15 protein and said IL15Rα protein have a set of amino acid substitutions selected from the group consisting of E87C:D96/P97/C98; E87C:D96/C97/A98; V49C:S40C; L52C:S40C; E89C:K34C; Q48C:G38C; E53C:L42C; C42S:A37C; and L45C:A37C, respectively. 
     
     
         51 . The heterodimeric protein according to any one of  claims 46  to  50 , wherein said heterodimer protein comprises:
 i) said first fusion protein has a polypeptide sequence of SEQ ID NO:XX (17023) said second fusion protein has a polypeptide sequence of SEQ ID NO:XX (17023), said third protein domain has a polypeptide sequence of SEQ ID NO:XX (16484), and said fourth protein domain has a polypeptide sequence of SEQ ID NO:XX (16484) or 
 ii) said first fusion protein has a polypeptide sequence of SEQ ID NO:XX (17581), said second fusion protein has a polypeptide sequence of SEQ ID NO:XX (17581), said third protein domain has a polypeptide sequence of SEQ ID NO:XX (17074), and said fourth protein domain has a polypeptide sequence of SEQ ID NO:XX (17074). 
 
     
     
         52 . The heterodimeric protein according to any one of  claims 46  to  51 , wherein said heterodimeric protein is XENP21978, XENP22634, XENP24342, and XENP24306. 
     
     
         53 . A nucleic acid composition encoding the first fusion protein of any one of  claims 46  to  52 . 
     
     
         54 . A nucleic acid composition encoding the second fusion protein of any one of  claims 46  to  53 . 
     
     
         55 . An expression vector comprising the nucleic acid composition of  claim 39 . 
     
     
         56 . An expression vector comprising the nucleic acid composition of  claim 55 . 
     
     
         57 . The expression vector of  claim 56 , further comprising the nucleic acid composition of  claim 53 . 
     
     
         58 . The expression vector of any one of  claims 55  to  57 , further comprising a nucleic acid composition encoding said third protein domain. 
     
     
         59 . The expression vector of any one of  claims 55  to  58 , further comprising a nucleic acid composition encoding said fourth protein domain. 
     
     
         60 . A host cell comprising one or more expression vectors of any one of  claim 56  to  claim 59 . 
     
     
         61 . A heterodimeric protein comprising:
 a) a first fusion protein comprising a first Fc domain and a first protein domain, wherein said first Fc domain is covalently attached to the N-terminus of said first protein domain using a domain linker;   b) a second Fc domain, and   c) a second protein domain noncovalently attached to said first protein domain of said first fusion protein;   wherein said first and said second Fc domains have a set of amino acid substitutions selected from the group consisting of S267K/L368D/K370S:S267K/LS364K/E357Q; S364K/E357Q:L368D/K370S; L368D/K370S:S364K; L368E/K370S:S364K; T411T/E360E/Q362E:D401K; L368D/K370S:S364K/E357L and K370S:S364K/E357Q, according to EU numbering and wherein said first protein domain comprises an IL15Rα protein and said second protein domain comprises an IL15 protein.   
     
     
         62 . The heterodimeric protein according to  claim 61 , wherein said first and/or said second Fc domains have an additional set of amino acid substitutions comprising Q295E/N384D/Q418E/N421D, according to EU numbering. 
     
     
         63 . The heterodimeric protein according to  claim 61  or  62 , wherein said first or said second Fc domains have an additional set of amino acid substitutions consisting of G236R/L328R, E233P/L234V/L235A/G236del/S239K, E233P/L234V/L235A/G236del/S267K, E233P/L234V/L235A/G236del/S239K/A327G, E233P/L234V/L235A/G236del/S267K/A327G and E233P/L234V/L235A/G236del, according to EU numbering. 
     
     
         64 . The heterodimeric protein according to any one of  claims 61  to  63 , wherein said IL15 protein has a polypeptide sequence selected from the group consisting of SEQ ID NO:1 (full-length human IL15) and SEQ ID NO:2 (truncated human IL15), and said IL15Rα protein has a polypeptide sequence selected from the group consisting of SEQ ID NO:3 (full-length human IL15Rα) and SEQ ID NO:4 (sushi domain of human IL15Rα). 
     
     
         65 . The heterodimeric protein according to any one of  claims 61  to  64 , wherein said IL15 protein and said IL15Rα protein have a set of amino acid substitutions selected from the group consisting of E87C:D96/P97/C98; E87C:D96/C97/A98; V49C:S40C; L52C:S40C; E89C:K34C; Q48C:G38C; E53C:L42C; C42S:A37C; and L45C:A37C, respectively. 
     
     
         66 . The heterodimeric protein according to any one of  claims 61  to  65 , wherein heterodimeric protein comprises
 i) said first fusion protein having a polypeptide sequence of SEQ ID NO: XX (17603), said second Fc domain having a polypeptide sequence of SEQ ID NO: XX (8927), and said second protein domain having a polypeptide sequence of SEQ ID NO: XX (16484); or 
 ii) said first fusion protein having a polypeptide sequence of SEQ ID NO: XX (17605), said second Fc domain having a polypeptide sequence of SEQ ID NO: XX (8927), and said second protein domain having a polypeptide sequence of SEQ ID NO: XX (17074). 
 
     
     
         67 . The heterodimeric protein according to any one of  claims 61  to  66 , wherein said heterodimeric protein is XENP22637 or XENP22639. 
     
     
         68 . A nucleic acid composition encoding the first fusion protein of any one of  claims 61  to  67 . 
     
     
         69 . A nucleic acid composition encoding the second Fc domain of any one of  claims 61  to  67 . 
     
     
         70 . An expression vector comprising the nucleic acid composition of  claim 68 . 
     
     
         71 . An expression vector comprising the nucleic acid composition of  claim 69 . 
     
     
         72 . The expression vector of  claim 71 , further comprising the nucleic acid composition of  claim 68 . 
     
     
         73 . The expression vector of any one of  claims 70  to  72 , further comprising a nucleic acid composition encoding said second protein domain. 
     
     
         74 . A host cell comprising one or more expression vectors of any one of  claim 70  to  claim 73 . 
     
     
         75 . A heterodimeric protein selected from the group consisting of XENP20818, XENP20819, XENP21471, XENP21472, XENP21473, XENP21474, XENP21475, XENP21476, XENP21477, XENP22013, XENP22815, XENP22816, XENP22817, XENP22818, XENP22819, XENP22820, XENP22821, XENP22822, XENP22823, XENP22824, XENP22825, XENP22826, XENP22827, XENP22828, XENP22829, XENP22830, XENP22831, XENP22832, XENP22833, XENP22834, XENP23343, XENP23504, XENP23554, XENP23555, XENP23557, XENP23559, XENP24019, XENP24020, XENP24045, XENP24051, XENP24052, XENP24113, XENP24301, XENP24306, XENP24341, XENP21478, XENP21479, XENP22357, XENP22354, XENP22355, XENP22356, XENP22357, XENP22358, XENP22359, XENP22360, XENP22361, XENP22362, XENP22363, XENP22364, XENP22365, XENP22366, XENP22637, XENP24349, XENP24383, XENP21978, XENP22634, XENP24342, XENP24306, XENP22637, and XENP22639. 
     
     
         76 . A nucleic acid composition comprising one or more nucleic acids encoding a heterodimeric protein selected from the group consisting of XENP20818, XENP20819, XENP21471, XENP21472, XENP21473, XENP21474, XENP21475, XENP21476, XENP21477, XENP22013, XENP22815, XENP22816, XENP22817, XENP22818, XENP22819, XENP22820, XENP22821, XENP22822, XENP22823, XENP22824, XENP22825, XENP22826, XENP22827, XENP22828, XENP22829, XENP22830, XENP22831, XENP22832, XENP22833, XENP22834, XENP23343, XENP23504, XENP23554, XENP23555, XENP23557, XENP23559, XENP24019, XENP24020, XENP24045, XENP24051, XENP24052, XENP24113, XENP24301, XENP24306, XENP24341, XENP21478, XENP21479, XENP22357, XENP22354, XENP22355, XENP22356, XENP22357, XENP22358, XENP22359, XENP22360, XENP22361, XENP22362, XENP22363, XENP22364, XENP22365, XENP22366, XENP22637, XENP24349, XENP24383, XENP21978, XENP22634, XENP24342, XENP24306, XENP22637, and XENP22639. 
     
     
         77 . An expression vector composition comprising one or more expression vectors each comprising a nucleic acid such that the one or more expression vectors encode a heterodimeric protein selected from the group consisting of XENP20818, XENP20819, XENP21471, XENP21472, XENP21473, XENP21474, XENP21475, XENP21476, XENP21477, XENP22013, XENP22815, XENP22816, XENP22817, XENP22818, XENP22819, XENP22820, XENP22821, XENP22822, XENP22823, XENP22824, XENP22825, XENP22826, XENP22827, XENP22828, XENP22829, XENP22830, XENP22831, XENP22832, XENP22833, XENP22834, XENP23343, XENP23504, XENP23554, XENP23555, XENP23557, XENP23559, XENP24019, XENP24020, XENP24045, XENP24051, XENP24052, XENP24113, XENP24301, XENP24306, XENP24341, XENP21478, XENP21479, XENP22357, XENP22354, XENP22355, XENP22356, XENP22357, XENP22358, XENP22359, XENP22360, XENP22361, XENP22362, XENP22363, XENP22364, XENP22365, XENP22366, XENP22637, XENP24349, XENP24383, XENP21978, XENP22634, XENP24342, XENP24306, XENP22637, and XENP22639. 
     
     
         78 . A host cell comprising the nucleic acid composition of  claim 76 . 
     
     
         79 . A host cell comprising the expression vector composition of  claim 77 . 
     
     
         80 . A method of producing the heterodimeric protein of  claim 75  comprising culturing the host cell  claim 78  or  79  under suitable conditions wherein said heterodimeric protein is expressed, and recovering said protein. 
     
     
         81 . A method of treating cancer in a patient in need thereof comprising administering a therapeutically effective amount of the heterodimeric protein of  claim 75  to said patient.