IL-15 Variants and Uses Thereof

Abstract

The present invention relates to human interleukin 15 (IL-15) variants that have therapeutic and diagnostic use, and methods for making thereof. The present invention also provides fusion proteins comprising a human IL-15 variant. Also provided are methods of stimulating or suppressing immune responses in a mammal, and methods of treating a disorder (e.g., cancer) using the IL-15 variants or the fusion protein of such IL-15 variants.

It is claimed: 
     
         1 . An isolated human interleukin 15 (IL-15) variant comprising amino acid substitution at positions a) V49 and I51 or b) V49, I50, and S51 of SEQ ID NO: 1 and further comprising one or more amino acid substitutions at positions N1, N4, S7, K10, K11, Y26, S29, D30, V31, H32, E53, G55, E64, I68, L69, E89, L91, M109, and/or I111 of SEQ ID NO: 1, wherein the IL-15 variant has decreased or no binding to the human IL-15 receptor alpha (IL-15Rα) and the human IL-2 receptor beta/gamma (IL-2Rβγ) as compared to the wild-type human IL-15 polypeptide or a wild-type IL-15 receptor alpha-IL-15 fusion polypeptide, and wherein the amino acid substitution at position V49 is glycosylated. 
     
     
         2 . The isolated IL-15 variant of  claim 1 , wherein the IL-15 variant comprises amino acid substitutions at positions selected from the group consisting of:
 a) V49, I50, S51, N4, D30, and E64;   b) V49, I50, S51, N4, D30, E64, and I68;   c) V49, I50, S51, N4, D30, E64, M109;   d) V49, I50, S51, N4, D30, E64, I68, and M109;   e) V49, I50, S51, D30, E64, and I68;   f) V49, I50, S51, D30, E64, M109;   g) V49, I50, S51, D30, E64, I68, and M109;   h) N1, V49, I50, and S51;   i) N4, V49, I50, and S51;   j) S7, V49, I50, and S51;   k) K10, V49, I50, and S51;   l) K11, V49, I50, and S51;   m) S29, V49, I50, and S51;   n) V31, V49, I50, and S51;   o) H32, V49, I50, and S51;   p) V49, I50, S51, and E64;   q) V49, I50, S51, and I68;   r) V49, I50, S51, and L69;   s) V49, I50, S51, and I111;   t) N4, V49, I50, S51, and E64;   u) N1, D30, V49, I50, and S51;   v) N4, D30, V49, I50, and S51;   w) S7 D30, V49, I50, and S51;   x) K10, D30, V49, I50, and S51;   y) K11, D30, V49, I50, and S51;   z) S29, D30, V49, I50, and S51;   aa) D30, V49, I50, S51, and E64;   bb) D30, V49, I50, S51, and I68;   cc) D30, V49, I50, S51, and L69; and   dd) D30, V49, I50, S51, and I111.   
     
     
         3 . The isolated IL-15 variant of  claim 1 , wherein the amino acid substitutions comprise one or more specific substitutions at:
 a) V49N, V49K, V49E, V49H, V49Q or V49R;   b) I50A or I50G;   c) S51T;   d) N1K, N1G, N1Q, N1R, N1E, N1A, or N1D;   e) N4K, N4G, N4A, N4S, N4D, N4E, N4I, N4L, N4R, N4T, N4W, or N4Q;   f) S7E, S7G, S7D, S7K, S7N, S7R, S7H, or S7T;   g) K10A, K10S, K10E, K10L, K10M, K10D, or K10G;   h) K11D, K11S, or K11W;   i) D30N;   j) E64Q, E64K, E64A, E64S, E64N, E64H, E64T, or E64R;   k) E53N;   l) G55S or G55T;   m) E89N;   n) L91S or L91T;   o) Y26K, Y26R, or Y26H;   p) S29N;   q) V31S, V31D, or V31K;   r) H32G;   s) I68S, I68A, I68R, I68T, I68K, I68N, I68M, I68F, I68Y, I68E, or I68H;   t) L69A, L69S, L69D, L69T, L69M, L69G, L69Q, L69I, L69E, or L69V;   u) M109A, M109S, M109D, or M109K; and/or   v) I111A, I111K, I111S, or I111D.   
     
     
         4 . The isolated IL-15 variant of  claim 1 , wherein the IL-15 variant comprises amino acid substitutions at positions selected from the group consisting of:
 a) N4K, D30N, V49N, I50A, S51T, and E64Q;   b) N4Q, D30N, V49N, I50A, and S51T;   c) D30N, V49N, I50A, S51T, and E64Q;   d) N4Q, D30N, V49N, I50A, S51T, and E64Q;   e) N4Q, V49N, I50A, and S51T;   f) V49N, I50A, S51T, and E64Q; and   g) N4Q, V49N, I50A, S51T, and E64Q.   
     
     
         5 . An isolated human interleukin 15 (IL-15) variant comprising amino acid substitutions at positions E46 and V49 of SEQ ID NO: 1, and at least one or more amino acid substitution(s) at positions N1, N4, S7, K10, K11, D22, Y26, S29, D30, V31, H32, E53, G55, E64, I68, L69, E89, E93, M109 and/or I111 of SEQ ID NO: 1, wherein the IL-15 variant has no binding to the human IL-15 receptor alpha (IL-15Rα) and decreased binding to the human IL-2 receptor beta/gamma (IL-2Rβγ) as compared to the wild-type human IL-15 polypeptide or a wild-type IL-15 receptor alpha-IL-15 fusion polypeptide. 
     
     
         6 . The isolated IL-15 variant of  claim 5 , wherein the IL-15 variant comprises amino acid substitutions at positions selected from the group consisting of:
 a) N1, E46, and V49;   b) N4, E46, and V49;   c) S7, E46, and V49;   d) K10, E46, and V49;   e) K11, E46, and V49;   f) S29, E46, and V49;   g) V31, E46, and V49;   h) H32, E46, and V49;   i) E46, V49, and E64;   j) E46, V49, and I68;   k) E46, V49, and L69;   l) E46, V49, and I111;   m) N4, E46, V49, and E64;   n) E46, V49, N4, D30, and E64;   o) E46, V49, N4, D30, E64, and I68;   p) E46, V49, N4, D30, E64, and M109;   q) E46, V49, N4, D30, E64, I68, and M109;   r) N1, D30, E46, and V49;   s) N4, D30, E46, and V49;   t) S7, D30, E46, and V49;   u) K10, D30, E46, and V49;   v) K11, D30, E46, and V49;   w) S29, D30, E46, and V49;   x) D30, E46, V49, and E64;   y) D30, E46, V49R, and I68;   z) D30, E46, V49R, and L69;   aa) D30, E46, V49R, and I111;   bb) N1, D30, E46, V49, and M109;   cc) N4, D30, E46, V49, and M109;   dd)S7, D30, E46, V49, and M109;   ee) K10, D30, E46, V49, and M109;   if) K11, D30, E46, V49, and M109;   gg) D30, E46, V49, E64, and M109;   hh) D30, E46, V49, I68, and M109;   ii) D30, E46, V49, L69 and M109;   ii) D30, E46, V49, M109, and I111;   kk) D30, E46, V49, E64, I68, and M109;   ll) E46, V49, D30, E64, and I68;   mm) E46, V49, E64, and M109;   nn) E46, V49, D30, E64, I68, and M109;   oo) D22, Y26, V49, E46, E53, E89, and E93; and   pp) N1, D30, E46, V49, and E64.   
     
     
         7 . The isolated IL-15 variant of  claim 5 , wherein the amino acid substitutions comprise one or more specific substitutions at:
 a) N1Q, N1K, N1R, N1E, N1A, N1D, or N1G;   b) N4K, N4G, N4A, N4S, N4D, N4E, N4R, N4T, n4I, N4L, N4W, or N4Q;   c) S7E, S7G, S7D, S7K, S7N, S7R, S7H, or S7T;   d) K10D, K10A, K10S, K10E, K10L, K10M, K10D, or K10G;   e) K11D, K11S, or K11W;   f) D22N;   g) Y26K, Y26R, or Y26H;   h) S29N;   i) D30N;   j) V31S, V31D, or V31K;   k) H32G;   l) E46G or E46Q;   m) V49N, V49K, or V49R V49E, V49H, or V49Q;   n) E53Q;   o) G55S or G55T   p) E64Q, E64K, E64A, E64S, E64N, E64H, E64T, or E64R;   q) I68S, I68A, I68R, I68T, I68K, I68N, I68M, I68F, I68Y, I68E, or I68H;   r) L69S, L69A, L69D, L69T, L69M, L69G, L69Q, L69I, L69E, or L69V;   S) E89Q;   t) E93Q;   u) M109A, M109S, M109D, or M109K; and/or   v) I111A, I111K, I111S, or I111D.   
     
     
         8 . The isolated IL-15 variant of  claim 5 , wherein the IL-15 variant comprises amino acid substitutions at positions selected from the group consisting of:
 a) N1K, E46G, and V49R;   b) N4K, E46G, and V49R;   c) N4Q, E46G, and V49R;   d) S7T, E46G, and V49R;   e) V31S, E46G, and V49R;   f) V31K, E46G, and V49R;   g) E46G, V49R, and E64Q;   h) E46G, V49R, and E64K;   i) N4Q, E46G, V49R, and E64Q;   j) N1G, D30N, E46G, and V49R;   k) N1K, D30N, E46G, and V49R;   l) N1Q, D30N, E46G, and V49R;   m) N4G, D30N, E46G, and V49R;   n) N4K, D30N, E46G, and V49R;   o) N4Q, D30N, E46G, and V49R;   p) S7E, D30N, E46G, and V49R;   q) S7G, D30N, E46G, and V49R;   r) S7T, D30N, E46G, and V49R;   S) K10D, D30N, E46G, and V49R;   t) D30N, E46G, V49R, and E64A;   u) D30N, E46G, V49R, and E64Q;   v) D30N, E46G, V49R, and E64K;   w) D30N, E46G, V49R, and I68S;   x) D30N, E46G, V49R, and I68K;   y) N4K, D30N, E46G, V49R, and E64K;   z) N4Q, D30N, E46G, V49R, and E64K;   aa) N4K, D30N, E46G, V49R, and E64Q;   bb) N4Q, D30N, E46G, V49R, and E64Q;   cc) N4K, D30N, E46G, V49R, and I68S;   dd) D30N, E46G, V49R, E64Q, and I68S;   ee) N1A, D30N, E46G, and V49R; and   if) N1G, D30N, E46G, V49R, and E64Q.   
     
     
         9 . An isolated fusion protein comprising: 1) an antibody comprising a Fc domain; and b) a human interleukin 15 (IL-15) variant comprising amino acid substitution at positions a) V49 and I51 or b) V49, I50, and S51 of SEQ ID NO: 1 wherein the amino acid substitution at position V49 of SEQ ID NO: 1 is glycosylated, and further comprising one or more amino acid substitutions at positions N1, N4, S7, K10, K11, Y26, S29, D30, V31, H32, E53, G55, E64, I68, L69, E89, L91, M109, and/or I111 of SEQ ID NO: 1, wherein the IL-15 variant is covalently linked to the Fc domain of the antibody, and wherein the Fc domain has decreased or no antibody dependent cellular cytotoxicity (ADCC) activity compared to the wild-type Fc. 
     
     
         10 . The fusion protein of  claim 9 , wherein the IL-15 variant comprises amino acid substitutions at positions selected from the group consisting of:
 a) V49, I50, S51, N4, D30, and E64;   b) V49, I50, S51, N4, D30, E64, and I68;   c) V49, I50, S51, N4, D30, E64, M109;   d) V49, I50, S51, N4, D30, E64, I68, and M109;   e) V49, I50, S51, D30, E64, and I68;   f) V49, I50, S51, D30, E64, M109;   g) V49, I50, S51, D30, E64, I68, and M109;   h) N1, V49, I50, and S51;   i) N4, V49, I50, and S51;   j) S7, V49, I50, and S51;   k) K10, V49, I50, and S51;   l) K11, V49, I50, and S51;   m) S29, V49, I50, and S51;   n) V31, V49, I50, and S51;   o) H32, V49, I50, and S51;   p) V49, I50, S51, and E64;   q) V49, I50, S51, and I68;   r) V49, I50, S51, and L69;   s) V49, I50, S51, and I111;   t) N4, V49, I50, S51, and E64;   u) N1, D30, V49, I50, and S51;   v) N4, D30, V49, I50, and S51;   w) S7 D30, V49, I50, and S51;   x) K10, D30, V49, I50, and S51;   y) K11, D30, V49, I50, and S51;   z) S29, D30, V49, I50, and S51;   aa) D30, V49, I50, S51, and E64;   bb) D30, V49, I50, S51, and I68;   cc) D30, V49, I50, S51, and L69; and   dd) D30, V49, I50, S51, and I111.   
     
     
         11 . The fusion protein of  claim 9 , wherein the amino acid substitutions comprise one or more specific substitutions at:
 a) V49N, V49K, or V49R;   b) I50A or I50G;   c) S51T;   d) N1K, N1G, N1Q, N1R, N1E, N1A, or N1D;   e) N4K, N4G, N4A, N4S, N4D, N4E, N4L, N4R, N4T, or N4Q;   f) S7E, S7G, S7D, S7K, S7N, S7R, S7H, or S7T;   g) K10A, K10S, K10E, K10L, K10M, K10D, or K10G;   h) K11D, K11S, or K11W;   i) D30N;   j) E64Q, E64K, E64A, E64S, E64N, E64H, E64T, or E64R;   k) E53N;   l) G55S or G55T;   m) E89N;   n) L91S or L91T;   o) Y26K, Y26R, or Y26H;   p) S29N;   q) V31S, V31D, or V31K;   r) H32G;   s) I68S, I68A, I68R, I68T, I68K, I68N, I68M, I68F, I68Y, I68E, or I68H;   t) L69S, L69A, L69D, L69T, L69M, L69G, L69Q, L69I, L69E, or L69V;   u) M109A, M109S, M109D, or M109K; and/or   v) I111A, I111K, I111S, or I111D.   
     
     
         12 . The fusion protein of  claim 9 , wherein the IL-15 variant comprises amino acid substitutions at positions selected from the group consisting of:
 a) N4K, D30N, V49N, I50A, S51T, and E64Q;   b) Y26K, V49R, N4K, D30N, and E64Q;   c) Y26K, V49K, N4K, D30N, and E64Q.   d) N4Q, D30N, V49N, I50A, and S51T;   e) D30N, V49N, I50A, S51T, and E64Q;   f) N4Q, D30N, V49N, I50A, S51T, and E64Q;   g) N4Q, V49N, I50A, and S51T;   h) V49N, I50A, S51T, and E64Q; and   i) N4Q, V49N, I50A, S51T, and E64Q.   
     
     
         13 . An isolated fusion protein comprising: 1) an antibody comprising a Fc domain; and b) a human interleukin 15 (IL-15) variant comprising amino acid substitutions at positions E46 and V49 of SEQ ID NO: 1, and at least one or more amino acid substitution(s) at positions N1, N4, S7, K10, K11, D22, Y26, S29, D30, V31, H32, E53, G55, E64, I68, L69, E89, E93, M109 and/or I111 of SEQ ID NO: 1, wherein the IL-15 variant is covalently linked to the Fc domain of the antibody, and wherein the Fc domain has decreased or no antibody dependent cellular cytotoxicity (ADCC) activity compared to the wild-type Fc. 
     
     
         14 . The fusion protein of  claim 13 , wherein the IL-15 variant comprises amino acid substitutions at positions selected from the group consisting of:
 a) N1, E46, and V49;   b) N4, E46, and V49;   c) S7, E46, and V49;   d) K10, E46, and V49;   e) K11, E46, and V49;   f) S29, E46, and V49;   g) V31, E46, and V49;   h) H32, E46, and V49;   i) E46, V49, and E64;   j) E46, V49, and I68;   k) E46, V49, and L69;   l) E46, V49, and I111;   m) N4, E46, V49, and E64;   n) E46, V49, N4, D30, and E64;   o) E46, V49, N4, D30, E64, and I68;   p) E46, V49, N4, D30, E64, and M109;   q) E46, V49, N4, D30, E64, I68, and M109;   r) N1, D30, E46, and V49;   s) N4, D30, E46, and V49;   t) S7, D30, E46, and V49;   u) K10, D30, E46, and V49;   v) K11, D30, E46, and V49;   w) S29, D30, E46, and V49;   x) D30, E46, V49, and E64;   y) D30, E46, V49R, and I68;   z) D30, E46, V49R, and L69;   aa) D30, E46, V49R, and I111;   bb) N1, D30, E46, V49, and M109;   cc) N4, D30, E46, V49, and M109;   dd)S7, D30, E46, V49, and M109;   ee) K10, D30, E46, V49, and M109;   if) K11, D30, E46, V49, and M109;   gg) D30, E46, V49, E64, and M109;   hh) D30, E46, V49, I68, and M109;   ii) D30, E46, V49, L69, and M109;   jj) D30, E46, V49, M109, and I111;   kk) D30, E46, V49, E64, I68, and M109;   ll) E46, V49, D30, E64, and I68;   mm) E46, V49, E64, and M109;   nn) E46, V49, D30, E64, I68, and M109;   oo) D22, Y26, V49, E46, E53, E89, and E93; and   pp) N1, D30, E46, V49, and E64.   
     
     
         15 . The fusion protein of  claim 13 , wherein the IL-15 variant comprises amino acid substitutions at positions selected from the group consisting of:
 a) N1Q, N1K, N1R, N1E, N1A, N1D, or N1G;   b) N4K N4G, N4A, N4S, N4D, N4E, N4L, N4R, N4T, or N4Q;   c) S7E, S7G, S7D, S7K, S7N, S7R, S7H, or S7T;   d) K10D, K10A, K10S, K10E, K10L, K10M, K10D, K10G;   e) K11D, K11S, or K11W;   f) D22N;   g) Y26K, Y26R, or Y26H;   h) S29N;   i) D30N;   j) V31S, V31D, or V31K k) H32G;   l) E46G or E46Q;   m) V49N, V49K, or V49R V49E, V49H, or V49Q;   n) E53Q;   o) G55S or G55T;   p) E64Q, E64K, E64A, E64S, E64N, E64H, E64T, or E64R;   q) I68S, I68A, I68R, I68T, I68K, I68N, I68M, I68F, I68Y, I68E or I68H;   r) L69S, L69A, L69D, L69T, L69M, L69G, L69Q, L69I, L69E, or L69V;   s) E89Q;   t) E93Q;   u) M109A, M109S, M109D, or M109K and   v) I111A, I111K, I111S, or I111D.   
     
     
         16 . The fusion protein of  claim 13 , wherein the IL-15 variant comprises amino acid substitutions at positions selected from the group consisting of:
 a) N1K, E46G, and V49R;   b) N4K, E46G, and V49R;   c) N4Q, E46G, and V49R;   d) S7T, E46G, and V49R;   e) V31S, E46G, and V49R;   f) V31K, E46G, and V49R;   g) E46G, V49R, and E64Q;   h) E46G, V49R, and E64K;   i) N4Q, E46G, V49R, and E64Q;   j) N1G, D30N, E46G, and V49R;   k) N1K, D30N, E46G, and V49R;   l) N1Q, D30N, E46G, and V49R;   m) N4G, D30N, E46G, and V49R;   n) N4K, D30N, E46G, and V49R;   o) N4Q, D30N, E46G, and V49R;   p) S7E, D30N, E46G, and V49R;   q) S7G, D30N, E46G, and V49R;   r) S7T, D30N, E46G, and V49R;   s) K10D, D30N, E46G, and V49R;   t) D30N, E46G, V49R, and E64A;   u) D30N, E46G, V49R, and E64Q;   v) D30N, E46G, V49R, and E64K;   w) D30N, E46G, V49R, and I68S;   x) D30N, E46G, V49R, and I68K;   y) N4K, D30N, E46G, V49R, and E64K;   z) N4Q, D30N, E46G, V49R, and E64K;   aa) N4K, D30N, E46G, V49R, and E64Q;   bb) N4Q, D30N, E46G, V49R, and E64Q;   cc) N4K, D30N, E46G, V49R, and I68S;   dd) D30N, E46G, V49R, E64Q, and I68S;   ee) N1A, D30N, E46G, and V49R; and   if) N1G, D30N, E46G, V49R, and E64Q.   
     
     
         17 . The fusion protein of  claim 13  comprising an amino acid sequence of SEQ ID NO: 86, 87, 89, or 90. 
     
     
         18 . The fusion protein of  claim 13 , wherein the antibody has an isotype that is selected from the group consisting of IgG 1 , IgG 2 , IgG 2Δa , IgG 4 , IgG 4Δb , IgG 4Δc , IgG 4  S228P, IgG 4Δb  S228P, and IgG 4Δc  S228P. 
     
     
         19 . The fusion protein of  claim 18 , wherein the antibody is a) an IgG2, and the antibody variable domain comprises amino acid modifications at positions 223, 225, and/or 228 in the hinge region and at position 409 and/or 368 (EU numbering scheme) in the CH3 region of the human IgG2 (SEQ ID NO: 3); b) an IgG1, and the antibody variable domain comprises amino acid modifications at positions 221 and/or 228 in the hinge region and at position 409 and/or 368 (EU numbering scheme) in the CH3 region of the human IgG1 (SEQ ID NO: 2); or c) an IgG1, and the antibody variable domain comprise amino acid modifications at positions 349, 354, 366, 368, and/or 407 (EU numbering scheme) in the CH3 region of the human IgG1 (SEQ ID NO: 2). 
     
     
         20 . The fusion protein of  claim 19 , wherein the antibody further comprises an amino acid modification at a) one or more positions 265, 330, and/or 331 of the human IgG2 (SEQ ID NO: 3); or b) one or more positions 234, 235, and/or 237 of the human IgG1 (SEQ ID NO: 2). 
     
     
         21 . The fusion protein of  claim 13 , wherein the antibody is selected from the group consisting of an anti-CTLA-4 antibody, an anti-CD3 antibody, an anti-CD4 antibody, an anti-CD8 antibody, an anti-4-1 BB antibody, an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-TIM3 antibody, an anti-LAG3 antibody, an anti-TIGIT antibody, an anti-OX40 antibody, an anti-IL-8 antibody, an anti-IL-7Ralpha (CD127) antibody, an anti-IL15 antibody, an anti-HVEM antibody, an anti-BTLA antibody, an anti-CD40 antibody, an anti-CD40L antibody, anti-CD47 antibody, an anti-CSF1R antibody, an anti-CSF1 antibody, an anti-MARCO antibody, an anti-CXCR4 antibodies, an anti-VEGFR1 antibody, an anti-VEGFR2 antibody, an anti-TNFR1 antibody, an anti-TNFR2 antibody, an anti-CD3 bispecific antibody, an anti-CD19 antibody, an anti-CD20, an anti-Her2 antibody, an anti-EGFR antibody, an anti-ICOS antibody, an anti-CD22 antibody, an anti-CD 52 antibody, an anti-CCR4 antibody, an anti-CCR8 antibody, an anti-CD200R antibody, an anti-VISG4 antibody, an anti-CCR2 antibody, an anti-LILRb2 antibody, an anti-CXCR4 antibody, an anti-CD206 antibody, an anti-CD163 antibody, an anti-KLRG1 antibody, an anti-FLT3 antibody, an anti-B7-H4 antibody, an anti-B7-H3 antibody, an KLRG1 antibody, and an anti-GITR antibody. 
     
     
         22 . The fusion protein of  claim 21 , wherein the antibody is a PD-1 antibody comprising a heavy chain variable (VH) region comprising a VH complementarity determining region one (CDR1) comprising the amino acid sequence of SEQ ID NO: 14, 15, 80, 81, 91, or 92, a VH CDR2 comprising the amino acid sequence of SEQ ID NO: 16, 17, 82, or 83, and a VH CDR3 comprising the amino acid sequence shown in SEQ ID NO: 18 or 62; and/or a VL CDR1 comprising the amino acid sequence shown in SEQ ID NO: 19 or 31, a VL CDR2 comprising the amino acid sequence shown in SEQ ID NO: 20 or 32, and a VL CDR3 comprising the amino acid sequence shown in SEQ ID NO: 21 or 33. 
     
     
         23 . The fusion protein of  claim 21 , wherein the antibody is a PD-1 antibody comprising a VH region comprising a CDR1, CDR2, and CDR3 of the VH having an amino acid sequence of SEQ ID NO: 12, 34, 78, or 36, and/or a VL region comprising a CDR1, CDR2, and CDR3 of the VL having an amino acid sequence of SEQ ID NO: 13, 35, 79, or 37. 
     
     
         24 . The fusion protein of  claim 13 , wherein the IL-15 variant is covalently linked to the antibody by a polypeptide linker and/or a polypeptide tag. 
     
     
         25 . An isolated cell line that produces the IL-15 variant of  claim 5  or the IL-15 fusion protein of  claim 13 . 
     
     
         26 . An isolated nucleic acid encoding the IL-15 variant of  claim 5  or the fusion protein of  claim 13 . 
     
     
         27 . A recombinant expression vector comprising the nucleic acid of  claim 26 . 
     
     
         28 . A host cell comprising the isolated nucleic acid of  claim 26 . 
     
     
         29 . A pharmaceutical composition comprising the IL-15 variant of claim or the fusion protein of  claim 13 , and a pharmaceutically acceptable carrier. 
     
     
         30 . A kit for the treatment of cancer comprising the pharmaceutical composition of  claim 29 . 
     
     
         31 . A method for treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of the pharmaceutical composition of  claim 29 , such that one or more symptoms associated with the cancer is ameliorated in the subject. 
     
     
         32 . The method of  claim 31 , wherein the cancer is a solid cancer or a liquid cancer. 
     
     
         33 . The method of  claim 32 , wherein the solid cancer is selected from the group consisting of gastric cancer, small intestine cancer, sarcoma, head and neck cancer, thymic cancer, epithelial cancer, salivary cancer, liver cancer, biliary cancer, neuroendocrine tumors, stomach cancer, thyroid cancer, lung cancer, mesothelioma, ovarian cancer, breast cancer, prostate cancer, esophageal cancer, pancreatic cancer, glioma, renal cancer, bladder cancer, cervical cancer, uterine cancer, vulvar cancer, penile cancer, testicular cancer, anal cancer, choriocarcinoma, colorectal cancer, oral cancer, skin cancer, Merkel cell carcinoma, glioblastoma, brain tumor, bone cancer, eye cancer, and melanoma. 
     
     
         34 . The method of  claim 32 , wherein the liquid cancer is selected from the group consisting of multiple myeloma, malignant plasma cell neoplasm, Hodgkin's lymphoma, nodular lymphocyte predominant Hodgkin's lymphoma, Kahler's disease and Myelomatosis, plasma cell leukemia, plasmacytoma, B-cell prolymphocytic leukemia, hairy cell leukemia, B-cell non-Hodgkin's lymphoma (NHL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML), follicular lymphoma, Burkitt's lymphoma, marginal zone lymphoma, mantle cell lymphoma, large cell lymphoma, precursor B-lymphoblastic lymphoma, myeloid leukemia, Waldenstrom's macroglobulienemia, diffuse large B cell lymphoma, follicular lymphoma, marginal zone lymphoma, mucosa-associated lymphatic tissue lymphoma, small cell lymphocytic lymphoma, mantle cell lymphoma, Burkitt lymphoma, primary mediastinal (thymic) large B-cell lymphoma, lymphoplasmactyic lymphoma, Waldenstrom macroglobulinemia, nodal marginal zone B cell lymphoma, splenic marginal zone lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, lymphomatoid granulomatosis, T cell/histiocyte-rich large B-cell lymphoma, primary central nervous system lymphoma, primary cutaneous diffuse large B-cell lymphoma (leg type), EBV positive diffuse large B-cell lymphoma of the elderly, diffuse large B-cell lymphoma associated with inflammation, intravascular large B-cell lymphoma, ALK-positive large B-cell lymphoma, plasmablastic lymphoma, large B-cell lymphoma arising in HHV8-associated multicentric Castleman disease, B-cell lymphoma unclassified with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma, B-cell lymphoma unclassified with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma, and other hematopoietic cells related cancer. 
     
     
         35 . The method of  claim 31 , wherein the cancer is relapsed, refractory, or metastatic. 
     
     
         36 . The method of  claim 31 , wherein the method further comprises administering an effective amount of a second therapeutic agent, optionally wherein the administration is separate, sequential, or simultaneous. 
     
     
         37 . The method of  claim 36 , wherein the second therapeutic agent is an antibody selected from the group consisting of an anti-CTLA-4 antibody, an anti-CD3 antibody, an anti-CD4 antibody, an anti-CD8 antibody, an anti-4-1BB antibody, an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-TIM3 antibody, an anti-LAG3 antibody, an anti-TIGIT antibody, an anti-OX40 antibody, an anti-IL-7Ralpha (CD127) antibody, an anti-IL-8 antibody, an anti-IL-15 antibody, an anti-HVEM antibody, an anti-BTLA antibody, an anti-CD40 antibody, an anti-CD40L antibody, anti-CD47 antibody, an anti-CSF1R antibody, an anti-CSF1 antibody, an anti-IL-7R antibody, an anti-MARCO antibody, an anti-CXCR4 antibodies, an anti-VEGF antibody, an anti-VEGFR1 antibody, an anti-VEGFR2 antibody, an anti-TNFR1 antibody, an anti-TNFR2 antibody, an anti-CD3 bispecific antibody, an anti-CD19 antibody, an anti-CD20, an anti-Her2 antibody, an anti-EGFR antibody, an anti-ICOS antibody, an anti-CD22 antibody, an anti-CD 52 antibody, an anti-CCR4 antibody, an anti-CCR8 antibody, an anti-CD200R antibody, an anti-VISG4 antibody, an anti-CCR2 antibody, an anti-LILRb2 antibody, an anti-CXCR4 antibody, an anti-CD206 antibody, an anti-CD163 antibody, an anti-KLRG1 antibody, an anti-FLT3 antibody, an anti-B7-H4 antibody, an anti-B7-H3 antibody, an KLRG1 antibody, a BTN1A1 antibody, and an anti-GITR antibody. 
     
     
         38 . The method of  claim 36 , wherein the second therapeutic agent is a cytokine, an immunocytokine, TNFα, a PAP inhibitor, an oncolytic virus, a kinase inhibitor, an ALK inhibitor, a MEK inhibitor, an IDO inhibitor, a GLS1 inhibitor, a tyrosine kinase inhibitor, a CART cell or T cell therapy, a TLR agonist, or a tumor vaccine. 
     
     
         39 . The pharmaceutical composition of  claim 29  for use in the treatment of cancer, optionally wherein the cancer is a solid cancer or a liquid cancer and/or the cancer is relapsed, refractory, or metastatic. 
     
     
         40 . The pharmaceutical composition of  claim 39 , wherein the use is in combination with a second therapeutic agent, optionally wherein the combination is for administration simultaneously, concurrently, or simultaneously.