IL-2RBETA BINDING COMPOUNDS
IL-2Rβ ligands and IL-2Rγc ligands and compounds comprising the ligands are disclosed. The ligands and compounds such as heterodimers and fusion proteins comprising the IL-2Rβ ligands and/or the IL-2Rγc ligands can be IL-2 receptor agonists.
1 . An IL-2Rβ ligand comprising the amino acid sequence of Formula (10) (SEQ ID NO: 578):
-X 191 -X 192 -X 193 -X 194 -X 195 -C-X 196 -X 197 -X 198 -X 199 -X 200 -X 201 -X 202 -X 203 -C-X 204 -X 205 -X 206 -X 207 -X 208 - (10)
wherein,
X 191 is selected from A, D, E, F, G, H, I, K, L, N, M, P, Q, R, S, T, V, W, and Y;
X 192 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y;
X 193 is selected from A, C, D, F, G, H, I, L, M, N P, R, S, T, V, W, and Y;
X 194 is selected from F, H, I, K, L, N, P, Q, R, S, T, V, W, and Y;
X 195 is selected from A, D, E, F, G, H, K, L, M, N, P, Q, S, W, and Y;
X 196 is selected from A, E, F, G, H, Q, R, S, W, and Y;
X 197 is selected from A, D, E, F, I, K, L, M, N, Q, R, S, T, V, W, and Y;
X 198 is A;
X 199 is selected from A, D, H, K, L, N, P, Q, R, S, and Y;
X 200 is selected from I, L, M, P, and V;
X 201 is selected from G, H, and W;
X 202 is selected from D, E, and Q;
X 203 is L;
X 204 is selected from A, D, E, H, I, L, T, V, and Y;
X 205 is selected from F, I, L, M, V, W, and Y;
X 206 is selected from A, D, E, F, G, H, I, K, L, M, N, P, Q, R, S, T, V, W, and Y;
X 207 is selected from A, C, D, E, F, G, H, I, L, M, N, P, Q, R, S, T, V, W, and Y; and
X 208 is selected from A, D, E, F, G, H, K, L, M, N, P, Q, R, S, T, V, W, and Y.
2 . The IL-2Rβ ligand of claim 1 , wherein,
X 193 is selected from F, H, W, and Y; and
X 194 is selected from F, H, L, W, and Y.
3 . The IL-2Rβ ligand of claim 1 , wherein,
X 195 is selected from D, E, and P; and
X 196 is selected from F, H, R, S, W, and Y.
4 . The IL-2Rβ ligand of claim 1 , wherein,
X 197 is selected from F, I, L, M, and V; and
X 199 is selected from H, K, Q, N, and R.
5 . The IL-2Rβ ligand of claim 1 , wherein,
X 200 is selected from I, L, and V; and
X 202 is selected from D, E, and Q.
6 . The IL-2Rβ ligand of claim 1 , wherein,
X 204 is selected from D and E; and
X 205 is selected from F, I, L, M, V, and W.
7 . The IL-2Rβ ligand of claim 1 , wherein,
X 193 is selected from F, H, W, and Y;
X 194 is selected from F, H, L, W, and Y;
X 195 is selected from D, E, and P;
X 196 is selected from F, H, R, S, W, and Y;
X 197 is selected from F, I, L, M, and V;
X 198 is A;
X 199 is selected from H, K, Q, N, and R;
X 200 is selected from I, L, and V;
X 201 is G;
X 202 is selected from D, E, and Q;
X 203 is L;
X 204 is selected from D and E; and
X 205 is selected from F, I, L, M, V, and W.
8 . The IL-2Rβ ligand of claim 1 , wherein,
X 193 is selected from F, H, W, and Y;
X 194 is selected from F, H, L, W, and Y;
X 195 is selected from D, E, and P;
X 196 is selected from F, H, R, S, W, and Y;
X 197 is selected from F, I, L, M, and V; and
X 198 is A.
9 . The IL-2Rβ ligand of claim 1 , wherein,
X 199 is selected from H, K, Q, N, and R; and
X 200 is selected from I, L, and V.
10 . The IL-2Rβ ligand of claim 1 , wherein,
X 201 is G;
X 202 is selected from D, E, and Q;
X 203 is L;
X 204 is selected from D and E; and
X 205 is selected from F, I, L, M, V, and W.
11 . The IL-2Rβ ligand of claim 10 , wherein,
X 202 is E;
X 204 is D; and
X 205 is L.
12 . The IL-2Rβ ligand of claim 1 , wherein the amino acid sequence of Formula (10) comprises from 1 to 5 of the following conservative substitutions: amino acids having a small hydrophobic side chain comprising alanine (A), glycine (G), proline (P), serine (S), or threonine (T); amino acids having a hydroxyl-containing side chain comprising serine (S), threonine (T), or tyrosine (Y); amino acids having an acidic side chain comprising aspartate (D) or glutamate (E); amino acids having a polar-neutral side chain comprising histidine (H), asparagine (N), glutamine (Q), serine (S), threonine (T), or tyrosine (Y); amino acids having a basic side chain comprising arginine (R), lysine (K), or histidine (H); amino acids having a large hydrophobic side chain comprising isoleucine (I), leucine (L), methionine (M), valine (V), phenylalanine (F), tyrosine (Y), or tryptophan (W); and amino acids having an aromatic side chain comprising phenylalanine (F), histidine (H), tryptophan (W), or tyrosine (Y).
13 . The IL-2β ligand of claim 1 , wherein the IL-2Rβ ligand exhibits a binding affinity (IC 50 ) to the human IL-21213 subunit of less than 100 μM.
14 . The IL-2Rβ ligand of claim 1 , wherein the amino acid sequence is terminated with amino acids -G-G- on the N-terminus, on the C-terminus, or on both the N- and C-termini.
15 . A pharmaceutical composition comprising the IL-2Rβ ligand of claim 1 .
16 . A compound comprising at least one IL-2Rβ ligand of claim 1 .
17 . The compound of claim 16 , wherein the compound is selected from a peptide comprising the IL-2Rβ ligand, a conjugate, and a fusion protein.
18 . The compound of claim 16 , wherein the compound comprises an IL-2Rα ligand, an IL-2Rγc ligand, or both an IL-2Rα ligand and an IL-2Rγc ligand.
19 . A pharmaceutical composition comprising the compound of claim 16 .