IL-15 conjugates and uses thereof

Abstract

Disclosed herein are interleukin (IL)-15 conjugates and their uses in treating one or more indications. Also described herein are pharmaceutical compositions and kits comprising one or more of the IL-15 conjugates. In some embodiments, at least one amino acid residue in the IL-15 conjugate is replaced with the structure of formula (I) described herein.

Description

[Technical Field]

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 890,741, filed August 23, 2019, U.S. Provisional Patent Application No. 62 / 931,663, filed November 6, 2019, and U.S. Provisional Patent Application No. 62 / 958,177, filed January 7, 2020, the contents of each of which are incorporated herein by reference in their entirety for all purposes. [Background technology]

[0002] Introduction and Overview Distinct populations of T cells regulate the immune system to maintain immune homeostasis and immune tolerance. For example, regulatory T (Treg) cells prevent inappropriate responses by the immune system by preventing pathological autoreactivity, while cytotoxic T cells target and destroy infected and / or cancerous cells. In some embodiments, modulation of different populations of T cells provides options for treating diseases or conditions. Summary of the Invention [Means for solving the problem]

[0003] Described herein is an IL-15 conjugate comprising the amino acid sequence of SEQ ID NO: 1, wherein at least one amino acid residue in the IL-15 conjugate has the structure of formula (I): [ka] (In the formula: Z is CH2 and Y is [ka] and; Y is CH2 and Z is [ka] and; Z is CH2 and Y is [ka] is; or Y is CH2 and Z is [ka] and; W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, 45 kDa, 50 kDa, and 60 kDa; X has the structure: [ka] having; X-1 indicates the point of attachment to the preceding amino acid residue, X+1 indicates the point of attachment to the subsequent amino acid residue). In some embodiments, the IL-15 conjugate is a pharmaceutically acceptable salt, solvate, or hydrate.

[0004] Described herein is an IL-15 conjugate comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-15 conjugate has the structure of formula (I): [ka] (In the formula: Z is CH2 and Y is [ka] and; Y is CH2 and Z is [ka] and; Z is CH2 and Y is [ka] is; or Y is CH2 and Z is [ka] and; W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, 45 kDa, 50 kDa, and 60 kDa; X has the structure: [ka] having; X-1 indicates the point of attachment to the preceding amino acid residue, X+1 indicates the point of attachment to the subsequent amino acid residue. In some embodiments, the IL-15 conjugate is a pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments, Z is CH2 and Y is [ka] In some embodiments, Y is CH2 and Z is [ka] In some embodiments, Z is CH2 and Y is [ka] In some embodiments, Y is CH2 and Z is [ka] Here and throughout, embodiments of Z and Y also encompass pharmaceutically acceptable salts, solvates, or hydrates thereof. In some embodiments, the PEG group has an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, and 45 kDa. In some embodiments, the PEG group has an average molecular weight of 5 kDa. In some embodiments, the PEG group has an average molecular weight of 10 kDa. In some embodiments, the PEG group has an average molecular weight of 15 kDa. In some embodiments, the PEG group has an average molecular weight of 20 kDa. In some embodiments, the PEG group has an average molecular weight of 25 kDa. In some embodiments, the PEG group has an average molecular weight of 30 kDa. In some embodiments, the PEG group has an average molecular weight of 35 kDa. In some embodiments, the PEG group has an average molecular weight of 40 kDa. In some embodiments, the PEG group has an average molecular weight of 45 kDa. In some embodiments, the PEG group has an average molecular weight of 50 kDa. In some embodiments, the PEG group has an average molecular weight of 55 kDa. In some embodiments, the PEG group has an average molecular weight of 60 kDa.

[0005] In some embodiments, the position of the structure of Formula (I) in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO:1 is selected from S18, L25, E46, E53, N77, and S83. In some embodiments, the position of the structure of Formula (I) in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO:1 is selected from L25, E53, and N77. In some embodiments, the position of the structure of Formula (I) in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO:1 is S18. In some embodiments, the position of the structure of Formula (I) in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO:1 is L25. In some embodiments, the position of the structure of Formula (I) in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO:1 is E46. In some embodiments, the position of the structure of Formula (I) in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO:1 is E53. In some embodiments, the position of the structure of Formula (I) in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO:1 is N77. In some embodiments, the position of the structure of formula (I) in the amino acid sequence of the IL-15 conjugate comprising SEQ ID NO:1 is S83.

[0006] In some embodiments, the position of the structure of Formula (I) in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 3 is selected from S19, L26, E47, E54, N78, and S84. In some embodiments, the position of the structure of Formula (I) in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 3 is selected from L26, E54, and N78. In some embodiments, the position of the structure of Formula (I) in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 3 is S19. In some embodiments, the position of the structure of Formula (I) in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 3 is L26. In some embodiments, the position of the structure of Formula (I) in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 3 is E47. In some embodiments, the position of the structure of Formula (I) in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 3 is E54. In some embodiments, the position of the structure of Formula (I) in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 3 is N78. In some embodiments, the position of the structure of formula (I) in the amino acid sequence of the IL-15 conjugate comprising SEQ ID NO: 3 is S84.

[0007] Described herein are IL-15 conjugates comprising the amino acid sequence of any one of SEQ ID NOs: 16-21, wherein [AzK_PEG] has the structure of Formula (II) or Formula (III), or a mixture of Formulas (II) and (III): [ka] (In the formula: W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, 45 kDa, 50 kDa, and 60 kDa; X has the structure: [ka] having; X-1 indicates the point of attachment to the preceding amino acid residue, X+1 indicates the point of attachment to the subsequent amino acid residue).

[0008] In some embodiments, the IL-15 conjugate is a pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments, [AzK_PEG] is a mixture of Formula (II) and Formula (III). In some embodiments, [AzK_PEG] has the structure of Formula (II): [ka]

[0023] Herein and throughout, the structure of Formula (II) encompasses pharmaceutically acceptable salts, solvates, or hydrates thereof. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 16. In some embodiments, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, and 45 kDa. In some embodiments, W is a PEG group having an average molecular weight selected from 30 kDa and 40 kDa. In some embodiments, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments, W is a PEG group having an average molecular weight of 40 kDa. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 17. In some embodiments, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, and 45 kDa. In some embodiments, W is a PEG group having an average molecular weight selected from 30 kDa and 40 kDa. In some embodiments, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments, W is a PEG group having an average molecular weight of 40 kDa. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 18. In some embodiments, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, and 45 kDa. In some embodiments, W is a PEG group having an average molecular weight selected from 30 kDa and 40 kDa. In some embodiments, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments, W is a PEG group having an average molecular weight of 40 kDa. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 19. In some embodiments, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, and 45 kDa.In some embodiments, W is a PEG group having an average molecular weight selected from 30 kDa and 40 kDa. In some embodiments, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments, W is a PEG group having an average molecular weight of 40 kDa. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 20. In some embodiments, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, and 45 kDa. In some embodiments, W is a PEG group having an average molecular weight selected from 30 kDa and 40 kDa. In some embodiments, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments, W is a PEG group having an average molecular weight of 40 kDa. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 21. In some embodiments, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, and 45 kDa. In some embodiments, W is a PEG group having an average molecular weight selected from 30 kDa and 40 kDa. In some embodiments, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments, W is a PEG group having an average molecular weight of 40 kDa.

[0009] In some embodiments, [AzK_PEG] has the structure of formula (III): [ka]

[0023] Herein and throughout, the structure of Formula (III) encompasses pharmaceutically acceptable salts, solvates, or hydrates thereof. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 16. In some embodiments, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, and 45 kDa. In some embodiments, W is a PEG group having an average molecular weight selected from 30 kDa and 40 kDa. In some embodiments, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments, W is a PEG group having an average molecular weight of 40 kDa. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 17. In some embodiments, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, and 45 kDa. In some embodiments, W is a PEG group having an average molecular weight selected from 30 kDa and 40 kDa. In some embodiments, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments, W is a PEG group having an average molecular weight of 40 kDa. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 18. In some embodiments, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, and 45 kDa. In some embodiments, W is a PEG group having an average molecular weight selected from 30 kDa and 40 kDa. In some embodiments, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments, W is a PEG group having an average molecular weight of 40 kDa. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 19. In some embodiments, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, and 45 kDa.In some embodiments, W is a PEG group having an average molecular weight selected from 30 kDa and 40 kDa. In some embodiments, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments, W is a PEG group having an average molecular weight of 40 kDa. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 20. In some embodiments, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, and 45 kDa. In some embodiments, W is a PEG group having an average molecular weight selected from 30 kDa and 40 kDa. In some embodiments, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments, W is a PEG group having an average molecular weight of 40 kDa. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 21. In some embodiments, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, and 45 kDa. In some embodiments, W is a PEG group having an average molecular weight selected from 30 kDa and 40 kDa. In some embodiments, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments, W is a PEG group having an average molecular weight of 40 kDa.

[0010] Described herein are IL-15 conjugates comprising the amino acid sequence of any one of SEQ ID NOs: 16-21, wherein [AzK_PEG] has the structure of formula (II) and formula (III): [ka] (In the formula: W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, 45 kDa, 50 kDa, and 60 kDa; X has the structure: [ka] having; X-1 indicates the point of attachment to the preceding amino acid residue, and X+1 indicates the point of attachment to the subsequent amino acid residue). In some embodiments, the IL-15 conjugate is a pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments, the ratio of the amount of the structure of Formula (II), including the total amount of [AzK_PEG], to the amount of the structure of Formula (III) in the IL-15 conjugate is about 1:1. In some embodiments, the ratio of the amount of the structure of Formula (II), including the total amount of [AzK_PEG], to the amount of the structure of Formula (III) in the IL-15 conjugate is greater than 1:1. In some embodiments, the ratio of the amount of the structure of Formula (II), including the total amount of [AzK_PEG], to the amount of the structure of Formula (III) in the IL-15 conjugate is less than 1:1. In some embodiments, W is a linear or branched PEG group. In some embodiments, W is a linear PEG group. In some embodiments, W is a branched PEG group. In some embodiments, W is a methoxy PEG group. In some embodiments, the methoxy PEG group is linear or branched. In some embodiments, the methoxy PEG group is linear. In some embodiments, the methoxy PEG group is branched.

[0011] Described herein are IL-15 conjugates comprising the amino acid sequence of any one of SEQ ID NOs: 22-27, wherein [AzK_PEG30] has the structure of Formula (II) or Formula (III), or a mixture of Formulas (II) and (III): [ka] (In the formula: W is a PEG group having an average molecular weight of 30 kDa; X has the structure: [ka] having; X-1 indicates the point of attachment to the preceding amino acid residue, X+1 indicates the point of attachment to the subsequent amino acid residue. In some embodiments, the IL-15 conjugate is a pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 22. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 23. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 24. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 25. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 26. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 27.

[0012] In some embodiments, [AzK_PEG30] has the structure of formula (II) [ka] In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 22. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 23. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 24. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 25. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 26. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 27.

[0013] In some embodiments, [AzK_PEG30] has the structure of formula (III): [ka] Herein and throughout, the structure of Formula (III) encompasses pharmaceutically acceptable salts, solvates, or hydrates thereof. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 22. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 23. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 24. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 25. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 26. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 27.

[0014] Described herein are IL-15 conjugates comprising the amino acid sequence of any one of SEQ ID NOs: 22-27, wherein [AzK_PEG30] has the structure of formula (II) and formula (III): [ka] (In the formula: W is a PEG group having an average molecular weight of 30 kDa; X has the structure: [ka] having; X-1 indicates the point of attachment to the preceding amino acid residue, and X+1 indicates the point of attachment to the subsequent amino acid residue). In some embodiments, the IL-15 conjugate is a pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments, the ratio of the amount of the structure of Formula (II), including the total amount of [AzK_PEG30], to the amount of the structure of Formula (III) in the IL-15 conjugate is about 1:1. In some embodiments, the ratio of the amount of the structure of Formula (II), including the total amount of [AzK_PEG30], to the amount of the structure of Formula (III) in the IL-15 conjugate is greater than 1:1. In some embodiments, the ratio of the amount of the structure of Formula (II), including the total amount of [AzK_PEG30], to the amount of the structure of Formula (III) in the IL-15 conjugate is less than 1:1. In some embodiments, W is a linear or branched PEG group. In some embodiments, W is a linear PEG group. In some embodiments, W is a branched PEG group. In some embodiments, W is a methoxy PEG group. In some embodiments, the methoxy PEG group is linear or branched. In some embodiments, the methoxy PEG group is linear. In some embodiments, the methoxy PEG group is branched.

[0015] Described herein are IL-15 conjugates comprising the amino acid sequence of any one of SEQ ID NOs: 28-33, wherein [AzK_PEG40] has a structure of formula (II) or formula (III), or a mixture of the structures of formula (II) and formula (III): [ka] (In the formula: W is a PEG group with an average molecular weight of 40 kDa; X has the structure: [ka] having; X-1 indicates the point of attachment to the preceding amino acid residue, X+1 indicates the point of attachment to the subsequent amino acid residue). In some embodiments, the IL-15 conjugate is a pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 28. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 29. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 30. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 31. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 32. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 33.

[0016] In some embodiments, [AzK_PEG40] has the structure of formula (II): [ka] In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 28. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 29. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 30. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 31. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 32. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 33.

[0017] In some embodiments, [AzK_PEG40] has the structure of formula (III): [ka] In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 28. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 29. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 30. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 31. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 32. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 33.

[0018] Described herein are IL-15 conjugates comprising the amino acid sequence of any one of SEQ ID NOs: 28-33, wherein [AzK_PEG40] has the structure of formula (II) and formula (III): [ka] (In the formula: W is a PEG group with an average molecular weight of 40 kDa; X has the structure: [ka] having; X-1 indicates the point of attachment to the preceding amino acid residue, and X+1 indicates the point of attachment to the subsequent amino acid residue). In some embodiments, the IL-15 conjugate is a pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments, the ratio of the amount of the structure of Formula (II), including the total amount of [AzK_PEG40], to the amount of the structure of Formula (III) in the IL-15 conjugate is about 1:1. In some embodiments, the ratio of the amount of the structure of Formula (II), including the total amount of [AzK_PEG40], to the amount of the structure of Formula (III) in the IL-15 conjugate is greater than 1:1. In some embodiments, the ratio of the amount of the structure of Formula (II), including the total amount of [AzK_PEG40], to the amount of the structure of Formula (III) in the IL-15 conjugate is less than 1:1. In some embodiments, W is a linear or branched PEG group. In some embodiments, W is a linear PEG group. In some embodiments, W is a branched PEG group. In some embodiments, W is a methoxy PEG group. In some embodiments, the methoxy PEG group is linear or branched. In some embodiments, the methoxy PEG group is linear. In some embodiments, the methoxy PEG group is branched.

[0019] Described herein are IL-15 conjugates comprising the amino acid sequence of any one of SEQ ID NOs: 34-39, wherein [AzK_L1_PEG] has the structure of Formula (IV) or Formula (V), or a mixture of Formulas (IV) and (V): [ka] (In the formula: W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, 45 kDa, 50 kDa, and 60 kDa; X has the structure: [ka] having; X-1 indicates the point of attachment to the preceding amino acid residue, X+1 indicates the point of attachment to the subsequent amino acid residue. In some embodiments, the IL-15 conjugate is a pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments, [AzK_L1_PEG] is a mixture of Formula (IV) and Formula (V).

[0020] In some embodiments, [AzK_L1_PEG] has the structure of formula (IV): [ka]

[0023] Herein and throughout, the structure of formula (IV) encompasses pharmaceutically acceptable salts, solvates, or hydrates thereof. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 34. In some embodiments, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, and 45 kDa. In some embodiments, W is a PEG group having an average molecular weight selected from 30 kDa and 40 kDa. In some embodiments, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments, W is a PEG group having an average molecular weight of 40 kDa. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 35. In some embodiments, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, and 45 kDa. In some embodiments, W is a PEG group having an average molecular weight selected from 30 kDa and 40 kDa. In some embodiments, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments, W is a PEG group having an average molecular weight of 40 kDa. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 36. In some embodiments, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, and 45 kDa. In some embodiments, W is a PEG group having an average molecular weight selected from 30 kDa and 40 kDa. In some embodiments, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments, W is a PEG group having an average molecular weight of 40 kDa. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 37. In some embodiments, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, and 45 kDa.In some embodiments, W is a PEG group having an average molecular weight selected from 30 kDa and 40 kDa. In some embodiments, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments, W is a PEG group having an average molecular weight of 40 kDa. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 38. In some embodiments, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, and 45 kDa. In some embodiments, W is a PEG group having an average molecular weight selected from 30 kDa and 40 kDa. In some embodiments, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments, W is a PEG group having an average molecular weight of 40 kDa. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 39. In some embodiments, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, and 45 kDa. In some embodiments, W is a PEG group having an average molecular weight selected from 30 kDa and 40 kDa. In some embodiments, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments, W is a PEG group having an average molecular weight of 40 kDa.

[0021] In some embodiments, [AzK_L1_PEG] has the structure of formula (V): [ka]

[0023] Herein and throughout, the structure of Formula (V) encompasses pharmaceutically acceptable salts, solvates, or hydrates thereof. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 34. In some embodiments, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, and 45 kDa. In some embodiments, W is a PEG group having an average molecular weight selected from 30 kDa and 40 kDa. In some embodiments, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments, W is a PEG group having an average molecular weight of 40 kDa. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 35. In some embodiments, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, and 45 kDa. In some embodiments, W is a PEG group having an average molecular weight selected from 30 kDa and 40 kDa. In some embodiments, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments, W is a PEG group having an average molecular weight of 40 kDa. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 36. In some embodiments, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, and 45 kDa. In some embodiments, W is a PEG group having an average molecular weight selected from 30 kDa and 40 kDa. In some embodiments, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments, W is a PEG group having an average molecular weight of 40 kDa. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 37. In some embodiments, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, and 45 kDa.In some embodiments, W is a PEG group having an average molecular weight selected from 30 kDa and 40 kDa. In some embodiments, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments, W is a PEG group having an average molecular weight of 40 kDa. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 38. In some embodiments, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, and 45 kDa. In some embodiments, W is a PEG group having an average molecular weight selected from 30 kDa and 40 kDa. In some embodiments, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments, W is a PEG group having an average molecular weight of 40 kDa. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 39. In some embodiments, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, and 45 kDa. In some embodiments, W is a PEG group having an average molecular weight selected from 30 kDa and 40 kDa. In some embodiments, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments, W is a PEG group having an average molecular weight of 40 kDa.

[0022] Described herein are IL-15 conjugates comprising the amino acid sequence of any one of SEQ ID NOs: 34-39, wherein [AzK_L1_PEG] has the structure of formula (IV) and formula (V): [ka] (In the formula: W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, 45 kDa, 50 kDa, and 60 kDa; X has the structure: [ka] having; X-1 indicates the point of attachment to the preceding amino acid residue, and X+1 indicates the point of attachment to the subsequent amino acid residue). In some embodiments, the IL-15 conjugate is a pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments, the ratio of the amount of the structure of Formula (IV), including the total amount of [AzK_L1_PEG], to the amount of the structure of Formula (V) in the IL-15 conjugate is about 1:1. In some embodiments, the ratio of the amount of the structure of Formula (IV), including the total amount of [AzK_L1_PEG], to the amount of the structure of Formula (V) in the IL-15 conjugate is greater than 1:1. In some embodiments, the ratio of the amount of the structure of Formula (IV), including the total amount of [AzK_L1_PEG], to the amount of the structure of Formula (V) in the IL-15 conjugate is less than 1:1. In some embodiments, W is a linear or branched PEG group. In some embodiments, W is a linear PEG group. In some embodiments, W is a branched PEG group. In some embodiments, W is a methoxy PEG group. In some embodiments, the methoxy PEG group is linear or branched. In some embodiments, the methoxy PEG group is linear. In some embodiments, the methoxy PEG group is branched.

[0023] Described herein are IL-15 conjugates comprising the amino acid sequence of any one of SEQ ID NOs: 40-45, wherein [AzK_L1_PEG30] has the structure of Formula (IV) or Formula (V), or a mixture of Formulas (IV) and (V): [ka] (In the formula: W is a PEG group having an average molecular weight of 30 kDa; X has the structure: [ka] having; X-1 indicates the point of attachment to the preceding amino acid residue, wherein X+1 indicates the point of attachment to the subsequent amino acid residue. In some embodiments, the IL-15 conjugate is a pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 40. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 41. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 42. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 43. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 44. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 45. In some embodiments, [AzK_L1_PEG30] has the structure of formula (IV): [ka] In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 40. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 41. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 42. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 43. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 44. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 45. In some embodiments, [AzK_L1_PEG30] has the structure of formula (V): [ka] In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 40. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 41. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 42. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 43. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 44. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 45.

[0024] Described herein are IL-15 conjugates comprising the amino acid sequence of any one of SEQ ID NOs: 40-45, wherein [AzK_L1_PEG30] has the structure of formula (IV) and formula (V): [ka] (In the formula: W is a PEG group having an average molecular weight of 30 kDa; X has the structure: [ka] having; X-1 indicates the point of attachment to the preceding amino acid residue, and X+1 indicates the point of attachment to the subsequent amino acid residue). In some embodiments, the IL-15 conjugate is a pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments, the ratio of the amount of the structure of Formula (IV), including the total amount of [AzK_L1_PEG30], to the amount of the structure of Formula (V) in the IL-15 conjugate is about 1:1. In some embodiments, the ratio of the amount of the structure of Formula (IV), including the total amount of [AzK_L1_PEG30], to the amount of the structure of Formula (V) in the IL-15 conjugate is greater than 1:1. In some embodiments, the ratio of the amount of the structure of Formula (IV), including the total amount of [AzK_L1_PEG30], to the amount of the structure of Formula (V) in the IL-15 conjugate is less than 1:1. In some embodiments, W is a linear or branched PEG group. In some embodiments, W is a linear PEG group. In some embodiments, W is a branched PEG group. In some embodiments, W is a methoxy PEG group. In some embodiments, the methoxy PEG group is linear or branched. In some embodiments, the methoxy PEG group is linear. In some embodiments, the methoxy PEG group is branched.

[0025] Described herein are IL-15 conjugates comprising the amino acid sequence of any one of SEQ ID NOs: 46-51, wherein [AzK_L1_PEG40] has a structure of formula (IV) or formula (V), or a mixture of the structures of formula (IV) and formula (V): [ka] (In the formula: W is a PEG group with an average molecular weight of 40 kDa; X has the structure: [ka] having; X-1 indicates the point of attachment to the preceding amino acid residue, X+1 indicates the point of attachment to the subsequent amino acid residue). In some embodiments, the IL-15 conjugate is a pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 46. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 47. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 48. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 49. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 50. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 51.

[0026] In some embodiments, [AzK_L1_PEG40] has the structure of formula (IV): [ka] In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 46. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 47. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 48. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 49. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 50. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 51.

[0027] In some embodiments, [AzK_L1_PEG40] has the structure of formula (V): [ka] In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 46. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 47. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 48. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 49. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 50. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 51.

[0028] Described herein are IL-15 conjugates comprising the amino acid sequence of any one of SEQ ID NOs: 46-51, wherein [AzK_L1_PEG40] has the structure of formula (IV) and formula (V): [ka] (In the formula: W is a PEG group with an average molecular weight of 40 kDa; X has the structure: [ka] having; X-1 indicates the point of attachment to the preceding amino acid residue, and X+1 indicates the point of attachment to the subsequent amino acid residue). In some embodiments, the IL-15 conjugate is a pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments, the ratio of the amount of the structure of Formula (IV), including the total amount of [AzK_L1_PEG40], to the amount of the structure of Formula (V) in the IL-15 conjugate is about 1:1. In some embodiments, the ratio of the amount of the structure of Formula (IV), including the total amount of [AzK_L1_PEG40], to the amount of the structure of Formula (V) in the IL-15 conjugate is greater than 1:1. In some embodiments, the ratio of the amount of the structure of Formula (IV), including the total amount of [AzK_L1_PEG40], to the amount of the structure of Formula (V) in the IL-15 conjugate is less than 1:1. In some embodiments, W is a linear or branched PEG group. In some embodiments, W is a linear PEG group. In some embodiments, W is a branched PEG group. In some embodiments, W is a methoxy PEG group. In some embodiments, the methoxy PEG group is linear or branched. In some embodiments, the methoxy PEG group is linear. In some embodiments, the methoxy PEG group is branched.

[0029] Described herein are IL-15 conjugates comprising the amino acid sequence of any one of SEQ ID NOs: 64-69, wherein [AzK_PEG] has the structure of Formula (II) or Formula (III), or a mixture of Formulas (II) and (III): [ka] (In the formula: W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, 45 kDa, 50 kDa, and 60 kDa; X has the structure: [ka] having; X-1 indicates the point of attachment to the preceding amino acid residue, X+1 indicates the point of attachment to the subsequent amino acid residue. In some embodiments, the IL-15 conjugate is a pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments, [AzK_PEG] is a mixture of Formula (II) and Formula (III).

[0030] In some embodiments, [AzK_PEG] has the structure of formula (II): [ka] In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 64. In some embodiments, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, and 45 kDa. In some embodiments, W is a PEG group having an average molecular weight selected from 30 kDa and 40 kDa. In some embodiments, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments, W is a PEG group having an average molecular weight of 40 kDa. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 65. In some embodiments, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, and 45 kDa. In some embodiments, W is a PEG group having an average molecular weight selected from 30 kDa and 40 kDa. In some embodiments, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments, W is a PEG group having an average molecular weight of 40 kDa. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 66. In some embodiments, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, and 45 kDa. In some embodiments, W is a PEG group having an average molecular weight selected from 30 kDa and 40 kDa. In some embodiments, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments, W is a PEG group having an average molecular weight of 40 kDa. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 67. In some embodiments, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, and 45 kDa. In some embodiments, W is a PEG group having an average molecular weight selected from 30 kDa and 40 kDa. In some embodiments, W is a PEG group having an average molecular weight of 30 kDa.In some embodiments, W is a PEG group having an average molecular weight of 40 kDa. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 68. In some embodiments, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, and 45 kDa. In some embodiments, W is a PEG group having an average molecular weight selected from 30 kDa and 40 kDa. In some embodiments, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments, W is a PEG group having an average molecular weight of 40 kDa. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 69. In some embodiments, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, and 45 kDa. In some embodiments, W is a PEG group having an average molecular weight selected from 30 kDa and 40 kDa. In some embodiments, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments, W is a PEG group having an average molecular weight of 40 kDa.

[0031] In some embodiments, [AzK_PEG] has the structure of formula (III) [ka] In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 64. In some embodiments, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, and 45 kDa. In some embodiments, W is a PEG group having an average molecular weight selected from 30 kDa and 40 kDa. In some embodiments, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments, W is a PEG group having an average molecular weight of 40 kDa. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 65. In some embodiments, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, and 45 kDa. In some embodiments, W is a PEG group having an average molecular weight selected from 30 kDa and 40 kDa. In some embodiments, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments, W is a PEG group having an average molecular weight of 40 kDa. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 66. In some embodiments, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, and 45 kDa. In some embodiments, W is a PEG group having an average molecular weight selected from 30 kDa and 40 kDa. In some embodiments, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments, W is a PEG group having an average molecular weight of 40 kDa. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 67. In some embodiments, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, and 45 kDa. In some embodiments, W is a PEG group having an average molecular weight selected from 30 kDa and 40 kDa. In some embodiments, W is a PEG group having an average molecular weight of 30 kDa.In some embodiments, W is a PEG group having an average molecular weight of 40 kDa. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 68. In some embodiments, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, and 45 kDa. In some embodiments, W is a PEG group having an average molecular weight selected from 30 kDa and 40 kDa. In some embodiments, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments, W is a PEG group having an average molecular weight of 40 kDa. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 69. In some embodiments, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, and 45 kDa. In some embodiments, W is a PEG group having an average molecular weight selected from 30 kDa and 40 kDa. In some embodiments, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments, W is a PEG group having an average molecular weight of 40 kDa.

[0032] Described herein are IL-15 conjugates comprising the amino acid sequence of any one of SEQ ID NOs: 64-69, wherein [AzK_PEG] has the structure of formula (II) and formula (III): [ka] (In the formula: W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, 45 kDa, 50 kDa, and 60 kDa; X has the structure: [ka] having; X-1 indicates the point of attachment to the preceding amino acid residue, and X+1 indicates the point of attachment to the subsequent amino acid residue). In some embodiments, the IL-15 conjugate is a pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments, the ratio of the amount of the structure of Formula (II), including the total amount of [AzK_PEG], to the amount of the structure of Formula (III) in the IL-15 conjugate is about 1:1. In some embodiments, the ratio of the amount of the structure of Formula (II), including the total amount of [AzK_PEG], to the amount of the structure of Formula (III) in the IL-15 conjugate is greater than 1:1. In some embodiments, the ratio of the amount of the structure of Formula (II), including the total amount of [AzK_PEG], to the amount of the structure of Formula (III) in the IL-15 conjugate is less than 1:1. In some embodiments, W is a linear or branched PEG group. In some embodiments, W is a linear PEG group. In some embodiments, W is a branched PEG group. In some embodiments, W is a methoxy PEG group. In some embodiments, the methoxy PEG group is linear or branched. In some embodiments, the methoxy PEG group is linear. In some embodiments, the methoxy PEG group is branched.

[0033] Described herein are IL-15 conjugates comprising the amino acid sequence of any one of SEQ ID NOs: 70-75, wherein [AzK_PEG] has the structure of Formula (II) or Formula (III), or a mixture of Formulas (II) and (III): [ka] (In the formula: W is a PEG group having an average molecular weight of 30 kDa; X has the structure: [ka] having; X-1 indicates the point of attachment to the preceding amino acid residue, X+1 indicates the point of attachment to the subsequent amino acid residue. In some embodiments, the IL-15 conjugate is a pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 70. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 71. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 72. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 73. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 74. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 75.

[0034] In some embodiments, [AzK_PEG30] has the structure of formula (II) [ka] In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 70. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 71. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 72. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 73. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 74. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 75.

[0035] In some embodiments, [AzK_PEG30] has the structure of formula (III) [ka] In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 70. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 71. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 72. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 73. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 74. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 75.

[0036] Described herein are IL-15 conjugates comprising the amino acid sequence of any one of SEQ ID NOs: 70-75, wherein [AzK_PEG30] has the structure of formula (II) and formula (III): [ka] (In the formula: W is a PEG group having an average molecular weight of 30 kDa; X has the structure: [ka] having; X-1 indicates the point of attachment to the preceding amino acid residue, and X+1 indicates the point of attachment to the subsequent amino acid residue). In some embodiments, the IL-15 conjugate is a pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments, the ratio of the amount of the structure of Formula (II), including the total amount of [AzK_PEG30], to the amount of the structure of Formula (III) in the IL-15 conjugate is about 1:1. In some embodiments, the ratio of the amount of the structure of Formula (II), including the total amount of [AzK_PEG30], to the amount of the structure of Formula (III) in the IL-15 conjugate is greater than 1:1. In some embodiments, the ratio of the amount of the structure of Formula (II), including the total amount of [AzK_PEG30], to the amount of the structure of Formula (III) in the IL-15 conjugate is less than 1:1. In some embodiments, W is a linear or branched PEG group. In some embodiments, W is a linear PEG group. In some embodiments, W is a branched PEG group. In some embodiments, W is a methoxy PEG group. In some embodiments, the methoxy PEG group is linear or branched. In some embodiments, the methoxy PEG group is linear. In some embodiments, the methoxy PEG group is branched.

[0037] Described herein are IL-15 conjugates comprising the amino acid sequence of any one of SEQ ID NOs: 76-81, wherein [AzK_PEG40] has a structure of formula (II) or formula (III), or a mixture of the structures of formula (II) and formula (III): [ka] (In the formula: W is a PEG group with an average molecular weight of 40 kDa; X has the structure: [ka] having; X-1 indicates the point of attachment to the preceding amino acid residue, X+1 indicates the point of attachment to the subsequent amino acid residue). In some embodiments, the IL-15 conjugate is a pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 76. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 77. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 78. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 79. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 80. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 81.

[0038] In some embodiments, [AzK_PEG40] has the structure of formula (II): [ka] In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 76. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 77. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 78. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 79. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 80. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 81.

[0039] In some embodiments, [AzK_PEG40] has the structure of formula (III): [ka] In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 76. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 77. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 78. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 79. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 80. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 81.

[0040] Described herein are IL-15 conjugates comprising the amino acid sequence of any one of SEQ ID NOs: 76-81, wherein [AzK_PEG40] has the structure of formula (II) and formula (III): [ka] (In the formula: W is a PEG group with an average molecular weight of 40 kDa; X has the structure: [ka] having; X-1 indicates the point of attachment to the preceding amino acid residue, X+1 indicates the point of attachment to the subsequent amino acid residue), an IL-15 conjugate. In some embodiments, the IL-15 conjugate is a pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments, the ratio of the amount of the structure of Formula (II) to the amount of the structure of Formula (III), including the total amount of [AzK_PEG40] in the IL-15 conjugate, is about 1:1. In some embodiments, the ratio of the amount of the structure of Formula (II) to the amount of the structure of Formula (III), including the total amount of [AzK_PEG40] in the IL-15 conjugate, is greater than 1:1. In some embodiments, the ratio of the amount of the structure of Formula (II) to the amount of the structure of Formula (III), including the total amount of [AzK_PEG40] in the IL-15 conjugate, is less than 1:1. In some embodiments, W is a linear or branched PEG group. In some embodiments, W is a linear PEG group. In some embodiments, W is a branched PEG group. In some embodiments, W is a methoxy PEG group. In some embodiments, the methoxy PEG group is linear or branched. In some embodiments, the methoxy PEG group is linear. In some embodiments, the methoxy PEG group is branched.

[0041] Described herein are IL-15 conjugates comprising the amino acid sequence of any one of SEQ ID NOs: 82-87, wherein [AzK_L1_PEG] has the structure of Formula (IV) or Formula (V), or a mixture of Formulas (IV) and (V): [ka] (In the formula: W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, 45 kDa, 50 kDa, and 60 kDa; X has the structure: [ka] having; X-1 indicates the point of attachment to the preceding amino acid residue, X+1 indicates the point of attachment to the subsequent amino acid residue. In some embodiments, the IL-15 conjugate is a pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments, [AzK_L1_PEG] is a mixture of Formula (IV) and Formula (V).

[0042] In some embodiments, [AzK_L1_PEG] has the structure of formula (IV): [ka]

[0023] Herein and throughout, the structure of formula (IV) encompasses pharmaceutically acceptable salts, solvates, or hydrates thereof. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 82. In some embodiments, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, and 45 kDa. In some embodiments, W is a PEG group having an average molecular weight selected from 30 kDa and 40 kDa. In some embodiments, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments, W is a PEG group having an average molecular weight of 40 kDa. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 83. In some embodiments, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, and 45 kDa. In some embodiments, W is a PEG group having an average molecular weight selected from 30 kDa and 40 kDa. In some embodiments, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments, W is a PEG group having an average molecular weight of 40 kDa. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 84. In some embodiments, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, and 45 kDa. In some embodiments, W is a PEG group having an average molecular weight selected from 30 kDa and 40 kDa. In some embodiments, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments, W is a PEG group having an average molecular weight of 40 kDa. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 85. In some embodiments, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, and 45 kDa.In some embodiments, W is a PEG group having an average molecular weight selected from 30 kDa and 40 kDa. In some embodiments, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments, W is a PEG group having an average molecular weight of 40 kDa. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 86. In some embodiments, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, and 45 kDa. In some embodiments, W is a PEG group having an average molecular weight selected from 30 kDa and 40 kDa. In some embodiments, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments, W is a PEG group having an average molecular weight of 40 kDa. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 87. In some embodiments, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, and 45 kDa. In some embodiments, W is a PEG group having an average molecular weight selected from 30 kDa and 40 kDa. In some embodiments, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments, W is a PEG group having an average molecular weight of 40 kDa.

[0043] In some embodiments, [AzK_L1_PEG] has the structure of formula (V): [ka]

[0039] Herein and throughout, the structure of Formula (V) encompasses pharmaceutically acceptable salts, solvates, or hydrates thereof. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 82. In some embodiments, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, and 45 kDa. In some embodiments, W is a PEG group having an average molecular weight selected from 30 kDa and 40 kDa. In some embodiments, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments, W is a PEG group having an average molecular weight of 40 kDa. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 83. In some embodiments, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, and 45 kDa. In some embodiments, W is a PEG group having an average molecular weight selected from 30 kDa and 40 kDa. In some embodiments, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments, W is a PEG group having an average molecular weight of 40 kDa. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 84. In some embodiments, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, and 45 kDa. In some embodiments, W is a PEG group having an average molecular weight selected from 30 kDa and 40 kDa. In some embodiments, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments, W is a PEG group having an average molecular weight of 40 kDa. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 85. In some embodiments, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, and 45 kDa.In some embodiments, W is a PEG group having an average molecular weight selected from 30 kDa and 40 kDa. In some embodiments, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments, W is a PEG group having an average molecular weight of 40 kDa. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 86. In some embodiments, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, and 45 kDa. In some embodiments, W is a PEG group having an average molecular weight selected from 30 kDa and 40 kDa. In some embodiments, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments, W is a PEG group having an average molecular weight of 40 kDa. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 87. In some embodiments, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, and 45 kDa. In some embodiments, W is a PEG group having an average molecular weight selected from 30 kDa and 40 kDa. In some embodiments, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments, W is a PEG group having an average molecular weight of 40 kDa.

[0044] Described herein are IL-15 conjugates comprising the amino acid sequence of any one of SEQ ID NOs: 82-87, wherein [Azk_L1_PEG] has the structure of formula (IV) and formula (V): [ka] (In the formula: W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, 45 kDa, 50 kDa, and 60 kDa; X has the structure: [ka] having; X-1 indicates the point of attachment to the preceding amino acid residue, and X+1 indicates the point of attachment to the subsequent amino acid residue). In some embodiments, the IL-15 conjugate is a pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments, the ratio of the amount of the structure of Formula (IV), including the total amount of [AzK_L1_PEG], to the amount of the structure of Formula (V) in the IL-15 conjugate is about 1:1. In some embodiments, the ratio of the amount of the structure of Formula (IV), including the total amount of [AzK_L1_PEG], to the amount of the structure of Formula (V) in the IL-15 conjugate is greater than 1:1. In some embodiments, the ratio of the amount of the structure of Formula (IV), including the total amount of [AzK_L1_PEG], to the amount of the structure of Formula (V) in the IL-15 conjugate is less than 1:1. In some embodiments, W is a linear or branched PEG group. In some embodiments, W is a linear PEG group. In some embodiments, W is a branched PEG group. In some embodiments, W is a methoxy PEG group. In some embodiments, the methoxy PEG group is linear or branched. In some embodiments, the methoxy PEG group is linear. In some embodiments, the methoxy PEG group is branched.

[0045] Described herein are IL-15 conjugates comprising the amino acid sequence of any one of SEQ ID NOs: 88-93, wherein [AzK_L1_PEG30] has the structure of Formula (IV) or Formula (V), or a mixture of Formulas (IV) and (V): [ka] (In the formula: W is a PEG group having an average molecular weight of 30 kDa; X has the structure: [ka] having; X-1 indicates the point of attachment to the preceding amino acid residue, X+1 indicates the point of attachment to the subsequent amino acid residue). In some embodiments, the IL-15 conjugate is a pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 88. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 89. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 90. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 91. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 92. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 93.

[0046] In some embodiments, [AzK_L1_PEG30] has the structure of formula (IV) [ka] In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 88. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 89. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 90. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 91. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 92. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 93.

[0047] In some embodiments, [AzK_L1_PEG30] has the structure of formula (V): [ka] In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 88. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 89. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 90. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 91. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 92. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 93.

[0048] Described herein are IL-15 conjugates comprising the amino acid sequence of any one of SEQ ID NOs: 88-93, wherein [AzK_L1_PEG30] has the structure of formula (IV) and formula (V): [ka] (In the formula: W is a PEG group having an average molecular weight of 30 kDa; X has the structure: [ka] having; X-1 indicates the point of attachment to the preceding amino acid residue, X+1 indicates the point of attachment to the subsequent amino acid residue), an IL-15 conjugate. In some embodiments, the IL-15 conjugate is a pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments, the ratio of the amount of the structure of Formula (IV), including the total amount of [AzK_L1_PEG30], to the amount of the structure of Formula (V) in the IL-15 conjugate is about 1:1. In some embodiments, the ratio of the amount of the structure of Formula (IV), including the total amount of [AzK_L1_PEG30], to the amount of the structure of Formula (V) in the IL-15 conjugate is greater than 1:1. In some embodiments, the ratio of the amount of the structure of Formula (IV), including the total amount of [AzK_L1_PEG30], to the amount of the structure of Formula (V) in the IL-15 conjugate is less than 1:1. In some embodiments, W is a linear or branched PEG group. In some embodiments, W is a linear PEG group. In some embodiments, W is a branched PEG group. In some embodiments, W is a methoxy PEG group. In some embodiments, the methoxy PEG group is linear or branched. In some embodiments, the methoxy PEG group is linear. In some embodiments, the methoxy PEG group is branched.

[0049] Described herein are IL-15 conjugates comprising the amino acid sequence of any one of SEQ ID NOs: 94-99, wherein [AzK_L1_PEG40] has a structure of formula (IV) or formula (V), or a mixture of the structures of formula (IV) and formula (V): [ka] (In the formula: W is a PEG group with an average molecular weight of 40 kDa; X has the structure: [ka] having; X-1 indicates the point of attachment to the preceding amino acid residue, X+1 indicates the point of attachment to the subsequent amino acid residue), an IL-15 conjugate. In some embodiments, the IL-15 conjugate is a pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 94. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 95. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 96. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 97. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 98. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 99.

[0050] In some embodiments, [AzK_L1_PEG40] has the structure of formula (IV): [ka] In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 94. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 95. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 96. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 97. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 98. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 99.

[0051] In some embodiments, [AzK_L1_PEG40] has the structure of formula (V): [ka] In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 94. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 95. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 96. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 97. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 98. In some embodiments, the IL-15 conjugate has the amino acid sequence of SEQ ID NO: 99.

[0052] Described herein are IL-15 conjugates comprising the amino acid sequence of any one of SEQ ID NOs: 94-99, wherein [AzK_L1_PEG40] has the structure of formula (IV) and formula (V): [ka] (In the formula: W is a PEG group with an average molecular weight of 40 kDa; X has the structure: [ka] having; X-1 indicates the point of attachment to the preceding amino acid residue, X+1 indicates the point of attachment to the subsequent amino acid residue), an IL-15 conjugate. In some embodiments, the IL-15 conjugate is a pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments, the ratio of the amount of the structure of Formula (IV), including the total amount of [AzK_L1_PEG40], in the IL-15 conjugate to the amount of the structure of Formula (V) is about 1:1. In some embodiments, the ratio of the amount of the structure of Formula (IV), including the total amount of [AzK_L1_PEG40], in the IL-15 conjugate to the amount of the structure of Formula (V) is greater than 1:1. In some embodiments, the ratio of the amount of the structure of Formula (IV), including the total amount of [AzK_L1_PEG40], in the IL-15 conjugate to the amount of the structure of Formula (V) is less than 1:1. In some embodiments, W is a linear or branched PEG group. In some embodiments, W is a linear PEG group. In some embodiments, W is a branched PEG group. In some embodiments, W is a methoxy PEG group. In some embodiments, the methoxy PEG group is linear or branched. In some embodiments, the methoxy PEG group is linear. In some embodiments, the methoxy PEG group is branched.

[0053] Described herein is an IL-15 conjugate comprising the amino acid sequence of SEQ ID NO: 1, wherein at least one amino acid residue in the IL-15 conjugate has the structure of formula (VI) or (VII), or a mixture of (VI) and (VII): [ka] (In the formula: n is an integer ranging from about 2 to about 5000; X has the structure: [ka] having; X-1 indicates the point of attachment to the preceding amino acid residue, X+1 indicates the point of attachment to the subsequent amino acid residue). In some embodiments, the IL-15 conjugate is a pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments, the position of the structure of Formula (VI) or (VII), or a mixture of (VI) and (VII), in the amino acid sequence of the IL-15 conjugate comprising SEQ ID NO: 1 is selected from S18, L25, E46, E53, N77, and S83. In some embodiments, the position of the structure of Formula (VI) or (VII), or a mixture of (VI) and (VII), in the amino acid sequence of the IL-15 conjugate comprising SEQ ID NO: 1 is selected from L25, E53, and N77. In some embodiments, the position of the structure of Formula (VI) or (VII), or a mixture of (VI) and (VII) in the amino acid sequence of the IL-15 conjugate comprising SEQ ID NO: 1 is S18. In some embodiments, the position of the structure of Formula (VI) or (VII), or a mixture of (VI) and (VII), in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 1 is L25. In some embodiments, the position of the structure of Formula (VI) or (VII), or a mixture of (VI) and (VII), in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 1 is E46. In some embodiments, the position of the structure of Formula (VI) or (VII), or a mixture of (VI) and (VII), in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 1 is E53. In some embodiments, the position of the structure of Formula (VI) or (VII), or a mixture of (VI) and (VII), in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 1 is N77. In some embodiments, the position of the structure of Formula (VI) or (VII), or a mixture of (VI) and (VII) in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 1 is S83. In some embodiments, n is from about 75 to about 1000. In some embodiments, n is from about 100 to about 1000. In some embodiments, n is from about 200 to about 5000. In some embodiments, n is from about 500 to about 1000. In some embodiments, n is from about 400 to about 800.In some embodiments described herein, n is an integer from about 450 to about 800, or from about 454 to about 796, or from about 454 to about 682, or from about 568 to about 909. In some embodiments, n is an integer selected from 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910. In some embodiments, n is from about 500 to about 1000. In some embodiments, n is from about 550 to about 800. In some embodiments, n is about 681. In some embodiments, n is about 681. In some embodiments, n is about 795. In some embodiments, n is about 909. In some embodiments, n is about 1022. In some embodiments, n is about 1136.

[0054] Described herein is an IL-15 conjugate comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-15 conjugate has the structure of formula (VI) or (VII), or a mixture of (VI) and (VII): [ka] (In the formula: n is an integer ranging from about 2 to about 5000; X has the structure: [ka] having; X-1 indicates the point of attachment to the preceding amino acid residue, X+1 indicates the point of attachment to the subsequent amino acid residue). In some embodiments, the IL-15 conjugate is a pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments, the position of the structure of Formula (VI) or (VII), or a mixture of (VI) and (VII), in the amino acid sequence of the IL-15 conjugate comprising SEQ ID NO: 3 is selected from S19, L26, E47, E54, N78, and S84. In some embodiments, the position of the structure of Formula (VI) or (VII), or a mixture of (VI) and (VII), in the amino acid sequence of the IL-15 conjugate comprising SEQ ID NO: 3 is selected from L26, E54, and N78. In some embodiments, the position of the structure of Formula (VI) or (VII), or a mixture of (VI) and (VII) in the amino acid sequence of the IL-15 conjugate comprising SEQ ID NO: 3 is S19. In some embodiments, the position of the structure of Formula (VI) or (VII), or a mixture of (VI) and (VII), in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 3 is L26. In some embodiments, the position of the structure of Formula (VI) or (VII), or a mixture of (VI) and (VII), in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 3 is E47. In some embodiments, the position of the structure of Formula (VI) or (VII), or a mixture of (VI) and (VII), in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 3 is E54. In some embodiments, the position of the structure of Formula (VI) or (VII), or a mixture of (VI) and (VII), in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 3 is N78. In some embodiments, the position of the structure of Formula (VI) or (VII), or a mixture of (VI) and (VII) in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 3 is S84. In some embodiments, n is from about 75 to about 1000. In some embodiments, n is from about 100 to about 1000. In some embodiments, n is from about 200 to about 5000. In some embodiments, n is from about 500 to about 1000. In some embodiments, n is from about 400 to about 800.In some embodiments described herein, n is an integer from about 450 to about 800, or from about 454 to about 796, or from about 454 to about 682, or from about 568 to about 909. In some embodiments, n is an integer selected from 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910. In some embodiments, n is from about 500 to about 1000. In some embodiments, n is from about 550 to about 800. In some embodiments, n is about 681. In some embodiments, n is about 795. In some embodiments, n is about 909. In some embodiments, n is about 1022. In some embodiments, n is about 1136.

[0055] Described herein is an IL-15 conjugate comprising the amino acid sequence of SEQ ID NO: 1, wherein at least one amino acid residue in the IL-15 conjugate has the structure of formula (VIII) or (IX), or a mixture of (VIII) and (IX): [ka] (In the formula: n is an integer ranging from about 2 to about 5000; X has the structure: [ka] having; X-1 indicates the point of attachment to the preceding amino acid residue, X+1 indicates the point of attachment to the subsequent amino acid residue). In some embodiments, the IL-15 conjugate is a pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments, the position of the structure of Formula (VIII) or (IX), or a mixture of (VIII) and (IX), in the amino acid sequence of the IL-15 conjugate comprising SEQ ID NO: 1 is selected from S18, L25, E46, E53, N77, and S83. In some embodiments, the position of the structure of Formula (VIII) or (IX), or a mixture of (VIII) and (IX), in the amino acid sequence of the IL-15 conjugate comprising SEQ ID NO: 1 is selected from L25, E53, and N77. In some embodiments, the position of the structure of Formula (VIII) or (IX), or a mixture of (VIII) and (IX) in the amino acid sequence of the IL-15 conjugate comprising SEQ ID NO: 1 is S18. In some embodiments, the position of the structure of Formula (VIII) or (IX), or a mixture of (VIII) and (IX), in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 1 is L25. In some embodiments, the position of the structure of Formula (VIII) or (IX), or a mixture of (VIII) and (IX), in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 1 is E46. In some embodiments, the position of the structure of Formula (VIII) or (IX), or a mixture of (VIII) and (IX), in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 1 is E53. In some embodiments, the position of the structure of Formula (VIII) or (IX), or a mixture of (VIII) and (IX), in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 1 is N77. In some embodiments, the position of the structure of Formula (VIII) or (IX), or a mixture of (VIII) and (IX) in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 1 is S83. In some embodiments, n is from about 75 to about 1000. In some embodiments, n is from about 100 to about 1000. In some embodiments, n is from about 200 to about 5000. In some embodiments, n is from about 500 to about 1000. In some embodiments, n is from about 400 to about 800.In some embodiments described herein, n is an integer from about 450 to about 800, or from about 454 to about 796, or from about 454 to about 682, or from about 568 to about 909. In some embodiments, n is an integer selected from 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910. In some embodiments, n is from about 500 to about 1000. In some embodiments, n is from about 550 to about 800. In some embodiments, n is about 681. In some embodiments, n is about 795. In some embodiments, n is about 909. In some embodiments, n is about 1022. In some embodiments, n is about 1136.

[0056] Described herein is an IL-15 conjugate comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-15 conjugate has the structure of formula (VIII) or (IX), or a mixture of (VIII) and (IX): [ka] (In the formula: n is an integer ranging from about 2 to about 5000; X has the structure: [ka] having; X-1 indicates the point of attachment to the preceding amino acid residue, X+1 indicates the point of attachment to the subsequent amino acid residue). In some embodiments, the IL-15 conjugate is a pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments, the position of the structure of Formula (VIII) or (IX), or a mixture of (VIII) and (IX), in the amino acid sequence of the IL-15 conjugate comprising SEQ ID NO: 3 is selected from S19, L26, E47, E54, N78, and S84. In some embodiments, the position of the structure of Formula (VIII) or (IX), or a mixture of (VIII) and (IX), in the amino acid sequence of the IL-15 conjugate comprising SEQ ID NO: 3 is selected from L26, E54, and N78. In some embodiments, the position of the structure of Formula (VIII) or (IX), or a mixture of (VIII) and (IX) in the amino acid sequence of the IL-15 conjugate comprising SEQ ID NO: 3 is S19. In some embodiments, the position of the structure of Formula (VIII) or (IX), or a mixture of (VIII) and (IX), in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 3 is L26. In some embodiments, the position of the structure of Formula (VIII) or (IX), or a mixture of (VIII) and (IX), in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 3 is E47. In some embodiments, the position of the structure of Formula (VIII) or (IX), or a mixture of (VIII) and (IX), in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 3 is E54. In some embodiments, the position of the structure of Formula (VIII) or (IX), or a mixture of (VIII) and (IX), in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 3 is N78. In some embodiments, the position of the structure of Formula (VIII) or (IX), or a mixture of (VIII) and (IX) in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 3 is S84. In some embodiments, n is from about 75 to about 1000. In some embodiments, n is from about 100 to about 1000. In some embodiments, n is from about 200 to about 5000. In some embodiments, n is from about 500 to about 1000. In some embodiments, n is from about 400 to about 800.In some embodiments described herein, n is an integer from about 450 to about 800, or from about 454 to about 796, or from about 454 to about 682, or from about 568 to about 909. In some embodiments, n is an integer selected from 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910. In some embodiments, n is from about 500 to about 1000. In some embodiments, n is from about 550 to about 800. In some embodiments, n is about 681. In some embodiments, n is about 795. In some embodiments, n is about 909. In some embodiments, n is about 1022. In some embodiments, n is about 1136.

[0057] Described herein is an IL-15 conjugate comprising the amino acid sequence set forth in SEQ ID NO: 1 or SEQ ID NO: 3, wherein at least one amino acid residue in the IL-15 conjugate has the structure of formula (X) or (XI), or a mixture of (X) and (XI): [ka] (In the formula: n is an integer ranging from about 2 to about 5000; (The wavy line indicates a covalent bond to the unreplaced amino acid residue in SEQ ID NO: 1 or SEQ ID NO: 3.) In some embodiments, the IL-15 conjugate is a pharmaceutically acceptable salt, solvate, or hydrate.

[0058] In some embodiments, the stereochemistry of the chiral centers in Formula (X) and Formula (XI) is racemic, (R)-rich, (S)-rich, substantially (R), substantially (S), (R), or (S). In some embodiments, the stereochemistry of the chiral centers in Formula (X) and Formula (XI) is racemic. In some embodiments, the stereochemistry of the chiral centers in Formula (X) and Formula (XI) is (R)-rich. In some embodiments, the stereochemistry of the chiral centers in Formula (X) and Formula (XI) is (S)-rich. In some embodiments, the stereochemistry of the chiral centers in Formula (X) and Formula (XI) is substantially (R). In some embodiments, the stereochemistry of the chiral centers in Formula (X) and Formula (XI) is substantially (S). In some embodiments, the stereochemistry of the chiral centers in Formula (X) and Formula (XI) is (R). In some embodiments, the stereochemistry of the chiral centers in Formula (X) and Formula (XI) is (S).

[0059] In some embodiments, the position of the structure of formula (X) or (XI), or a mixture of (X) and (XI), in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 1 is selected from S18, L25, E46, E53, N77, and S83. In some embodiments, the position of the structure of formula (X) or (XI), or a mixture of (X) and (XI), in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 1 is selected from L25, E53, and N77. In some embodiments, the position of the structure of formula (X) or (XI), or a mixture of (X) and (XI) in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 1 is S18. In some embodiments, the position of the structure of formula (X) or (XI), or a mixture of (X) and (XI) in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 1 is L25. In some embodiments, the position of the structure of Formula (X) or (XI), or a mixture of (X) and (XI), in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 1 is E46. In some embodiments, the position of the structure of Formula (X) or (XI), or a mixture of (X) and (XI), in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 1 is E53. In some embodiments, the position of the structure of Formula (X) or (XI), or a mixture of (X) and (XI) in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 1 is N77. In some embodiments, the position of the structure of Formula (X) or (XI), or a mixture of (X) and (XI) in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 1 is S83. In some embodiments, n is about 75 to about 1000. In some embodiments, n is about 100 to about 1000. In some embodiments, n is about 200 to about 5000. In some embodiments, n is about 500 to about 1000. In some embodiments, n is from about 400 to about 800. In some embodiments described herein, n is an integer from about 450 to about 800, or from about 454 to about 796, or from about 454 to about 682, or from about 568 to about 909.In some embodiments, n is an integer selected from 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910. In some embodiments, n is about 500 to about 1000. In some embodiments, n is about 550 to about 800. In some embodiments, n is about 681. In some embodiments, n is about 795. In some embodiments, n is about 909. In some embodiments, n is about 1022. In some embodiments, n is about 1136.

[0060] In some embodiments, the position of the structure of Formula (X) or (XI), or a mixture of (X) and (XI), in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 3 is selected from S19, L26, E47, E54, N78, and S84. In some embodiments, the position of the structure of Formula (X) or (XI), or a mixture of (X) and (XI), in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 3 is selected from L26, E54, and N78. In some embodiments, the position of the structure of Formula (X) or (XI), or a mixture of (X) and (XI) in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 3 is S19. In some embodiments, the position of the structure of Formula (X) or (XI), or a mixture of (X) and (XI) in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 3 is L26. In some embodiments, the position of the structure of Formula (X) or (XI), or a mixture of (X) and (XI), in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 3 is E47. In some embodiments, the position of the structure of Formula (X) or (XI), or a mixture of (X) and (XI), in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 3 is E54. In some embodiments, the position of the structure of Formula (X) or (XI), or a mixture of (X) and (XI) in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 3 is N78. In some embodiments, the position of the structure of Formula (X) or (XI), or a mixture of (X) and (XI) in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 3 is S84. In some embodiments, n is about 75 to about 1000. In some embodiments, n is about 100 to about 1000. In some embodiments, n is about 200 to about 5000. In some embodiments, n is about 500 to about 1000. In some embodiments, n is from about 400 to about 800. In some embodiments described herein, n is an integer from about 450 to about 800, or from about 454 to about 796, or from about 454 to about 682, or from about 568 to about 909.In some embodiments, n is an integer selected from 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910. In some embodiments, n is about 500 to about 1000. In some embodiments, n is about 550 to about 800. In some embodiments, n is about 681. In some embodiments, n is about 795. In some embodiments, n is about 909. In some embodiments, n is about 1022. In some embodiments, n is about 1136.

[0061] Described herein is an IL-15 conjugate comprising the amino acid sequence set forth in SEQ ID NO: 1 or SEQ ID NO: 3, wherein at least one amino acid residue in the IL-15 conjugate has the structure of formula (XII) or (XIII), or a mixture of (XII) and (XIII): [ka] (In the formula: n is an integer ranging from about 2 to about 5000; (The wavy line indicates a covalent bond to the unreplaced amino acid residue in SEQ ID NO: 1 or SEQ ID NO: 3.) In some embodiments, the IL-15 conjugate is a pharmaceutically acceptable salt, solvate, or hydrate.

[0062] In some embodiments, the stereochemistry of the chiral centers in Formula (XII) and Formula (XIII) is racemic, (R)-rich, (S)-rich, substantially (R), substantially (S), (R), or (S). In some embodiments, the stereochemistry of the chiral centers in Formula (XII) and Formula (XIII) is racemic. In some embodiments, the stereochemistry of the chiral centers in Formula (XII) and Formula (XIII) is (R)-rich. In some embodiments, the stereochemistry of the chiral centers in Formula (XII) and Formula (XIII) is (S)-rich. In some embodiments, the stereochemistry of the chiral centers in Formula (XII) and Formula (XIII) is substantially (R). In some embodiments, the stereochemistry of the chiral centers in Formula (XII) and Formula (XIII) is substantially (S). In some embodiments, the stereochemistry of the chiral centers in Formula (XII) and Formula (XIII) is (R). In some embodiments, the stereochemistry of the chiral centers in Formula (XII) and Formula (XIII) is (S).

[0063] In some embodiments, the position of the structure of Formula (XII) or (XIII), or a mixture of (XII) and (XIII), in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 1 is selected from S18, L25, E46, E53, N77, and S83. In some embodiments, the position of the structure of Formula (XII) or (XIII), or a mixture of (XII) and (XIII), in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 1 is selected from L25, E53, and N77. In some embodiments, the position of the structure of Formula (XII) or (XIII), or a mixture of (XII) and (XIII), in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 1 is S18. In some embodiments, the position of the structure of Formula (XII) or (XIII), or a mixture of (XII) and (XIII), in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 1 is L25. In some embodiments, the position of the structure of Formula (XII) or (XIII), or a mixture of (XII) and (XIII), in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 1 is E46. In some embodiments, the position of the structure of Formula (XII) or (XIII), or a mixture of (XII) and (XIII), in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 1 is E53. In some embodiments, the position of the structure of Formula (XII) or (XIII), or a mixture of (XII) and (XIII), in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 1 is N77. In some embodiments, the position of the structure of Formula (XII) or (XIII), or a mixture of (XII) and (XIII) in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 1 is S83. In some embodiments, n is about 75 to about 1000. In some embodiments, n is about 100 to about 1000. In some embodiments, n is about 200 to about 5000. In some embodiments, n is from about 500 to about 1000. In some embodiments, n is from about 400 to about 800. In some embodiments described herein, n is an integer from about 450 to about 800, or from about 454 to about 796, or from about 454 to about 682, or from about 568 to about 909.In some embodiments, n is an integer selected from 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910. In some embodiments, n is about 500 to about 1000. In some embodiments, n is about 550 to about 800. In some embodiments, n is about 681. In some embodiments, n is about 795. In some embodiments, n is about 909. In some embodiments, n is about 1022. In some embodiments, n is about 1136.

[0064] In some embodiments, the position of the structure of Formula (XII) or (XIII), or a mixture of (XII) and (XIII), in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 3 is selected from S19, L26, E47, E54, N78, and S84. In some embodiments, the position of the structure of Formula (XII) or (XIII), or a mixture of (XII) and (XIII), in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 3 is selected from L26, E54, and N78. In some embodiments, the position of the structure of Formula (XII) or (XIII), or a mixture of (XII) and (XIII), in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 3 is S19. In some embodiments, the position of the structure of Formula (XII) or (XIII), or a mixture of (XII) and (XIII), in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 3 is L26. In some embodiments, the position of the structure of Formula (XII) or (XIII), or a mixture of (XII) and (XIII), in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 3 is E47. In some embodiments, the position of the structure of Formula (XII) or (XIII), or a mixture of (XII) and (XIII), in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 3 is E54. In some embodiments, the position of the structure of Formula (XII) or (XIII), or a mixture of (XII) and (XIII), in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 3 is N78. In some embodiments, the position of the structure of Formula (XII) or (XIII), or a mixture of (XII) and (XIII) in the amino acid sequence of an IL-15 conjugate comprising SEQ ID NO: 3 is S84. In some embodiments, n is about 75 to about 1000. In some embodiments, n is about 100 to about 1000. In some embodiments, n is about 200 to about 5000. In some embodiments, n is from about 500 to about 1000. In some embodiments, n is from about 400 to about 800. In some embodiments described herein, n is an integer from about 450 to about 800, or from about 454 to about 796, or from about 454 to about 682, or from about 568 to about 909.In some embodiments, n is an integer selected from 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910. In some embodiments, n is about 500 to about 1000. In some embodiments, n is about 550 to about 800. In some embodiments, n is about 681. In some embodiments, n is about 795. In some embodiments, n is about 909. In some embodiments, n is about 1022. In some embodiments, n is about 1136.

[0065] Described herein is an IL-15 conjugate comprising the amino acid sequence set forth in SEQ ID NO: 1 or SEQ ID NO: 3, wherein at least one amino acid residue in the IL-15 conjugate has the structure of formula (XIV) or (XV), or a mixture of (XIV) and (XV): [ka] (In the formula: m is an integer from 0 to 20; p is an integer from 0 to 20; n is an integer ranging from about 2 to about 5000; The IL-15 conjugate is an IL-15 conjugate in which at least one amino acid residue in the IL-15 conjugate is replaced by a structure of formula (XIV) or (XV), or a mixture of (XIV) and (XV), wherein m, p, n, and the wavy line are defined above. In some embodiments, the IL-15 conjugate is a pharmaceutically acceptable salt, solvate, or hydrate. Some embodiments described herein are IL-15 conjugates comprising the amino acid sequence of SEQ ID NO: 1, wherein at least one amino acid residue in the IL-15 conjugate is replaced by a structure of formula (XIV) or (XV), or a mixture of (XIV) and (XV), wherein m, p, n, and the wavy line are defined above. Some embodiments described herein are IL-15 conjugates comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-15 conjugate is replaced by a structure of formula (XIV) or (XV), or a mixture of (XIV) and (XV), wherein m, p, n, and the wavy line are defined above.

[0066] In some embodiments, the stereochemistry of the chiral centers in Formula (XIV) and Formula (XV) is racemic, (R)-rich, (S)-rich, substantially (R), substantially (S), (R), or (S). In some embodiments, the stereochemistry of the chiral centers in Formula (XIV) and Formula (XV) is racemic. In some embodiments, the stereochemistry of the chiral centers in Formula (XIV) and Formula (XV) is (R)-rich. In some embodiments, the stereochemistry of the chiral centers in Formula (XIV) and Formula (XV) is (S)-rich. In some embodiments, the stereochemistry of the chiral centers in Formula (XIV) and Formula (XV) is substantially (R). In some embodiments, the stereochemistry of the chiral centers in Formula (XIV) and Formula (XV) is substantially (S). In some embodiments, the stereochemistry of the chiral centers in Formula (XIV) and Formula (XV) is (R). In some embodiments, the stereochemistry of the chiral centers in Formula (XIV) and Formula (XV) is (S).

[0067] In some embodiments of the IL-15 conjugates described herein, m in the compounds of Formula (XIV) and (XV) is 0 to 20, or 1 to 18, or 1 to 16, or 1 to 14, or 1 to 12, or 1 to 10, or 1 to 9, or 1 to 8, or 1 to 7, or 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3, or 1 to 2. In some embodiments of the IL-15 conjugates described herein, m in the compounds of Formula (XIV) and (XV) is 1. In some embodiments of the IL-15 conjugates described herein, m in the compounds of Formula (XIV) and (XV) is 2. In some embodiments of the IL-15 conjugates described herein, m in the compounds of Formula (XIV) and (XV) is 3. In some embodiments of the IL-15 conjugates described herein, m in the compounds of Formula (XIV) and (XV) is 4. In some embodiments of the IL-15 conjugates described herein, m in the compounds of Formula (XIV) and (XV) is 5. In some embodiments of the IL-15 conjugates described herein, m in the compounds of Formula (XIV) and (XV) is 6. In some embodiments of the IL-15 conjugates described herein, m in the compounds of Formula (XIV) and (XV) is 7. In some embodiments of the IL-15 conjugates described herein, m in the compounds of Formula (XIV) and (XV) is 8. In some embodiments of the IL-15 conjugates described herein, m in the compounds of Formula (XIV) and (XV) is 9. In some embodiments of the IL-15 conjugates described herein, m in the compounds of Formula (XIV) and (XV) is 10. In some embodiments of the IL-15 conjugates described herein, m in the compounds of Formula (XIV) and (XV) is 11. In some embodiments of the IL-15 conjugates described herein, m in the compounds of formula (XIV) and (XV) is 12. In some embodiments of the IL-15 conjugates described herein, m in the compounds of formula (XIV) and (XV) is 13.In some embodiments of the IL-15 conjugates described herein, m in the compounds of Formula (XIV) and (XV) is 14. In some embodiments of the IL-15 conjugates described herein, m in the compounds of Formula (XIV) and (XV) is 15. In some embodiments of the IL-15 conjugates described herein, m in the compounds of Formula (XIV) and (XV) is 16. In some embodiments of the IL-15 conjugates described herein, m in the compounds of Formula (XIV) and (XV) is 17. In some embodiments of the IL-15 conjugates described herein, m in the compounds of Formula (XIV) and (XV) is 18. In some embodiments of the IL-15 conjugates described herein, m in the compounds of Formula (XIV) and (XV) is 19. In some embodiments of the IL-15 conjugates described herein, m in the compounds of Formula (XIV) and (XV) is 20.

[0068] In some embodiments of the IL-15 conjugates described herein, p in the compounds of Formula (XIV) and (XV) is 1 to 20, or 1 to 18, or 1 to 16, or 1 to 14, or 1 to 12, or 1 to 10, or 1 to 9, or 1 to 8, or 1 to 7, or 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3, or 1 to 2. In some embodiments of the IL-15 conjugates described herein, p in the compounds of Formula (XIV) and (XV) is 1. In some embodiments of the IL-15 conjugates described herein, p in the compounds of Formula (XIV) and (XV) is 2. In some embodiments of the IL-15 conjugates described herein, p in the compounds of Formula (XIV) and (XV) is 3. In some embodiments of the IL-15 conjugates described herein, p in the compounds of Formula (XIV) and (XV) is 4. In some embodiments of the IL-15 conjugates described herein, p in the compounds of Formula (XIV) and (XV) is 5. In some embodiments of the IL-15 conjugates described herein, p in the compounds of Formula (XIV) and (XV) is 6. In some embodiments of the IL-15 conjugates described herein, p in the compounds of Formula (XIV) and (XV) is 7. In some embodiments of the IL-15 conjugates described herein, p in the compounds of Formula (XIV) and (XV) is 8. In some embodiments of the IL-15 conjugates described herein, p in the compounds of Formula (XIV) and (XV) is 9. In some embodiments of the IL-15 conjugates described herein, p in the compounds of Formula (XIV) and (XV) is 10. In some embodiments of the IL-15 conjugates described herein, p in the compounds of Formula (XIV) and (XV) is 11. In some embodiments of the IL-15 conjugates described herein, p in the compounds of formula (XIV) and (XV) is 12. In some embodiments of the IL-15 conjugates described herein, p in the compounds of formula (XIV) and (XV) is 13.In some embodiments of the IL-15 conjugates described herein, p in the compounds of Formula (XIV) and (XV) is 14. In some embodiments of the IL-15 conjugates described herein, p in the compounds of Formula (XIV) and (XV) is 15. In some embodiments of the IL-15 conjugates described herein, p in the compounds of Formula (XIV) and (XV) is 16. In some embodiments of the IL-15 conjugates described herein, p in the compounds of Formula (XIV) and (XV) is 17. In some embodiments of the IL-15 conjugates described herein, p in the compounds of Formula (XIV) and (XV) is 18. In some embodiments of the IL-15 conjugates described herein, p in the compounds of Formula (XIV) and (XV) is 19. In some embodiments of the IL-15 conjugates described herein, p in the compounds of Formula (XIV) and (XV) is 20.

[0069] In some embodiments of the IL-15 conjugates described herein, n in the compounds of formula (XIV) and (XV) is from about 5 to about 4600, or from about 10 to about 4000, or from about 20 to about 3000, or from about 100 to about 3000, or from about 100 to about 2900, or from about 150 to about 2900, or from about 125 to about 2900, or from about 100 to about 2500, or from about 100 to about 2000, or from about 100 to about 1900, or from about 100 to about 1850, or from about 100 to about 1750. , or about 100 to about 1650, or about 100 to about 1500, or about 100 to about 1400, or about 100 to about 1300, or about 100 to about 1250, or about 100 to about 1150, or about 100 to about 1100, or about 100 to about 1000, or about 100 to about 900, or about 100 to about 750, or about 100 to about 700, or about 100 to about 600, or about 100 to about 575, or about 100 to about 500, or about 100 to about 450, or about 100 to about 350, or about 100 to about 275, or about 100 to about 230, or about 150 to about 475, or about 150 to about 340, or about 113 to about 340, or about 450 to about 800, or about 454 to about 796, or about 454 to about 682, or about 340 to about 795, or about 341 to about 682, or about 568 to about 909, or about 227 to about 1500, or about 225 to about 2280, or about 460 to about 2160, or about 460 to about 2050, or about 341 to about 1820, or about The molecular weight range is from 341 to about 1710, or from about 341 to about 1250, or from about 225 to about 1250, or from about 341 to about 1250, or from about 341 to about 1136, or from about 341 to about 1023, or from about 341 to about 910, or from about 341 to about 796, or from about 341 to about 682, or from about 341 to about 568, or from about 114 to about 1000, or from about 114 to about 950, or from about 114 to about 910, or from about 114 to about 800, or from about 114 to about 690, or from about 114 to about 575.

[0070] In some embodiments of the IL-15 conjugates described herein, in the compounds of formula (XIV) and (XV), m is an integer from 1 to 6, p is an integer from 1 to 6, and n is an integer selected from 113, 114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137. In some embodiments of the IL-15 conjugates described herein, in the compounds of formula (XIV) and (XV), m is an integer from 2 to 6, p is an integer from 2 to 6, and n is an integer selected from 113, 114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137. In some embodiments of the IL-15 conjugates described herein, in the compounds of formula (XIV) and (XV), m is an integer from 2 to 4, p is an integer from 2 to 4, and n is an integer selected from 113, 114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137. In some embodiments of the IL-15 conjugates described herein, in the compounds of formula (XIV) and (XV), m is 1, p is 2, and n is an integer selected from 113, 114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137. In some embodiments of the IL-15 conjugates described herein, in the compounds of formula (XIV) and (XV), m is 2, p is 2, and n is an integer selected from 113, 114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137.In some embodiments of the IL-15 conjugates described herein, in the compounds of formula (XIV) and (XV), m is 3, p is 2, and n is an integer selected from 113, 114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137. In some embodiments of the IL-15 conjugates described herein, in the compounds of formula (XIV) and (XV), m is 4, p is 2, and n is an integer selected from 113, 114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137. In some embodiments of the IL-15 conjugates described herein, in the compounds of formula (XIV) and (XV), m is 5, p is 2, and n is an integer selected from 113, 114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137. In some embodiments of the IL-15 conjugates described herein, in the compounds of formula (XIV) and (XV), m is 6, p is 2, and n is an integer selected from 113, 114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137. In some embodiments of the IL-15 conjugates described herein, in the compounds of formula (XIV) and (XV), m is 7, p is 2, and n is an integer selected from 113, 114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137.In some embodiments of the IL-15 conjugates described herein, in the compounds of formula (XIV) and (XV), m is 8, p is 2, and n is an integer selected from 113, 114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137. In some embodiments of the IL-15 conjugates described herein, in the compounds of formula (XIV) and (XV), m is 9, p is 2, and n is an integer selected from 113, 114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137. In some embodiments of the IL-15 conjugates described herein, in the compounds of formula (XIV) and (XV), m is 10, p is 2, and n is an integer selected from 113, 114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137. In some embodiments of the IL-15 conjugates described herein, in the compounds of formula (XIV) and (XV), m is 11, p is 2, and n is an integer selected from 113, 114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137. In some embodiments of the IL-15 conjugates described herein, in the compounds of formula (XIV) and (XV), m is 11, p is 2, and n is an integer selected from 113, 114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137.In some embodiments of the IL-15 conjugates described herein, in the compounds of formula (XIV) and (XV), m is 2, p is 2, and n is an integer selected from 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137.

[0071] In some embodiments of the IL-15 conjugates described herein, n in the compounds of formula (XIV) and (XV) is 2, 5, 10, 11, 22, 23, 113, 114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, 1137, 1249, 1250, 1251, 1362, 1363, 1364, is an integer selected from 1476, 1477, 1478, 1589, 1590, 1591, 1703, 1704, 1705, 1817, 1818, 1819, 1930, 1931, 1932, 2044, 2045, 2046, 2158, 2159, 2160, 2271, 2272, 2273, 2839, 2840, 2841, 2953, 2954, 2955, 3408, 3409, 3410, 3976, 3977, 3978, 4544, 4545, and 4546.

[0072] In some embodiments of the IL-15 conjugates described herein, when the IL-15 conjugate comprises SEQ ID NO: 1, the position of the structure of Formula (XIV) and (XV), or a mixture of Formulas (XIV) and (XV), in the amino acid sequence of the IL-15 conjugate is selected from S18, L25, E46, E53, N77, and S83. Further described herein are IL-15 conjugates wherein the position of the structure of Formula (XIV) or (XV), or a mixture of (XIV) and (XV), in the amino acid sequence of the IL-15 conjugate is selected from S18, L25, and E46. Further described herein are IL-15 conjugates wherein the position of the structure of Formula (XIV) or (XV), or a mixture of (XIV) and (XV), in the amino acid sequence of the IL-15 conjugate is selected from E53, N77, and S83. Further described herein are IL-15 conjugates wherein the position of the structure of formula (XIV) or (XV), or a mixture of (XIV) and (XV), in the amino acid sequence of the IL-15 conjugate is S18. Further described herein are IL-15 conjugates wherein the position of the structure of formula (XIV) or (XV), or a mixture of (XIV) and (XV), in the amino acid sequence of the IL-15 conjugate is L25. Further described herein are IL-15 conjugates wherein the position of the structure of formula (XIV) or (XV), or a mixture of (XIV) and (XV), in the amino acid sequence of the IL-15 conjugate is E46. Further described herein are IL-15 conjugates wherein the position of the structure of formula (XIV) or (XV), or a mixture of (XIV) and (XV), in the amino acid sequence of the IL-15 conjugate is E53. Further described herein are IL-15 conjugates wherein the position of the structure of formula (XIV) or (XV), or a mixture of (XIV) and (XV), in the amino acid sequence of the IL-15 conjugate is N77. Further described herein are IL-15 conjugates wherein the position of the structure of formula (XIV) or (XV), or a mixture of (XIV) and (XV), in the amino acid sequence of the IL-15 conjugate is S83.In some embodiments of the IL-15 conjugates described herein, the ratio of the amount of the structure of formula (XIV) to the amount of the structure of formula (XV), including the total amount in the IL-15 conjugate, is about 1:1. In some embodiments of the IL-15 conjugates described herein, the ratio of the amount of the structure of formula (XIV) to the amount of the structure of formula (XV), including the total amount in the IL-15 conjugate, is greater than 1:1. In some embodiments of the IL-15 conjugates described herein, the ratio of the amount of the structure of formula (XIV) to the amount of the structure of formula (XV), including the total amount in the IL-15 conjugate, is less than 1:1.

[0073] In some embodiments of the IL-15 conjugates described herein, when the IL-15 conjugate comprises SEQ ID NO: 3, the position of the structure of Formula (XIV) and (XV), or a mixture of Formulas (XIV) and (XV), in the amino acid sequence of the IL-15 conjugate is selected from S19, L26, E47, E54, N78, and S84. Further described herein are IL-15 conjugates wherein the position of the structure of Formula (XIV) or (XV), or a mixture of (XIV) and (XV), in the amino acid sequence of the IL-15 conjugate is selected from S19, L26, and E47. Further described herein are IL-15 conjugates wherein the position of the structure of Formula (XIV) or (XV), or a mixture of (XIV) and (XV), in the amino acid sequence of the IL-15 conjugate is selected from E54, N78, and S84. Further described herein is an IL-15 conjugate, wherein the position of the structure of formula (XIV) or (XV), or a mixture of (XIV) and (XV), in the amino acid sequence of the IL-15 conjugate is S19. Further described herein is an IL-15 conjugate, wherein the position of the structure of formula (XIV) or (XV), or a mixture of (XIV) and (XV), in the amino acid sequence of the IL-15 conjugate is L26. Further described herein is an IL-15 conjugate, wherein the position of the structure of formula (XIV) or (XV), or a mixture of (XIV) and (XV), in the amino acid sequence of the IL-15 conjugate is E47. Further described herein is an IL-15 conjugate, wherein the position of the structure of formula (XIV) or (XV), or a mixture of (XIV) and (XV), in the amino acid sequence of the IL-15 conjugate is E54. Further described herein is an IL-15 conjugate, wherein the position of the structure of formula (XIV) or (XV), or a mixture of (XIV) and (XV), in the amino acid sequence of the IL-15 conjugate is N78. Further described herein is an IL-15 conjugate, wherein the position of the structure of formula (XIV) or (XV), or a mixture of (XIV) and (XV), in the amino acid sequence of the IL-15 conjugate is S84.In some embodiments of the IL-15 conjugates described herein, the ratio of the amount of the structure of formula (XIV) comprising the total amount in the IL-15 conjugate to the amount of the structure of formula (XV) is about 1:1. In some embodiments of the IL-15 conjugates described herein, the ratio of the amount of the structure of formula (XIV) comprising the total amount in the IL-15 conjugate to the amount of the structure of formula (XV) is greater than 1:1. In some embodiments of the IL-15 conjugates described herein, the ratio of the amount of the structure of formula (XIV) comprising the total amount in the IL-15 conjugate to the amount of the structure of formula (XV) is less than 1:1.

[0074] In some embodiments, described herein is an IL-15 conjugate comprising the amino acid sequence of SEQ ID NO: 1, wherein at least one amino acid residue in the IL-15 conjugate is replaced with a structure of formula (XIV) or (XV), or a mixture of (XIV) and (XV), wherein the replaced amino acid residue in SEQ ID NO: 1 is selected from S18, L25, E46, E53, N77, and S83, and n is 100. to about 1150, or about 100 to about 1100, or about 100 to about 1000, or about 100 to about 900, or about 100 to about 750, or about 100 to about 700, or about 100 to about 600, or about 100 to about 575, or about 100 to about 500, or about 100 to about 450, or about 100 to about 350, or about 100 to about 275, or about 100 to about 230, or about 150 to about 475, or about 150 to about 340, or about 113 to about 340, or about 450 to about 800, or about 454 to about 796, or about 454 to about 682, or about 340 to about 795, or about 341 to about 682, or about 568 to about 909, or about 227 to about 1500, or about 225 to about 2280, or about 460 to about 2160, or about 460 to about 2050, or about 341 to about 1820, or about 341 to about 1710, or about 341 to about 1250, or is an integer from about 225 to about 1250, or from about 341 to about 1250, or from about 341 to about 1136, or from about 341 to about 1023, or from about 341 to about 910, or from about 341 to about 796, or from about 341 to about 682, or from about 341 to about 568, or from about 114 to about 1000, or from about 114 to about 950, or from about 114 to about 910, or from about 114 to about 800, or from about 114 to about 690, or from about 114 to about 575.In some embodiments of the IL-15 conjugates described herein, n in the compounds of formula (XIV) and (XV) is 2, 5, 10, 11, 22, 23, 113, 114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, 1137, 1249, 1250, 1251, 1362, 1363, 1364, and an integer selected from 1476, 1477, 1478, 1589, 1590, 1591, 1703, 1704, 1705, 1817, 1818, 1819, 1930, 1931, 1932, 2044, 2045, 2046, 2158, 2159, 2160, 2271, 2272, 2273, 2839, 2840, 2841, 2953, 2954, 2955, 3408, 3409, 3410, 3976, 3977, 3978, 4544, 4545 and 4546.

[0075] In some embodiments, described herein is an IL-15 conjugate comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-15 conjugate is replaced with a structure of formula (XIV) or (XV), or a mixture of (XIV) and (XV), wherein the replaced amino acid residue in SEQ ID NO: 3 is selected from S19, L26, E47, E54, N78, and S84, and n is 100. to about 1150, or about 100 to about 1100, or about 100 to about 1000, or about 100 to about 900, or about 100 to about 750, or about 100 to about 700, or about 100 to about 600, or about 100 to about 575, or about 100 to about 500, or about 100 to about 450, or about 100 to about 350, or about 100 to about 275, or about 100 to about 230, or about 150 to about 475, or about 150 to about 340, or about 113 to about 340, or about 450 to about 800, or about 454 to about 796, or about 454 to about 682, or about 340 to about 795, or about 341 to about 682, or about 568 to about 909, or about 227 to about 1500, or about 225 to about 2280, or about 460 to about 2160, or about 460 to about 2050, or about 341 to about 1820, or about 341 to about 1710, or about 341 to about 1250, or is an integer from about 225 to about 1250, or from about 341 to about 1250, or from about 341 to about 1136, or from about 341 to about 1023, or from about 341 to about 910, or from about 341 to about 796, or from about 341 to about 682, or from about 341 to about 568, or from about 114 to about 1000, or from about 114 to about 950, or from about 114 to about 910, or from about 114 to about 800, or from about 114 to about 690, or from about 114 to about 575.In some embodiments of the IL-15 conjugates described herein, n in the compounds of formula (XIV) and (XV) is 2, 5, 10, 11, 22, 23, 113, 114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, 1137, 1249, 1250, 1251, 1362, 1363, 1364, and an integer selected from 1476, 1477, 1478, 1589, 1590, 1591, 1703, 1704, 1705, 1817, 1818, 1819, 1930, 1931, 1932, 2044, 2045, 2046, 2158, 2159, 2160, 2271, 2272, 2273, 2839, 2840, 2841, 2953, 2954, 2955, 3408, 3409, 3410, 3976, 3977, 3978, 4544, 4545 and 4546.

[0076] Described herein is an IL-15 conjugate comprising the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 3, wherein at least one amino acid residue in the IL-15 conjugate is replaced with a structure of formula (XIV) or (XV), or a mixture of (XIV) and (XV), and n is a number ranging from about 1,000 daltons to about 200,000 daltons, or from about 2,000 daltons to about 150,000 daltons, or from about 3,000 daltons to about 125,000 daltons, or from about 4,000 daltons to about 100,000 daltons. or about 5,000 daltons to about 100,000 daltons, or about 6,000 daltons to about 90,000 daltons, or about 7,000 daltons to about 80,000 daltons, or about 8,000 daltons to about 70,000 daltons, or about 5,000 daltons to about 70,000 daltons, or about 5,000 daltons to about 65,000 daltons, or about 5,000 daltons to about 60,000 daltons, or about 5,000 daltons to about 50,000 daltons, or about 6,000 daltons to about 50,000 daltons, or about 7,000 daltons to about 50,000 daltons, or about 7,000 daltons to about 45,000 daltons, or about 7,000 daltons to about 40,000 daltons, or about 8,000 daltons to about 40,000 daltons, or about 8,500 daltons to about 40,000 daltons, or about 8,500 daltons to about 35,000 daltons, or about 9,000 daltons to about 50,000 daltons, or about 9,000 daltons to about 45,000 daltons, or about 9,000 daltons to about 40,000 daltons, or about 9,000 daltons to about 35,000 daltons or about 9,000 daltons to about 30,000 daltons, or about 9,500 daltons to about 35,000 daltons, or about 9,500 daltons to about 30,000 daltons, or about 10,000 daltons to about 50,000 daltons, or about 10,000 daltons to about 45,000 daltons, or about 10,000 daltons to about 40,000 daltons, or about 10,000 daltons to about 35,000 daltons, or about 10,000 daltons to about 30,000 daltons, or about 15,000 daltons to about 50,000 daltons, or about 15,20,000 daltons to about 45,000 daltons, or about 15,000 daltons to about 40,000 daltons, or about 15,000 daltons to about 35,000 daltons, or about 15,000 daltons to about 30,000 daltons, or about 20,000 daltons to about 50,000 daltons, or about 20,000 daltons to about 45,000 daltons, or about 20,000 daltons to about 40,000 daltons, or about 20,000 daltons to about 35,000 daltons, or about 20,000 daltons to about 30,000 daltons. Described herein are IL-15 conjugates comprising the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 3, wherein at least one amino acid residue in the IL-15 conjugate is replaced with a structure of formula (XIV) or (XV), or a mixture of (XIV) and (XV), and n is a molecular weight of the PEG moiety of about 5,000 daltons, about 7,500 daltons, about 10,000 daltons, about 15,000 daltons, about 20,000 daltons, or about 30,000 daltons. about 25,000 daltons, about 30,000 daltons, about 35,000 daltons, about 40,000 daltons, about 45,000 daltons, about 50,000 daltons, about 60,000 daltons, about 70,000 daltons, about 80,000 daltons, about 90,000 daltons, about 100,000 daltons, about 125,000 daltons, about 150,000 daltons, about 175,000 daltons or about 200,000 daltons. Described herein are IL-15 conjugates comprising the amino acid sequence of SEQ ID NO:1 or SEQ ID NO:3, wherein at least one amino acid residue in the IL-15 conjugate is replaced with a structure of formula (XIV) or (XV), or a mixture of (XIV) and (XV), and n is an integer such that the molecular weight of the PEG moiety is about 5,000 daltons, about 7,500 daltons, about 10,000 daltons, about 15,000 daltons, about 20,000 daltons, about 25,000 daltons, about 30,000 daltons, about 35,000 daltons, about 40,000 daltons, about 45,000 daltons, or about 50,000 daltons.

[0077] In some embodiments, described herein are IL-15 conjugates comprising the amino acid sequence of SEQ ID NO: 1, wherein at least one amino acid residue in the IL-15 conjugate is replaced with a structure of formula (XIV) or (XV), or a mixture of (XIV) and (XV), wherein the replaced amino acid residue in SEQ ID NO: 1 is L25, m is an integer from 1 to 6, p is an integer from 1 to 6, and n is an integer from about 450 to about 800, or from about 454 to about 796, or from about 454 to about 682, or from about 568 to about 909. In some embodiments of the IL-15 conjugates described herein, in the compounds of formula (XIV) and (XV), m is 2, p is 2, and n is an integer selected from 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910.

[0078] In some embodiments, described herein are IL-15 conjugates comprising the amino acid sequence of SEQ ID NO: 1, wherein at least one amino acid residue in the IL-15 conjugate is replaced with a structure of formula (XIV) or (XV), or a mixture of (XIV) and (XV), wherein the replaced amino acid residue in SEQ ID NO: 1 is L25, m is an integer from 1 to 6, p is an integer from 1 to 6, and n is an integer from about 450 to about 800, or from about 454 to about 796, or from about 454 to about 682, or from about 568 to about 909. In some embodiments of the IL-15 conjugates described herein, in the compounds of formula (XIV) and (XV), m is 2, p is 2, and n is an integer selected from 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910. In some embodiments, n is about 500 to about 1000. In some embodiments, n is about 550 to about 800. In some embodiments, n is about 681. In some embodiments, n is about 909.

[0079] In some embodiments, described herein are IL-15 conjugates comprising the amino acid sequence of SEQ ID NO: 1, wherein at least one amino acid residue in the IL-15 conjugate is replaced with a structure of formula (XIV) or (XV), or a mixture of (XIV) and (XV), wherein the replaced amino acid residue in SEQ ID NO: 1 is L25, m is an integer from 1 to 6, p is an integer from 1 to 6, and n is an integer from about 450 to about 800, or from about 454 to about 796, or from about 454 to about 682, or from about 568 to about 909. In some embodiments of the IL-15 conjugates described herein, in the compounds of formula (XIV) and (XV), m is 2, p is 2, and n is an integer selected from 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910.

[0080] In some embodiments, described herein are IL-15 conjugates comprising the amino acid sequence of SEQ ID NO: 1, wherein at least one amino acid residue in the IL-15 conjugate is replaced with a structure of formula (XIV) or (XV), or a mixture of (XIV) and (XV), wherein the replaced amino acid residue in SEQ ID NO: 1 is E53, m is an integer from 1 to 6, p is an integer from 1 to 6, and n is an integer from about 450 to about 800, or from about 454 to about 796, or from about 454 to about 682, or from about 568 to about 909. In some embodiments of the IL-15 conjugates described herein, in the compounds of formula (XIV) and (XV), m is 2, p is 2, and n is an integer selected from 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910. In some embodiments, n is about 500 to about 1000. In some embodiments, n is about 550 to about 800. In some embodiments, n is about 681. In some embodiments, n is about 909.

[0081] In some embodiments, described herein are IL-15 conjugates comprising the amino acid sequence of SEQ ID NO: 1, wherein at least one amino acid residue in the IL-15 conjugate is replaced with a structure of formula (XIV) or (XV), or a mixture of (XIV) and (XV), wherein the replaced amino acid residue in SEQ ID NO: 1 is E53, m is an integer from 1 to 6, p is an integer from 1 to 6, and n is an integer from about 450 to about 800, or from about 454 to about 796, or from about 454 to about 682, or from about 568 to about 909. In some embodiments of the IL-15 conjugates described herein, in the compounds of formula (XIV) and (XV), m is 2, p is 2, and n is an integer selected from 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910.

[0082] In some embodiments, described herein are IL-15 conjugates comprising the amino acid sequence of SEQ ID NO: 1, wherein at least one amino acid residue in the IL-15 conjugate is replaced with a structure of formula (XIV) or (XV), or a mixture of (XIV) and (XV), wherein the replaced amino acid residue in SEQ ID NO: 1 is N77, m is an integer from 1 to 6, p is an integer from 1 to 6, and n is an integer from about 450 to about 800, or from about 454 to about 796, or from about 454 to about 682, or from about 568 to about 909. In some embodiments of the IL-15 conjugates described herein, in the compounds of formula (XIV) and (XV), m is 2, p is 2, and n is an integer selected from 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910. In some embodiments, n is about 500 to about 1000. In some embodiments, n is about 550 to about 800. In some embodiments, n is about 681. In some embodiments, n is about 909.

[0083] In some embodiments, described herein are IL-15 conjugates comprising the amino acid sequence of SEQ ID NO: 1, wherein at least one amino acid residue in the IL-15 conjugate is replaced with a structure of formula (XIV) or (XV), or a mixture of (XIV) and (XV), wherein the replaced amino acid residue in SEQ ID NO: 1 is N77, m is an integer from 1 to 6, p is an integer from 1 to 6, and n is an integer from about 450 to about 800, or from about 454 to about 796, or from about 454 to about 682, or from about 568 to about 909. In some embodiments of the IL-15 conjugates described herein, in the compounds of formula (XIV) and (XV), m is 2, p is 2, and n is an integer selected from 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910.

[0084] In some embodiments, described herein are IL-15 conjugates comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-15 conjugate is replaced with a structure of formula (XIV) or (XV), or a mixture of (XIV) and (XV), wherein the replaced amino acid residue in SEQ ID NO: 3 is L26, m is an integer from 1 to 6, p is an integer from 1 to 6, and n is an integer from about 450 to about 800, or from about 454 to about 796, or from about 454 to about 682, or from about 568 to about 909. In some embodiments of the IL-15 conjugates described herein, in the compounds of formula (XIV) and (XV), m is 2, p is 2, and n is an integer selected from 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910.

[0085] In some embodiments, described herein are IL-15 conjugates comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-15 conjugate is replaced with a structure of formula (XIV) or (XV), or a mixture of (XIV) and (XV), wherein the replaced amino acid residue in SEQ ID NO: 3 is L26, m is an integer from 1 to 6, p is an integer from 1 to 6, and n is an integer from about 450 to about 800, or from about 454 to about 796, or from about 454 to about 682, or from about 568 to about 909. In some embodiments of the IL-15 conjugates described herein, in the compounds of formula (XIV) and (XV), m is 2, p is 2, and n is an integer selected from 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910. In some embodiments, n is about 500 to about 1000. In some embodiments, n is about 550 to about 800. In some embodiments, n is about 681. In some embodiments, n is about 909.

[0086] In some embodiments, described herein are IL-15 conjugates comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-15 conjugate is replaced with a structure of formula (XIV) or (XV), or a mixture of (XIV) and (XV), wherein the replaced amino acid residue in SEQ ID NO: 3 is E54, m is an integer from 1 to 6, p is an integer from 1 to 6, and n is an integer from about 450 to about 800, or from about 454 to about 796, or from about 454 to about 682, or from about 568 to about 909. In some embodiments of the IL-15 conjugates described herein, in the compounds of formula (XIV) and (XV), m is 2, p is 2, and n is an integer selected from 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910.

[0087] In some embodiments, described herein are IL-15 conjugates comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-15 conjugate is replaced with a structure of formula (XIV) or (XV), or a mixture of (XIV) and (XV), wherein the replaced amino acid residue in SEQ ID NO: 3 is E54, m is an integer from 1 to 6, p is an integer from 1 to 6, and n is an integer from about 450 to about 800, or from about 454 to about 796, or from about 454 to about 682, or from about 568 to about 909. In some embodiments of the IL-15 conjugates described herein, in the compounds of formula (XIV) and (XV), m is 2, p is 2, and n is an integer selected from 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910. In some embodiments, n is about 500 to about 1000. In some embodiments, n is about 550 to about 800. In some embodiments, n is about 681. In some embodiments, n is about 909.

[0088] In some embodiments, described herein are IL-15 conjugates comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-15 conjugate is replaced with a structure of formula (XIV) or (XV), or a mixture of (XIV) and (XV), wherein the replaced amino acid residue in SEQ ID NO: 3 is N78, m is an integer from 1 to 6, p is an integer from 1 to 6, and n is an integer from about 450 to about 800, or from about 454 to about 796, or from about 454 to about 682, or from about 568 to about 909. In some embodiments of the IL-15 conjugates described herein, in the compounds of formula (XIV) and (XV), m is 2, p is 2, and n is an integer selected from 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910.

[0089] In some embodiments, described herein are IL-15 conjugates comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-15 conjugate is replaced with a structure of formula (XIV) or (XV), or a mixture of (XIV) and (XV), wherein the replaced amino acid residue in SEQ ID NO: 3 is N78, m is an integer from 1 to 6, p is an integer from 1 to 6, and n is an integer from about 450 to about 800, or from about 454 to about 796, or from about 454 to about 682, or from about 568 to about 909. In some embodiments of the IL-15 conjugates described herein, in the compounds of formula (XIV) and (XV), m is 2, p is 2, and n is an integer selected from 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910. In some embodiments, n is about 500 to about 1000. In some embodiments, n is about 550 to about 800. In some embodiments, n is about 681. In some embodiments, n is about 909.

[0090] Described herein is an IL-15 conjugate comprising the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 3, wherein at least one amino acid residue in the IL-15 conjugate is replaced with a structure of formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), [ka] (In the formula: m is an integer from 0 to 20; n is an integer ranging from about 2 to about 5000; The wavy line indicates a covalent bond to the unreplaced amino acid residue in SEQ ID NO:1 or SEQ ID NO:3.) In some embodiments, the IL-15 conjugate is a pharmaceutically acceptable salt, solvate, or hydrate. In some embodiments, described herein is an IL-15 conjugate comprising the amino acid sequence of SEQ ID NO:1, wherein at least one amino acid residue in the IL-15 conjugate is replaced by a structure of formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), wherein m, p, n, and the wavy line have the meanings described above. In some embodiments, described herein is an IL-15 conjugate comprising the amino acid sequence of SEQ ID NO:3, wherein at least one amino acid residue in the IL-15 conjugate is replaced by a structure of formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), wherein m, p, n, and the wavy line have the meanings described above.

[0091] In some embodiments, the stereochemistry of the chiral centers in Formula (XVI) and Formula (XVII) is racemic, (R)-rich, (S)-rich, substantially (R), substantially (S), (R), or (S). In some embodiments, the stereochemistry of the chiral centers in Formula (XVI) and Formula (XVII) is racemic. In some embodiments, the stereochemistry of the chiral centers in Formula (XVI) and Formula (XVII) is (R)-rich. In some embodiments, the stereochemistry of the chiral centers in Formula (XVI) and Formula (XVII) is (S)-rich. In some embodiments, the stereochemistry of the chiral centers in Formula (XVI) and Formula (XVII) is substantially (R). In some embodiments, the stereochemistry of the chiral centers in Formula (XVI) and Formula (XVII) is substantially (S). In some embodiments, the stereochemistry of the chiral centers in Formula (XVI) and Formula (XVII) is (R). In some embodiments, the stereochemistry of the chiral centers in Formula (XVI) and Formula (XVII) is (S).

[0092] In some embodiments of the IL-15 conjugates described herein, m in the compounds of Formula (XVI) and (XVII) is 1 to 20, or 1 to 18, or 1 to 16, or 1 to 14, or 1 to 12, or 1 to 10, or 1 to 9, or 1 to 8, or 1 to 7, or 1 to 6, or 1 to 5, or 1 to 4, or 1 to 3, or 1 to 2. In some embodiments of the IL-15 conjugates described herein, m in the compounds of Formula (XVI) and (XVII) is 1. In some embodiments of the IL-15 conjugates described herein, m in the compounds of Formula (XVI) and (XVII) is 2. In some embodiments of the IL-15 conjugates described herein, m in the compounds of Formula (XVI) and (XVII) is 3. In some embodiments of the IL-15 conjugates described herein, m in the compounds of Formula (XVI) and (XVII) is 4. In some embodiments of the IL-15 conjugates described herein, m in the compounds of Formula (XVI) and (XVII) is 5. In some embodiments of the IL-15 conjugates described herein, m in the compounds of Formula (XVI) and (XVII) is 6. In some embodiments of the IL-15 conjugates described herein, m in the compounds of Formula (XVI) and (XVII) is 7. In some embodiments of the IL-15 conjugates described herein, m in the compounds of Formula (XVI) and (XVII) is 8. In some embodiments of the IL-15 conjugates described herein, m in the compounds of Formula (XVI) and (XVII) is 9. In some embodiments of the IL-15 conjugates described herein, m in the compounds of Formula (XVI) and (XVII) is 10. In some embodiments of the IL-15 conjugates described herein, m in the compounds of formula (XVI) and (XVII) is 11. In some embodiments of the IL-15 conjugates described herein, m in the compounds of formula (XVI) and (XVII) is 12. In some embodiments of the IL-15 conjugates described herein, m in the compounds of formula (XVI) and (XVII) is 13.In some embodiments of the IL-15 conjugates described herein, m in the compounds of Formula (XVI) and (XVII) is 14. In some embodiments of the IL-15 conjugates described herein, m in the compounds of Formula (XVI) and (XVII) is 15. In some embodiments of the IL-15 conjugates described herein, m in the compounds of Formula (XVI) and (XVII) is 16. In some embodiments of the IL-15 conjugates described herein, m in the compounds of Formula (XVI) and (XVII) is 17. In some embodiments of the IL-15 conjugates described herein, m in the compounds of Formula (XVI) and (XVII) is 18. In some embodiments of the IL-15 conjugates described herein, m in the compounds of Formula (XVI) and (XVII) is 19. In some embodiments of the IL-15 conjugates described herein, m in the compounds of formula (XVI) and (XVII) is 20.

[0093] In some embodiments of the IL-15 conjugates described herein, n in the compounds of formula (XVI) and (XVII) is from about 5 to about 4600, or from about 10 to about 4000, or from about 20 to about 3000, or from about 100 to about 3000, or from about 100 to about 2900, or from about 150 to about 2900, or from about 125 to about 2900, or from about 100 to about 2500, or from about 100 to about 2000, or from about 100 to about 1900, or from about 100 to about 1850, or from about 100 to about 17 50, or about 100 to about 1650, or about 100 to about 1500, or about 100 to about 1400, or about 100 to about 1300, or about 100 to about 1250, or about 100 to about 1150, or about 100 to about 1100, or about 100 to about 1000, or about 100 to about 900, or about 100 to about 750, or about 100 to about 700, or about 100 to about 600, or about 100 to about 575, or about 100 to about 500, or about 100 to about 450, or about 100 to about 350 , or about 100 to about 275, or about 100 to about 230, or about 150 to about 475, or about 150 to about 340, or about 113 to about 340, or about 450 to about 800, or about 454 to about 796, or about 454 to about 682, or about 340 to about 795, or about 341 to about 682, or about 568 to about 909, or about 227 to about 1500, or about 225 to about 2280, or about 460 to about 2160, or about 460 to about 2050, or about 341 to about 1820, or It is in the range of about 341 to about 1710, or about 341 to about 1250, or about 225 to about 1250, or about 341 to about 1250, or about 341 to about 1136, or about 341 to about 1023, or about 341 to about 910, or about 341 to about 796, or about 341 to about 682, or about 341 to about 568, or about 114 to about 1000, or about 114 to about 950, or about 114 to about 910, or about 114 to about 800, or about 114 to about 690, or about 114 to about 575.

[0094] In some embodiments of the IL-15 conjugates described herein, in the compounds of formula (XVI) and (XVII), m is an integer from 1 to 6 and n is an integer selected from 113, 114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137. In some embodiments of the IL-15 conjugates described herein, in the compounds of formula (XVI) and (XVII), m is an integer from 2 to 6 and n is an integer selected from 113, 114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137. In some embodiments of the IL-15 conjugates described herein, in the compounds of formula (XVI) and (XVII), m is an integer from 2 to 4 and n is an integer selected from 113, 114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137. In some embodiments of the IL-15 conjugates described herein, in the compounds of formula (XVI) and (XVII), m is 1 and n is an integer selected from 113, 114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137. In some embodiments of the IL-15 conjugates described herein, in the compounds of formula (XVI) and (XVII), m is 2 and n is an integer selected from 113, 114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137.In some embodiments of the IL-15 conjugates described herein, in the compounds of formula (XVI) and (XVII), m is 3 and n is an integer selected from 113, 114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137. In some embodiments of the IL-15 conjugates described herein, in the compounds of formula (XVI) and (XVII), m is 4 and n is an integer selected from 113, 114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137. In some embodiments of the IL-15 conjugates described herein, in the compounds of formula (XVI) and (XVII), m is 5 and n is an integer selected from 113, 114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137. In some embodiments of the IL-15 conjugates described herein, in the compounds of formula (XVI) and (XVII), m is 6 and n is an integer selected from 113, 114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137. In some embodiments of the IL-15 conjugates described herein, in the compounds of formula (XVI) and (XVII), m is 7 and n is an integer selected from 113, 114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137.In some embodiments of the IL-15 conjugates described herein, in the compounds of formula (XVI) and (XVII), m is 8 and n is an integer selected from 113, 114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137. In some embodiments of the IL-15 conjugates described herein, in the compounds of formula (XVI) and (XVII), m is 9 and n is an integer selected from 113, 114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137. In some embodiments of the IL-15 conjugates described herein, in the compounds of formula (XVI) and (XVII), m is 10 and n is an integer selected from 113, 114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137. In some embodiments of the IL-15 conjugates described herein, in the compounds of formula (XVI) and (XVII), m is 11 and n is an integer selected from 113, 114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137. In some embodiments of the IL-15 conjugates described herein, in the compounds of formula (XVI) and (XVII), m is 12 and n is an integer selected from 113, 114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137.In some embodiments of the IL-15 conjugates described herein, in the compounds of formula (XVI) and (XVII), m is 2 and n is an integer selected from 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137.

[0095] In some embodiments of the IL-15 conjugates described herein, n in the compounds of formula (XVI) and (XVII) is 2, 5, 10, 11, 22, 23, 113, 114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, 1137, 1249, 1250, 1251, 1362, 1363, 1364 , 1476, 1477, 1478, 1589, 1590, 1591, 1703, 1704, 1705, 1817, 1818, 1819, 1930, 1931, 1932, 2044, 2045, 2046, 2158, 2159, 2160, 2271, 2272, 2273, 2839, 2840, 2841, 2953, 2954, 2955, 3408, 3409, 3410, 3976, 3977, 3978, 4544, 4545, and 4546.

[0096] In some embodiments of the IL-15 conjugates described herein, the position of the structures of Formula (XVI) and (XVII), or a mixture of Formula (XVI) and (XVII), in the amino acid sequence of the IL-15 conjugate comprising SEQ ID NO: 1 is selected from S18, L25, E46, E53, N77, and S83. In some embodiments of the IL-15 conjugates described herein, the position of the structures of Formula (XVI) and (XVII), or a mixture of Formula (XVI) and (XVII), in the amino acid sequence of the IL-15 conjugate of SEQ ID NO: 1 is selected from S18, L25, and E46. Further described herein are IL-15 conjugates where the position of the structures of Formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), in the amino acid sequence of the IL-15 conjugate is selected from E53, N77, and S83. Further described herein are IL-15 conjugates wherein the position of the structure of formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), in the amino acid sequence of the IL-15 conjugate is S18. Further described herein are IL-15 conjugates wherein the position of the structure of formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), in the amino acid sequence of the IL-15 conjugate is L25. Further described herein are IL-15 conjugates wherein the position of the structure of formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), in the amino acid sequence of the IL-15 conjugate is E46. Further described herein are IL-15 conjugates wherein the position of the structure of formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), in the amino acid sequence of the IL-15 conjugate is E53. Further described herein are IL-15 conjugates, wherein the position of the structure of formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), in the amino acid sequence of the IL-15 conjugate is N77. Further described herein are IL-15 conjugates, wherein the position of the structure of formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), in the amino acid sequence of the IL-15 conjugate is S83.In some embodiments of the IL-15 conjugates described herein, the ratio of the amount of the structure of formula (XVI) comprising the total amount in the IL-15 conjugate to the amount of the structure of formula (XVII) is about 1:1. In some embodiments of the IL-15 conjugates described herein, the ratio of the amount of the structure of formula (XVI) comprising the total amount in the IL-15 conjugate to the amount of the structure of formula (XVII) is greater than 1:1. In some embodiments of the IL-15 conjugates described herein, the ratio of the amount of the structure of formula (XVI) comprising the total amount in the IL-15 conjugate to the amount of the structure of formula (XVII) is less than 1:1.

[0097] In some embodiments, described herein is an IL-15 conjugate comprising the amino acid sequence of SEQ ID NO: 1, wherein at least one amino acid residue in the IL-15 conjugate is replaced with a structure of formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), wherein the replaced amino acid residue in SEQ ID NO: 1 is selected from S18, L25, E46, E53, N77, and S83; is 100 to about 1150, or about 100 to about 1100, or about 100 to about 1000, or about 100 to about 900, or about 100 to about 750, or about 100 to about 700, or about 100 to about 600, or about 100 to about 575, or about 100 to about 500, or about 100 to about 450, or about 100 to about 350, or about 100 to about 275, or about 100 to about 230, or about 150 to about 475, or about 150 to about 3 40, or about 113 to about 340, or about 450 to about 800, or about 454 to about 796, or about 454 to about 682, or about 340 to about 795, or about 341 to about 682, or about 568 to about 909, or about 227 to about 1500, or about 225 to about 2280, or about 460 to about 2160, or about 460 to about 2050, or about 341 to about 1820, or about 341 to about 1710, or about 341 to about 1250, or an integer from about 225 to about 1250, or from about 341 to about 1250, or from about 341 to about 1136, or from about 341 to about 1023, or from about 341 to about 910, or from about 341 to about 796, or from about 341 to about 682, or from about 341 to about 568, or from about 114 to about 1000, or from about 114 to about 950, or from about 114 to about 910, or from about 114 to about 800, or from about 114 to about 690, or from about 114 to about 575.In some embodiments of the IL-15 conjugates described herein, n in the compounds of formula (XVI) and (XVII) is 2, 5, 10, 11, 22, 23, 113, 114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, 1137, 1249, 1250, 1251, 1362, 1363, 1364 , 1476, 1477, 1478, 1589, 1590, 1591, 1703, 1704, 1705, 1817, 1818, 1819, 1930, 1931, 1932, 2044, 2045, 2046, 2158, 2159, 2160, 2271, 2272, 2273, 2839, 2840, 2841, 2953, 2954, 2955, 3408, 3409, 3410, 3976, 3977, 3978, 4544, 4545, and 4546.

[0098] In some embodiments, described herein are IL-15 conjugates comprising the amino acid sequence of SEQ ID NO: 1, wherein at least one amino acid residue in the IL-15 conjugate is replaced with a structure of formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), wherein the replaced amino acid residue in SEQ ID NO: 1 is selected from L25, and n is an integer from about 450 to about 800, or from about 454 to about 796, or from about 454 to about 682, or from about 568 to about 909. In some embodiments of the IL-15 conjugates described herein, n in the compounds of formula (XVI) and (XVII) is an integer selected from 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, 1137, and 1249.

[0099] In some embodiments, described herein are IL-15 conjugates comprising the amino acid sequence of SEQ ID NO: 1, wherein at least one amino acid residue in the IL-15 conjugate is replaced with a structure of formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), wherein the replaced amino acid residue in SEQ ID NO: 1 is selected from L25, and n is an integer from about 450 to about 800, or from about 454 to about 796, or from about 454 to about 682, or from about 568 to about 909. In some embodiments of the IL-15 conjugates described herein, n in the compounds of Formulas (XVI) and (XVII) is an integer selected from 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910.

[0100] In some embodiments, described herein are IL-15 conjugates comprising the amino acid sequence of SEQ ID NO: 1, wherein at least one amino acid residue in the IL-15 conjugate is replaced with a structure of formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), wherein the replaced amino acid residue in SEQ ID NO: 1 is L25, and n is an integer from about 450 to about 800, or from about 454 to about 796, or from about 454 to about 682, or from about 568 to about 909. In some embodiments of the IL-15 conjugates described herein, n in the compounds of formula (XVI) and (XVII) is an integer selected from 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910. In some embodiments, n is from about 500 to about 1000. In some embodiments, n is about 550 to about 800. In some embodiments, n is about 681. In some embodiments, n is about 909.

[0101] In some embodiments of the IL-15 conjugates described herein, the position of the structure of Formula (XVI) and (XVII), or a mixture of Formulas (XVI) and (XVII), in the amino acid sequence of the IL-15 conjugate comprising SEQ ID NO: 3 is selected from S19, L26, E47, E54, N78, and S84. Further described herein are IL-15 conjugates wherein the position of the structure of Formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), in the amino acid sequence of the IL-15 conjugate is selected from K95, L26, and E47. Further described herein are IL-15 conjugates wherein the position of the structure of Formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), in the amino acid sequence of the IL-15 conjugate is selected from E54, N78, and S84. Further described herein are IL-15 conjugates in which the position of the structure of formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), in the amino acid sequence of the IL-15 conjugate is K95. Further described herein are IL-15 conjugates in which the position of the structure of formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), in the amino acid sequence of the IL-15 conjugate is L26. Further described herein are IL-15 conjugates in which the position of the structure of formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), in the amino acid sequence of the IL-15 conjugate is E47. Further described herein are IL-15 conjugates in which the position of the structure of formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), in the amino acid sequence of the IL-15 conjugate is E54. Further described herein are IL-15 conjugates, wherein the position of the structure of formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), in the amino acid sequence of the IL-15 conjugate is N78. Further described herein are IL-15 conjugates, wherein the position of the structure of formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), in the amino acid sequence of the IL-15 conjugate is S84.

[0102] Described herein is an IL-15 conjugate comprising the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 3, wherein at least one amino acid residue in the IL-15 conjugate is replaced with a structure of formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), and n is an integer from 1 to 2,000 daltons, or from 2,000 daltons to 150,000 daltons, or from 3,000 daltons to 125,000 daltons, or from 4,000 daltons to 100,000 daltons. Daltons, or about 5,000 Daltons to about 100,000 Daltons, or about 6,000 Daltons to about 90,000 Daltons, or about 7,000 Daltons to about 80,000 Daltons, or about 8,000 Daltons to about 70,000 Daltons, or about 5,000 Daltons to about 70,000 Daltons, or about 5,000 Daltons to about 65,000 Daltons, or about 5,000 Daltons to about 60,000 Daltons, or about 5,000 Daltons to about 50,000 Daltons, or about 6,000 Daltons to about 50,000 Daltons, or about 7,000 Daltons to about 50,000 Daltons, or about 7,000 Daltons to about 45,000 Daltons, or about 7,000 Daltons to about 40,000 Daltons, or about 8,000 Daltons to about 40,000 Daltons, or about 8,500 Daltons to about 40,000 Daltons, or about 8,500 Daltons to about 35,000 Daltons, or about 9,000 Daltons to about 50,000 Daltons, or about 9,000 Daltons to about 45,000 Daltons, or about 9,000 Daltons to about 40,000 Daltons, or about 9,000 Daltons to about 35,000 Daltons or about 9,000 daltons to about 30,000 daltons, or about 9,500 daltons to about 35,000 daltons, or about 9,500 daltons to about 30,000 daltons, or about 10,000 daltons to about 50,000 daltons, or about 10,000 daltons to about 45,000 daltons, or about 10,000 daltons to about 40,000 daltons, or about 10,000 daltons to about 35,000 daltons, or about 10,000 daltons to about 30,000 daltons, or about 15,000 daltons to about 50,000 daltons, or about 15,The integer is in the range of about 1,000 daltons to about 45,000 daltons, or about 15,000 daltons to about 40,000 daltons, or about 15,000 daltons to about 35,000 daltons, or about 15,000 daltons to about 30,000 daltons, or about 20,000 daltons to about 50,000 daltons, or about 20,000 daltons to about 45,000 daltons, or about 20,000 daltons to about 40,000 daltons, or about 20,000 daltons to about 35,000 daltons, or about 20,000 daltons to about 30,000 daltons. Described herein are IL-15 conjugates comprising the amino acid sequence of SEQ ID NO:1 or SEQ ID NO:3, wherein at least one amino acid residue in the IL-15 conjugate is replaced with a structure of formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), and n is a number representing a molecular weight of the PEG moiety of about 5,000 daltons, about 7,500 daltons, about 10,000 daltons, about 15,000 daltons, about 20,000 daltons, or about 30,000 daltons. daltons, about 25,000 daltons, about 30,000 daltons, about 35,000 daltons, about 40,000 daltons, about 45,000 daltons, about 50,000 daltons, about 60,000 daltons, about 70,000 daltons, about 80,000 daltons, about 90,000 daltons, about 100,000 daltons, about 125,000 daltons, about 150,000 daltons, about 175,000 daltons or about 200,000 daltons. Described herein are IL-15 conjugates comprising the amino acid sequence of SEQ ID NO:1 or SEQ ID NO:3, wherein at least one amino acid residue in the IL-15 conjugate is replaced with a structure of formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), and n is an integer such that the molecular weight of the PEG moiety is about 5,000 daltons, about 7,500 daltons, about 10,000 daltons, about 15,000 daltons, about 20,000 daltons, about 25,000 daltons, about 30,000 daltons, about 35,000 daltons, about 40,000 daltons, about 45,000 daltons, or about 50,000 daltons.

[0103] In some embodiments, described herein are IL-15 conjugates comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-15 conjugate is replaced with a structure of formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), wherein the amino acid residue in SEQ ID NO: 3 is L26, m is an integer from 1 to 6, and n is an integer from about 450 to about 800, or from about 454 to about 796, or from about 454 to about 682, or from about 568 to about 909. In some embodiments of the IL-15 conjugates described herein, in the compounds of formula (XVI) and (XVII), m is 2 and n is an integer selected from 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, 1137, and 1249.

[0104] In some embodiments, described herein are IL-15 conjugates comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-15 conjugate is replaced with a structure of formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), wherein the replaced amino acid residue in SEQ ID NO: 3 is L26, m is an integer from 1 to 6, and n is an integer from about 450 to about 800, or from about 454 to about 796, or from about 454 to about 682, or from about 568 to about 909. In some embodiments of the IL-15 conjugates described herein, in the compounds of formula (XVI) and (XVII), m is 2 and n is an integer selected from 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910.

[0105] In some embodiments, described herein are IL-15 conjugates comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-15 conjugate is replaced with a structure of formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), wherein the replaced amino acid residue in SEQ ID NO: 3 is L26, m is an integer from 1 to 6, and n is an integer from about 450 to about 800, or from about 454 to about 796, or from about 454 to about 682, or from about 568 to about 909. In some embodiments of the IL-15 conjugates described herein, in the compounds of formula (XVI) and (XVII), m is 2 and n is an integer selected from 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910. In some embodiments, n is about 500 to about 1000. In some embodiments, n is about 550 to about 800. In some embodiments, n is about 681. In some embodiments, n is about 909.

[0106] In some embodiments, described herein are IL-15 conjugates comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-15 conjugate is replaced with a structure of formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), wherein the replaced amino acid residue in SEQ ID NO: 3 is E54, m is an integer from 1 to 6, and n is an integer from about 450 to about 800, or from about 454 to about 796, or from about 454 to about 682, or from about 568 to about 909. In some embodiments of the IL-15 conjugates described herein, in the compounds of formula (XVI) and (XVII), m is 2 and n is an integer selected from 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, 1137 and 1249.

[0107] In some embodiments, described herein are IL-15 conjugates comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-15 conjugate is replaced with a structure of formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), wherein the replaced amino acid residue in SEQ ID NO: 3 is E54, m is an integer from 1 to 6, and n is an integer from about 450 to about 800, or from about 454 to about 796, or from about 454 to about 682, or from about 568 to about 909. In some embodiments of the IL-15 conjugates described herein, in the compounds of formula (XVI) and (XVII), m is 2 and n is an integer selected from 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910.

[0108] In some embodiments, described herein are IL-15 conjugates comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-15 conjugate is replaced with a structure of formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), wherein the replaced amino acid residue in SEQ ID NO: 3 is E54, m is an integer from 1 to 6, and n is an integer from about 450 to about 800, or from about 454 to about 796, or from about 454 to about 682, or from about 568 to about 909. In some embodiments of the IL-15 conjugates described herein, in the compounds of formula (XVI) and (XVII), m is 2 and n is an integer selected from 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910. In some embodiments, n is about 500 to about 1000. In some embodiments, n is about 550 to about 800. In some embodiments, n is about 681. In some embodiments, n is about 909.

[0109] In some embodiments, described herein are IL-15 conjugates comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-15 conjugate is replaced with a structure of formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), wherein the replaced amino acid residue in SEQ ID NO: 3 is N78, m is an integer from 1 to 6, and n is an integer from about 450 to about 800, or from about 454 to about 796, or from about 454 to about 682, or from about 568 to about 909. In some embodiments of the IL-15 conjugates described herein, in the compounds of formula (XVI) and (XVII), m is 2 and n is an integer selected from 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, 1137 and 1249.

[0110] In some embodiments, described herein are IL-15 conjugates comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-15 conjugate is replaced with a structure of formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), wherein the replaced amino acid residue in SEQ ID NO: 3 is N78, m is an integer from 1 to 6, and n is an integer from about 450 to about 800, or from about 454 to about 796, or from about 454 to about 682, or from about 568 to about 909. In some embodiments of the IL-15 conjugates described herein, in the compounds of formula (XVI) and (XVII), m is 2 and n is an integer selected from 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910.

[0111] In some embodiments, described herein are IL-15 conjugates comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-15 conjugate is replaced with a structure of formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), wherein the replaced amino acid residue in SEQ ID NO: 3 is N78, m is an integer from 1 to 6, and n is an integer from about 450 to about 800, or from about 454 to about 796, or from about 454 to about 682, or from about 568 to about 909. In some embodiments of the IL-15 conjugates described herein, in the compounds of formula (XVI) and (XVII), m is 2 and n is an integer selected from 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910. In some embodiments, n is about 500 to about 1000. In some embodiments, n is about 550 to about 800. In some embodiments, n is about 681. In some embodiments, n is about 909.

[0112]

[0010] Described herein are methods of treating cancer in a subject, comprising administering to a subject in need thereof an effective amount of an IL-15 conjugate described herein. In some embodiments, the cancer is a solid tumor cancer. In some embodiments, the solid tumor cancer is bladder cancer, bone cancer, brain cancer, breast cancer, colorectal cancer, esophageal cancer, eye cancer, head and neck cancer, kidney cancer, lung cancer, melanoma, ovarian cancer, pancreatic cancer, or prostate cancer. In some embodiments, the cancer is a hematological malignancy. In some embodiments, the hematological malignancy is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, Burkitt's lymphoma, non-Burkitt's lymphoma, or other lymphomas. High-grade B-cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis. In some embodiments, the cancer of interest is selected from renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), classical Hodgkin lymphoma (cHL), primary mediastinal large B-cell lymphoma (PMBCL), urothelial carcinoma, microsatellite unstable cancer, microsatellite stable cancer, gastric cancer, cervical cancer, hepatocellular carcinoma (HCC), Merkel cell carcinoma (MCC), melanoma, small cell lung cancer (SCLC), esophageal, glioblastoma, mesothelioma, breast cancer, triple-negative breast cancer, prostate cancer, bladder cancer, ovarian cancer, tumors with moderate to low mutational burden, cutaneous squamous cell carcinoma (CSCC), squamous cell skin cancer (SCSC), tumors with low to no PD-L1 expression, tumors that have disseminated systemically beyond their primary anatomic site of origin to the liver and CNS, and diffuse large B-cell lymphoma. In some embodiments, the subject's cancer is selected from renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), urothelial carcinoma, and melanoma.In some embodiments, the subject's cancer is non-Hodgkin's lymphoma (NHL). In some embodiments, the subject's cancer is multiple myeloma.

[0113] In some embodiments, the IL-15 conjugate is administered to a subject in need thereof once weekly, every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, or once every eight weeks. In some embodiments, the IL-15 conjugate is administered to a subject in need thereof once per week, once every two weeks, once every three weeks, or once every four weeks. In some embodiments, the IL-15 conjugate is administered to a subject in need thereof once per week. In some embodiments, the IL-15 conjugate is administered to a subject in need thereof once every two weeks. In some embodiments, the IL-15 conjugate is administered to a subject in need thereof once every three weeks. In some embodiments, the IL-15 conjugate is administered to a subject in need thereof once every four weeks.

[0114] In some embodiments, the amount of a given agent corresponding to such an amount will vary depending on factors such as the particular compound, the severity of the disease, the personality (e.g., body weight) of the subject or host requiring treatment, and the like, but will nevertheless be routinely determined in a manner known in the art according to the particular circumstances, including, for example, the particular agent to be administered, the route of administration, and the subject or host to be treated. In some instances, the desired dose is conveniently presented as a single dose, or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example, as two, three, four, or more sub-doses per day.

[0115] In some embodiments, the method comprises administering from 1 μg of IL-15 conjugate per kg of subject body weight to about 200 μg of IL-15 conjugate per kg of subject body weight, or from about 2 μg of IL-15 conjugate per kg of subject body weight to about 200 μg of IL-15 conjugate per kg of subject body weight, or from about 4 μg of IL-15 conjugate per kg of subject body weight to about 200 μg of IL-15 conjugate per kg of subject body weight, or from about 6 μg of IL-15 conjugate per kg of subject body weight to about 200 μg of IL-15 conjugate per kg of subject body weight. up to about 200 μg of IL-15 conjugate, or from about 8 μg of IL-15 conjugate per kg of subject body weight to about 200 μg of IL-15 conjugate per kg of subject body weight, or from about 10 μg of IL-15 conjugate per kg of subject body weight to about 200 μg of IL-15 conjugate per kg of subject body weight, or from about 12 μg of IL-15 conjugate per kg of subject body weight to about 200 μg of IL-15 conjugate per kg of subject body weight, or about 14 μg of IL-15 conjugate per kg of subject body weight g to about 200 μg of IL-15 conjugate per kg of subject body weight, or from about 16 μg of IL-15 conjugate per kg of subject body weight to about 200 μg of IL-15 conjugate per kg of subject body weight, or from about 18 μg of IL-15 conjugate per kg of subject body weight to about 200 μg of IL-15 conjugate per kg of subject body weight, or from about 20 μg of IL-15 conjugate per kg of subject body weight to about 200 μg of IL-15 conjugate per kg of subject body weight, or from about 10 μg of IL-15 conjugate per kg of subject body weight to about 200 μg of IL-15 conjugate per kg of subject body weight from about 22 μg of IL-15 conjugate per kg of subject body weight to about 200 μg of IL-15 conjugate per kg of subject body weight, or from about 24 μg of IL-15 conjugate per kg of subject body weight to about 200 μg of IL-15 conjugate per kg of subject body weight, or from about 26 μg of IL-15 conjugate per kg of subject body weight to about 200 μg of IL-15 conjugate per kg of subject body weight, or from about 28 μg of IL-15 conjugate per kg of subject body weight to about 200 μg of IL-15 conjugate per kg of subject body weight;or from about 32 μg of IL-15 conjugate per kg of subject body weight to about 200 μg of IL-15 conjugate per kg of subject body weight, or from about 34 μg of IL-15 conjugate per kg of subject body weight to about 200 μg of IL-15 conjugate per kg of subject body weight, or from about 36 μg of IL-15 conjugate per kg of subject body weight to about 200 μg of IL-15 conjugate per kg of subject body weight, or from about 40 μg of IL-15 conjugate per kg of subject body weight to about 200 μg of IL-15 conjugate per kg of subject body weight. or from about 45 μg of IL-15 conjugate per kg of subject body weight to about 200 μg of IL-15 conjugate per kg of subject body weight, or from about 50 μg of IL-15 conjugate per kg of subject body weight to about 200 μg of IL-15 conjugate per kg of subject body weight, or from about 55 μg of IL-15 conjugate per kg of subject body weight to about 200 μg of IL-15 conjugate per kg of subject body weight, or from about 60 μg of IL-15 conjugate per kg of subject body weight from about 65 μg of IL-15 conjugate per kg of subject body weight to about 200 μg of IL-15 conjugate per kg of subject body weight, or from about 70 μg of IL-15 conjugate per kg of subject body weight to about 200 μg of IL-15 conjugate per kg of subject body weight, or from about 75 μg of IL-15 conjugate per kg of subject body weight to about 200 μg of IL-15 conjugate per kg of subject body weight, or from about 80 μg of IL-15 conjugate per kg of subject body weight to about 200 μg of IL-15 conjugate per kg of subject body weight, or from about 85 μg of IL-15 conjugate per kg of subject body weight to about 200 μg of IL-15 conjugate per kg of subject body weight, or from about 90 μg of IL-15 conjugate per kg of subject body weight to about 200 μg of IL-15 conjugate per kg of subject body weight, or from about 95 μg of IL-15 conjugate per kg of subject body weight to about 200 μg of IL-15 conjugate per kg of subject body weight,or from about 100 μg of IL-15 conjugate per kg of subject body weight to about 200 μg of IL-15 conjugate per kg of subject body weight, or from about 110 μg of IL-15 conjugate per kg of subject body weight to about 200 μg of IL-15 conjugate per kg of subject body weight, or from about 120 μg of IL-15 conjugate per kg of subject body weight to about 200 μg of IL-15 conjugate per kg of subject body weight, or from about 130 μg of IL-15 conjugate per kg of subject body weight to about 200 μg of IL-15 conjugate per kg of subject body weight, or from about 140 μg of IL-15 conjugate per kg of subject body weight to about 200 μg of IL-15 conjugate per kg of subject body weight, or This includes administration of an IL-15 conjugate at a dose within the range of from about 150 μg of IL-15 conjugate to about 200 μg of IL-15 conjugate per kg of subject body weight, or from about 160 μg of IL-15 conjugate per kg of subject body weight to about 200 μg of IL-15 conjugate per kg of subject body weight, or from about 170 μg of IL-15 conjugate per kg of subject body weight to about 200 μg of IL-15 conjugate per kg of subject body weight, or from about 180 μg of IL-15 conjugate per kg of subject body weight to about 200 μg of IL-15 conjugate per kg of subject body weight, or from about 190 μg of IL-15 conjugate per kg of subject body weight to about 200 μg of IL-15 conjugate per kg of subject body weight. The foregoing ranges are merely suggestive. Because the number of variables regarding a particular treatment regime is large, and significant excursions from these recommended values ​​are not unusual, such dosages will vary depending on several variables, including but not limited to, the activity of the compound employed, the disease or condition being treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner. In some embodiments, the toxicity and therapeutic efficacy of such treatment regimens can be assessed by determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population),Therapeutic index is determined by standard pharmaceutical procedures in cell cultures or experimental animals. The dose ratio between toxic and therapeutic effects is the therapeutic index, and it is expressed as the ratio between LD50 and ED50. Compounds that exhibit high therapeutic indices are preferred. Data obtained from cell culture assays and animal studies are used to formulate dosages in a range for use in humans. The dosage of such compounds preferably lies within a range of circulating concentrations that include the ED50 with minimal toxicity. Dosages vary within this range depending on the dosage form used and the route of administration utilized.

[0116] In some embodiments, the method comprises administering about 1 μg of IL-15 conjugate per kg of subject body weight, or about 2 μg of IL-15 conjugate per kg of subject body weight, about 4 μg of IL-15 conjugate per kg of subject body weight, about 6 μg of IL-15 conjugate per kg of subject body weight, about 8 μg of IL-15 conjugate per kg of subject body weight, about 10 μg of IL-15 conjugate per kg of subject body weight, about 12 μg of IL-15 conjugate per kg of subject body weight, about 14 μg of IL-15 conjugate per kg of subject body weight, about 16 μg of IL-15 conjugate per kg of subject body weight, about 18 μg of IL-15 conjugate per kg of subject body weight, about 19 μg of IL-15 conjugate per kg of subject body weight, about 20 μg of IL-15 conjugate per kg of subject body weight, about 21 μg of IL-15 conjugate per kg of subject body weight, about 22 μg of IL-15 conjugate per kg of subject body weight, about 23 μg of IL-15 conjugate per kg of subject body weight, about 24 μg of IL-15 conjugate per kg of subject body weight, about 25 μg of IL-15 conjugate per kg of subject body weight, about 26 μg of IL-15 conjugate per kg of subject body weight, about 27 μg of IL-15 conjugate per kg of subject body weight, about 28 μg of IL-15 conjugate per kg of subject body weight, about 29 μg of IL-15 conjugate per kg of subject body weight, about 30 μg of IL-15 conjugate per kg of subject body weight, about 31 μg of IL-15 conjugate per kg of subject body weight, About 16 μg of IL-15 conjugate per kg of subject body weight, about 18 μg of IL-15 conjugate per kg of subject body weight, about 20 μg of IL-15 conjugate per kg of subject body weight, about 22 μg of IL-15 conjugate per kg of subject body weight, about 24 μg of IL-15 conjugate per kg of subject body weight, about 26 μg of IL-15 conjugate per kg of subject body weight, about 28 μg of IL-15 conjugate per kg of subject body weight, about 30 μg of IL-15 conjugate per kg of subject body weight, about ... about 32 μg of IL-15 conjugate per kg of subject body weight, about 34 μg of IL-15 conjugate per kg of subject body weight, about 36 μg of IL-15 conjugate per kg of subject body weight, about 38 μg of IL-15 conjugate per kg of subject body weight, about 40 μg of IL-15 conjugate per kg of subject body weight, about 42 μg of IL-15 conjugate per kg of subject body weight, about 44 μg of IL-15 conjugate per kg of subject body weight, about 46 μg of IL-15 conjugate per kg of subject body weight, about 48 μg of IL-15 conjugate per kg of subject body weight about 50 μg of IL-15 conjugate, about 55 μg of IL-15 conjugate per kg of subject body weight, about 60 μg of IL-15 conjugate per kg of subject body weight, about 65 μg of IL-15 conjugate per kg of subject body weight, about 70 μg of IL-15 conjugate per kg of subject body weight, about 75 μg of IL-15 conjugate per kg of subject body weight, about 80 μg of IL-15 conjugate per kg of subject body weight, about 85 μg of IL-15 conjugate per kg of subject body weight, about 90 μg of IL-15 conjugate per kg of subject body weight,About 95 μg of IL-15 conjugate per kg of subject body weight, about 100 μg of IL-15 conjugate per kg of subject body weight, about 110 μg of IL-15 conjugate per kg of subject body weight, about 120 μg of IL-15 conjugate per kg of subject body weight, about 130 μg of IL-15 conjugate per kg of subject body weight, about 140 μg of IL-15 conjugate per kg of subject body weight, about 150 μg of IL-15 conjugate per kg of subject body weight This includes administering an IL-15 conjugate to a subject in need thereof at a dose of about 0 μg, about 160 μg of IL-15 conjugate per kg of subject body weight, about 170 μg of IL-15 conjugate per kg of subject body weight, about 180 μg of IL-15 conjugate per kg of subject body weight, about 190 μg of IL-15 conjugate per kg of subject body weight, or about 200 μg of IL-15 conjugate per kg of subject body weight. The foregoing amounts are merely suggestive, as the number of variables regarding individual treatment regimes is large and significant deviations from these recommended values ​​are not unusual. Such dosages will vary depending on several variables, including, but not limited to, the activity of the compound used, the disease or condition being treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner. In some embodiments, toxicity and therapeutic efficacy of such treatment regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, determination of the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it is expressed as the ratio between LD50 and ED50. Compounds that exhibit high therapeutic indices are preferred. Data obtained from cell culture assays and animal studies are used to formulate a range of dosages for use in humans. The dosage of such compounds preferably lies within a range of circulating concentrations that includes the ED50 with minimal toxicity. Dosages vary within this range depending on the dosage form used and the route of administration utilized.

[0117] Once improvement of the patient's symptoms occurs, a maintenance dose is administered, if necessary, after which the dosage or frequency of administration, or both, can be reduced, depending on the symptoms, to a level at which improvement of the disease, disorder, or condition is maintained.

[0118] In some embodiments, the amount of a given agent corresponding to such an amount will vary depending on factors such as the particular compound, the severity of the disease, the personality (e.g., body weight) of the subject or host requiring treatment, and the like, but will nevertheless be routinely determined in a manner known in the art according to the particular circumstances, including, for example, the particular agent to be administered, the route of administration, and the subject or host to be treated. In some instances, the desired dose is conveniently presented as a single dose, or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example, as two, three, four, or more sub-doses per day.

[0119] Described herein are methods for expanding effector T (Teff) cell, memory T (Tmem) cell, and natural killer (NK) cell populations, comprising: (a) contacting cells with an IL-15 conjugate described herein; and (b) allowing IL-15 to interact with the IL-15Rβ and IL-15Rγ subunits to form an IL-15 / IL-15Rβγ complex, wherein the IL-15 conjugate has reduced affinity for the IL-15Rα subunit, and the IL-15 / IL-15Rβγ complex stimulates the expansion of Teff, Tmem, and NK cells. In some embodiments, the cells are eukaryotic cells. In some embodiments, the cells are mammalian cells. In some embodiments, the cells are human cells.

[0120] Described herein are pharmaceutical compositions comprising an effective amount of an IL-conjugate described herein and one or more pharmaceutically acceptable excipients.

[0121] Various aspects of the present disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings. [Brief explanation of the drawings]

[0122] [Figure 1A] Figure 1 shows the dose response (EC50) of STAT5 signaling in cynomolgus monkey whole blood treated with native IL-15 or the IL-15 conjugate from Example 2. Figure 1A shows the dose response in CD8+ T cells. Figure 1B shows the dose response in NK cells. (Native IL-15 = closed triangles; IL-15_N78[AzK_PEG30] = closed circles; IL-15_L26[AzK_PEG30] = closed diamonds; IL-15_E54[AzK_PEG30] = closed squares.) [Figure 1B] Figure 1 shows the dose response (EC50) of STAT5 signaling in cynomolgus monkey whole blood treated with native IL-15 or the IL-15 conjugate from Example 2. Figure 1A shows the dose response in CD8+ T cells. Figure 1B shows the dose response in NK cells. (Native IL-15 = closed triangles; IL-15_N78[AzK_PEG30] = closed circles; IL-15_L26[AzK_PEG30] = closed diamonds; IL-15_E54[AzK_PEG30] = closed squares.) [Figure 2] FIG. 1 illustrates the plasma concentration versus time curves of mice in groups 2, 3, and 4 administered test compound IL-15_N77[AzK_L1_PEG30] in Example 3 (group 4 (1 mg / kg dose) = filled triangles; group 3 (0.3 mg / kg dose) = filled squares; group 2 (0.1 mg / kg dose) = filled circles). [Figure 3] FIG. 1 illustrates % pSTAT5 in NK cell populations in mice after administration of test compound IL-15_N77[AzK_L1_PEG30] according to Example 3 (Group 1 (vehicle = open circles); Group 4 (1 mg / kg dose) = closed triangles; Group 3 (0.3 mg / kg dose) = closed squares; Group 2 (0.1 mg / kg dose) = closed circles). [Figure 4] FIG. 1 illustrates % pSTAT5 in CD8 T cell populations in mice after administration of test compound IL-15_N77[AzK_L1_PEG30] according to Example 3 (Group 1 (vehicle) = open circles; Group 4 (1 mg / kg dose) = closed triangles; Group 3 (0.3 mg / kg dose) = closed squares; Group 2 (0.1 mg / kg dose) = closed circles). [Figure 5] FIG. 1 illustrates % pSTAT5 in Treg cell populations in mice after administration of test compound IL-15_N77[AzK_L1_PEG30] according to Example 3 (Group 1 (vehicle) = open circles; Group 4 (1 mg / kg dose) = closed triangles; Group 3 (0.3 mg / kg dose) = closed squares; Group 2 (0.1 mg / kg dose) = closed circles). [Figure 6] FIG. 1 illustrates the % Ki67 in the NK cell population in mice after administration of the test compound IL-15_N77[AzK_L1_PEG30] according to Example 3 (Group 1 (vehicle) = open circles; Group 4 (1 mg / kg dose) = closed triangles; Group 3 (0.3 mg / kg dose) = closed squares; Group 2 (0.1 mg / kg dose) = closed circles). [Figure 7] FIG. 1 illustrates the % Ki67 in the CD8 T cell population in mice after administration of the test compound IL-15_N77[AzK_L1_PEG30] according to Example 3 (Group 1 (vehicle) = open circles; Group 4 (1 mg / kg dose) = closed triangles; Group 3 (0.3 mg / kg dose) = closed squares; Group 2 (0.1 mg / kg dose) = closed circles). [Figure 8] FIG. 1 illustrates % Ki67 in Treg cell populations in mice after administration of test compound IL-15_N77[AzK_L1_PEG30] according to Example 3 (Group 1 (vehicle) = open circles; Group 4 (1 mg / kg dose) = closed triangles; Group 3 (0.3 mg / kg dose) = closed squares; Group 2 (0.1 mg / kg dose) = closed circles). [Figure 9]FIG. 1 illustrates % NK cell expansion versus days post-dose in mice following administration of test compound IL-15_N77[AzK_L1_PEG30] according to Example 3 (Group 1 (vehicle) = open circles; Group 4 (1 mg / kg dose) = closed triangles; Group 3 (0.3 mg / kg dose) = closed squares; Group 2 (0.1 mg / kg dose) = closed circles). [Figure 10] FIG. 1 illustrates % memory CD8 T cell expansion versus days post-dose in mice following administration of test compound IL-15_N77[AzK_L1_PEG30] according to Example 3 (Group 1 (vehicle) = open circles; Group 4 (1 mg / kg dose) = closed triangles; Group 3 (0.3 mg / kg dose) = closed squares; Group 2 (0.1 mg / kg dose) = closed circles). [Figure 11] 11A-11B show flow cytometry plots showing NK cell populations (gated from all peripheral cells) 5 days after administration of vehicle (FIG. 11A) and test compound IL-15_N77[AzK_L1_PEG30] 1 mg / kg (FIG. 11B) in C57BL / 6 mice according to Example 3. [Figure 12] 12A-12B show flow cytometry plots showing memory CD8+ T populations (gated from CD3+ T cells) 5 days after administration of vehicle (FIG. 12A) and test compound IL-15_N77[AzK_L1_PEG30] 1 mg / kg (FIG. 12B) in C57BL / 6 mice according to Example 3. DETAILED DESCRIPTION OF THE INVENTION

[0123] Cancer is a complex group of diseases involving abnormal cell growth that can invade or spread to other parts of the body. Cancer therapies, such as radiation and chemotherapy, that target cancer drivers and pathways can be successful. In some cases, cancer cells can adapt to these therapies, limiting their effectiveness. Immunotherapy, unlike surgery, chemotherapy, or radiation, stimulates the immune system to recognize and kill tumor cells.

[0124] Due to their ability to induce immune response, some cytokines are used in immunotherapy.However, current immunotherapy using cytokines causes some adverse effects, including toxicity and uncontrolled cell proliferation.Provided herein is modified cytokine or cytokine conjugate for use in cancer treatment, which has the ability to stimulate or expand specific T cell and NK population, resulting in improved treatment and reduced adverse events.

[0125] Cytokines include a family of cell signaling proteins, such as chemokines, interferons, interleukins, lymphokines, and tumor necrosis factors. Cytokines are produced by immune cells, such as macrophages, B lymphocytes, T lymphocytes, and mast cells, endothelial cells, fibroblasts, and various stromal cells. In some cases, cytokines regulate the balance between humoral and cellular immune responses.

[0126] Interleukins are signaling proteins that regulate the development and differentiation of T and B lymphocytes and hematopoietic cells. They are produced by helper CD4 T lymphocytes, monocytes, macrophages, and endothelial cells. There are approximately 15 interleukins, interleukin 1-13, interleukin 15, and interleukin 17.

[0127] Interleukin-15 (IL-15) is a pleiotropic cytokine whose structure is a glycoprotein of 14–15 kDa. IL-15 transcription, translation, and secretion are regulated through multiple complex mechanisms. IL-15 and IL-15 receptor α (IL-15Rα, CD215) proteins are coexpressed primarily by activated monocytes and dendritic cells (DCs). Transcription of the heterodimer IL-15 / IL-15Rα occurs after interaction of monocytes / DCs with type 1 or type 2 interferons (IFNs) or agents acting through CD40 ligation or Toll-like receptors (TLRs) that activate NF-κB. Furthermore, IL-15 / IL-15Rα protein expression is primarily controlled at the level of translation and secretion.

[0128] IL-15 signals through a heterotrimeric receptor containing a unique α chain (IL-15Rα), a β subunit (IL-15Rβ, CD132) shared with IL-2 (CD122), and a common γ subunit (CD132; IL-15Rγ) shared with several cytokines. IL-15Rα has high affinity for IL-15 and binds to K d is about 10 -11 It's M.

[0129] In some embodiments, IL-15 signaling is utilized to regulate T cell responses and subsequently for the treatment of cancer. In some embodiments, IL-15 signaling is utilized to regulate activated CD4 - CD8 - , CD4 + CD8 + , CD4 + and CD8 +In some embodiments, IL-15 signaling is utilized to simulate the proliferation of T cells and their differentiation into defined effector T cell subsets. In some embodiments, IL-15 signaling is utilized to simulate the generation and proliferation of natural killer (NK) cells. In some embodiments, IL-15 signaling is utilized to promote the maintenance and survival of memory CD8 T cells, naive CD8 T cells, and NK cells. In some embodiments, IL-15 signaling is utilized to induce the formation of memory CD8 T cells. In some embodiments, IL-15 signaling is utilized to prime NK cell target-specific activation. In some embodiments, IL-15 signaling does not result in the expansion of Tregs.

[0130] Described herein, in some embodiments, are modified IL-15 polypeptides or IL-15 conjugates for modulating T cell responses and subsequently treating cancer. In some embodiments, the modified IL-15 polypeptides comprise reduced binding to interleukin-15 receptor alpha (IL-15Rα). In some embodiments, the reduced binding affinity is relative to the binding affinity between wild-type IL-15 polypeptide and IL-15Rα. In some embodiments, the modified IL-15 polypeptides have little or no effect on the interaction of the modified IL-15 polypeptide with interleukin-2 / interleukin-15 receptor beta gamma (IL-2 / IL-15Rβγ). In some embodiments, the modified IL-15 polypeptides comprise one or more modifications that have little or no effect on the binding affinity of the modified IL-15 polypeptide with IL-15Rα and IL-15Rβγ. In some embodiments, the modified IL-15 polypeptides comprise reduced binding to IL-2 / IL-15Rβγ, and the IL-15Rα interaction is unaffected.

[0131] Described herein are modified IL-15 polypeptides or IL-15 conjugates with improved ability to stimulate anti-tumor responses. In some embodiments, the modified IL-15 polypeptides or IL-15 conjugates have an improved safety profile. In some embodiments, the modified IL-15 polypeptides or IL-15 conjugates comprise site-specific PEGylation to increase half-life. In some embodiments, site-specific PEGylation increases half-life with little or no effect on biological activity. In some embodiments, signaling of the modified IL-15 polypeptides or IL-15 conjugates is biased toward IL-15Rβγ. In some embodiments, the modified IL-15 polypeptides or IL-15 conjugates comprise site-specific PEGylation to increase half-life and reduce toxicity. In some embodiments, site-specific PEGylation results in lower administration of the modified IL-15 polypeptides or IL-15 conjugates. In some embodiments, toxicity is reduced by the modified IL-15 polypeptides or IL-15 conjugates blocking IL-15Rα interaction. In some embodiments, the activity of the modified IL-15 polypeptide or IL-15 conjugate is limited to tumor sites. In some embodiments, the modified IL-15 polypeptide or IL-15 conjugate comprises site-specific PEGylation such that trans-presentation of IL-15 is not required for the proliferation and function of natural killer (NK) and effector cells. In some embodiments, the modified IL-15 polypeptide or IL-15 conjugate comprises site-specific PEGylation such that clearance is inhibited or prevented.

[0132] Modified IL-15 Polypeptides and IL-15 Conjugates Described herein, in some embodiments, are modified IL-15 polypeptides. In some examples, the modification is a change to a natural amino acid. In some examples, the modification is a change to a non-natural amino acid. In some examples, described herein are isolated, modified IL-15 polypeptides comprising at least one non-natural amino acid. In some examples, the IL-15 polypeptide is an isolated and purified mammalian IL-15, such as a human IL-15 protein. In some cases, the IL-15 polypeptide is a human IL-15 protein. In some cases, the IL-15 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 1, 2, or 3. In some cases, the IL-15 polypeptide comprises or consists of the sequence of SEQ ID NO: 1 or 2. In some cases, the IL-15 polypeptide comprises or consists of the sequence of SEQ ID NO: 2 or 3.

[0133] In some examples, the modified IL-15 polypeptide is a truncated variant. In some examples, the truncation is an N-terminal deletion. In other examples, the truncation is a C-terminal deletion. In additional examples, the truncation includes deletion of both the N-terminus and the C-terminus. For example, the truncation can be deletion of at least or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, or more residues from the N-terminus or C-terminus, or both. In some cases, the modified IL-15 polypeptide includes an N-terminal deletion of at least or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, or more residues. In some cases, the modified IL-15 polypeptide includes an N-terminal deletion of at least or about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 residues. In some cases, the modified IL-15 polypeptide includes an N-terminal deletion of at least or about 2 residues. In some cases, the modified IL-15 polypeptide comprises an N-terminal deletion of at least or about 3 residues. In some cases, the modified IL-15 polypeptide comprises an N-terminal deletion of at least or about 4 residues. In some cases, the modified IL-15 polypeptide comprises an N-terminal deletion of at least or about 5 residues. In some cases, the modified IL-15 polypeptide comprises an N-terminal deletion of at least or about 6 residues. In some cases, the modified IL-15 polypeptide comprises an N-terminal deletion of at least or about 7 residues. In some cases, the modified IL-15 polypeptide comprises an N-terminal deletion of at least or about 8 residues. In some cases, the modified IL-15 polypeptide comprises an N-terminal deletion of at least or about 9 residues. In some cases, the modified IL-15 polypeptide comprises an N-terminal deletion of at least or about 10 residues.

[0134] In some embodiments, the modified IL-15 polypeptide is a functionally active fragment. In some cases, the functionally active fragment comprises the IL-15 region 5-114, 10-114, 15-114, 20-114, 1-110, 5-110, 10-110, 15-110, 20-110, 1-105, 5-105, 10-105, 15-105, 20-105, 1-100, 5-100, 10-100, 15-100, or 20-100, where the residue positions are relative to the positions in SEQ ID NO:1. In some examples, the functionally active fragment comprises the IL-15 region 5-114, 10-114, 15-114, or 20-114, where the residue positions are relative to the positions in SEQ ID NO:1. In some examples, functionally active fragments include IL-15 regions 1-110, 5-110, 10-110, 15-110, or 20-110, where the residue positions are relative to the positions in SEQ ID NO: 1. In some examples, functionally active fragments include IL-15 regions 1-105, 5-105, 10-105, 15-105, or 20-105, where the residue positions are relative to the positions in SEQ ID NO: 1. In some examples, functionally active fragments include IL-15 regions 1-100, 5-100, 10-100, 15-100, or 20-100, where the residue positions are relative to the positions in SEQ ID NO: 1.

[0135] In some embodiments, the functionally active IL-15 fragment comprises an internal deletion. Optionally, the internal deletion comprises a loop region. Optionally, the internal deletion comprises a deletion of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more residues.

[0136] In some embodiments, the IL-15 polypeptides described herein comprise at least one unnatural amino acid. In some examples, the residue position of the at least one unnatural amino acid is N1, W2, V3, N4, 16, S7, D8, K10, K11, E13, D14, L15, Q17, S18, M19, H20, 121, D22, A23, T24, L25, Y26, T27, E28, S29, D30, V31, H32, P33, S34, C35, K36, V37, T38, A39, K41, L44, L45, E46, Q48, V49, S51, L52, E53, S54, G55, D56, A57, S58, H60, D61, T62 , V63, E64, N65, 167, 168, L69, N71, N72, S73, L74, S75, S76, N77, G78, N79, V80, T81, E82, S83, G84, C85, K86, E87, C88, E89, E90, L91, E92, E93, K94, N95, 196, K97, E98, L100, Q101, S102, V104, H105, Q108, M109, F110, 1111, N112, T113 and S114, wherein the residue positions correspond to those shown in SEQ ID NO:1. In some embodiments, the residue position of at least one unnatural amino acid is N1, W2, V3, N4, 16, S7, D8, K10, K11, E13, D14, L15, Q17, S18, M19, H20, 121, D22, A23, T24, L25, Y26, E28, S29, D30, V31, H32, P33, S34, C35, K36, V37, T38, K41, L44, E46, Q48, V49, S51, L52, E53, S54, G55, D56, A57, S58, H60, D61, T62, V63 , E64, N65, 167, 168, L69, N71, N72, S73, L74, S75, S76, N77, G78, N79, V80, T81, E82, S83, G84, C85, K86, E87, C88, E89, E90, L91, E92, E93, K94, N95, 196, K97, E98, L100, Q101, S102, V104, H105, Q108, M109, F110, 1111, N112, T113 and S114, wherein the residue positions correspond to those shown in SEQ ID NO:1.In some embodiments, the residue position of the at least one unnatural amino acid is selected from E13, D14, L15, Q17, S18, M19, H20, I21, S34, C35, K36, V37, T38, K41, L44, S51, L52, S54, G55, D56, A57, S58, H60, V63, I67, N71, S73, L74, S75, S76, N77, G78, N79, V80, T81, E82, S83, G84, C85, K86, E87, C88, L91, E92, K94, N95, I96, K97, E98, L100, Q101, and F110. In some embodiments, the residue position of the at least one unnatural amino acid is selected from D14, Q17, S18, K41, S51, L52, G55, D56, A57, S58, S75, S76, N77, N79, V80, T81, S83, G84, E92, K94, N95, K97, and E98. In some embodiments, the residue position of the at least one unnatural amino acid is selected from N1, N4, S7, D8, K11, D61, T62, E64, N65, I68, L69, and N72. In some embodiments, the residue position of at least one unnatural amino acid is selected from V3, 16, K10, E28, S29, D30, V31, H32, P33, S102, V104, H105, Q108, M109, I111, N112, T113, and S114. In some embodiments, the residue position of at least one unnatural amino acid is selected from D22, A23, T24, L25, Y26, L44, E46, Q48, V49, E53, E89, E90, and E93. In some embodiments, the residue position of at least one unnatural amino acid is selected from Y26, E46, V49, E53, and L25. In some embodiments, the residue position of at least one unnatural amino acid is selected from V3, K10, S29, D30, H32, H105, Q108, M109, I111, N112, T113, and S114. In some embodiments, the residue position of at least one unnatural amino acid is selected from N4, S7, K11, and D61. In some embodiments, the residue position of at least one unnatural amino acid is selected from L25, E53, N77, and S83. In some embodiments, the residue position of at least one unnatural amino acid is selected from L25 and E53.In some embodiments, the residue position of at least one unnatural amino acid is selected from E46, Y26, V49, E53, T24, N4, K11, N65, L69, S18, H20, and S83. In some embodiments, the residue position of at least one unnatural amino acid is selected from E46, Y26, V49, E53, and T24. In some embodiments, the residue position of at least one unnatural amino acid is selected from E46, V49, E53, and T24. In some embodiments, the residue position of at least one unnatural amino acid is selected from Y26, V49, E53, and T24. In some embodiments, the residue position of at least one unnatural amino acid is selected from V49, E53, and T24. In some embodiments, the residue position of at least one unnatural amino acid is selected from E46 and Y26. In some embodiments, the residue position of at least one unnatural amino acid is E46. In some embodiments, the residue position of at least one unnatural amino acid is L25. In some embodiments, the residue position of at least one unnatural amino acid is Y26. In some embodiments, the residue position of at least one unnatural amino acid is V49. In some embodiments, the residue position of at least one unnatural amino acid is E53. In some embodiments, the residue position of at least one unnatural amino acid is T24. In some embodiments, the residue position of at least one unnatural amino acid is N77. In some embodiments, the residue position of at least one unnatural amino acid is selected from N4, K11, N65, L69, S18, H20, and S83. Exemplary amino acid sequences for IL-15 are illustrated in Table 1 below.

[0137] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8]

[0138] [AzK] = N6-((2-azidoethoxy)-carbonyl)-L-lysine. The compound has Chemical Abstracts Registry Number 1167421-25-1. [AzK_PEG]=N6-((2-azidoethoxy)-carbonyl)-L-lysine is stably conjugated to PEG via DBCO-mediated click chemistry to form a compound having the structure of Formula (II) or Formula (III). For example, PEG30 is specified to represent a linear polyethylene glycol chain having an average molecular weight of 30 kilodaltons and capped with a methoxy group. For example, PEG40 is specified to represent a branched polyethylene glycol chain having an average molecular weight of 40 kilodaltons and capped with a methoxy group. The ratio of positional isomers produced from the click reaction is about 1:1 or greater. The term "DBCO" refers to a chemical moiety containing a dibenzocyclooctyne group, including, for example, the mPEG-DBCO compound shown in Scheme 1 of Example 1. Exemplary structures of methoxy PEG groups are shown in the mPEG-DBCO structures in Schemes 1 and 2 of Example 1. [AzK_L1_PEG]=N6-((2-azidoethoxy)-carbonyl)-L-lysine is stably conjugated to PEG via DBCO-mediated click chemistry to form a compound comprising the structure of formula (IV) or formula (V). For example, PEG30 is specified to represent a linear polyethylene glycol chain having an average molecular weight of 30 kilodaltons and capped with a methoxy group. The ratio of positional isomers produced from the click chemistry reaction is about 1:1 or greater. The term "DBCO" refers to a chemical moiety comprising a dibenzocyclooctyne group, for example, the mPEG-DBCO compound shown in Scheme 1 or 2 of Example 1. In some examples, the sequences in Table 1 include an N-terminal methionine (Met). In some examples, the sequences in Table 1 include an N-terminal methionine, and the N-terminal methionine is N-formylmethionine (fMet). In some examples, the IL-15 conjugates described herein include a mixture of peptides, where the mixture includes sequences both with and without an N-terminal methionine residue. In some examples, the IL-15 conjugates described herein include a mixture of peptides, where the mixture includes sequences both with an N-terminal methionine residue and an N-formylmethionine residue. In some examples, the IL-15 conjugates described herein include a mixture of peptides, where the mixture includes sequences both with and without an N-terminal N-formylmethionine residue.

[0139] In some instances, at least one unnatural amino acid is located near the N-terminus. As used herein, near refers to a residue at least one residue away from the N-terminal residue and up to about 50 residues away from the N-terminal residue. Optionally, at least one unnatural amino acid is located within the first 10, 20, 30, 40, or 50 residues from the N-terminal residue. Optionally, at least one unnatural amino acid is located within the first 10 residues from the N-terminal residue. Optionally, at least one unnatural amino acid is located within the first 20 residues from the N-terminal residue. Optionally, at least one unnatural amino acid is located within the first 30 residues from the N-terminal residue. Optionally, at least one unnatural amino acid is located within the first 40 residues from the N-terminal residue. Optionally, at least one unnatural amino acid is located within the first 50 residues from the N-terminal residue.

[0140] In some instances, at least one unnatural amino acid is the N-terminal residue.

[0141] In some instances, at least one unnatural amino acid is located near the C-terminus. As used herein, near refers to a residue that is at least one residue away from the C-terminal residue and up to about 50 residues away from the C-terminal residue. Optionally, at least one unnatural amino acid is located within the first 10, 20, 30, 40, or 50 residues from the C-terminal residue. Optionally, at least one unnatural amino acid is located within the first 10 residues from the C-terminal residue. Optionally, at least one unnatural amino acid is located within the first 20 residues from the C-terminal residue. Optionally, at least one unnatural amino acid is located within the first 30 residues from the C-terminal residue. Optionally, at least one unnatural amino acid is located within the first 40 residues from the C-terminal residue. Optionally, at least one unnatural amino acid is located within the first 50 residues from the C-terminal residue.

[0142] In some instances, at least one unnatural amino acid is the C-terminal residue.

[0143] In some embodiments, described herein are methods of treating a proliferative disease or condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a cytokine conjugate (e.g., an IL-15 conjugate) described herein.

[0144] Described herein are pharmaceutical compositions comprising an effective amount of an IL-15 conjugate described herein and one or more pharmaceutically acceptable excipients.

[0145] In some embodiments, described herein are methods of treating a proliferative disease or condition in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a cytokine conjugate (e.g., an IL-15 conjugate) described in Table 1. In some embodiments, the IL-15 conjugate comprises SEQ ID NOs: 1-99. In some embodiments, the IL-15 conjugate comprises SEQ ID NOs: 4-99. In some embodiments, the IL-15 conjugate comprises SEQ ID NOs: 4-9. In some embodiments, the IL-15 conjugate comprises SEQ ID NOs: 10-15. In some embodiments, the IL-15 conjugate comprises SEQ ID NOs: 16-21. In some embodiments, the IL-15 conjugate comprises SEQ ID NOs: 22-27. In some embodiments, the IL-15 conjugate comprises SEQ ID NOs: 28-33. In some embodiments, the IL-15 conjugate comprises the structure of Formula (I). In some embodiments, the IL-15 conjugate comprises the structure of Formula (II). In some embodiments, the IL-15 conjugate comprises the structure of Formula (III). In some embodiments, the IL-15 conjugate comprises the structure of Formula (IV). In some embodiments, the IL-15 conjugate comprises the structure of Formula (V). In some embodiments, the IL-15 conjugate comprises the structure of Formula (VI). In some embodiments, the IL-15 conjugate comprises the structure of Formula (VII). In some embodiments, the IL-15 conjugate comprises the structure of Formula (VIII). In some embodiments, the IL-15 conjugate comprises the structure of Formula (IX). In some embodiments, the IL-15 conjugate comprises the structure of Formula (X). In some embodiments, the IL-15 conjugate comprises the structure of Formula (XI). In some embodiments, the IL-15 conjugate comprises the structure of Formula (XII). In some embodiments, the IL-15 conjugate comprises the structure of Formula (XIII). In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 1. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 2. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 3. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 4. In some embodiments, the IL-15 conjugate comprises SEQ ID NO:5.In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 6. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 7. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 8. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 9. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 10. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 11. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 12. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 13. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 14. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 15. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 16. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 17. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 18. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 19. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 20. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 21. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 22. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 23. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 24. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 25. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 26. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 27. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 28. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 24. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 25. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 26. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 27. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 28. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 28. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 29. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 30.In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 31. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 32. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 33. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 34. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 35. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 36. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 37. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 38. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 39. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 40. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 41. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 42. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 43. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 44. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 45. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 46. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 47. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 48. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 49. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 50. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 51. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 52. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 53. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 54. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 55. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 56. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 57. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 58. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 59. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 60.In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 61. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 62. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 63. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 64. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 65. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 66. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 67. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 68. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 69. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 70. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 71. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 72. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 73. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 74. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 75. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 76. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 77. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 78. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 79. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 80. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 81. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 82. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 83. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 84. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 85. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 86. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 87. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 88. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 89. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 90.In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 91. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 92. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 93. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 94. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 95. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 96. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 97. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 98. In some embodiments, the IL-15 conjugate comprises SEQ ID NO: 99.

[0146] In some embodiments, the present specification describes IL-15 conjugates modified at an amino acid position. In some examples, the modification is a change to a natural amino acid. In some examples, the modification is a change to a non-natural amino acid. In some examples, the present specification describes isolated and modified IL-15 polypeptides comprising at least one non-natural amino acid. In some cases, the IL-15 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to any one of SEQ ID NOs: 4-99.

[0147] In some cases, the PEG group is not limited to a specific structure. In some cases, the PEG is linear (e.g., end-capped, e.g., alkoxy PEG or bifunctional PEG), branched or multi-armed (e.g., forked PEG, or PEG attached to a polyol core), dendritic (or star) structure, each of which may or may not have one or more degradable linkages. Furthermore, the internal structure of the water-soluble polymer can be organized in any number of different repeating patterns and can be selected from the group consisting of homopolymers, alternating copolymers, random copolymers, block copolymers, alternating tripolymers, random tripolymers, and block tripolymers.

[0148] PEG typically comprises multiple (OCH2CH2) monomers [or (CH2CH2O) monomers, depending on how PEG is defined]. As used herein, the number of repeating units is referred to as "(OCH2CH2) n " is identified by the subscript "n." Thus, the value of (n) typically falls within one or more of the following ranges: 2 to about 3400, about 100 to about 2300, about 100 to about 2270, about 136 to about 2050, about 225 to about 1930, about 450 to about 1930, about 1200 to about 1930, about 568 to about 2727, about 660 to about 2730, about 795 to about 2730, about 795 to about 2730, about 909 to about 2730, and about 1,200 to about 1,900. For any given polymer whose molecular weight is known, it is possible to determine the number of repeat units (i.e., "n") by dividing the total weight-average molecular weight of the polymer by the molecular weight of the repeating monomer.

[0149] In some instances, PEG is an end-capped polymer, i.e., a polymer end-capped with a relatively inert group, e.g., a lower C 1~6 It is a polymer having at least one end capped with an alkoxy group or a hydroxyl group. When the polymer is PEG, for example, methoxy-PEG (commonly referred to as mPEG) can be used, which is a linear form of PEG in which one end of the polymer is a methoxy (-OCH3) group, and the other end is a hydroxyl or other functional group that can be optionally chemically modified.

[0150] In some embodiments, the PEG group comprising an IL-15 conjugate disclosed herein is a linear or branched PEG group. In some embodiments, the PEG group is a linear PEG group. In some embodiments, the PEG group is a branched PEG group. In some embodiments, the PEG group is a methoxy PEG group. In some embodiments, the PEG group is a linear or branched methoxy PEG group. In some embodiments, the PEG group is a linear methoxy PEG group. In some embodiments, the PEG group is a branched methoxy PEG group. In some embodiments, the PEG group is a linear or branched PEG group having an average molecular weight of about 100 daltons to about 150,000 daltons. Exemplary ranges include, for example, weight-average molecular weights in the range of greater than 5,000 daltons to about 100,000 daltons, about 6,000 daltons to about 90,000 daltons, about 10,000 daltons to about 85,000 daltons, greater than 10,000 daltons to about 85,000 daltons, about 20,000 daltons to about 85,000 daltons, about 53,000 daltons to about 85,000 daltons, about 25,000 daltons to about 120,000 daltons, about 29,000 daltons to about 120,000 daltons, about 35,000 daltons to about 120,000 daltons, and about 40,000 daltons to about 120,000 daltons.Exemplary weight-average molecular weights for PEG groups include about 100 daltons, about 200 daltons, about 300 daltons, about 400 daltons, about 500 daltons, about 600 daltons, about 700 daltons, about 750 daltons, about 800 daltons, about 900 daltons, about 1,000 daltons, about 1,500 daltons, about 2,000 daltons, about 2,200 daltons, about 2,500 daltons, about 3,000 daltons, about 4,000 daltons, about 4,400 daltons, about 4,500 daltons, about 5,000 daltons, about 5,500 daltons, about 6,000 daltons, about 7,000 daltons, about 7,500 daltons, about 8,000 daltons, and about 9,000 daltons. daltons, about 10,000 daltons, about 11,000 daltons, about 12,000 daltons, about 13,000 daltons, about 14,000 daltons, about 15,000 daltons, about 20,000 daltons, about 22,500 daltons, about 25,000 daltons, about 30,000 daltons, about 35,000 daltons, about 40,000 daltons, about 45,000 daltons, about 50,000 daltons, about 55,000 daltons, about 60,000 daltons, about 65,000 daltons, about 70,000 daltons, about 75,000 daltons, about 80,000 daltons, about 90,000 daltons, about 95,000 daltons and about 100,000 daltons. In some embodiments, the PEG group is a linear PEG group having an average molecular weight as disclosed above. In some embodiments, the PEG group is a branched PEG group having an average molecular weight as disclosed above. In some embodiments, the PEG group comprising the IL-15 conjugates disclosed herein is a linear or branched PEG group having a defined molecular weight ± 10%, or 15%, or 20%, or 25%. For example, IL-15 conjugates comprising a PEG group having a molecular weight of 30,000 Da ± 3,000 Da, or 30,000 Da ± 4,500 Da, or 30,000 Da ± 6,000 Da are within the scope of the present disclosure.

[0151] In some embodiments, the PEG group comprising the IL-15 conjugates disclosed herein is a linear or branched PEG group having an average molecular weight of about 5,000 daltons to about 60,000 daltons. In some embodiments, the PEG group is about 5,000 daltons, about 5,500 daltons, about 6,000 daltons, about 7,000 daltons, about 7,500 daltons, about 8,000 daltons, about 9,000 daltons, about 10,000 daltons, about 11,000 daltons, about 12,000 daltons, about 13,000 daltons, about 14,000 daltons, about 15,000 daltons, about 20,000 daltons, about 22,500 daltons, or about 25,000 daltons. In some embodiments, the PEG group is a linear or branched PEG group having an average molecular weight of about 30,000 daltons, about 35,000 daltons, about 40,000 daltons, about 45,000 daltons, about 50,000 daltons, about 55,000 daltons, about 60,000 daltons, about 65,000 daltons, about 70,000 daltons, about 75,000 daltons, about 80,000 daltons, about 90,000 daltons, about 95,000 daltons, and about 100,000 daltons. In some embodiments, the PEG group is a linear or branched PEG group having an average molecular weight of about 5,000 daltons, about 10,000 daltons, about 20,000 daltons, about 30,000 daltons, about 50,000 daltons, or about 60,000 daltons. In some embodiments, the PEG group is a linear or branched PEG group having an average molecular weight of about 5,000 daltons, about 30,000 daltons, about 50,000 daltons, or about 60,000 daltons. In some embodiments, the PEG group is a linear PEG group having an average molecular weight of about 5,000 daltons, about 10,000 daltons, about 20,000 daltons, about 30,000 daltons, about 50,000 daltons, or about 60,000 daltons. In some embodiments, the PEG group is a branched PEG group having an average molecular weight of about 5,000 daltons, about 10,000 daltons, about 20,000 daltons, about 30,000 daltons, about 50,000 daltons, or about 60,000 daltons.

[0152] In some embodiments, the PEG group comprising the IL-15 conjugates disclosed herein is a linear methoxy PEG group having an average molecular weight of about 5,000 daltons to about 60,000 daltons. In some embodiments, the PEG group is about 5,000 daltons, about 5,500 daltons, about 6,000 daltons, about 7,000 daltons, about 7,500 daltons, about 8,000 daltons, about 9,000 daltons, about 10,000 daltons, about 11,000 daltons, about 12,000 daltons, about 13,000 daltons, about 14,000 daltons, about 15,000 daltons, about 20,000 daltons, about 22,500 daltons, or about 25,000 daltons. In some embodiments, the PEG group is a linear methoxy PEG group having an average molecular weight of about 5,000 daltons, about 10,000 daltons, about 20,000 daltons, about 30,000 daltons, about 35,000 daltons, about 40,000 daltons, about 45,000 daltons, about 50,000 daltons, about 55,000 daltons, about 60,000 daltons, about 65,000 daltons, about 70,000 daltons, about 75,000 daltons, about 80,000 daltons, about 90,000 daltons, about 95,000 daltons, and about 100,000 daltons. In some embodiments, the PEG group is a linear methoxy PEG group having an average molecular weight of about 5,000 daltons, about 10,000 daltons, about 20,000 daltons, about 30,000 daltons, about 50,000 daltons, or about 60,000 daltons. In some embodiments, the PEG group is a linear methoxy PEG group having an average molecular weight of about 5,000 daltons, about 30,000 daltons, about 50,000 daltons, or about 60,000 daltons. In some embodiments, the PEG group is a linear methoxy PEG group having an average molecular weight of about 5,000 daltons, about 10,000 daltons, about 20,000 daltons, about 30,000 daltons, about 50,000 daltons, or about 60,000 daltons. In some embodiments, the PEG group is a linear methoxy PEG group having an average molecular weight of about 5,000 daltons. In some embodiments, the PEG group is a linear methoxy PEG group having an average molecular weight of about 10,000 daltons. In some embodiments, the PEG group is a linear methoxy PEG group having an average molecular weight of about 20,000 daltons.In some embodiments, the PEG group is a linear methoxy PEG group having an average molecular weight of about 30,000 daltons. In some embodiments, the PEG group is a linear methoxy PEG group having an average molecular weight of about 50,000 daltons. In some embodiments, the PEG group is a linear methoxy PEG group having an average molecular weight of about 60,000 daltons. In some embodiments, the PEG group comprising the IL-15 conjugates disclosed herein is a linear methoxy PEG group having a defined molecular weight ± 10%, or 15%, or 20%, or 25%. For example, IL-15 conjugates comprising a linear methoxy PEG group having a molecular weight of 30,000 Da ± 3,000 Da, or 30,000 Da ± 4,500 Da, or 30,000 Da ± 6,000 Da are within the scope of the present disclosure.

[0153] In some embodiments, when present, n is from 100 to about 1150, or from about 100 to about 1100, or from about 100 to about 1000, or from about 100 to about 900, or from about 100 to about 750, or from about 100 to about 700, or from about 100 to about 600, or from about 100 to about 575, or from about 100 to about 500, or from about 100 to about 450, or from about 10 0 to about 350, or about 100 to about 275, or about 100 to about 230, or about 150 to about 475, or about 150 to about 340, or about 113 to about 340, or about 450 to about 800, or about 454 to about 796, or about 454 to about 682, or about 340 to about 795, or about 341 to about 682, or about 568 to about 909, or about 2 27 to about 1500, or about 225 to about 2280, or about 460 to about 2160, or about 460 to about 2050, or about 341 to about 1820, or about 341 to about 1710, or about 341 to about 1250, or about 225 to about 1250, or about 341 to about 1250, or about 341 to about 1136, or about 341 to about 1023, or about 34 Disclosed herein are IL-15 conjugates wherein the IL-15 conjugate is an integer from 1 to about 910, or from about 341 to about 796, or from about 341 to about 682, or from about 341 to about 568, or from about 114 to about 1000, or from about 114 to about 950, or from about 114 to about 910, or from about 114 to about 800, or from about 114 to about 690, or from about 114 to about 575.In some embodiments, if present, n is 2, 5, 10, 11, 22, 23, 113, 114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, 1137, 1249, 1250, 1251, 1362, 1363, 1364, 1476, 1477, 1478, 1589, 1590, 1591, 1 Disclosed herein is an IL-15 conjugate wherein the IL-15 conjugate is an integer selected from 703, 1704, 1705, 1817, 1818, 1819, 1930, 1931, 1932, 2044, 2045, 2046, 2158, 2159, 2160, 2271, 2272, 2273, 2839, 2840, 2841, 2953, 2954, 2955, 3408, 3409, 3410, 3976, 3977, 3978, 4544, 4545 and 4546.

[0154] In some embodiments, the PEG group comprising the IL-15 conjugates disclosed herein is a branched methoxy PEG group having an average molecular weight of about 5,000 daltons to about 60,000 daltons. In some embodiments, the PEG group is about 5,000 daltons, about 5,500 daltons, about 6,000 daltons, about 7,000 daltons, about 7,500 daltons, about 8,000 daltons, about 9,000 daltons, about 10,000 daltons, about 11,000 daltons, about 12,000 daltons, about 13,000 daltons, about 14,000 daltons, about 15,000 daltons, about 20,000 daltons, about 22,500 daltons, or about 25,000 daltons. In some embodiments, the PEG group is a branched methoxy PEG group having an average molecular weight of about 5,000 daltons, about 10,000 daltons, about 20,000 daltons, about 30,000 daltons, about 35,000 daltons, about 40,000 daltons, about 45,000 daltons, about 50,000 daltons, about 55,000 daltons, about 60,000 daltons, about 65,000 daltons, about 70,000 daltons, about 75,000 daltons, about 80,000 daltons, about 90,000 daltons, about 95,000 daltons, and about 100,000 daltons. In some embodiments, the PEG group is a branched methoxy PEG group having an average molecular weight of about 5,000 daltons, about 10,000 daltons, about 20,000 daltons, about 30,000 daltons, about 50,000 daltons, or about 60,000 daltons. In some embodiments, the PEG group is a branched methoxy PEG group having an average molecular weight of about 5,000 daltons, about 30,000 daltons, about 50,000 daltons, or about 60,000 daltons. In some embodiments, the PEG group is a branched methoxy PEG group having an average molecular weight of about 5,000 daltons, about 10,000 daltons, about 20,000 daltons, about 30,000 daltons, about 50,000 daltons, or about 60,000 daltons. In some embodiments, the PEG group is a branched methoxy PEG group having an average molecular weight of about 5,000 daltons, about 10,000 daltons, about 20,000 daltons, about 30,000 daltons, about 50,000 daltons, or about 60,000 daltons. In some embodiments, the PEG group is a branched methoxy PEG group having an average molecular weight of about 5,000 daltons.In some embodiments, the PEG group is a branched methoxy PEG group having an average molecular weight of about 10,000 daltons. In some embodiments, the PEG group is a branched methoxy PEG group having an average molecular weight of about 20,000 daltons. In some embodiments, the PEG group is a branched methoxy PEG group having an average molecular weight of about 30,000 daltons. In some embodiments, the PEG group is a branched methoxy PEG group having an average molecular weight of about 50,000 daltons. In some embodiments, the PEG group is a branched methoxy PEG group having an average molecular weight of about 60,000 daltons. In some embodiments, the PEG group comprising the IL-15 conjugates disclosed herein is a branched methoxy PEG group having a defined molecular weight ± 10%, or 15%, or 20%, or 25%. For example, IL-15 conjugates comprising branched methoxy PEG groups having molecular weights of 30,000 Da±3000 Da, or 30,000 Da±4,500 Da, or 30,000 Da±6,000 Da are included within the scope of the present disclosure.

[0155] In some embodiments, exemplary PEG groups include, but are not limited to, linear or branched discrete PEG (dPEG) from Quanta Biodesign, Ltd.; linear, branched, or forked PEG from Nektar Therapeutics; and Y-shaped PEG derivatives from JenKem Technology.

[0156] In some embodiments, the modified IL-15 polypeptide comprises at least one unnatural amino acid, and the at least one unnatural amino acid is at a residue position that selectively decreases the binding affinity of the IL-15 polypeptide to interleukin-15 receptor alpha (IL-15Rα). In some embodiments, the decrease in binding affinity is relative to the binding affinity between wild-type IL-15 polypeptide and IL-15Rα. In some embodiments, binding of the modified IL-15 polypeptide to IL-15Rα does not affect the interaction of the modified IL-15 polypeptide with interleukin-2 / interleukin-15 receptor beta-gamma (IL-2 / IL-15Rβγ) or increases the interaction of the modified IL-15 polypeptide with IL-2 / IL-15Rβγ. In some examples, the residue position of the at least one unnatural amino acid is selected from D22, A23, T24, L25, Y26, L44, E46, Q48, V49, E53, E89, E90, and E93, wherein the residue positions correspond to the positions set forth in SEQ ID NO: 1. In some embodiments, the residue position of the at least one unnatural amino acid is selected from Y26, E46, V49, E53, and L25, wherein the residue positions correspond to the positions set forth in SEQ ID NO: 1. In some embodiments, the residue position of the at least one unnatural amino acid is selected from A23, T24, E89, and E93, wherein the residue positions correspond to the positions set forth in SEQ ID NO: 1. In some embodiments, the residue position of the at least one unnatural amino acid is selected from D22, L44, Q48, and E90, wherein the residue positions correspond to the positions set forth in SEQ ID NO: 1. In some examples, the residue position of the at least one unnatural amino acid is Y26. In some examples, the residue position of the at least one unnatural amino acid is E46. In some examples, the residue position of the at least one unnatural amino acid is V49. In some examples, the residue position of the at least one unnatural amino acid is E53. In some examples, the residue position of the at least one unnatural amino acid is L25. In some embodiments, the modified IL-15 polypeptide further comprises PEG. In some cases, PEG is conjugated at a residue position selected from D22, A23, T24, L25, Y26, L44, E46, Q48, V49, E53, E89, E90, and E93.In some embodiments, the modified IL-15 polypeptide further comprises PEG to extend half-life. In some cases, PEG is conjugated at a residue position selected from E13, D14, L15, Q17, S18, M19, H20, I21, S34, C35, K36, V37, T38, K41, L44, S51, L52, S54, G55, D56, A57, S58, H60, V63, I67, N71, S73, L74, S75, S76, N77, G78, N79, V80, T81, E82, S83, G84, C85, K86, E87, C88, L91, E92, K94, N95, I96, K97, E98, L100, Q101 and F110 to extend half-life. In some cases, PEG is conjugated at a residue position selected from N71, N72 and N77. In some cases, the residue conjugated to PEG is mutated to a natural amino acid. In other cases, the residue conjugated to PEG is mutated to a non-natural amino acid. In further cases, mutation of N71, N72 or N77 further improves CMC condition (e.g., yield, purity, stability, reduced aggregation and / or improved protein folding), potency, or a combination thereof.

[0157] In some examples, the modified IL-15 polypeptide comprises at least one unnatural amino acid, wherein the at least one unnatural amino acid is located at a residue position that selectively decreases the binding affinity of the modified IL-15 polypeptide with IL-2 / IL-15Rβ, IL-15Rγ, or a combination thereof. In some embodiments, the modified IL-15 polypeptide has little or no effect on interaction with IL-15Rα. In some embodiments, the residue position of the at least one unnatural amino acid is selected from N1, V3, N4, 16, S7, D8, K10, K11, E28, S29, D30, V31, H32, P33, D61, T62, E64, N65, 168, L69, N72, S102, V104, H105, Q108, M109, I111, N112, T113, and S114, wherein the residue positions correspond to those set forth in SEQ ID NO: 1. In some embodiments, the at least one unnatural amino acid is at a residue position that selectively decreases the binding affinity of the modified IL-15 polypeptide to IL-2 / IL-15Rβ. In some examples, the residue position of the at least one unnatural amino acid is selected from N1, N4, S7, D8, K11, D61, T62, E64, N65, 168, L69, and N72, where the residue positions correspond to the positions set forth in SEQ ID NO: 1. In some examples, the residue position of the at least one unnatural amino acid is selected from N4, S7, K11, and D61. In some examples, the residue position of the at least one unnatural amino acid is selected from D8, E64, N65, 168, and N72. In some examples, the residue position of the at least one unnatural amino acid is selected from N1, T62, and L69. In some examples, the residue position of the at least one unnatural amino acid is N4. In some examples, the residue position of the at least one unnatural amino acid is S7. In some examples, the residue position of the at least one unnatural amino acid is K11. In some examples, the residue position of the at least one unnatural amino acid is D61. In some embodiments, the at least one unnatural amino acid is at a residue position that selectively decreases the binding affinity of the modified IL-15 polypeptide to IL-2 / IL-15Rγ.In some examples, the residue position of the at least one unnatural amino acid is selected from V3, 16, K10, E28, S29, D30, V31, H32, P33, S102, V104, H105, Q108, M109, I111, N112, T113, and S114, where the residue positions correspond to the positions set forth in SEQ ID NO: 1. In some examples, the residue position of the at least one unnatural amino acid is selected from V3, K10, S29, D30, H32, H105, Q108, M109, I111, N112, T113, and S114. In some examples, the residue position of the at least one unnatural amino acid is selected from E28, P33, S102, and V104. In some examples, the residue position of the at least one unnatural amino acid is selected from 16 and V31. In some examples, the residue position of the at least one unnatural amino acid is V3. In some examples, the residue position of the at least one unnatural amino acid is K10. In some examples, the residue position of the at least one unnatural amino acid is S29. In some examples, the residue position of the at least one unnatural amino acid is D30. In some examples, the residue position of the at least one unnatural amino acid is H32. In some examples, the residue position of the at least one unnatural amino acid is H105. In some examples, the residue position of the at least one unnatural amino acid is Q108. In some examples, the residue position of the at least one unnatural amino acid is M109. In some examples, the residue position of the at least one unnatural amino acid is I111. In some examples, the residue position of the at least one unnatural amino acid is N112. In some examples, the residue position of the at least one unnatural amino acid is T113. In some examples, the residue position of the at least one unnatural amino acid is S114. In some embodiments, the modified IL-15 polypeptide further comprises PEG. In some cases, the PEG is conjugated at a residue position selected from N1, V3, N4, 16, S7, D8, K10, K11, E28, S29, D30, V31, H32, P33, D61, T62, E64, N65, 168, L69, N72, S102, V104, H105, Q108, M109, I111, N112, T113, and S114. In some embodiments, the modified IL-15 polypeptide further comprises PEG to extend half-life.In some cases, PEG is conjugated at a residue position selected from E13, D14, L15, Q17, S18, M19, H20, I21, S34, C35, K36, V37, T38, K41, L44, S51, L52, S54, G55, D56, A57, S58, H60, V63, I67, N71, S73, L74, S75, S76, N77, G78, N79, V80, T81, E82, S83, G84, C85, K86, E87, C88, L91, E92, K94, N95, I96, K97, E98, L100, Q101 and F110 to extend half-life. In some cases, PEG is conjugated at a residue position selected from N71, N72 and N77. In some cases, the residue conjugated to PEG is mutated to a natural amino acid. In other cases, the residue conjugated to PEG is mutated to a non-natural amino acid. In further cases, mutation of N71, N72 or N77 further improves CMC condition (e.g., yield, purity, stability, reduced aggregation and / or improved protein folding), efficacy, or a combination thereof.

[0158] In some embodiments, the modified IL-15 polypeptide comprises at least one unnatural amino acid, and the at least one unnatural amino acid is at a residue position that does not affect the binding affinity of the modified IL-15 polypeptide to IL-15Rα and IL-15Rβγ. In some embodiments, the modified IL-15 polypeptide further comprises a PEG to extend half-life. In some embodiments, the modified IL-15 polypeptide comprises a PEG that does not alter biological activity. In some embodiments, the residue is modified to extend half-life. In some cases, the residue position of the at least one unnatural amino acid is selected from E13, D14, L15, Q17, S18, M19, H20, 121, S34, C35, K36, V37, T38, K41, L44, S51, L52, S54, G55, D56, A57, S58, H60, V63, 167, N71, S73, L74, S75, S76, N77, G78, N79, V80, T81, E82, S83, G84, C85, K86, E87, C88, L91, E92, K94, N95, 196, K97, E98, L100, Q101 and F110, where the residue positions correspond to those set forth in SEQ ID NO:1. In some embodiments, the residue position of the at least one unnatural amino acid is selected from D14, Q17, S18, K41, S51, L52, G55, D56, A57, S58, S75, S76, N77, N79, V80, T81, S83, G84, E92, K94, N95, K97, and E98, where the residue positions correspond to the positions set forth in SEQ ID NO: 1. In some embodiments, the residue position of the at least one unnatural amino acid is selected from E13, L15, M19, H20, K36, V37, T38, S54, H60, 167, N71, G78, K86, E87, and Q101, where the residue positions correspond to the positions set forth in SEQ ID NO: 1. In some embodiments, the residue position of the at least one unnatural amino acid is selected from 121, S34, C35, L44, V63, S73, L74, E82, C85, C88, L91, 196, L100, and F110, where the residue positions correspond to the positions set forth in SEQ ID NO: 1. In some embodiments, the residue position of the at least one unnatural amino acid is selected from N71, N72, and N77, where the residue positions correspond to the positions set forth in SEQ ID NO: 1.In some embodiments, the residue position of at least one unnatural amino acid is selected from N77 and S83. In some embodiments, the residue position of at least one unnatural amino acid is D14. In some embodiments, the residue position of at least one unnatural amino acid is Q17. In some embodiments, the residue position of at least one unnatural amino acid is S18. In some embodiments, the residue position of at least one unnatural amino acid is K41. In some embodiments, the residue position of at least one unnatural amino acid is S51. In some embodiments, the residue position of at least one unnatural amino acid is L52. In some embodiments, the residue position of at least one unnatural amino acid is G55. In some embodiments, the residue position of at least one unnatural amino acid is D56. In some embodiments, the residue position of at least one unnatural amino acid is A57. In some embodiments, the residue position of at least one unnatural amino acid is S58. In some embodiments, the residue position of at least one unnatural amino acid is S75. In some embodiments, the residue position of at least one unnatural amino acid is S76. In some embodiments, the residue position of at least one unnatural amino acid is N77. In some embodiments, the residue position of at least one unnatural amino acid is N79. In some embodiments, the residue position of at least one unnatural amino acid is V80. In some embodiments, the residue position of at least one unnatural amino acid is T81. In some embodiments, the residue position of at least one unnatural amino acid is S83. In some embodiments, the residue position of at least one unnatural amino acid is G84. In some embodiments, the residue position of at least one unnatural amino acid is E92. In some embodiments, the residue position of at least one unnatural amino acid is K94. In some embodiments, the residue position of at least one unnatural amino acid is N95. In some embodiments, the residue position of at least one unnatural amino acid is K97. In some embodiments, the residue position of at least one unnatural amino acid is E98. In some embodiments, the mutation at N71, N72, or N77 comprises a mutation to a natural amino acid.In some cases, mutations at N71, N72, or N77 further improve CMC conditions (e.g., yield, purity, stability, reduced aggregation and / or improved protein folding), potency, or a combination thereof.

[0159] In some embodiments, the IL-15 polypeptide comprising at least one unnatural amino acid is further conjugated to a conjugation moiety to generate an IL-15 conjugate. In some cases, the amino acid position of the at least one unnatural amino acid is N1, W2, V3, N4, 16, S7, D8, K10, K11, E13, D14, L15, Q17, S18, M19, H20, 121, D22, A23, T24, L25, Y26, T27, E28, S29, D30, V31, H32, P33, S34, C35, K36, V37, T38, A39, K41, L44, L45, E46, Q48, V49, S51, L52, E53, S54, G55, D56, A57, S58, H60, D61 , T62, V63, E64, N65, I67, I68, L69, N71, N72, S73, L74, S75, S76, N77, G78, N79, V80, T81, E82, S83, G84, C85, K86, E87, C88, E89, E90, L91, E92, E93, K94, N95, I96, K97, E98, L100, Q101, S102, V104, H105, Q108, M109, F110, I111, N112, T113 or S114, wherein the residue positions correspond to those shown in SEQ ID NO:1. In some cases, the amino acid position of the at least one unnatural amino acid is N1, W2, V3, N4, 16, S7, D8, K10, K11, E13, D14, L15, Q17, S18, M19, H20, 121, D22, A23, T24, L25, Y26, E28, S29, D30, V31, H32, P33, S34, C35, K36, V37, T38, K41, L44, E46, Q48, V49, S51, L52, E53, S54, G55, D56, A57, S58, H6 0, D61, T62, V63, E64, N65, I67, I68, L69, N71, N72, S73, L74, S75, S76, N77, G78, N79, V80, T81, E82, S83, G84, C85, K86, E87, C88, E89, E90, L91, E92, E93, K94, N95, I96, K97, E98, L100, Q101, S102, V104, H105, Q108, M109, F110, I111, N112, T113 or S114.In some cases, the conjugation moiety is attached to at least one unnatural amino acid. In some cases, the conjugation moiety is attached to the N-terminal or C-terminal amino acid residue. In some cases, the conjugation moiety is attached directly to at least one unnatural amino acid or terminal residue. In other cases, the conjugation moiety is attached indirectly to at least one unnatural amino acid or terminal residue through a linker as described below.

[0160] In some embodiments, the reduction in affinity of the IL-15 polypeptide or IL-15 conjugate for the IL-15 receptor alpha (IL-15Rα) subunit compared to the wild-type IL-15 polypeptide is about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99%. In some embodiments, the reduction in affinity is about 10%. In some embodiments, the reduction in affinity is about 20%. In some embodiments, the reduction in affinity is about 40%. In some embodiments, the reduction in affinity is about 50%. In some embodiments, the reduction in affinity is about 60%. In some embodiments, the reduction in affinity is about 80%. In some embodiments, the reduction in affinity is about 90%. In some embodiments, the reduction in affinity is about 95%. In some embodiments, the reduction in affinity is 100%.

[0161] In some embodiments, the affinity reduction of an IL-15 polypeptide or IL-15 conjugate for the IL-15 receptor alpha (IL-15Rα) subunit compared to a wild-type IL-15 polypeptide is about 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, or less. In some embodiments, the affinity reduction is about 1-fold. In some embodiments, the affinity reduction is about 2-fold. In some embodiments, the affinity reduction is about 4-fold. In some embodiments, the affinity reduction is about 5-fold. In some embodiments, the affinity reduction is about 6-fold. In some embodiments, the affinity reduction is about 8-fold. In some embodiments, the affinity reduction is about 10-fold.

[0162] In some embodiments, the IL-15 polypeptide or IL-15 conjugate did not interact with IL-15Rα.

[0163] In some embodiments, the reduction in affinity of the IL-15 polypeptide or IL-15 conjugate for an IL-2 receptor (IL-2R) subunit compared to a wild-type IL-15 polypeptide is about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99%. In some embodiments, the IL-2R subunit is IL-2Rβγ. In some embodiments, the reduction in affinity is about 10%. In some embodiments, the reduction in affinity is about 20%. In some embodiments, the reduction in affinity is about 40%. In some embodiments, the reduction in affinity is about 50%. In some embodiments, the reduction in affinity is about 60%. In some embodiments, the reduction in affinity is about 80%. In some embodiments, the reduction in affinity is about 90%. In some embodiments, the reduction in affinity is about 95%. In some embodiments, the reduction in affinity is 100%.

[0164] In some embodiments, the affinity reduction of an IL-15 polypeptide or IL-15 conjugate for an IL-2 receptor (IL-2R) subunit compared to a wild-type IL-15 polypeptide is about 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, or less. In some embodiments, the IL-2R subunit is IL-2Rβγ. In some embodiments, the affinity reduction is about 1-fold. In some embodiments, the affinity reduction is about 2-fold. In some embodiments, the affinity reduction is about 4-fold. In some embodiments, the affinity reduction is about 5-fold. In some embodiments, the affinity reduction is about 6-fold. In some embodiments, the affinity reduction is about 8-fold. In some embodiments, the affinity reduction is about 10-fold.

[0165] In some embodiments, the IL-15 polypeptide or IL-15 conjugate does not interact with IL-2Rα.

[0166] In some embodiments, the IL-15 polypeptide or IL-15 conjugate has an increased half-life, in some cases compared to the half-life of a wild-type IL-15 protein or wild-type IL-15 conjugate.

[0167] In some cases, the increased half-life of the IL-15 polypeptide or IL-15 conjugate is at least 90 minutes, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 18 hours, 24 hours, 36 hours, 48 ​​hours, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 14 days, 21 days, 28 days, 30 days, or longer than the half-life of a wild-type IL-15 protein or wild-type IL-15 conjugate. In some cases, the increased half-life of an IL-15 polypeptide or IL-15 conjugate is at least 90 minutes or longer than the half-life of a wild-type IL-15 protein or wild-type IL-15 conjugate. In some cases, the increased half-life of the IL-15 polypeptide or IL-15 conjugate is at least 2 hours or longer than the half-life of the wild-type IL-15 protein or wild-type IL-15 conjugate. In some cases, the increased half-life of the IL-15 polypeptide or IL-15 conjugate is at least 3 hours or longer than the half-life of the wild-type IL-15 protein or wild-type IL-15 conjugate. In some cases, the increased half-life of the IL-15 polypeptide or IL-15 conjugate is at least 4 hours or longer than the half-life of the wild-type IL-15 protein or wild-type IL-15 conjugate. In some cases, the increased half-life of the IL-15 polypeptide or IL-15 conjugate is at least 5 hours or longer than the half-life of the wild-type IL-15 protein or wild-type IL-15 conjugate. In some cases, the increased half-life of the IL-15 polypeptide or IL-15 conjugate is at least 6 hours or longer than the half-life of the wild-type IL-15 protein or wild-type IL-15 conjugate. In some cases, the increased half-life of the IL-15 polypeptide or IL-15 conjugate is at least 10 hours or longer than the half-life of the wild-type IL-15 protein or wild-type IL-15 conjugate. In some cases, the increased half-life of the IL-15 polypeptide or IL-15 conjugate is at least 12 hours or longer than the half-life of the wild-type IL-15 protein or wild-type IL-15 conjugate.In some cases, the increased half-life of the IL-15 polypeptide or IL-15 conjugate is at least 18 hours or longer than the half-life of the wild-type IL-15 protein or wild-type IL-15 conjugate. In some cases, the increased half-life of the IL-15 polypeptide or IL-15 conjugate is at least 24 hours or longer than the half-life of the wild-type IL-15 protein or wild-type IL-15 conjugate. In some cases, the increased half-life of the IL-15 polypeptide or IL-15 conjugate is at least 36 hours or longer than the half-life of the wild-type IL-15 protein or wild-type IL-15 conjugate. In some cases, the increased half-life of the IL-15 polypeptide or IL-15 conjugate is at least 48 hours or longer than the half-life of the wild-type IL-15 protein or wild-type IL-15 conjugate. In some cases, the increased half-life of the IL-15 polypeptide or IL-15 conjugate is at least 3 days or longer than the half-life of the wild-type IL-15 protein or wild-type IL-15 conjugate. In some cases, the increased half-life of the IL-15 polypeptide or IL-15 conjugate is at least 4 days or longer than the half-life of the wild-type IL-15 protein or wild-type IL-15 conjugate. In some cases, the increased half-life of the IL-15 polypeptide or IL-15 conjugate is at least 5 days or longer than the half-life of the wild-type IL-15 protein or wild-type IL-15 conjugate. In some cases, the increased half-life of the IL-15 polypeptide or IL-15 conjugate is at least 6 days or longer than the half-life of the wild-type IL-15 protein or wild-type IL-15 conjugate. In some cases, the increased half-life of the IL-15 polypeptide or IL-15 conjugate is at least 7 days or longer than the half-life of the wild-type IL-15 protein or wild-type IL-15 conjugate. In some cases, the increased half-life of the IL-15 polypeptide or IL-15 conjugate is at least 10 days or longer than the half-life of the wild-type IL-15 protein or wild-type IL-15 conjugate.In some cases, the increased half-life of the IL-15 polypeptide or IL-15 conjugate is at least 12 days or longer than the half-life of the wild-type IL-15 protein or wild-type IL-15 conjugate. In some cases, the increased half-life of the IL-15 polypeptide or IL-15 conjugate is at least 14 days or longer than the half-life of the wild-type IL-15 protein or wild-type IL-15 conjugate. In some cases, the increased half-life of the IL-15 polypeptide or IL-15 conjugate is at least 21 days or longer than the half-life of the wild-type IL-15 protein or wild-type IL-15 conjugate. In some cases, the increased half-life of the IL-15 polypeptide or IL-15 conjugate is at least 28 days or longer than the half-life of the wild-type IL-15 protein or wild-type IL-15 conjugate. In some cases, the increased half-life of the IL-15 polypeptide or IL-15 conjugate is at least 30 days or longer than the half-life of the wild-type IL-15 protein or wild-type IL-15 conjugate.

[0168] In some cases, the increased half-life of the IL-15 polypeptide or IL-15 conjugate compared to the half-life of the wild-type IL-15 protein or wild-type IL-15 conjugate is about 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 18 hours, 24 hours, 36 hours, 48 ​​hours, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 14 days, 21 days, 28 days, or 30 days. In some cases, the biologically active IL-15 polypeptide or IL-15 conjugate has an increased half-life of about 90 minutes. In some cases, the biologically active IL-15 polypeptide or IL-15 conjugate has an increased half-life of about 2 hours. In some cases, the biologically active IL-15 polypeptide or IL-15 conjugate has an increased half-life of about 3 hours. In some cases, the biologically active IL-15 polypeptide or IL-15 conjugate has an increased half-life of about 4 hours. In some cases, the biologically active IL-15 polypeptide or IL-15 conjugate has an increased half-life of about 5 hours. In some cases, the biologically active IL-15 polypeptide or IL-15 conjugate has an increased half-life of about 6 hours. In some cases, the biologically active IL-15 polypeptide or IL-15 conjugate has an increased half-life of about 7 hours. In some cases, the biologically active IL-15 polypeptide or IL-15 conjugate has an increased half-life of about 8 hours. In some cases, the biologically active IL-15 polypeptide or IL-15 conjugate has an increased half-life of about 9 hours. In some cases, the biologically active IL-15 polypeptide or IL-15 conjugate has an increased half-life of about 10 hours. In some cases, the biologically active IL-15 polypeptide or IL-15 conjugate has an increased half-life of about 11 hours. In some cases, the biologically active IL-15 polypeptide or IL-15 conjugate has an increased half-life of about 12 hours. In some cases, the biologically active IL-15 polypeptide or IL-15 conjugate has an increased half-life of about 18 hours.In some cases, the biologically active IL-15 polypeptide or IL-15 conjugate has an increased half-life of about 24 hours. In some cases, the biologically active IL-15 polypeptide or IL-15 conjugate has an increased half-life of about 36 hours. In some cases, the biologically active IL-15 polypeptide or IL-15 conjugate has an increased half-life of about 48 hours. In some cases, the biologically active IL-15 polypeptide or IL-15 conjugate has an increased half-life of about 3 days. In some cases, the biologically active IL-15 polypeptide or IL-15 conjugate has an increased half-life of about 4 days. In some cases, the biologically active IL-15 polypeptide or IL-15 conjugate has an increased half-life of about 5 days. In some cases, the biologically active IL-15 polypeptide or IL-15 conjugate has an increased half-life of about 6 days. In some cases, the biologically active IL-15 polypeptide or IL-15 conjugate has an increased half-life of about 7 days. In some cases, the biologically active IL-15 polypeptide or IL-15 conjugate has an increased half-life of about 10 days. In some cases, the biologically active IL-15 polypeptide or IL-15 conjugate has an increased half-life of about 12 days. In some cases, the biologically active IL-15 polypeptide or IL-15 conjugate has an increased half-life of about 14 days. In some cases, the biologically active IL-15 polypeptide or IL-15 conjugate has an increased half-life of about 21 days. In some cases, the biologically active IL-15 polypeptide or IL-15 conjugate has an increased half-life of about 28 days. In some cases, the biologically active IL-15 polypeptide or IL-15 conjugate has an increased half-life of about 30 days.

[0169] In some embodiments, the modified IL-15 polypeptide retains substantial signaling potency with the interleukin-15 receptor βγ (IL-15Rβγ) signaling complex. Optionally, the signaling potency is compared to the signaling potency between a wild-type IL-15 polypeptide and IL-15Rβγ. Optionally, the difference in receptor signaling potency between the modified IL-15 / IL-15Rβγ complex and the wild-type IL-15 / IL-15Rβγ complex is less than 1000-fold, less than 500-fold, less than 200-fold, less than 100-fold, less than 50-fold, less than 10-fold, less than 5-fold, less than 4-fold, less than 3-fold, less than 2-fold, or less than 1-fold. In some cases, the difference in receptor signaling potency between the modified IL-15 / IL-15Rβγ complex and the wild-type IL-15 / IL-15Rβγ complex is at least 10-fold, at least 20-fold, at least 30-fold, at least 40-fold, at least 50-fold, at least 100-fold, at least 200-fold, at least 300-fold, at least 400-fold, or at least 500-fold. In some cases, the modified IL-15 polypeptide is a partial agonist, e.g., an agonist that activates a receptor (e.g., an IL-15βγ signaling complex) but has only partial efficacy at the receptor compared to a full agonist. In some examples, the modified IL-15 polypeptide is a full agonist, e.g., an agonist that activates a receptor (e.g., an IL-15βγ signaling complex) with a maximal response.

[0170] In some examples, receptor signaling potency is measured by EC50 values. In some examples, modified IL-15 polypeptides provide EC50 values ​​that differ by less than 1000-fold, less than 500-fold, less than 200-fold, less than 100-fold, less than 50-fold, less than 10-fold, less than 5-fold, less than 4-fold, less than 3-fold, less than 2-fold, or less than 1-fold from the EC50 value of the wild-type IL-15 / IL-15Rβγ complex. In some examples, modified IL-15 polypeptides provide EC50 values ​​that differ by at least 10-fold, at least 20-fold, at least 30-fold, at least 40-fold, at least 50-fold, at least 100-fold, at least 200-fold, at least 300-fold, at least 400-fold, or at least 500-fold from the EC50 value of the wild-type IL-15 / IL-15Rβγ complex.

[0171] In some examples, receptor signaling potency is measured by ED50 values. In some examples, the modified IL-15 polypeptides provide an ED50 value that differs by less than 1000-fold, less than 500-fold, less than 200-fold, less than 100-fold, less than 50-fold, less than 10-fold, less than 5-fold, less than 4-fold, less than 3-fold, less than 2-fold, or less than 1-fold from the ED50 value of the wild-type IL-15 / IL-15Rβγ complex. In some examples, the modified IL-15 polypeptides provide an ED50 value that differs by at least 10-fold, at least 20-fold, at least 30-fold, at least 40-fold, at least 50-fold, at least 100-fold, at least 200-fold, at least 300-fold, at least 400-fold, or at least 500-fold from the ED50 value of the wild-type IL-15 / IL-15Rβγ complex.

[0172] In some embodiments, an IL-15 polypeptide is modified (e.g., PEGylated) during the chemistry, manufacturing, and control (CMC) stage to increase half-life, improve stability, improve purification yield, improve purity, reduce aggregation, improve protein folding, or a combination thereof. In some embodiments, the IL-15 polypeptide is modified at amino acid position N71, N72, or N77, where the residue positions correspond to those set forth in SEQ ID NO: 1. In some embodiments, the IL-15 polypeptide is modified at residue N77, e.g., through PEGylation, to increase half-life, improve stability, improve purification yield, improve purity, reduce aggregation, improve protein folding, or a combination thereof during the CMC stage. In some cases, the IL-15 polypeptide is selected from the group consisting of N1, W2, V3, N4, 16, S7, D8, K10, K11, E13, D14, L15, Q17, S18, M19, H20, 121, D22, A23, T24, L25, Y26, E28, S29, D30, V31, H32, P33, S34, C35, K36, V37, T38, K41, L44, E46, Q48, V49, S51, L52, E53, S54, G55, D56, A57, S58, H60, D61, T62, Further modifications are made at positions V63, E64, N65, I67, I68, L69, N71, N72, S73, L74, S75, S76, N77, G78, N79, V80, T81, E82, S83, G84, C85, K86, E87, C88, E89, E90, L91, E92, E93, K94, N95, I96, K97, E98, L100, Q101, S102, V104, H105, Q108, M109, F110, I111, N112, T113 or S114. In some cases, the IL-15 polypeptide is further modified at positions D22, A23, T24, L25, Y26, L44, E46, Q48, V49, E53, E89, E90, or E93, where the modification impairs interaction with IL-15Rα. In some cases, the IL-15 polypeptide is further modified at positions N1, N4, S7, D8, K11, D61, T62, E64, N65, I68, L69, or N72, where the modification impairs interaction with IL-15Rβ.In some cases, the IL-15 polypeptide is further modified at positions V3, 16, K10, E28, S29, D30, V31, H32, P33, S102, V104, H105, Q108, M109, 1111, N112, T113 or S114, wherein the modification impairs interaction with IL-15Rγ. In some cases, the IL-15 polypeptide is further modified at positions E13, D14, L15, Q17, S18, M19, H20, 121, S34, C35, K36, V37, T38, K41, L44, S51, L52, S54, G55, D56, A57, S58, H60, V63, 167, N71, S73, L74, S75, S76, N77, G78, N79, V80, T81, E82, S83, G84, C85, K86, E87, C88, L91, E92, K94, N95, 196, K97, E98, L100, Q101 or F110, wherein the modification enhances extended half-life. In some cases, the IL-15 polypeptide is further modified at one or more of the above positions to impair interaction with IL-15Rα, impair interaction with IL-15Rβ, impair interaction with IL-15Rγ, enhance half-life extension, or a combination thereof.

[0173] IL-15 conjugate precursor Disclosed herein are IL-15 conjugate precursors comprising modified IL-15 polypeptides in which one or more amino acids have been mutated from the wild-type amino acid. Such precursors are often used in conjunction with the methods disclosed herein for treating diseases or conditions. In some embodiments, the IL-15 precursor is not conjugated. Such mutations may include additions, deletions, or substitutions. In some cases, additions include the incorporation of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more residues at the N-terminus, C-terminus, or internal region of the IL-15 polypeptide. In further cases, deletions include the removal of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more residues from the N-terminus, C-terminus, or internal region of the IL-15 polypeptide.

[0174] Natural and Unnatural Amino Acids In some embodiments, an amino acid residue disclosed herein (e.g., within an IL-15 polypeptide) is mutated to lysine, cysteine, histidine, arginine, aspartic acid, glutamic acid, serine, threonine, or tyrosine before being attached to (or reacted with) a conjugation moiety. For example, the side chain of lysine, cysteine, histidine, arginine, aspartic acid, glutamic acid, serine, threonine, or tyrosine can be attached to a conjugation moiety disclosed herein. In some examples, the amino acid residue is mutated to cysteine, lysine, or histidine. In some cases, the amino acid residue is mutated to cysteine. In some cases, the amino acid residue is mutated to lysine. In some cases, the amino acid residue is mutated to histidine. In some cases, the amino acid residue is mutated to tyrosine. In some cases, the amino acid residue is mutated to tryptophan. In some examples, the amino acid residue is located near the N-terminus or C-terminus, at the N-terminus or C-terminus, or at an internal residue position. In some examples, the amino acid residue is an N-terminus or C-terminus residue, and the mutation is to a cysteine ​​or lysine. In some examples, the amino acid residue is located near the N-terminus or C-terminus residue (e.g., within 50, 40, 30, 20, or 10 residues from the N-terminus or C-terminus residue), and the mutation is to a cysteine ​​or lysine.

[0175] In some examples, the amino acid residue is added to the N- or C-terminal residue, i.e., the IL-15 polypeptide includes an additional amino acid residue at either the N- or C-terminus, and the additional amino acid residue is cysteine ​​or lysine. In some cases, the additional amino acid residue is cysteine. In some cases, the additional amino acid is conjugated to a conjugation moiety.

[0176] In some embodiments, an amino acid residue described herein (e.g., in an IL-15 polypeptide) is mutated to a non-natural amino acid. In some embodiments, the non-natural amino acid is not conjugated to a conjugation moiety. In some embodiments, an IL-15 polypeptide disclosed herein comprises a non-natural amino acid, and IL-15 is conjugated to a protein and the point of attachment is not the non-natural amino acid.

[0177] In some embodiments, an amino acid residue disclosed herein (e.g., within an IL-15 polypeptide) is mutated to a non-natural amino acid before attachment to a conjugation moiety. In some cases, mutation to a non-natural amino acid prevents or minimizes an autoantigen response of the immune system. As used herein, the term "non-natural amino acid" refers to an amino acid other than the 20 amino acids naturally occurring in proteins. Non-limiting examples of non-natural amino acids include p-acetyl-L-phenylalanine, p-iodo-L-phenylalanine, p-methoxyphenylalanine, O-methyl-L-tyrosine, p-propargyloxyphenylalanine, p-propargyl-phenylalanine, L-3-(2-naphthyl)alanine, 3-methyl-phenylalanine, O-4-allyl-L-tyrosine, 4-propyl-L-tyrosine, tri-O-acetyl-GlcNAcp-serine, L-Dopa, fluorinated phenylalanine, isopropyl-L-phenylalanine, p-azido-L-phenylalanine, p-acyl-L-phenylalanine, p-benzoyl-L-phenylalanine, p-boronophenylalanine, O-propargyltyrosine, L-phosphoserine, phosphonoserine, phosphonotyrosine, p-bromophenylalanine, selenocysteine, p-amino-L-phenylalanine, isopropyl-L-phenylalanine , N6-[(2-azidoethoxy)carbonyl]-L-lysine (AzK), non-natural analogs of tyrosine amino acids; non-natural analogs of glutamine amino acids; non-natural analogs of phenylalanine amino acids; non-natural analogs of serine amino acids; non-natural analogs of threonine amino acids; alkyl, aryl, acyl, azido, cyano, halo, hydrazine, hydrazide, hydroxyl, alkenyl, alkynyl, ether, thiol, sulfonyl, seleno, ester, thioacid, borate, boronate, phospho, phosphono, phosphine, heterocyclic, enone, imine, aldehyde, hydroxylamine, keto, or amino substituted amino acids, or combinations thereof; amino acids comprising photoactivatable crosslinkers; spin-labeled amino acids; fluorescent amino acids; metal-binding amino acids; metal-containing amino acids; radioactive amino acids; photocaged and / or photoisomerizable amino acids; amino acids comprising biotin or a biotin analog; keto-containing amino acids;These include polyethylene glycol or polyether-containing amino acids; heavy atom-substituted amino acids; chemically or photocleavable amino acids; amino acids with extended side chains; amino acids containing toxic groups; sugar-substituted amino acids; carbon-linked sugar-containing amino acids; redox-active amino acids; α-hydroxy-containing acids; aminothioacids; α,α-disubstituted amino acids; β-amino acids; cyclic amino acids other than proline or histidine, and aromatic amino acids other than phenylalanine, tyrosine, or tryptophan;

[0178] In some embodiments, the unnatural amino acid comprises a selectively reactive group or a reactive group for site-selective labeling of a target polypeptide. In some instances, the chemical reaction is a bioorthogonal reaction (e.g., a biocompatible and selective reaction). In some cases, the chemistry is a Cu(I)-catalyzed or "copper-free" alkyne-azide triazole formation reaction, Staudinger ligation, inverse electron demand Diels-Alder (IEDDA) reaction, "photoclick" chemistry, or a metal-mediated process such as olefin metathesis and Suzuki-Miyaura or Sonogashira cross-coupling.

[0179] In some embodiments, the unnatural amino acid comprises a photoreactive group and crosslinks upon irradiation with, for example, UV light.

[0180] In some embodiments, the unnatural amino acid comprises a photocaged amino acid.

[0181] In some instances, the unnatural amino acid is a para-substituted, meta-substituted, or ortho-substituted amino acid derivative.

[0182] In some examples, the unnatural amino acid comprises p-acetyl-L-phenylalanine, p-azidomethyl-L-phenylalanine (pAMF), p-iodo-L-phenylalanine, O-methyl-L-tyrosine, p-methoxyphenylalanine, p-propargyloxyphenylalanine, p-propargyl-phenylalanine, L-3-(2-naphthyl)alanine, 3-methyl-phenylalanine, O-4-allyl-L-tyrosine, 4-propyl-L-tyrosine, tri-O-acetyl-GlcNAcp-serine, L-Dopa, fluorinated phenylalanine, isopropyl-L-phenylalanine, p-azido-L-phenylalanine, p-acyl-L-phenylalanine, p-benzoyl-L-phenylalanine, L-phosphoserine, phosphonoserine, phosphonotyrosine, p-bromophenylalanine, p-amino-L-phenylalanine, or isopropyl-L-phenylalanine.

[0183] In some cases, the unnatural amino acid is 3-aminotyrosine, 3-nitrotyrosine, 3,4-dihydroxyphenylalanine, or 3-iodotyrosine.

[0184] In some cases, the unnatural amino acid is phenylselenocysteine.

[0185] In some examples, the unnatural amino acid is a benzophenone, ketone, iodide, methoxy, acetyl, benzoyl, or azide-containing phenylalanine derivative.

[0186] In some examples, the unnatural amino acid is a benzophenone, ketone, iodide, methoxy, acetyl, benzoyl, or azide-containing lysine derivative.

[0187] In some cases, the unnatural amino acid comprises an aromatic side chain.

[0188] In some cases, the unnatural amino acid does not comprise an aromatic side chain.

[0189] In some examples, the unnatural amino acid comprises an azide group.

[0190] In some examples, the unnatural amino acid comprises a Michael-acceptor group. In some examples, the Michael-acceptor group comprises an unsaturated moiety that can form a covalent bond via a 1,2-addition reaction. In some examples, the Michael-acceptor group comprises an electron-deficient alkene or alkyne. In some examples, the Michael-acceptor group includes, but is not limited to, an α,β-unsaturated: ketone, aldehyde, sulfoxide, sulfone, nitrile, imine, or aromatic.

[0191] In some examples, the unnatural amino acid is dehydroalanine.

[0192] In some examples, the unnatural amino acid comprises an aldehyde or ketone group.

[0193] In some examples, the unnatural amino acid is a lysine derivative that includes an aldehyde or ketone group.

[0194] In some examples, the unnatural amino acid is a lysine derivative containing one or more O, N, Se, or S atoms at the beta, gamma, or delta position. In some examples, the unnatural amino acid is a lysine derivative containing an O, N, Se, or S atom at the gamma position.

[0195] In some examples, the unnatural amino acid is a lysine derivative in which the epsilon N atom is replaced with an oxygen atom.

[0196] In some instances, the unnatural amino acid is a lysine derivative that is not a naturally occurring post-translationally modified lysine.

[0197] In some instances, the unnatural amino acid is an amino acid comprising a side chain, wherein the sixth atom from the alpha position comprises a carbonyl group. In some instances, the unnatural amino acid is an amino acid comprising a side chain, wherein the sixth atom from the alpha position comprises a carbonyl group and the fifth atom from the alpha position is nitrogen. In some instances, the unnatural amino acid is an amino acid comprising a side chain, wherein the seventh atom from the alpha position is an oxygen atom.

[0198] In some examples, the unnatural amino acid is a serine derivative that includes selenium. In some examples, the unnatural amino acid is selenoserine (2-amino-3-hydroselenopropanoic acid). In some examples, the unnatural amino acid is 2-amino-3-((2-((3-(benzyloxy)-3-oxopropyl)amino)ethyl)selanyl)propanoic acid. In some examples, the unnatural amino acid is 2-amino-3-(phenylselanyl)propanoic acid. In some examples, the unnatural amino acid includes selenium, and oxidation of the selenium results in the formation of an alkene-containing unnatural amino acid.

[0199] In some examples, the unnatural amino acid comprises a cyclooctynyl group.

[0200] In some examples, the unnatural amino acid comprises a trans cyclooctenyl group.

[0201] In some examples, the unnatural amino acid comprises a norbornenyl group.

[0202] In some examples, the unnatural amino acid comprises a cyclopropenyl group.

[0203] In some examples, the unnatural amino acid comprises a diazirine group.

[0204] In some examples, the unnatural amino acid comprises a tetrazine group.

[0205] In some examples, the unnatural amino acid is a lysine derivative and the side chain nitrogen is carbamylated. In some examples, the unnatural amino acid is a lysine derivative and the side chain nitrogen is acylated. In some examples, the unnatural amino acid is 2-amino-6-{[(tert-butoxy)carbonyl]amino}hexanoic acid. In some examples, the unnatural amino acid is 2-amino-6-{[(tert-butoxy)carbonyl]amino}hexanoic acid. In some examples, the unnatural amino acid is N6-Boc-N6-methyllysine. In some examples, the unnatural amino acid is N6-acetyllysine. In some examples, the unnatural amino acid is pyrrolysine. In some examples, the unnatural amino acid is N6-trifluoroacetyllysine. In some examples, the unnatural amino acid is 2-amino-6-{[(benzyloxy)carbonyl]amino}hexanoic acid. In some examples, the unnatural amino acid is 2-amino-6-{[(p-iodobenzyloxy)carbonyl]amino}hexanoic acid. In some examples, the unnatural amino acid is 2-amino-6-{[(p-nitrobenzyloxy)carbonyl]amino}hexanoic acid. In some examples, the unnatural amino acid is N6-prolyl lysine. In some examples, the unnatural amino acid is 2-amino-6-{[(cyclopentyloxy)carbonyl]amino}hexanoic acid. In some examples, the unnatural amino acid is N6-(cyclopentanecarbonyl)lysine. In some examples, the unnatural amino acid is N6-(tetrahydrofuran-2-carbonyl)lysine. In some examples, the unnatural amino acid is N6-(3-ethynyltetrahydrofuran-2-carbonyl)lysine. In some examples, the unnatural amino acid is N6-((prop-2-yn-1-yloxy)carbonyl)lysine. In some examples, the unnatural amino acid is 2-amino-6-{[(2-azidocyclopentyloxy)carbonyl]amino}hexanoic acid. In some examples, the unnatural amino acid is N6-[(2-azidoethoxy)carbonyl]lysine. In some examples, the unnatural amino acid is 2-amino-6-{[(2-nitrobenzyloxy)carbonyl]amino}hexanoic acid. In some examples, the unnatural amino acid is 2-amino-6-{[(2-cyclooctynyloxy)carbonyl]amino}hexanoic acid.In some examples, the unnatural amino acid is N6-(2-aminobut-3-ynoyl)lysine. In some examples, the unnatural amino acid is 2-amino-6-((2-aminobut-3-ynoyl)oxy)hexanoic acid. In some examples, the unnatural amino acid is N6-(allyloxycarbonyl)lysine. In some examples, the unnatural amino acid is N6-(butenyl-4-oxycarbonyl)lysine. In some examples, the unnatural amino acid is N6-(pentenyl-5-oxycarbonyl)lysine. In some examples, the unnatural amino acid is N6-((but-3-yn-1-yloxy)carbonyl)lysine. In some examples, the unnatural amino acid is N6-((pent-4-yn-1-yloxy)carbonyl)-lysine. In some examples, the unnatural amino acid is N6-(thiazolidine-4-carbonyl)lysine. In some examples, the unnatural amino acid is 2-amino-8-oxononanoic acid. In some examples, the unnatural amino acid is 2-amino-8-oxooctanoic acid. In some examples, the unnatural amino acid is N6-(2-oxoacetyl)lysine.

[0206] In some examples, the unnatural amino acid is N6-propionyl lysine. In some examples, the unnatural amino acid is N6-butyryl lysine. In some examples, the unnatural amino acid is N6-(but-2-enoyl) lysine. In some examples, the unnatural amino acid is N6-((bicyclo[2.2.1]hept-5-en-2-yloxy)carbonyl) lysine. In some examples, the unnatural amino acid is N6-((spiro[2.3]hex-1-en-5-ylmethoxy)carbonyl) lysine. In some examples, the unnatural amino acid is N6-(((4-(1-(trifluoromethyl)cycloprop-2-en-1-yl)benzyl)oxy)carbonyl) lysine. In some examples, the unnatural amino acid is N6-((bicyclo[2.2.1]hept-5-en-2-ylmethoxy)carbonyl) lysine. In some examples, the unnatural amino acid is cysteinyl lysine. In some examples, the unnatural amino acid is N6-((1-(6-nitrobenzo[d][1,3]dioxol-5-yl)ethoxy)carbonyl)lysine. In some examples, the unnatural amino acid is N6-((2-(3-methyl-3H-diazirin-3-yl)ethoxy)carbonyl)lysine. In some examples, the unnatural amino acid is N6-((3-(3-methyl-3H-diazirin-3-yl)propoxy)carbonyl)lysine. In some examples, the unnatural amino acid is N6-((metanitrobenzyloxy)N6-methylcarbonyl)lysine. In some examples, the unnatural amino acid is N6-((bicyclo[6.1.0]non-4-yn-9-ylmethoxy)carbonyl)-lysine. In some examples, the unnatural amino acid is N6-((cyclohept-3-en-1-yloxy)carbonyl)-L-lysine.

[0207] In some examples, the unnatural amino acid is 2-amino-3-(((((benzyloxy)carbonyl)amino)methyl)selanyl)propanoic acid.

[0208] In some embodiments, the unnatural amino acid is incorporated into an IL-15 polypeptide via an otherwise used amber, opal, or ochre stop codon.

[0209] In some embodiments, the unnatural amino acid is incorporated into the IL-15 polypeptide via a four-base codon.

[0210] In some embodiments, the unnatural amino acid is incorporated into the IL-15 polypeptide by an alternatively used rare-sense codon or an alternatively used common-sense codon.

[0211] In some embodiments, the unnatural amino acid is incorporated into the IL-15 polypeptide by a synthetic codon, including an unnatural nucleic acid.

[0212] In some examples, unnatural amino acids are incorporated into L-15 by orthogonal modified synthetase / tRNA pairs. Such orthogonal pairs include a) unnatural synthetases that can add unnatural amino acids to unnatural tRNAs while minimizing the addition of other endogenous amino acids onto the unnatural tRNAs, and b) the addition of unnatural amino acids to other endogenous tRNAs. Such orthogonal pairs include tRNAs that can undergo addition by unnatural synthetases while avoiding the addition of other endogenous amino acids by endogenous synthetases. In some embodiments, such pairs are identified from various organisms, such as bacteria, yeast, archaea, or human sources. In some embodiments, the orthogonal synthetase / tRNA pair includes components from a single organism. In some embodiments, the orthogonal synthetase / tRNA pair includes components from two different organisms. In some embodiments, the orthogonal synthetase / tRNA pair includes components that facilitate the translation of two different amino acids prior to modification. In some embodiments, the orthogonal synthetase is a modified alanine synthetase. In some embodiments, the orthogonal synthetase is a modified arginine synthetase. In some embodiments, the orthogonal synthetase is a modified asparagine synthetase. In some embodiments, the orthogonal synthetase is a modified aspartate synthetase. In some embodiments, the orthogonal synthetase is a modified cysteine ​​synthetase. In some embodiments, the orthogonal synthetase is a modified glutamine synthetase. In some embodiments, the orthogonal synthetase is a modified glutamate synthetase. In some embodiments, the orthogonal synthetase is a modified alanine glycine synthetase. In some embodiments, the orthogonal synthetase is a modified histidine synthetase. In some embodiments, the orthogonal synthetase is a modified leucine synthetase. In some embodiments, the orthogonal synthetase is a modified isoleucine synthetase. In some embodiments, the orthogonal synthetase is a modified lysine synthetase. In some embodiments, the orthogonal synthetase is a modified methionine synthetase. In some embodiments, the orthogonal synthetase is a modified phenylalanine synthetase.In some embodiments, the orthogonal synthetase is a modified proline synthetase. In some embodiments, the orthogonal synthetase is a modified serine synthetase. In some embodiments, the orthogonal synthetase is a modified threonine synthetase. In some embodiments, the orthogonal synthetase is a modified tryptophan synthetase. In some embodiments, the orthogonal synthetase is a modified tyrosine synthetase. In some embodiments, the orthogonal synthetase is a modified valine synthetase. In some embodiments, the orthogonal synthetase is a modified phosphoserine synthetase. In some embodiments, the orthogonal tRNA is a modified alanine tRNA. In some embodiments, the orthogonal tRNA is a modified arginine tRNA. In some embodiments, the orthogonal tRNA is a modified asparagine tRNA. In some embodiments, the orthogonal tRNA is a modified aspartate tRNA. In some embodiments, the orthogonal tRNA is a modified cysteine ​​tRNA. In some embodiments, the orthogonal tRNA is a modified glutamine tRNA. In some embodiments, the orthogonal tRNA is a modified glutamate tRNA. In some embodiments, the orthogonal tRNA is a modified alanine glycine. In some embodiments, the orthogonal tRNA is a modified histidine tRNA. In some embodiments, the orthogonal tRNA is a modified leucine tRNA. In some embodiments, the orthogonal tRNA is a modified isoleucine tRNA. In some embodiments, the orthogonal tRNA is a modified lysine tRNA. In some embodiments, the orthogonal tRNA is a modified methionine tRNA. In some embodiments, the orthogonal tRNA is a modified phenylalanine tRNA. In some embodiments, the orthogonal tRNA is a modified proline tRNA. In some embodiments, the orthogonal tRNA is a modified serine tRNA. In some embodiments, the orthogonal tRNA is a modified threonine tRNA. In some embodiments, the orthogonal tRNA is a modified tryptophan tRNA. In some embodiments, the orthogonal tRNA is a modified tyrosine tRNA. In some embodiments, the orthogonal tRNA is a modified valine tRNA. In some embodiments, the orthogonal tRNA is a modified phosphoserine tRNA.

[0213] In some embodiments, the unnatural amino acid is incorporated into an IL-15 polypeptide by an aminoacyl (aaRS or RS)-tRNA synthetase-tRNA pair. Exemplary aaRS-tRNA pairs include, but are not limited to, the Methanococcus jannaschii (Mj-Tyr) aaRS / tRNA pair, the Escherichia coli TyrRS (Ec-Tyr) / Bacillus stearothermophilus tRNA pair, and the Bacillus stearothermophilus tRNA pair. CUA pair, Escherichia coli LeuRS (Ec-Leu) / Bacillus stearothermophilus tRNA CUA Mj-TyrRS / tRNA pairs include, but are not limited to, para-substituted phenylalanine derivatives, such as p-aminophenylalanine and p-methoxyphenylalanine; meta-substituted tyrosine derivatives, such as 3-aminotyrosine, 3-nitrotyrosine, 3,4-dihydroxyphenylalanine, and 3-iodotyrosine; phenylselenocysteine; p-boronophenylalanine; and o-nitrobenzyltyrosine. In some examples, unnatural amino acids are incorporated into cytokines (e.g., IL polypeptides) by Mj-TyrRS / tRNA pairs. Exemplary UAAs that can be incorporated by Mj-TyrRS / tRNA pairs include, but are not limited to, para-substituted phenylalanine derivatives, such as p-aminophenylalanine and p-methoxyphenylalanine; meta-substituted tyrosine derivatives, such as 3-aminotyrosine, 3-nitrotyrosine, 3,4-dihydroxyphenylalanine, and 3-iodotyrosine; phenylselenocysteine; p-boronophenylalanine; and o-nitrobenzyltyrosine.

[0214] In some instances, the unnatural amino acid is Ec-Tyr / tRNA CUA or Ec-Leu / tRNA CUA The Ec-Tyr / tRNA pair is incorporated into the IL-15 polypeptide. CUA or Ec-Leu / tRNA CUA Exemplary UAAs that can be incorporated pairwise include, but are not limited to, phenylalanine derivatives containing benzophenone, ketone, iodide, or azide substituents; O-propargyl tyrosine; α-aminocaprylic acid, O-methyl tyrosine, O-nitrobenzyl cysteine; and 3-(naphthalen-2-ylamino)-2-amino-propanoic acid.

[0215] In some examples, unnatural amino acids are incorporated into IL-15 polypeptides via a pyrrolysyl-tRNA pair. In some cases, the PylRS is obtained from an archaea, e.g., a methanogenic archaea. In some cases, the PylRS is obtained from Methanosarcina barkeri, Methanosarcina mazei, or Methanosarcina acetivorans. Exemplary UAAs that can be incorporated via a pyrrolysyl-tRNA pair include, but are not limited to, amide and carbamate substituted lysines, e.g., 2-amino-6-((R)-tetrahydrofuran-2-carboxamido)hexanoic acid, N-ε- D -Proluil- L -Lysine and N-ε-cyclopentyloxycarbonyl- L -Lysine;N-ε-Acryloyl- L -Lysine;N-ε-[(1-(6-nitrobenzo[d][1,3]dioxol-5-yl)ethoxy)carbonyl]- L -lysine; and N-ε-(1-methylcyclopro-2-enecarboxamido)lysine.

[0216] In some examples, unnatural amino acids are incorporated into IL-15 polypeptides by synthetases disclosed in U.S. Patent Nos. 9,988,619 and 9,938,516. Exemplary UAAs that can be incorporated by such synthetases include para-methylazido-L-phenylalanine, aralkyl, heterocyclyl, heteroaralkyl unnatural amino acids, and others. In some embodiments, such UAAs comprise pyridyl, pyrazinyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, or other heterocycles. In some embodiments, such amino acids comprise other chemical groups that can be conjugated to coupling partners, such as azides, tetrazines, or water-soluble moieties. In some embodiments, such synthetases are expressed and used to incorporate UAAs into cytokines in vivo. In some embodiments, such synthetases are used to incorporate UAAs into cytokines using cell-free translation systems.

[0217] In some examples, unnatural amino acids are incorporated into IL-15 polypeptides by naturally occurring synthetases. In some embodiments, unnatural amino acids are incorporated into cytokines by organisms that are auxotrophic for one or more amino acids. In some embodiments, a synthetase corresponding to an auxotrophic amino acid can add the unnatural amino acid to a corresponding tRNA. In some embodiments, the unnatural amino acid is selenocysteine ​​or a derivative thereof. In some embodiments, the unnatural amino acid is selenomethionine or a derivative thereof. In some embodiments, the unnatural amino acid is an aromatic amino acid, and the aromatic amino acid comprises an aryl halide, such as an iodide. In embodiments, the unnatural amino acid is structurally similar to an auxotrophic amino acid.

[0218] In some examples, the unnatural amino acid comprises a lysine or phenylalanine derivative or analog. In some examples, the unnatural amino acid comprises a lysine derivative or lysine analog. In some examples, the unnatural amino acid comprises pyrrolysine (Pyl). In some examples, the unnatural amino acid comprises a phenylalanine derivative or phenylalanine analog. In some examples, the unnatural amino acid is an unnatural amino acid described in Wan, et al., "Pyrrolysyl-tRNA synthetase: an ordinary enzyme but an outstanding genetic code expansion tool," Biochim Biophys Acta 1844(6):1059-4070 (2014).

[0219] In some embodiments, the unnatural amino acid incorporated into the IL-15 polypeptide is disclosed in U.S. Patent No. 9,840,493; U.S. Patent No. 9,682,934; U.S. Patent Application Publication No. 2017 / 0260137; U.S. Patent No. 9,938,516; or U.S. Patent Application Publication No. 2018 / 0086734. Exemplary UAAs incorporated by such synthetases include para-methylazido-L-phenylalanine, aralkyl, heterocyclyl, and heteroaralkyl, and lysine-derived unnatural amino acids. In some embodiments, such UAAs comprise pyridyl, pyrazinyl, pyrazolyl, triazolyl, oxazolyl, thiazolyl, thiophenyl, or other heterocycles. In some embodiments, such amino acids comprise azides, tetrazines, or other chemical groups capable of conjugation to coupling partners, such as water-soluble moieties. In some embodiments, the UAA comprises an azide linked to an aromatic moiety via an alkyl linker. In some embodiments, the alkyl linker is C-C 10In some embodiments, the UAA comprises a tetrazine linked to the aromatic moiety via an alkyl linker. In some embodiments, the UAA comprises a tetrazine linked to the aromatic moiety via an amino group. In some embodiments, the UAA comprises a tetrazine linked to the aromatic moiety via an alkylamino group. In some embodiments, the UAA comprises an azide linked to the terminal nitrogen of an amino acid side chain via an alkyl chain (e.g., N6 of a lysine derivative, or N5, N4, or N3 of a derivative containing a shorter alkyl side chain). In some embodiments, the UAA comprises a tetrazine linked to the terminal nitrogen of an amino acid side chain via an alkyl chain. In some embodiments, the UAA comprises an azide or tetrazine linked to an amide via an alkyl linker. In some embodiments, the UAA is an azide- or tetrazine-containing carbamate or amide of 3-aminoalanine, serine, lysine, or a derivative thereof. In some embodiments, such a UAA is incorporated into a cytokine in vivo. In some embodiments, such a UAA is incorporated into a cytokine in a cell-free system.

[0220] Conjugation Moiety In certain embodiments, disclosed herein are conjugation moieties attached to one or more modified IL-15 polypeptides described above. In some embodiments, the conjugation moiety is a molecule that disrupts the interaction of IL-15 with its receptor. In some embodiments, the conjugation moiety is any molecule that, when bound to IL-15, enables the IL-15 conjugate to modulate an immune response. In some embodiments, the conjugation moiety is attached to IL-15 via a covalent bond. In some examples, the IL-15 described herein is attached to a conjugation moiety having a triazole group. In some examples, the IL-15 described herein is attached to a conjugation moiety having a dihydropyridazine or pyridazine group. In some examples, the conjugation moiety comprises a water-soluble polymer. In other examples, the conjugation moiety comprises a protein o...

Claims

1. 1. An IL-15 conjugate comprising an IL-15 polypeptide comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 1, wherein one amino acid residue in the IL-15 polypeptide has the structure of formula (I): 【Chemistry 1】 (In the formula: Z is CH 2 and Y is 【Chemistry 2】 and Y is CH 2 and Z is 【Transformation 3】 and Z is CH 2 and Y is 【Chemistry 4】 or Y is CH 2 and Z is 【Transformation 5】 and W is a PEG group having a molecular weight selected from 5 kDa ± 15%, 10 kDa ± 15%, 15 kDa ± 15%, 20 kDa ± 15%, 25 kDa ± 15%, 30 kDa ± 15%, 35 kDa ± 15%, 40 kDa ± 15%, 45 kDa ± 15%, 50 kDa ± 15%, and 60 kDa ± 15%; X has the structure: 【Transformation 6】 having X-1 indicates the point of attachment to the preceding amino acid residue; X+1 indicates the point of attachment to the subsequent amino acid residue. is replaced by The IL-15 conjugate, wherein the amino acid residue replaced by the structure of formula (I) is located in the IL-15 polypeptide at a position selected from L25, E53, and N77, and the positions of the residues correspond to positions L25, E53, and N77 in SEQ ID NO:

1.

2. 2. The IL-15 conjugate of claim 1, wherein the IL-15 polypeptide comprises an amino acid sequence that is at least 98% identical to the amino acid sequence of SEQ ID NO:1, and wherein one amino acid residue that is replaced by the structure of formula (I) is located in the IL-15 polypeptide at a position selected from L25, E53, and N77, and the position of the residue corresponds to positions L25, E53, and N77 in SEQ ID NO:

1.

3. 10. The IL-15 conjugate of claim 1, wherein the IL-15 polypeptide comprises the amino acid sequence of SEQ ID NO: 1, and one amino acid residue replaced by the structure of formula (I) is located in the IL-15 polypeptide at a position selected from L25, E53, and N77, and the position of the residue is selected from positions L25, E53, and N77 in SEQ ID NO:

1. The IL-15 conjugate corresponds to the position.

4. 1. An IL-15 conjugate comprising an IL-15 polypeptide comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:3, wherein one amino acid residue in the IL-15 polypeptide has the structure of formula (I): 【Transformation 7】 (In the formula: Z is CH 2 and Y is 【Transformation 8】 and Y is CH 2 and Z is 【Chemistry 9】 and Z is CH 2 and Y is 【Chemistry 10】 or Y is CH 2 and Z is 【Chemistry 11】 and W is 5 kDa ± 15%, 10 kDa ± 15%, 15 kDa ± 15%, 20 kDa ± 15%, 25 kDa ± 15%, 30 kDa ± 15%, 35 kDa ± 15%, 40 kDa ± 1 PEG groups having a molecular weight selected from: 5%, 45 kDa±15%, 50 kDa±15%, and 60 kDa±15%; X has the structure: 【Chemistry 12】 having X-1 indicates the point of attachment to the preceding amino acid residue; X+1 indicates the point of attachment to the subsequent amino acid residue. is replaced by The amino acid residues replaced by the structure of formula (I) are located in the IL-15 polypeptide at positions selected from L26, E54, and N78, and the positions of the residues correspond to the positions of L26, E54, and N78 in SEQ ID NO:

3. L-15 conjugate.

5. 5. The IL-15 conjugate of claim 4, wherein the IL-15 polypeptide comprises an amino acid sequence that is at least 98% identical to the amino acid sequence of SEQ ID NO:3, and the amino acid residue replaced by the structure of formula (I) is located in the IL-15 polypeptide at a position selected from L26, E54, and N78, which residue positions correspond to L26, E54, and N78 in SEQ ID NO:

3.

6. 5. The IL-15 conjugate of claim 4, wherein the IL-15 polypeptide comprises the amino acid sequence of SEQ ID NO: 3, and the amino acid residue replaced by the structure of formula (I) is located in the IL-15 polypeptide at a position selected from L26, E54, and N78, the positions of the residues corresponding to L26, E54, and N78 in SEQ ID NO:

3.

7. Z is CH 2 and Y is 【Chemistry 13】 7. The IL-15 conjugate according to any one of claims 1 to 6, wherein

8. Y is CH 2 and Z is 【Chemistry 14】 7. The IL-15 conjugate according to any one of claims 1 to 6, wherein

9. Z is CH 2 and Y is 【Chemistry 15】 7. The IL-15 conjugate according to any one of claims 1 to 6, wherein

10. Y is CH 2 and Z is 【Chemistry 17】 7. The IL-15 conjugate according to any one of claims 1 to 6, wherein

11. 11. The IL-15 conjugate of any one of claims 1 to 10, wherein the PEG group has a molecular weight selected from 5 kDa ± 15%, 10 kDa ± 15%, 15 kDa ± 15%, 20 kDa ± 15%, 25 kDa ± 15%, 30 kDa ± 15%, 35 kDa ± 15%, 40 kDa ± 15%, and 45 kDa ± 15%.

12. 12. The IL-15 conjugate of claim 11, wherein the PEG group has a molecular weight of 30 kDa±15%.

13. 12. The IL-15 conjugate of claim 11, wherein the PEG group has a molecular weight of 40 kDa±15%.

14. IL-15 conjugate according to any one of claims 1 to 3 and claims 7 to 13 when relying on any one of claims 1 to 3, wherein the position is N77.

15. IL-15 conjugate according to any one of claims 1 to 3 and claims 7 to 13 with reference to any one of claims 1 to 3, wherein the position is L25.

16. IL-15 conjugate according to any one of claims 1 to 3 and claims 7 to 13 when relying on any one of claims 1 to 3, wherein the position is E53.

17. IL-15 conjugate according to any one of claims 4 to 6 and claims 7 to 13 when relying on any one of claims 4 to 6, wherein the position is L26.

18. IL-15 conjugate according to any one of claims 4 to 6 and claims 7 to 13 when relying on any one of claims 4 to 6, wherein the position is E54.

19. IL-15 conjugate according to any one of claims 4 to 6 and claims 7 to 13 when relying on any one of claims 4 to 6, wherein the position is N78.

20. An IL-15 conjugate comprising an IL-15 polypeptide comprising the amino acid sequence of any one of SEQ ID NOs: 17, 19, and 20, wherein [AzK_PEG] is a conjugate of formula (II): or a structure of formula (III): [Chemistry 18] (In the formula: W is a PEG group having a molecular weight selected from 5 kDa ± 15%, 10 kDa ± 15%, 15 kDa ± 15%, 20 kDa ± 15%, 25 kDa ± 15%, 30 kDa ± 15%, 35 kDa ± 15%, 40 kDa ± 15%, 45 kDa ± 15%, 50 kDa ± 15%, and 60 kDa ± 15%; X has the structure: 【Chemistry 19】 having X-1 indicates the point of attachment to the preceding amino acid residue; X+1 indicates the point of attachment to the subsequent amino acid residue. The IL-15 conjugate having the formula:

21. 1. A pharmaceutical composition comprising a mixture of IL-15 conjugates, the mixture comprising: (i) an IL-15 conjugate comprising an IL-15 polypeptide comprising the amino acid sequence of any one of SEQ ID NOs: 17, 19, and 20, wherein [AzK_PEG] has the structure of formula (II), and (ii) an IL-15 conjugate comprising an IL-15 polypeptide comprising the amino acid sequence of any one of SEQ ID NOs: 17, 19, and 20, wherein [AzK_PEG] has the structure of formula (III): 【Chemistry 20】 (In the formula: W is a PEG group having a molecular weight selected from 5 kDa ± 15%, 10 kDa ± 15%, 15 kDa ± 15%, 20 kDa ± 15%, 25 kDa ± 15%, 30 kDa ± 15%, 35 kDa ± 15%, 40 kDa ± 15%, 45 kDa ± 15%, 50 kDa ± 15%, and 60 kDa ± 15%; X has the structure: 【Chemistry 21】 having X-1 indicates the point of attachment to the preceding amino acid residue; X+1 indicates the point of attachment to the subsequent amino acid residue. The pharmaceutical composition comprising:

22. An IL-15 conjugate comprising an IL-15 polypeptide comprising the amino acid sequence of any one of SEQ ID NOs: 23, 25, and 26, wherein [AzK_PEG30] has the structure of formula (II) or formula (III): 【Chemistry 22】 (In the formula: W is a PEG group with a molecular weight of 30 kDa ± 15%; X has the structure: 【Chemistry 23】 having X-1 indicates the point of attachment to the preceding amino acid residue; X+1 indicates the point of attachment to the subsequent amino acid residue. The IL-15 conjugate having the formula:

23. A pharmaceutical composition comprising a mixture of IL-15 conjugates, the mixture comprising: (i) an IL-15 conjugate comprising an IL-15 polypeptide comprising the amino acid sequence of any one of SEQ ID NOs: 23, 25, and 26, wherein [AzK_PEG30] has the structure of formula (II), and (ii) an IL-15 conjugate comprising an IL-15 polypeptide comprising the amino acid sequence of any one of SEQ ID NOs: 23, 25, and 26, wherein [AzK_PEG30] has the structure of formula (III): 【Chemistry 24】 (In the formula: W is a PEG group with a molecular weight of 30 kDa ± 15%; X has the structure: 【Chemistry 25】 having X-1 indicates the point of attachment to the preceding amino acid residue; X+1 indicates the point of attachment to the subsequent amino acid residue. The pharmaceutical composition comprising:

24. An IL-15 conjugate comprising an IL-15 polypeptide comprising the amino acid sequence of any one of SEQ ID NOs: 29, 31, and 32, wherein [AzK_PEG40] has the structure of formula (II) or formula (III): 【Chemistry 26】 (In the formula: W is a PEG group with a molecular weight of 40 kDa ± 15%; X has the structure: 【Chemistry 27】 having X-1 indicates the point of attachment to the preceding amino acid residue; X+1 indicates the point of attachment to the subsequent amino acid residue. The IL-15 conjugate having the formula:

25. 1. A pharmaceutical composition comprising a mixture of IL-15 conjugates, the mixture comprising: (i) an IL-15 conjugate comprising an IL-15 polypeptide comprising the amino acid sequence of any one of SEQ ID NOs: 29, 31, and 32, wherein [AzK_PEG40] has the structure of formula (II), and (ii) an IL-15 conjugate comprising an IL-15 polypeptide comprising the amino acid sequence of any one of SEQ ID NOs: 29, 31, and 32, wherein [AzK_PEG40] has the structure of formula (III): 【Chemistry 28】 (In the formula: W is a PEG group with a molecular weight of 40 kDa ± 15%; X has the structure: 【Chemistry 29】 having X-1 indicates the point of attachment to the preceding amino acid residue; X+1 indicates the point of attachment to the subsequent amino acid residue. The pharmaceutical composition comprising:

26. An IL-15 conjugate comprising an IL-15 polypeptide comprising the amino acid sequence of any one of SEQ ID NOs: 35, 37, and 38, wherein [AzK_L1_PEG] has the structure of formula (IV) or formula (V): 【Transformation 30】 (In the formula: W is a PEG group having a molecular weight selected from 5 kDa ± 15%, 10 kDa ± 15%, 15 kDa ± 15%, 20 kDa ± 15%, 25 kDa ± 15%, 30 kDa ± 15%, 35 kDa ± 15%, 40 kDa ± 15%, 45 kDa ± 15%, 50 kDa ± 15%, and 60 kDa ± 15%; X has the structure: 【Chemistry 31】 having X-1 indicates the point of attachment to the preceding amino acid residue; X+1 indicates the point of attachment to the subsequent amino acid residue. The IL-15 conjugate having the formula:

27. 1. A pharmaceutical composition comprising a mixture of IL-15 conjugates, the mixture comprising: (i) an IL-15 conjugate comprising an IL-15 polypeptide comprising the amino acid sequence of any one of SEQ ID NOs: 35, 37, and 38, wherein [AzK_L1_PEG] has the structure of formula (IV), and (ii) an IL-15 conjugate comprising an IL-15 polypeptide comprising the amino acid sequence of any one of SEQ ID NOs: 35, 37, and 38, wherein [AzK_L1_PEG] has the structure of formula (V): 【Chemistry 32】 (In the formula: W is a PEG group having a molecular weight selected from 5 kDa ± 15%, 10 kDa ± 15%, 15 kDa ± 15%, 20 kDa ± 15%, 25 kDa ± 15%, 30 kDa ± 15%, 35 kDa ± 15%, 40 kDa ± 15%, 45 kDa ± 15%, 50 kDa ± 15%, and 60 kDa ± 15%; X has the structure: 【Transformation 33】 having X-1 indicates the point of attachment to the preceding amino acid residue; X+1 indicates the point of attachment to the subsequent amino acid residue. The pharmaceutical composition comprising:

28. An IL-15 conjugate comprising an IL-15 polypeptide comprising the amino acid sequence of any one of SEQ ID NOs: 41, 43, and 44, [AzK_L1_PEG30] having the structure of formula (IV) or formula (V): 【Transformation 34】 (In the formula: W is a PEG group with a molecular weight of 30 kDa ± 15%; X has the structure: 【Chemistry 35】 having X-1 indicates the point of attachment to the preceding amino acid residue; X+1 indicates the point of attachment to the subsequent amino acid residue. The IL-15 conjugate having the formula:

29. 29. The IL-15 conjugate of claim 28, wherein the IL-15 polypeptide comprises the amino acid sequence of SEQ ID NO:

44.

30. 1. A pharmaceutical composition comprising a mixture of IL-15 conjugates, the mixture comprising: (i) an IL-15 conjugate comprising an IL-15 polypeptide comprising the amino acid sequence of any one of SEQ ID NOs: 41, 43, and 44, wherein [AzK_L1_PEG30] has the structure of formula (IV), and (ii) an IL-15 conjugate comprising an IL-15 polypeptide comprising the amino acid sequence of any one of SEQ ID NOs: 41, 43, and 44, wherein [AzK_L1_PEG30] has the structure of formula (V): 【Transformation 36】 (In the formula: W is a PEG group with a molecular weight of 30 kDa ± 15%; X has the structure: 【Chemistry 37】 having X-1 indicates the point of attachment to the preceding amino acid residue; X+1 indicates the point of attachment to the subsequent amino acid residue. The pharmaceutical composition comprising:

31. An IL-15 conjugate comprising an IL-15 polypeptide comprising the amino acid sequence of any one of SEQ ID NOs: 47, 49, and 50, [AzK_L1_PEG40] having the structure of formula (IV) or formula (V): 【Transformation 38】 (In the formula: W is a PEG group with a molecular weight of 40 kDa ± 15%; X has the structure: 【Chemistry 39】 having X-1 indicates the point of attachment to the preceding amino acid residue; X+1 indicates the point of attachment to the subsequent amino acid residue. The IL-15 conjugate having the formula:

32. 1. A pharmaceutical composition comprising a mixture of IL-15 conjugates, the mixture comprising: (i) an IL-15 conjugate comprising an IL-15 polypeptide comprising the amino acid sequence of any one of SEQ ID NOs: 47, 49, and 50, wherein [AzK_L1_PEG40] has the structure of formula (IV), and (ii) an IL-15 conjugate comprising an IL-15 polypeptide comprising the amino acid sequence of any one of SEQ ID NOs: 47, 49, and 50, wherein [AzK_L1_PEG40] has the structure of formula (V): 【Chemistry 40】 (In the formula: W is a PEG group with a molecular weight of 40 kDa ± 15%; X has the structure: 【Chemistry 41】 having X-1 indicates the point of attachment to the preceding amino acid residue; X+1 indicates the point of attachment to the subsequent amino acid residue. The pharmaceutical composition comprising:

33. An IL-15 conjugate comprising an IL-15 polypeptide comprising the amino acid sequence of any one of SEQ ID NOs: 65, 67, and 68, wherein [AzK_PEG] has the structure of formula (II) or formula (III): 【Chemistry 42】 (In the formula: W is a PEG group having a molecular weight selected from 5 kDa ± 15%, 10 kDa ± 15%, 15 kDa ± 15%, 20 kDa ± 15%, 25 kDa ± 15%, 30 kDa ± 15%, 35 kDa ± 15%, 40 kDa ± 15%, 45 kDa ± 15%, 50 kDa ± 15%, and 60 kDa ± 15%; X has the structure: 【Chemistry 43】 having X-1 indicates the point of attachment to the preceding amino acid residue; X+1 indicates the point of attachment to the subsequent amino acid residue. The IL-15 conjugate having the formula:

34. 1. A pharmaceutical composition comprising a mixture of IL-15 conjugates, the mixture comprising: (i) an IL-15 conjugate comprising an IL-15 polypeptide comprising the amino acid sequence of any one of SEQ ID NOs: 65, 67, and 68, wherein [AzK_PEG] has the structure of formula (II), and (ii) an IL-15 conjugate comprising an IL-15 polypeptide comprising the amino acid sequence of any one of SEQ ID NOs: 65, 67, and 68, wherein [AzK_PEG] has the structure of formula (III): 【Chemistry 44】 (In the formula: W is a PEG group having a molecular weight selected from 5 kDa ± 15%, 10 kDa ± 15%, 15 kDa ± 15%, 20 kDa ± 15%, 25 kDa ± 15%, 30 kDa ± 15%, 35 kDa ± 15%, 40 kDa ± 15%, 45 kDa ± 15%, 50 kDa ± 15%, and 60 kDa ± 15%; X has the structure: 【Chemistry 45】 having X-1 indicates the point of attachment to the preceding amino acid residue; X+1 indicates the point of attachment to the subsequent amino acid residue. The pharmaceutical composition comprising:

35. An IL-15 conjugate comprising an IL-15 polypeptide comprising the amino acid sequence of any one of SEQ ID NOs: 71, 73, and 74, wherein [AzK_PEG30] has the structure of formula (II) or formula (III): 【Chemistry 46】 (In the formula: W is a PEG group with a molecular weight of 30 kDa ± 15%; X has the structure: 【Chemistry 47】 having X-1 indicates the point of attachment to the preceding amino acid residue; X+1 indicates the point of attachment to the subsequent amino acid residue. The IL-15 conjugate having the formula:

36. 36. The IL-15 conjugate of claim 35, wherein the IL-15 polypeptide comprises the amino acid sequence of SEQ ID NO:

71.

37. 36. The IL-15 conjugate of claim 35, wherein the IL-15 polypeptide comprises the amino acid sequence of SEQ ID NO:

73.

38. 36. The IL-15 conjugate of claim 35, wherein the IL-15 polypeptide comprises the amino acid sequence of SEQ ID NO:

74.

39. A pharmaceutical composition comprising a mixture of IL-15 conjugates, the mixture comprising: (i) an IL-15 conjugate comprising an IL-15 polypeptide comprising the amino acid sequence of any one of SEQ ID NOs: 71, 73, and 74, wherein [AzK_PEG30] has the structure of formula (II); and (ii) an IL-15 polypeptide comprising the amino acid sequence of any one of SEQ ID NOs: 71, 73, and 74, wherein [AzK_PEG30] has the structure of formula (III). An IL-15 conjugate comprising: 【Chemistry 48】 (In the formula: W is a PEG group with a molecular weight of 30 kDa ± 15%; X has the structure: 【Chemistry 49】 having X-1 indicates the point of attachment to the preceding amino acid residue; X+1 indicates the point of attachment to the subsequent amino acid residue. The pharmaceutical composition comprising:

40. An IL-15 conjugate comprising an IL-15 polypeptide comprising the amino acid sequence of any one of SEQ ID NOs: 77, 79, and 80, wherein [AzK_PEG40] has the structure of formula (II) or formula (III): [Transformation 50] (In the formula: W is a PEG group with a molecular weight of 40 kDa ± 15%; X has the structure: 【Chemistry 51】 having X-1 indicates the point of attachment to the preceding amino acid residue; X+1 indicates the point of attachment to the subsequent amino acid residue. The IL-15 conjugate having the formula:

41. 1. A pharmaceutical composition comprising a mixture of IL-15 conjugates, the mixture comprising: (i) an IL-15 conjugate comprising an IL-15 polypeptide comprising the amino acid sequence of any one of SEQ ID NOs: 77, 79, and 80, wherein [AzK_PEG40] has the structure of formula (II), and (ii) an IL-15 conjugate comprising an IL-15 polypeptide comprising the amino acid sequence of any one of SEQ ID NOs: 77, 79, and 80, wherein [AzK_PEG40] has the structure of formula (III): 【Chemistry 52】 (In the formula: W is a PEG group with a molecular weight of 40 kDa ± 15%; X has the structure: 【Chemistry 53】 having X-1 indicates the point of attachment to the preceding amino acid residue; X+1 indicates the point of attachment to the subsequent amino acid residue. The pharmaceutical composition comprising:

42. 42. The pharmaceutical composition of any one of claims 21, 23, 25, 34, 39, and 41, wherein the ratio of the amount of the structure of formula (II) to the amount of the structure of formula (III) is 1:

1.

43. 42. The pharmaceutical composition of any one of claims 21, 23, 25, 34, 39, and 41, wherein the ratio of the amount of the structure of formula (II) to the amount of the structure of formula (III) is greater than 1:

1.

44. 42. The pharmaceutical composition of any one of claims 21, 23, 25, 34, 39, and 41, wherein the ratio of the amount of the structure of formula (II) to the amount of the structure of formula (III) is less than 1:

1.

45. An IL-15 conjugate comprising an IL-15 polypeptide comprising the amino acid sequence of any one of SEQ ID NOs: 83, 85, and 86, wherein [AzK_L1_PEG] has the structure of formula (IV) or formula (V): 【Chemistry 54】 (In the formula: W is a PEG group having a molecular weight selected from 5 kDa ± 15%, 10 kDa ± 15%, 15 kDa ± 15%, 20 kDa ± 15%, 25 kDa ± 15%, 30 kDa ± 15%, 35 kDa ± 15%, 40 kDa ± 15%, 45 kDa ± 15%, 50 kDa ± 15%, and 60 kDa ± 15%; X has the structure: 【Transformation 55】 having X-1 indicates the point of attachment to the preceding amino acid residue; X+1 indicates the point of attachment to the subsequent amino acid residue. The IL-15 conjugate having the formula:

46. 1. A pharmaceutical composition comprising a mixture of IL-15 conjugates, the mixture comprising: (i) an IL-15 conjugate comprising an IL-15 polypeptide comprising the amino acid sequence of any one of SEQ ID NOs: 83, 85, and 86, wherein [AzK_L1_PEG] has the structure of formula (IV), and (ii) an IL-15 conjugate comprising an IL-15 polypeptide comprising the amino acid sequence of any one of SEQ ID NOs: 83, 85, and 86, wherein [AzK_L1_PEG] has the structure of formula (V): 【Transformation 56】 (In the formula: W is a PEG group having a molecular weight selected from 5 kDa ± 15%, 10 kDa ± 15%, 15 kDa ± 15%, 20 kDa ± 15%, 25 kDa ± 15%, 30 kDa ± 15%, 35 kDa ± 15%, 40 kDa ± 15%, 45 kDa ± 15%, 50 kDa ± 15%, and 60 kDa ± 15%; X has the structure: 【Chemistry 57】 having X-1 indicates the point of attachment to the preceding amino acid residue; X+1 indicates the point of attachment to the subsequent amino acid residue. The pharmaceutical composition comprising:

47. 1. An IL-15 conjugate comprising an IL-15 polypeptide comprising the amino acid sequence of any one of SEQ ID NOs: 89, 91 and 92, [AzK_L1_PEG30] having the structure of formula (IV) or formula (V): 【Chemistry 58】 (In the formula: W is a PEG group with a molecular weight of 30 kDa ± 15%; X has the structure: 【Chemistry 59】 having X-1 indicates the point of attachment to the preceding amino acid residue; X+1 indicates the point of attachment to the subsequent amino acid residue. The IL-15 conjugate having the formula:

48. 1. A pharmaceutical composition comprising a mixture of IL-15 conjugates, the mixture comprising: (i) an IL-15 conjugate comprising an IL-15 polypeptide comprising the amino acid sequence of any one of SEQ ID NOs: 89, 91, and 92, wherein [AzK_L1_PEG30] has the structure of formula (IV), and (ii) an IL-15 conjugate comprising an IL-15 polypeptide comprising the amino acid sequence of any one of SEQ ID NOs: 89, 91, and 92, wherein [AzK_L1_PEG30] has the structure of formula (V): 【Transformation 60】 (In the formula: W is a PEG group with a molecular weight of 30 kDa ± 15%; X has the structure: 【Chemistry 61】 having X-1 indicates the point of attachment to the preceding amino acid residue; X+1 indicates the point of attachment to the subsequent amino acid residue. The pharmaceutical composition comprising:

49. An IL-15 conjugate comprising an IL-15 polypeptide comprising the amino acid sequence of any one of SEQ ID NOs: 95, 97, and 98, [AzK_L1_PEG40] having the structure of formula (IV) or formula (V): 【Transformation 62】 (In the formula: W is a PEG group with a molecular weight of 40 kDa ± 15%; X has the structure: 【Transformation 63】 having X-1 indicates the point of attachment to the preceding amino acid residue; X+1 indicates the point of attachment to the subsequent amino acid residue. The IL-15 conjugate having the formula:

50. 1. A pharmaceutical composition comprising a mixture of IL-15 conjugates, The mixture comprises (i) an IL-15 conjugate comprising an IL-15 polypeptide comprising the amino acid sequence of any one of SEQ ID NOs: 95, 97, and 98, wherein [AzK_L1_PEG40] has the structure of formula (IV), and (ii) an IL-15 conjugate comprising an IL-15 polypeptide comprising the amino acid sequence of any one of SEQ ID NOs: 95, 97, and 98, wherein [AzK_L1_PEG40] has the structure of formula (V): 【Chemistry 64】 (In the formula: W is a PEG group with a molecular weight of 40 kDa ± 15%; X has the structure: 【Transformation 65】 having X-1 indicates the point of attachment to the preceding amino acid residue; X+1 indicates the point of attachment to the subsequent amino acid residue. The pharmaceutical composition comprising:

51. 51. The IL-15 conjugate or pharmaceutical composition of any one of claims 1 to 50, wherein W is a linear or branched PEG group.

52. 51. The IL-15 conjugate or pharmaceutical composition of any one of claims 1 to 50, wherein W is a methoxy PEG group.

53. 51. The pharmaceutical composition of any one of claims 27, 30, 32, 46, 48, and 50, wherein the ratio of the amount of structure of formula (IV) to the amount of structure of formula (V) is 1:

1.

54. 51. The pharmaceutical composition of any one of claims 27, 30, 32, 46, 48, and 50, wherein the ratio of the amount of structure of formula (IV) to the amount of structure of formula (V) is greater than 1:

1.

55. 51. The pharmaceutical composition of any one of claims 27, 30, 32, 46, 48, and 50, wherein the ratio of the amount of structure of formula (IV) to the amount of structure of formula (V) is less than 1:

1.

56. 1. An IL-15 conjugate comprising an IL-15 polypeptide comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 1, wherein one amino acid residue in the IL-15 polypeptide has the structure of formula (VI) or formula (VII): 【Chemical Formula 66】 (In the formula: n is -(OCH 2 CH 2 ) n-OCH 3 is an integer such that the PEG group having the structure: has a molecular weight selected from 5 kDa ± 15%, 10 kDa ± 15%, 15 kDa ± 15%, 20 kDa ± 15%, 25 kDa ± 15%, 30 kDa ± 15%, 35 kDa ± 15%, 40 kDa ± 15%, 45 kDa ± 15%, 50 kDa ± 15%, and 60 kDa ± 15%; X has the structure: 【Transformation 67】 having X-1 indicates the point of attachment to the preceding amino acid residue; X+1 indicates the point of attachment to the subsequent amino acid residue. is replaced by The IL-15 conjugate, wherein the amino acid residue replaced by the structure of formula (VI) or formula (VII) is located in the IL-15 polypeptide at a position selected from L25, E53, and N77, and the positions of the residues correspond to positions L25, E53, and N77 in SEQ ID NO:

1.

57. 57. The IL-15 conjugate of claim 56, wherein the IL-15 polypeptide comprises an amino acid sequence that is at least 98% identical to the amino acid sequence of SEQ ID NO: 1 and has the formula (V wherein the amino acid residue replaced by the structure of formula (I) or formula (VII) is located in the IL-15 polypeptide at a position selected from L25, E53, and N77, said residue positions corresponding to positions L25, E53, and N77 in SEQ ID NO:

1.

58. 57. The IL-15 conjugate of claim 56, wherein the IL-15 polypeptide comprises the amino acid sequence of SEQ ID NO: 1, and the amino acid residue replaced by the structure of formula (VI) or formula (VII) is located in the IL-15 polypeptide at a position selected from L25, E53, and N77, wherein the positions of the residues correspond to positions L25, E53, and N77 in SEQ ID NO:

1.

59. 1. An IL-15 conjugate comprising an IL-15 polypeptide comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 3, wherein one amino acid residue in the IL-15 polypeptide has the structure of formula (VI) or formula (VII): 【Transformation 68】 (In the formula: n is -(OCH 2 CH 2 ) n-OCH 3 is an integer such that the PEG group having the structure: has a molecular weight selected from 5 kDa ± 15%, 10 kDa ± 15%, 15 kDa ± 15%, 20 kDa ± 15%, 25 kDa ± 15%, 30 kDa ± 15%, 35 kDa ± 15%, 40 kDa ± 15%, 45 kDa ± 15%, 50 kDa ± 15%, and 60 kDa ± 15%; X has the structure: 【Transformation 69】 having X-1 indicates the point of attachment to the preceding amino acid residue; X+1 indicates the point of attachment to the subsequent amino acid residue. is replaced by The IL-15 conjugate, wherein the amino acid residue replaced by the position of the structure of formula (VI) or formula (VII) is located in the IL-15 polypeptide at a position selected from L26, E54, and N78, and the positions of said residues correspond to positions L26, E54, and N78 in SEQ ID NO:

3.

60. 60. The IL-15 conjugate of claim 59, wherein the IL-15 polypeptide comprises an amino acid sequence that is at least 98% identical to the amino acid sequence of SEQ ID NO:3, and wherein the amino acid residue that is replaced by the structure of formula (VI) or formula (VII) is located in the IL-15 polypeptide at a position selected from L26, E54, and N78, wherein the positions of the residues correspond to positions L26, E54, and N78 in SEQ ID NO:

3.

61. 60. The IL-15 conjugate of claim 59, wherein the IL-15 polypeptide comprises the amino acid sequence of SEQ ID NO: 3, and the amino acid residue replaced by the structure of formula (VI) or formula (VII) is located in the IL-15 polypeptide at a position selected from L26, E54, and N78, wherein the positions of the residues correspond to positions L26, E54, and N78 in SEQ ID NO:

3.

62. 1. An IL-15 conjugate comprising an IL-15 polypeptide comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 1, wherein one amino acid residue in the IL-15 polypeptide has the structure of formula (VIII) or formula (IX): 【Transformation 70】 (In the formula: n is -(OCH 2 CH 2 ) n-OCH 3 is an integer such that the PEG group having the structure: has a molecular weight selected from 5 kDa ± 15%, 10 kDa ± 15%, 15 kDa ± 15%, 20 kDa ± 15%, 25 kDa ± 15%, 30 kDa ± 15%, 35 kDa ± 15%, 40 kDa ± 15%, 45 kDa ± 15%, 50 kDa ± 15%, and 60 kDa ± 15%; X has the structure: 【Chemistry 71】 having X-1 indicates the point of attachment to the preceding amino acid residue; X+1 indicates the point of attachment to the subsequent amino acid residue. is replaced by The IL-15 conjugate, wherein the amino acid residue replaced by the structure of formula (VIII) or formula (IX) is located in the IL-15 polypeptide at a position selected from L25, E53, and N77, and the positions of the residues correspond to positions L25, E53, and N77 in SEQ ID NO:

1.

63. 63. The IL-15 conjugate of claim 62, wherein the IL-15 polypeptide comprises an amino acid sequence that is at least 98% identical to the amino acid sequence of SEQ ID NO:1, and wherein the amino acid residue that is replaced by the structure of formula (VIII) or formula (IX) is located in the IL-15 polypeptide at a position selected from L25, E53, and N77, wherein the positions of the residues correspond to positions L25, E53, and N77 in SEQ ID NO:

1.

64. 63. The IL-15 conjugate of claim 62, wherein the IL-15 polypeptide comprises the amino acid sequence of SEQ ID NO: 1, and the amino acid residue replaced by the structure of formula (VIII) or formula (IX) is located in the IL-15 polypeptide at a position selected from L25, E53, and N77, wherein the positions of the residues correspond to positions L25, E53, and N77 in SEQ ID NO:

1.

65. 1. An IL-15 conjugate comprising an IL-15 polypeptide comprising an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 3, wherein one amino acid residue in the IL-15 polypeptide has the structure of formula (VIII) or formula (IX): 【Chemistry 72】 (In the formula: n is -(OCH 2 CH 2 ) n-OCH 3 is an integer such that the PEG group having the structure: has a molecular weight selected from 5 kDa ± 15%, 10 kDa ± 15%, 15 kDa ± 15%, 20 kDa ± 15%, 25 kDa ± 15%, 30 kDa ± 15%, 35 kDa ± 15%, 40 kDa ± 15%, 45 kDa ± 15%, 50 kDa ± 15%, and 60 kDa ± 15%; X has the structure: 【Transformation 73】 having X-1 indicates the point of attachment to the preceding amino acid residue; X+1 indicates the point of attachment to the subsequent amino acid residue. is replaced by The IL-15 conjugate, wherein the amino acid residue replaced by the structure of formula (VIII) or formula (IX) is located in the IL-15 polypeptide at a position selected from L26, E54, and N78, and the positions of the residues correspond to positions L26, E54, and N78 in SEQ ID NO:

3.

66. n is -(OCH 2 CH 2 ) n-OCH 3 66. The IL-15 conjugate of any one of claims 56 to 65, wherein the PEG group having the structure: is an integer such that the conjugate has a molecular weight of 30 kDa±15%.

67. n is -(OCH 2 CH 2 ) n-OCH 3 66. The IL-15 conjugate of any one of claims 56 to 65, wherein the PEG group having the structure: is an integer such that the conjugate has a molecular weight of 40 kDa±15%.

68. 68. The pharmaceutical composition of any one of claims 1 to 67, wherein the IL-15 conjugate is a pharmaceutically acceptable salt, solvate, or hydrate.

69. A pharmaceutical composition comprising an effective amount of an IL-15 conjugate according to any one of claims 1 to 20, 22, 24, 26, 28, 29, 31, 33, 35 to 38, 40, 45, 47, 49 to 52 and 56 to 67.

70. 70. The pharmaceutical composition of claim 69, further comprising one or more pharmaceutically acceptable excipients.

71. 71. The pharmaceutical composition of any one of claims 21, 23, 25, 27, 30, 32, 34, 39, 41-44, 46, 48, 50-55, 69, and 70, for use in a method of treating cancer in a subject in need thereof.

72. 72. The pharmaceutical composition of claim 71, wherein the cancer is a hematological malignancy.

73. 72. The pharmaceutical composition of claim 71, wherein the cancer is selected from renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), classical Hodgkin lymphoma (cHL), primary mediastinal large B-cell lymphoma (PMBCL), urothelial carcinoma, microsatellite unstable cancer, microsatellite stable cancer, gastric cancer, cervical cancer, hepatocellular carcinoma (HCC), Merkel cell carcinoma (MCC), melanoma, small cell lung cancer (SCLC), esophageal cancer, glioblastoma, mesothelioma, breast cancer, triple-negative breast cancer, prostate cancer, bladder cancer, ovarian cancer, tumors with moderate to low mutational burden, cutaneous squamous cell carcinoma (CSCC), squamous cell skin cancer (SCSC), tumors with low to no PD-L1 expression, tumors that have systemically disseminated beyond their primary anatomic site of origin to the liver and CNS, and diffuse large B-cell lymphoma.

74. 1. An in vitro method of expanding one or more of effector T (Teff) cell, memory T (Tmem) cell, and natural killer (NK) cell populations, comprising: contacting a cell population comprising effector T (Teff) cells, memory T (Tmem) cells, and / or natural killer (NK) cells with an IL-15 conjugate according to any one of claims 1 to 20, 22, 24, 26, 28, 29, 31, 33, 35 to 38, 40, 45, 47, 49, 51, 52, and 56 to 68 or a pharmaceutical composition according to any one of claims 21, 23, 25, 27, 30, 32, 34, 39, 41 to 44, 46, 48, 50, 53 to 55, and 69 to 73; wherein the IL-15 conjugate interacts with IL-15Rβ and IL-15Rγ subunits to form an IL-15 / IL-15Rβγ complex, and the IL-15 / IL-15Rβγ complex stimulates the expansion of one or more of Teff, Tmem, and NK cell populations.

75. 75. The in vitro method of claim 74, wherein the IL-15 conjugate has a reduced affinity for the IL-15Rα subunit, optionally wherein the affinity is reduced compared to wild-type human IL-15.

76. 76. The in vitro method of claim 74 or 75, wherein the Teff cells, Tmem cells, and / or NK cells are human cells.

77. 1. A method of making an IL-15 conjugate, comprising: IL comprising an amino acid sequence at least 95% identical to the amino acid sequence of SEQ ID NO: 1 or 3 an IL-15 polypeptide, wherein one unnatural amino acid residue at position X of the IL-15 polypeptide is formula 【Chemistry 74】 where position X-1 indicates the point of attachment to the preceding amino acid residue and position X+1 indicates the point of attachment to the subsequent amino acid residue; i) said positions X are L25, E53, and N77, relative to amino acid positions in SEQ ID NO: 1; or ii) position X is L26, E54, or N78, based on amino acid position within SEQ ID NO:

3. the IL-15 polypeptide, wherein the unnatural amino acid has been replaced with an unnatural amino acid having the structure formula 【Chemistry 75】 mPEG-DBCO wherein n is such that the mPEG-DBCO comprises mPEG having a molecular weight of 5 kDa ± 15%, 10 kDa ± 15%, 15 kDa ± 15%, 20 kDa ± 15%, 25 kDa ± 15%, 30 kDa ± 15%, 35 kDa ± 15%, 40 kDa ± 15%, 45 kDa ± 15%, or 50 kDa ± 15%. and reacting the compound with This produces an IL-15 conjugate.

78. 78. The method of claim 77, wherein the IL-15 polypeptide comprises an amino acid sequence that is at least 98% identical to the amino acid sequence of SEQ ID NO:1, wherein one amino acid residue in the IL-15 polypeptide is replaced with a non-naturally occurring amino acid.

79. 78. The IL-15 polypeptide of claim 77, comprising the amino acid sequence of SEQ ID NO: 1, wherein one amino acid residue in the IL-15 polypeptide is replaced with a non-naturally occurring amino acid. The method described.

80. 80. The method of claim 79, wherein position X is L25, E53, or N77, relative to amino acid position in SEQ ID NO:

1.

81. 78. The method of claim 77, wherein the IL-15 polypeptide comprises an amino acid sequence that is at least 98% identical to the amino acid sequence of SEQ ID NO:3, wherein one amino acid residue in the IL-15 polypeptide is replaced with a non-naturally occurring amino acid.

82. 78. The method of claim 77, wherein the IL-15 polypeptide comprises the amino acid sequence of SEQ ID NO: 3, wherein one amino acid residue in the IL-15 polypeptide is replaced with a non-naturally occurring amino acid.

83. 83. The method of claim 82, wherein position X is L26, E54, or N78, relative to amino acid position in SEQ ID NO:

3.

84. 84. The method of any one of claims 77 to 83, wherein the mPEG has a molecular weight of 30 kDa ± 15%.

85. 84. The method of any one of claims 77 to 83, wherein the mPEG has a molecular weight of 40 kDa ± 15%.

86. 78. The method of claim 77, wherein the IL-15 conjugate is an IL-15 conjugate according to any one of claims 1 to 20, 22, 24, 26, 28, 29, 31, 33, 35 to 38, 40, 45, 47, 49, 51, 52, and 56 to 68.

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