ENGINEERED IL-2 Fc FUSION PROTEINS

1 .- 18 . (canceled)

19 . A variant human IL-2, wherein said variant IL-2 comprises amino acid substitution(s) as compared to SEQ ID NO:2 selected from the group consisting of T3A/D20N; T3A/R38E; T3A/C125A; D20N/R38E; D20N/C125A; R38E/C125A; T3A/D20N/R38E; T3A/D20N/C125A; T3A/R38E/C125A; D20N/R38E/C125A; T3A/D20N/R28E/C125A; T3A/E61Q; T3A/E62Q; T3A/C125A; E61Q/E62Q; E61Q/C125A; E62Q/C125A; T3A/E61Q/E62Q; T3A/E61Q/C125A; T3A/E62Q/C125A; E61Q/E62Q/C125A; T3A/E61Q/E62Q/C125A; T3A/F42Y; T3A/E62Q; T3A/C125A; F42Y/E62Q; F42Y/C125A; E62Q/C125A; T3A/F42Y/E62Q; T3A/F42Y/C125A; T3A/E62Q/C125A; F42Y/E62Q/C125A; T3A/F42Y/E62Q/C125A; T3A/D20N; T3A/F42Y; T3A/E62Q; T3A/C125A; D20N/F42Y; D20N/E62Q; D20N/C125A; F42Y/E62Q; F42Y/C125A; E62Q/C125A; T3A/D20N/F42Y; T3A/D20N/E62Q; T3A/D20N/C125A; T3A/F42Y/E62Q; T3A/F42Y/C125A; T3A/E62Q/C125A; D20N/F42Y/E62Q; D20N/F42Y/C125A; D20N/E62Q/C125A; F42Y/E62Q/C125A; T3A/D20N/F42Y/E62Q; T3A/D20N/F42Y/C125A; T3A/D20N/E62Q/C125A; T3A/F42Y/E62Q/C125A; D20N/F42Y/E62Q/C125A; T3A/D20N/F42Y/E62Q/C125A; T3A/F42A; T3A/N88D; T3A/C125A; F42A/N88D; F42A/C125A; N88D/C125A; T3A/F42A/N88D; T3A/F42A/C125A; T3A/N88D/C125A; F42A/N88D/C125A; T3A/F42A/N88D/C125A; T3A/F42A; T3A/C125A; F42A/C125A; T3A/F42A/C125A; T3A/F42Y; T3A/E62Q; T3A/N88R; T3A/C125A; F42Y/E62Q; F42Y/N88R; F42Y/C125A; E62Q/N88R; E62Q/C125A; N88R/C125A; T3A/F42Y/E62Q; T3A/F42Y/N88R; T3A/F42Y/C125A; T3A/E62Q/N88R; T3A/E62Q/C125A; T3A/N88R/C125A; F42Y/E62Q/N88R; F42Y/E62Q/C125A; F42Y/N88R/C125A; E62Q/N88R/C125A; T3A/F42Y/E62Q/N88R; T3A/F42Y/E62Q/C125A; T3A/F42Y/N88R/C125A; T3A/E62Q/N88R/C125A; F42Y/E62Q/N88R/C125A; T3A/F42Y/E62Q/N88R/C125A; T3A/D20N; T3A/F42Y; T3A/E62Q; T3A/C125A; D20N/F42Y; D20N/E62Q; D20N/C125A; F42Y/E62Q; F42Y/C125A; E62Q/C125A; T3A/D20N/F42Y; T3A/D20N/E62Q; T3A/D20N/C125A; T3A/F42Y/E62Q; T3A/F42Y/C125A; T3A/E62Q/C125A; D20N/F42Y/E62Q; D20N/F42Y/C125A; D20N/E62Q/C125A; F42Y/E62Q/C125A; T3A/D20N/F42Y/E62Q; T3A/D20N/F42Y/C125A; T3A/D20N/E62Q/C125A; T3A/F42Y/E62Q/C125A; D20N/F42Y/E62Q/C125A; T3A/D20N/F42Y/E62Q/C125A; T3A/D20N; T3A/E61Q; T3A/E62Q; T3A/C125A; D20N/E61Q; D20N/E62Q; D20N/C125A; E61Q/E62Q; E61Q/C125A; E62Q/C125A; T3A/D20N/E61Q; T3A/D20N/E62Q; T3A/D20N/C125A; T3A/E61Q/E62Q; T3A/E61Q/C125A; T3A/E62Q/C125A; D20N/E61Q/E62Q; D20N/E61Q/C125A; D20N/E62Q/C125A; E61Q/E62Q/C125A; T3A/D20N/E61Q/E62Q; T3A/D20N/E61Q/C125A; T3A/D20N/E62Q/C125A; T3A/E61Q/E62Q/C125A; D20N/E61Q/E62Q/C125A; and T3A/D20N/E61Q/E62Q/C125A.

20 . A heterodimeric protein comprising a first monomer comprising a variant IL-2 covalently attached to a first variant Fc domain and a second monomer comprising a second variant Fc domain, wherein said variant IL-2 comprises amino acid substitution(s) as compared to SEQ ID NO:2 selected from the group consisting of T3A/D20N; T3A/R38E; T3A/C125A; D20N/R38E; D20N/C125A; R38E/C125A; T3A/D20N/R38E; T3A/D20N/C125A; T3A/R38E/C125A; D20N/R38E/C125A; T3A/D20N/R28E/C125A; T3A/E61Q; T3A/E62Q; T3A/C125A; E61Q/E62Q; E61Q/C125A; E62Q/C125A; T3A/E61Q/E62Q; T3A/E61Q/C125A; T3A/E62Q/C125A; E61Q/E62Q/C125A; T3A/E61Q/E62Q/C125A; T3A/F42Y; T3A/E62Q; T3A/C125A; F42Y/E62Q; F42Y/C125A; E62Q/C125A; T3A/F42Y/E62Q; T3A/F42Y/C125A; T3A/E62Q/C125A; F42Y/E62Q/C125A; T3A/F42Y/E62Q/C125A; T3A/D20N; T3A/F42Y; T3A/E62Q; T3A/C125A; D20N/F42Y; D20N/E62Q; D20N/C125A; F42Y/E62Q; F42Y/C125A; E62Q/C125A; T3A/D20N/F42Y; T3A/D20N/E62Q; T3A/D20N/C125A; T3A/F42Y/E62Q; T3A/F42Y/C125A; T3A/E62Q/C125A; D20N/F42Y/E62Q; D20N/F42Y/C125A; D20N/E62Q/C125A; F42Y/E62Q/C125A; T3A/D20N/F42Y/E62Q; T3A/D20N/F42Y/C125A; T3A/D20N/E62Q/C125A; T3A/F42Y/E62Q/C125A; D20N/F42Y/E62Q/C125A; T3A/D20N/F42Y/E62Q/C125A; T3A/F42A; T3A/N88D; T3A/C125A; F42A/N88D; F42A/C125A; N88D/C125A; T3A/F42A/N88D; T3A/F42A/C125A; T3A/N88D/C125A; F42A/N88D/C125A; T3A/F42A/N88D/C125A; T3A/F42A; T3A/C125A; F42A/C125A; T3A/F42A/C125A; T3A/F42Y; T3A/E62Q; T3A/N88R; T3A/C125A; F42Y/E62Q; F42Y/N88R; F42Y/C125A; E62Q/N88R; E62Q/C125A; N88R/C125A; T3A/F42Y/E62Q; T3A/F42Y/N88R; T3A/F42Y/C125A; T3A/E62Q/N88R; T3A/E62Q/C125A; T3A/N88R/C125A; F42Y/E62Q/N88R; F42Y/E62Q/C125A; F42Y/N88R/C125A; E62Q/N88R/C125A; T3A/F42Y/E62Q/N88R; T3A/F42Y/E62Q/C125A; T3A/F42Y/N88R/C125A; T3A/E62Q/N88R/C125A; F42Y/E62Q/N88R/C125A; T3A/F42Y/E62Q/N88R/C125A; T3A/D20N; T3A/F42Y; T3A/E62Q; T3A/C125A; D20N/F42Y; D20N/E62Q; D20N/C125A; F42Y/E62Q; F42Y/C125A; E62Q/C125A; T3A/D20N/F42Y; T3A/D20N/E62Q; T3A/D20N/C125A; T3A/F42Y/E62Q; T3A/F42Y/C125A; T3A/E62Q/C125A; D20N/F42Y/E62Q; D20N/F42Y/C125A; D20N/E62Q/C125A; F42Y/E62Q/C125A; T3A/D20N/F42Y/E62Q; T3A/D20N/F42Y/C125A; T3A/D20N/E62Q/C125A; T3A/F42Y/E62Q/C125A; D20N/F42Y/E62Q/C125A; T3A/D20N/F42Y/E62Q/C125A; T3A/D20N; T3A/E61Q; T3A/E62Q; T3A/C125A; D20N/E61Q; D20N/E62Q; D20N/C125A; E61Q/E62Q; E61Q/C125A; E62Q/C125A; T3A/D20N/E61Q; T3A/D20N/E62Q; T3A/D20N/C125A; T3A/E61Q/E62Q; T3A/E61Q/C125A; T3A/E62Q/C125A; D20N/E61Q/E62Q; D20N/E61Q/C125A; D20N/E62Q/C125A; E61Q/E62Q/C125A; T3A/D20N/E61Q/E62Q; T3A/D20N/E61Q/C125A; T3A/D20N/E62Q/C125A; T3A/E61Q/E62Q/C125A; D20N/E61Q/E62Q/C125A; and T3A/D20N/E61Q/E62Q/C125A.

21 . A heterodimeric protein according to claim 19 or 20 , wherein said variant Fc domains are variant human IgG1 Fc domains comprising the amino acid substitutions M428L/N434S.

22 . A heterodimeric protein according to claim 19 or 20 , wherein said variant Fc domains are variant human IgG1 Fc domains comprising the amino acid substitutions E233P/L234V/L235A/G236del/S267K.

23 . A heterodimeric protein according to claim 19 or 20 , wherein said first and second variant Fc domains comprise a set of heterodimerization variants selected from the group consisting of those depicted in FIG. 2 .

24 . A heterodimeric protein according to claim 23 , wherein said set of heterodimerization variants selected from the group consisting of L368D/K370S:S364K/E357Q; L368D/K370S:S364K; L368E/K370S:S364K; T411E/K360E/Q362E:D401K; and T366S/L368A/Y407V:T366W.

25 . A heterodimeric protein according to claim 19 or 20 , wherein one of said variant Fc domains comprise a set of pI variants selected from the group consisting of those depicted in FIG. 3 .

26 . A heterodimeric protein according to claim 25 , wherein said pI variant set is A295E/N384D/Q418/N421D.

27 . A heterodimeric protein according to claim 19 or 20 , wherein said variant Fc domain contains a number of amino acid modifications as compared to the parental human IgG1, IgG2 or IgG4.

28 . A nucleic acid encoding the variant human IL-2 according to claim 19 .

29 . An expression vector comprising the nucleic acid of claim 28 .

30 . A host cell comprising the expression vector of claim 29 .

31 . A method of making a variant human IL-2 comprising culturing the host cell of claim 30 under conditions wherein the variant human IL-2 is produced and recovering the variant human IL-2.

32 . A nucleic acid composition comprising:

a. a first nucleic acid encoding said first monomer of claim 20 ; and

b. a second nucleic acid encoding said second monomer of claim 20 , respectively.

33 . An expression vector composition comprising:

a. a first expression vector comprising said first nucleic acid of claim 32 ; and

b. a second expression vector comprising said second nucleic acid of claim 32 .

34 . A host cell comprising the expression vector composition according to claim 33 .

35 . A method of making a polypeptide composition comprising culturing the host cell of claim 33 under conditions wherein the composition is produced and recovering the composition.