IL2 muteins
The present disclosures is related to IL2 muteins and their uses in the treatment of human disease.
1 . A polypeptide having decreased binding affinity, compared to wild type hIL2, to the extracellular domain of hCD132, the polypeptide comprising an amino acid sequence of the formula (SEQ ID NO:97):
(AA1) a -(AA2) b -(AA3) c -(AA4) d -(AA5) e -(AA6) f -(AA7) g -(AA8) h -(AA9) i -T10-Q11-L12-Q13-L14-E15-H16-L17-(AA18)-L19-D20-L21-(AA22)-M23-124-L25-N26-G27-128-N29-N30-Y31-K32-N33-P34-(AA35)-L36-T37-(AA38)-(AA39)-L40-T41-F42-K43-F44-Y45-M46-P47-K48-K49-A50-T51-E52-L53-K54-(AA55)-L56-Q57-C58-L59-E60-E61-E62-L63-K64-P65-L66-E67-E68-(AA69)-L70-N71-L72-A73-(AA74)-S75-K76-N77-F78-H79-(AA80-(AA81)-P82-R83-D84-(AA85)-(AA86)-S87-N88-(AA89)-N90-(AA91)-(AA92)-V93-L94-E95-L96-(AA97)-G98-S99-E100-T101-T102-F103-(AA104)-C105-E106-Y107-A108-(AA109)-E110-T111-A112-(AA113)-I114-V115-E116-F117-L118-N119-R120-W121-1122-T123-F124-(AA125)-(AA126)-S127-I128-I129-(AA130)-T131-L132-T133
wherein:
each of a, b, c, d, e, f, g, h, and i is individually selected from 0 or 1;
AA1 is A (wild type, a=1) or deleted (a=0);
AA2 is P (wild type, b=1) or deleted (b=0);
AA3 is T (wild type, c=1), C, A, G, Q, E, N, D, R, K, P, or deleted (c=0);
AA4 is S (wild type, d=1) or deleted (d=0);
AA5 is S (wild type, e=1) or deleted (e=0);
AA6 is S (wild type, f=1) or deleted (f=0);
AA7 is T (wild type, g=1) or deleted (g=0);
AA8 is K (wild type, h=1) or deleted (h=0);
AA9 is K (wild type, i=1) or deleted (i=0);
AA18 is R;
AA22 is T;
AA35 is K (wildtype) or E;
AA38 is R (wild type), W or G;
AA39 is M (wildtype), L or V;
AA55 is H (wildtype) or Y;
AA69 is V (wildtype) or A;
AA74 is Q (wild type), P, N, H, S;
AA80 is L (wild type), F or V;
AA81 is R (wild type), I, D or T;
AA85 is L (wild type) or V;
AA86 is I (wild type) or V;
AA89 is I (wild type) or V;
AA91 is V (wild type), R or K;
AA92 is I (wild type) or F;
AA97 is K (wild type) or Q;
AA104 is M (wild type) or A;
AA109 is D (wildtype), C or a non-natural amino acid with an activated side chain;
AA113 is T (wild type) or N;
AA125 is C (wild type), A or S;
AA126 is H; and
AA130 is S (wild type), T, G or R.
2 . The polypeptide of claim 1 wherein a=0.
3 . The polypeptide of claim 1 , wherein the polypeptide is PEGylated.
4 . The polypeptide of claim 1 , wherein the polypeptide is PEGylated and the PEG component of such PEGylated polypeptide has a molecular weight of from about 10 kD to about 70 kD.
5 . The polypeptide of claim 1 , wherein the polypeptide is a fusion protein.
6 . The polypeptide of claim 5 wherein the fusion protein comprises an Fc domain.
7 . A nucleic acid encoding a polypeptide of claim 1 .
8 . The nucleic acid of claim 7 wherein the nucleic acid is DNA.
9 . A recombinant expression vector comprising the nucleic acid of claim 7 .
10 . The vector of claim 9 wherein said vector is a viral vector.
11 . The vector of claim 9 wherein said vector is a non-viral vector.
12 . A host cell transformed with a vector of claim 9 .
13 . A pharmaceutical formulation comprising a polypeptide of claim 1 .
14 . The polypeptide of claim 1 wherein:
AA1 is A or deleted;
AA2 is P;
AA3 is T;
AA4 is S;
AA5 is S;
AA6 is S;
AA7 is T;
AA8 is K;
AA9 is K;
AA18 is R;
AA22 is T;
AA35 is K;
AA38 is R;
AA39 is M;
AA55 is H;
AA69 is V;
AA74 is Q;
AA80 is L;
AA81 is R;
AA85 is L;
AA86 is I;
AA89 is I;
AA91 is V;
AA92 is I;
AA97 is K;
AA104 is M;
AA109 is D;
AA113 is T;
AA125 is C;
AA126 is H; and
AA130 is S.