Il-2 conjugates and methods of use thereof

Abstract

To provide compositions, kits, and methods comprising interleukin (IL) conjugates useful for the treatment of one or more indications; and also, to provide pharmaceutical compositions and kits comprising one or more of the interleukin conjugates.SOLUTION: Provided is an IL-2 conjugate comprising a specific amino acid sequence, in which at least one amino acid residue in the IL-2 conjugate at an amino acid position selected from K35, F42, F44, K43, E62, P65, R38, T41, E68, Y45, V69, and L72 in reference to the amino acid positions within a specific amino acid sequence is replaced by a specific structure, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.SELECTED DRAWING: Figure 11A

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application No. 62 / 802,191, filed February 6, 2019, U.S. Provisional Patent Application No. 62 / 847,844, filed May 14, 2019, U.S. Provisional Patent Application No. 62 / 870,581, filed July 3, 2019, U.S. Provisional Patent Application No. 62 / 899,035, filed September 11, 2019, and U.S. Provisional Patent Application No. 62 / 940,173, filed November 25, 2019, which are incorporated herein by reference in their entireties.

[0002] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in ASCII format and is incorporated herein by reference in its entirety. The ASCII copy was created on February 4, 2020, is named 46085-729_601_SL.txt, and is 124,806 bytes in size. [Background technology]

[0003] Different 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 cases, regulating different populations of T cells provides options for treating diseases or conditions. Summary of the Invention [Means for solving the problem]

[0004] Described herein is an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 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;

[0005] X is of the structure: [ka] (having In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, Z is CH2 and Y is replaced by [ka] In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, Y is CH2 and Z is [ka] In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, Z is CH2 and Y is [ka] In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, Z is CH2 and Y is [ka] In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, Y is CH2 and Z is [ka] In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the PEG group has an average molecular weight selected from 5 kDa, 10 kDa, 20 kDa, and 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the PEG group has an average molecular weight of 5 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the PEG group has an average molecular weight of 10 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the PEG group has an average molecular weight of 15 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the PEG group has an average molecular weight of 20 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the PEG group has an average molecular weight of 25 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the PEG group has an average molecular weight of 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the PEG group has an average molecular weight of 35 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the PEG group has an average molecular weight of 40 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the PEG group has an average molecular weight of 45 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the PEG group has an average molecular weight of 50 kDa. In some embodiments of the IL-2 conjugate, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, the PEG group has an average molecular weight of 60 kDa. In some embodiments of the IL-2 conjugate, or a pharmaceutically acceptable salt, solvate, or hydrate thereof described herein, the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is selected from K35, F42, F44, K43, E62, P65, R38, T41, E68, Y45, V69, and L72, and the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is relative to the position in SEQ ID NO: 1. In some embodiments of the IL-2 conjugate, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, described herein, the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is selected from F42, E62, and P65, and the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is relative to the position of SEQ ID NO: 1. In some embodiments of the IL-2 conjugate, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, described herein, the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is K35, and the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is relative to the position of SEQ ID NO: 1. In some embodiments of the IL-2 conjugate, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, described herein, the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is F42, and the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is relative to the position of SEQ ID NO: 1. In some embodiments of the IL-2 conjugate, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, described herein, the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is F44, and the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is relative to the position of SEQ ID NO: 1.In some embodiments of the IL-2 conjugate, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, described herein, the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is K43, and the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is relative to the position of SEQ ID NO: 1. In some embodiments of the IL-2 conjugate, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, described herein, the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is E62, and the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is relative to the position of SEQ ID NO: 1. In some embodiments of the IL-2 conjugate, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, described herein, the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is P65, and the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is relative to the position of SEQ ID NO: 1. In some embodiments of the IL-2 conjugate, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, described herein, the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is R38, and the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is relative to the position of SEQ ID NO: 1. In some embodiments of the IL-2 conjugate, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, described herein, the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is T41, and the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is relative to the position of SEQ ID NO: 1. In some embodiments of the IL-2 conjugate, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, described herein, the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is E68, and the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is relative to the position of SEQ ID NO: 1.In some embodiments of the IL-2 conjugate described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is Y45, and the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is relative to the position in SEQ ID NO: 1. The IL-2 conjugate described herein, or a pharmaceutically acceptable salt thereof. In some embodiments of the IL-2 conjugate, or a pharmaceutically acceptable salt, solvate, or hydrate thereof described herein, the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is V69, and the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is relative to the position of SEQ ID NO: 1. In some embodiments of the IL-2 conjugate, or a pharmaceutically acceptable salt, solvate, or hydrate thereof described herein, the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is L72, and the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is relative to the position of SEQ ID NO: 1.

[0006] Described herein is an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 4, wherein at least one amino acid residue in the IL-2 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 is of the structure: [ka] (having In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, Z is CH2 and Y is replaced by [ka] In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, Y is CH2 and Z is [ka] In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, Z is CH2 and Y is [ka] In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, Z is CH2 and Y is [ka] In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, Y is CH2 and Z is [ka] In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the PEG group has an average molecular weight selected from 5 kDa, 10 kDa, 20 kDa, and 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the PEG group has an average molecular weight of 5 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the PEG group has an average molecular weight of 10 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the PEG group has an average molecular weight of 15 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the PEG group has an average molecular weight of 20 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the PEG group has an average molecular weight of 25 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the PEG group has an average molecular weight of 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the PEG group has an average molecular weight of 35 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the PEG group has an average molecular weight of 40 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the PEG group has an average molecular weight of 45 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the PEG group has an average molecular weight of 50 kDa.In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the PEG group has an average molecular weight of 60 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is selected from K35, F42, F44, K43, E62, P65, R38, T41, E68, Y45, V69, and L72, and the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is relative to the position of SEQ ID NO: 1. In some embodiments of the IL-2 conjugate, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, described herein, the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is selected from F42, E62, and P65, and the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is relative to the position of SEQ ID NO: 1. In some embodiments of the IL-2 conjugate, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, described herein, the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is K35, and the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is relative to the position of SEQ ID NO: 1. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is F42, and the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is relative to the position of SEQ ID NO: 1. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is F44. , the location of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is relative to the location of SEQ ID NO: 1. In some embodiments of the IL-2 conjugates, or pharmaceutically acceptable salts, solvates, or hydrates thereof, described herein, the location of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is K43, and the location of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is relative to the location of SEQ ID NO: 1. In some embodiments of the IL-2 conjugates, or pharmaceutically acceptable salts, solvates, or hydrates thereof, described herein, the location of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is E62, and the location of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is relative to the position of SEQ ID NO: 1. In some embodiments of the IL-2 conjugate, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, described herein, the location of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is P65, and the location of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is relative to the position of SEQ ID NO: 1. In some embodiments of the IL-2 conjugate, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, described herein, the location of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is R38, and the location of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is relative to the position of SEQ ID NO: 1. In some embodiments of the IL-2 conjugate, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, described herein, the location of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is T41, and the location of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is relative to the position of SEQ ID NO: 1. In some embodiments of the IL-2 conjugate described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is E68, and the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is relative to the position in SEQ ID NO: 1.In some embodiments of the IL-2 conjugate, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, described herein, the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is Y45, and the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is relative to the position of SEQ ID NO: 1. In some embodiments of the IL-2 conjugate, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, described herein, the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is V69, and the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is relative to the position of SEQ ID NO: 1. In some embodiments of the IL-2 conjugate, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, described herein, the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is L72, and the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is relative to the position of SEQ ID NO: 1.

[0007] Described herein are IL-2 conjugates comprising the amino acid sequence of any one of SEQ ID NOs: 15-19, 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;

[0008] X is of the structure: [ka] or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugate described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, [AzK_PEG] is a mixture of Formula (II) and Formula (III). In some embodiments of the IL-2 conjugate described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, [AzK_PEG] is a mixture of Formula (II): [ka] In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the IL-2 conjugate has the structure It has the amino acid sequence of sequence number 15. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, and 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight selected from 5 kDa and 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight of 5 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 16. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, and 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight selected from 5 kDa and 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight of 5 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 17.In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, and 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight selected from 5 kDa and 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight of 5 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 18. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, and 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight selected from 5 kDa and 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight of 5 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 19.The IL-2 conjugates described herein, or In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, and 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight selected from 5 kDa and 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight of 5 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments of the IL-2 conjugate described herein; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, [AzK_PEG] has the structure of formula (III): [ka] In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 15. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, and 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight selected from 5 kDa and 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight of 5 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 16. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, and 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight selected from 5 kDa and 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight of 5 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight of 30 kDa.In some embodiments of the IL-2 conjugate described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 17. The IL-2 conjugate described herein, or a pharmaceutically acceptable salt, solvate, thereof. or hydrate thereof, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, and 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight selected from 5 kDa and 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight of 5 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 18. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, and 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight selected from 5 kDa and 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight of 5 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO:19.In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, and 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight selected from 5 kDa and 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight of 5 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a linear or branched PEG group. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a linear PEG group. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a branched PEG group. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a methoxy PEG group. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the methoxy PEG group is linear or branched. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the methoxy PEG group is linear. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the methoxy PEG group is branched. An exemplary structure of a methoxy PEG group is shown in the mPEG-DBCO structure in Scheme 1 of Example 2.

[0009] In some embodiments of an IL-2 conjugate described herein having an amino acid sequence selected from any one of SEQ ID NOs: 15, 16, 17, 18, and 19, [AzK_PEG] contains 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. In some embodiments of an IL-2 conjugate described herein having an amino acid sequence selected from any one of SEQ ID NOs: 15, 16, 17, 18, and 19, [AzK_PEG] contains a PEG group having an average molecular weight of 5 kDa. In some embodiments of an IL-2 conjugate described herein having an amino acid sequence selected from any one of SEQ ID NOs: 15, 16, 17, 18, and 19, [AzK_PEG] contains a PEG group having an average molecular weight of 10 kDa. In some embodiments of an IL-2 conjugate described herein having an amino acid sequence selected from any one of SEQ ID NOs: 15, 16, 17, 18, and 19, [AzK_PEG] contains a PEG group having an average molecular weight of 15 kDa. In some embodiments of an IL-2 conjugate described herein having an amino acid sequence selected from any one of SEQ ID NOs: 15, 16, 17, 18, and 19, [AzK_PEG] contains a PEG group having an average molecular weight of 20 kDa. In some embodiments of an IL-2 conjugate described herein having an amino acid sequence selected from any one of SEQ ID NOs: 15, 16, 17, 18, and 19, [AzK_PEG] contains a PEG group having an average molecular weight of 25 kDa. In some embodiments of an IL-2 conjugate described herein having an amino acid sequence selected from any one of SEQ ID NOs: 15, 16, 17, 18, and 19, [AzK_PEG] contains a PEG group having an average molecular weight of 30 kDa. In some embodiments of the IL-2 conjugates described herein having an amino acid sequence selected from any one of SEQ ID NOs: 15, 16, 17, 18, and 19, [AzK_PEG] contains a PEG group having an average molecular weight of 35 kDa.In some embodiments of an IL-2 conjugate described herein having an amino acid sequence selected from any one of SEQ ID NOs: 15, 16, 17, 18, and 19, [AzK_PEG] contains a PEG group having an average molecular weight of 40 kDa. In some embodiments of an IL-2 conjugate described herein having an amino acid sequence selected from any one of SEQ ID NOs: 15, 16, 17, 18, and 19, [AzK_PEG] contains a PEG group having an average molecular weight of 45 kDa. In some embodiments of an IL-2 conjugate described herein having an amino acid sequence selected from any one of SEQ ID NOs: 15, 16, 17, 18, and 19, [AzK_PEG] contains a PEG group having an average molecular weight of 50 kDa. In some embodiments of an IL-2 conjugate described herein having an amino acid sequence selected from any one of SEQ ID NOs: 15, 16, 17, 18, and 19, [AzK_PEG] contains a PEG group having an average molecular weight of 60 kDa. In some embodiments of the IL-2 conjugate described herein having an amino acid sequence selected from any one of SEQ ID NOs: 15, 16, 17, 18, and 19, [AzK_PEG] contains 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 kD, and the PEG group is a methoxy PEG group, a linear methoxy PEG group, or a branched methoxy PEG group.

[0010] Described herein are IL-2 conjugates comprising the amino acid sequence of any one of SEQ ID NOs: 20-24, wherein [AzK_PEG5kD] 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 5 kDa;

[0011] X is of the structure: [ka] or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 20. In some embodiments of the IL-2 conjugates described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 21. In some embodiments of the IL-2 conjugates described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 22. In some embodiments of the IL-2 conjugates described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 23. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 24. In some embodiments of the IL-2 conjugates described herein; or pharmaceutically acceptable salts, solvates, or hydrates thereof, [AzK_PEG5kD] has the structure of formula (II): [ka] In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 20. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 21. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 22. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 23. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 24. In some embodiments of the IL-2 conjugate described herein; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, [AzK_PEG5kD] has the structure of formula (III): [ka] In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 20. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 21. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 22. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 23. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 24.

[0012] Described herein is an IL-2 conjugate comprising the amino acid sequence of any one of SEQ ID NOs: 25 to 29, wherein [AzK_PEG30kD] has a structure of formula (II) or formula (III), or is a mixture of the structures of formula (II) and formula (III). R: [ka] (In the formula: W is a PEG group having an average molecular weight of 30 kDa;

[0013] X is of the structure: [ka] or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugate described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 25. In some embodiments of the IL-2 conjugate described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 26. In some embodiments of the IL-2 conjugate described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 27. In some embodiments of the IL-2 conjugate described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 28. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 29. In some embodiments of the IL-2 conjugates described herein, [AzK_PEG30kD] has the structure of Formula (II): [ka] or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 25. In some embodiments of the IL-2 conjugates described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 26. In some embodiments of the IL-2 conjugates described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 27. In some embodiments of the IL-2 conjugates described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 28. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 29. In some embodiments of the IL-2 conjugates described herein; or pharmaceutically acceptable salts, solvates, or hydrates thereof, [AzK_PEG30kD] has the structure of formula (III): [ka] In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 25. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 26. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 27. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 28. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 29.

[0014] Described herein is an IL-2 conjugate comprising any one of the amino acid sequences of SEQ ID NOs: 15 to 19, wherein [AzK_PEG] is a compound represented by the formula (II) and the formula (III). ) is a mixture of structures: [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;

[0015] X is of the structure: [ka] (having the formula: ##STR00001##), an IL-2 conjugate; or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugate described herein, the ratio of the amount of the structure of formula (II), including the total amount of [AzK_PEG], in the IL-2 conjugate to the amount of the structure of formula (III) is about 1:1. In some embodiments of the IL-2 conjugate described herein, the ratio of the amount of the structure of formula (II), including the total amount of [AzK_PEG], in the IL-2 conjugate to the amount of the structure of formula (III) is greater than 1:1. In some embodiments of the IL-2 conjugate described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, W is a linear or branched PEG group. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a linear PEG group. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a branched PEG group. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a methoxy PEG group. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a methoxy PEG group. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the methoxy PEG group is linear or branched. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the methoxy PEG group is linear. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the methoxy PEG group is branched.

[0016] Described herein are IL-2 conjugates comprising the amino acid sequence of any one of SEQ ID NOs: 20-24, wherein [AzK_PEG5kD] is a mixture of structures of formula (II) and formula (III): [ka] (In the formula: W is a PEG group having an average molecular weight of 5 kDa;

[0017] X is of the structure: [ka] (having the formula: ##STR00001##), an IL-2 conjugate; or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the ratio of the amount of the structure of Formula (II), including the total amount of [AzK_PEG5kD], in the IL-2 conjugate to the amount of the structure of Formula (III) is about 1:1. In some embodiments of the IL-2 conjugates described herein, the ratio of the amount of the structure of Formula (II), including the total amount of [AzK_PEG5kD], in the IL-2 conjugate to the amount of the structure of Formula (III) is greater than 1:1. In some embodiments of the IL-2 conjugates described herein, the ratio of the amount of the structure of Formula (II), including the total amount of [AzK_PEG5kD], in the IL-2 conjugate is less than 1:1.

[0018] Described herein are IL-2 conjugates comprising the amino acid sequence of any one of SEQ ID NOs: 25-29, wherein [AzK_PEG30kD] is a mixture of structures of formula (II) and formula (III): [ka] (In the formula: W is a PEG group having an average molecular weight of 30 kDa;

[0019] X is of the structure: [ka] (having the formula: ##STR00001##), an IL-2 conjugate; or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the ratio of the amount of the structure of Formula (II), including the total amount of [AzK_PEG30kD] in the IL-2 conjugate, to the amount of the structure of Formula (III) is about 1:1. In some embodiments of the IL-2 conjugates described herein, the ratio of the amount of the structure of Formula (II), including the total amount of [AzK_PEG30kD] in the IL-2 conjugate, to the amount of the structure of Formula (III) is greater than 1:1. In some embodiments of the IL-2 conjugates described herein, the ratio of the amount of the structure of Formula (II), including the total amount of [AzK_PEG30kD] in the IL-2 conjugate, to the amount of the structure of Formula (III) is less than 1:1.

[0020] Described herein are IL-2 conjugates comprising the amino acid sequence of any one of SEQ ID NOs: 40-44, 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;

[0021] X is of the structure: [ka] or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, [AzK_L1_PEG] is a mixture of Formula (IV) and Formula (V). In some embodiments of the IL-2 conjugates described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, [AzK_L1_PEG] has the structure of Formula (IV): [ka] In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the IL-2 conjugate has the structure IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, have the amino acid sequence of sequence number 40. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, and 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight selected from 5 kDa and 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight of 5 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 41. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, and 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight selected from 5 kDa and 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight of 5 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO:42.In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, and 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight selected from 5 kDa and 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight of 5 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 43. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, and 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight selected from 5 kDa and 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight of 5 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO:44.The IL-2 conjugates described herein, or In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, and 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight selected from 5 kDa and 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight of 5 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, [AzK_L1_PEG] has the structure of formula (V): [ka] In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 40. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, and 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight selected from 5 kDa and 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight of 5 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 41. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, and 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight selected from 5 kDa and 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight of 5 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight of 30 kDa.In some embodiments of the IL-2 conjugate described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 42. The IL-2 conjugate described herein, or a pharmaceutically acceptable salt, solvate, thereof. or hydrate thereof, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, and 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight selected from 5 kDa and 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight of 5 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO:43. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, and 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight selected from 5 kDa and 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight of 5 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO:44.In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, and 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight selected from 5 kDa and 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight of 5 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a PEG group having an average molecular weight of 30 kDa. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a linear or branched PEG group. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a linear PEG group. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a branched PEG group. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a methoxy PEG group. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the methoxy PEG group is linear or branched. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the methoxy PEG group is linear. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the methoxy PEG group is branched.In some embodiments of the IL-2 conjugates described herein having an amino acid sequence selected from any one of SEQ ID NOs: 40, 41, 42, 43, and 44, [AzK_L1_PEG] is selected from the group consisting of 5 kDa, 10 kDa, 15 kDa, 20 kDa, 2.

[0033] In some embodiments of the IL-2 conjugate described herein having an amino acid sequence selected from any one of SEQ ID NOs: 40, 41, 42, 43, and 44, [AzK_L1_PEG] contains a PEG group having an average molecular weight selected from 5 kDa, 30 kDa, 35 kDa, 40 kDa, 45 kDa, 50 kDa, and 60 kDa. In some embodiments of the IL-2 conjugate described herein having an amino acid sequence selected from any one of SEQ ID NOs: 40, 41, 42, 43, and 44, [AzK_L1_PEG] contains a PEG group having an average molecular weight of 5 kDa. In some embodiments of the IL-2 conjugate described herein having an amino acid sequence selected from any one of SEQ ID NOs: 40, 41, 42, 43, and 44, [AzK_L1_PEG] contains a PEG group having an average molecular weight of 10 kDa. In some embodiments of the IL-2 conjugate described herein having an amino acid sequence selected from any one of SEQ ID NOs: 40, 41, 42, 43, and 44, [AzK_L1_PEG] contains a PEG group having an average molecular weight of 15 kDa. In some embodiments of an IL-2 conjugate described herein having an amino acid sequence selected from any one of SEQ ID NOs: 40, 41, 42, 43, and 44, [AzK_L1_PEG] contains a PEG group having an average molecular weight of 20 kDa. In some embodiments of an IL-2 conjugate described herein having an amino acid sequence selected from any one of SEQ ID NOs: 40, 41, 42, 43, and 44, [AzK_L1_PEG] contains a PEG group having an average molecular weight of 25 kDa. In some embodiments of an IL-2 conjugate described herein having an amino acid sequence selected from any one of SEQ ID NOs: 40, 41, 42, 43, and 44, [AzK_L1_PEG] contains a PEG group having an average molecular weight of 30 kDa. In some embodiments of the IL-2 conjugates described herein having an amino acid sequence selected from any one of SEQ ID NOs: 40, 41, 42, 43, and 44, [AzK_L1_PEG] contains a PEG group having an average molecular weight of 35 kDa.In some embodiments of an IL-2 conjugate described herein having an amino acid sequence selected from any one of SEQ ID NOs: 40, 41, 42, 43, and 44, [AzK_L1_PEG] contains a PEG group having an average molecular weight of 40 kDa. In some embodiments of an IL-2 conjugate described herein having an amino acid sequence selected from any one of SEQ ID NOs: 40, 41, 42, 43, and 44, [AzK_L1_PEG] contains a PEG group having an average molecular weight of 45 kDa. In some embodiments of an IL-2 conjugate described herein having an amino acid sequence selected from any one of SEQ ID NOs: 40, 41, 42, 43, and 44, [AzK_L1_PEG] contains a PEG group having an average molecular weight of 50 kDa. In some embodiments of the IL-2 conjugate described herein having an amino acid sequence selected from any one of SEQ ID NOs: 40, 41, 42, 43, and 44, [AzK_L1_PEG] contains a PEG group having an average molecular weight of 60 kDa. In some embodiments of the IL-2 conjugate described herein having an amino acid sequence selected from any one of SEQ ID NOs: 40, 41, 42, 43, and 44, [AzK_L1_PEG] contains 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 kD, wherein the PEG group is a methoxy PEG group, a linear methoxy PEG group, or a branched methoxy PEG group.

[0022] Described herein are IL-2 conjugates comprising the amino acid sequence of any one of SEQ ID NOs: 45-49, wherein [AzK_L1_PEG5kD] 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 5 kDa;

[0023] X is of the structure: [ka] or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 45. In some embodiments of the IL-2 conjugates described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 46. In some embodiments of the IL-2 conjugates described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 47. In some embodiments of the IL-2 conjugates described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 48. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 49. In some embodiments of the IL-2 conjugates described herein, [AzK_L1_PEG5kD] has the structure of formula (IV): [ka] or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 45. In some embodiments of the IL-2 conjugates described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 46. In some embodiments of the IL-2 conjugates described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 47. In some embodiments of the IL-2 conjugates described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 48. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 49. In some embodiments of the IL-2 conjugates described herein, [AzK_L1_PEG5kD] has the structure of formula (V): [ka] or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 45. In some embodiments of the IL-2 conjugates described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 46. In some embodiments of the IL-2 conjugates described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 47. In some embodiments of the IL-2 conjugates described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 48. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO:49.

[0024] Described herein is an IL-2 conjugate comprising the amino acid sequence of any one of SEQ ID NOs: 50 to 54, wherein [AzK_L1_PEG30kD] is also represented by formula (IV): or has the structure of formula (V), or is a mixture of the structures of formula (IV) and formula (V): [ka] (In the formula: W is a PEG group having an average molecular weight of 30 kDa;

[0025] X is of the structure: [ka] or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugate described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 50. In some embodiments of the IL-2 conjugate described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 51. In some embodiments of the IL-2 conjugate described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 52. In some embodiments of the IL-2 conjugate described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 53. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 54. In some embodiments of the IL-2 conjugates described herein; or pharmaceutically acceptable salts, solvates, or hydrates thereof, [AzK_L1_PEG30kD] has the structure of formula (IV): [ka] In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 50. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 51. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 52. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 53. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 54. In some embodiments of the IL-2 conjugate described herein; or a pharmaceutically acceptable salt, solvate, or hydrate thereof, [AzK_L1_PEG30kD] has the structure of formula (V): [ka] In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 50. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 51. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 52. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 53. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 54.

[0026] Described herein are IL-2 conjugates comprising the amino acid sequence of any one of SEQ ID NOs: 40-44, wherein [Azk_L1_PEG] is a mixture of structures 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;

[0027] X is of the structure: [ka] (having the formula: ##STR00001##), an IL-2 conjugate; or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugate described herein, the ratio of the amount of the structure of formula (IV), including the total amount of [Azk_L1_PEG], in the IL-2 conjugate to the amount of the structure of formula (V) is about 1:1. In some embodiments of the IL-2 conjugate described herein, the ratio of the amount of the structure of formula (IV), including the total amount of [Azk_L1_PEG], in the IL-2 conjugate to the amount of the structure of formula (V) is greater than 1:1. In some embodiments of the IL-2 conjugate described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, W is a linear or branched PEG group. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a linear PEG group. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a branched PEG group. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a methoxy PEG group. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, W is a methoxy P The EG group is linear or branched. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the methoxy PEG group is linear. In some embodiments of the IL-2 conjugates described herein, or pharmaceutically acceptable salts, solvates, or hydrates thereof, the methoxy PEG group is branched.

[0028] Described herein are IL-2 conjugates comprising the amino acid sequence of any one of SEQ ID NOs: 45-49, wherein [AzK_L1_PEG5kD] is a mixture of structures of formula (IV) and formula (V): [ka] (In the formula: W is a PEG group having an average molecular weight of 5 kDa;

[0029] X is of the structure: [ka] (having the formula: ##STR00001##), an IL-2 conjugate; or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the ratio of the amount of the structure of Formula (IV), including the total amount of [AzK_L1_PEG5kD], in the IL-2 conjugate to the amount of the structure of Formula (V) is about 1:1. In some embodiments of the IL-2 conjugates described herein, the ratio of the amount of the structure of Formula (IV), including the total amount of [AzK_L1_PEG5kD], in the IL-2 conjugate to the amount of the structure of Formula (V) is greater than 1:1. In some embodiments of the IL-2 conjugates described herein, the ratio of the amount of the structure of Formula (IV), including the total amount of [AzK_L1_PEG5kD], in the IL-2 conjugate is less than 1:1.

[0030] Described herein are antibodies comprising any one of the amino acid sequences of SEQ ID NOs: 50 to 54. The IL-2 conjugate, [AzK_L1_PEG30kD], is a mixture of structures of formula (IV) and formula (V): [ka] (In the formula: W is a PEG group having an average molecular weight of 30 kDa;

[0031] X is of the structure: [ka] (having the formula (IV)), an IL-2 conjugate; or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the ratio of the amount of the structure of Formula (IV), including the total amount of [AzK_L1_PEG30kD] in the IL-2 conjugate, to the amount of the structure of Formula (V) is about 1:1. In some embodiments of the IL-2 conjugates described herein, the ratio of the amount of the structure of Formula (IV), including the total amount of [AzK_L1_PEG30kD] in the IL-2 conjugate, to the amount of the structure of Formula (V) is greater than 1:1. In some embodiments of the IL-2 conjugates described herein, the ratio of the amount of the structure of Formula (IV), including the total amount of [AzK_L1_PEG30kD] in the IL-2 conjugate, to the amount of the structure of Formula (V) is less than 1:1.

[0032] Described herein is an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 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;

[0033] X is [ka] or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, n in the compounds of formula (VI) and (VII) 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 about 100 to about 2000, or about 100 to about 1900, or about 100 to about 1850, or 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 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. In some embodiments of the IL-2 conjugates described herein, n in the compounds of formula (VI) and (VII) 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, 1 is an integer selected from 476, 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. In some embodiments of the IL-2 conjugates described herein, the position of the structure of Formula (VI), Formula (VII), or a mixture of Formulas (VI) and (VII) in the amino acid sequence of the IL-2 conjugate is selected from K34, F41, F43, K42, E61, P64, R37, T40, E67, Y44, V68, and L71, and the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is relative to the position in SEQ ID NO:3.In some embodiments of the IL-2 conjugates described herein, the position of the structure of Formula (VI), Formula (VII), or a mixture of Formulas (VI) and (VII) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is selected from K34, F41, F43, K42, E61, P64, R37, T40, E67, Y44, V68, and L71. In some embodiments of the IL-2 conjugates described herein, the position of the structure of Formula (VI), Formula (VII), or a mixture of Formulas (VI) and (VII) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is K34. In some embodiments of the IL-2 conjugates described herein, the position of the structure of Formula (VI), Formula (VII), or a mixture of Formulas (VI) and (VII) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is F41. In some embodiments of the IL-2 conjugates described herein, the position of the structure of Formula (VI), Formula (VII), or a mixture of Formulas (VI) and (VII) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position F43. In some embodiments of the IL-2 conjugates described herein, the position of the structure of Formula (VI), Formula (VII), or a mixture of Formulas (VI) and (VII) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position K42. In some embodiments of the IL-2 conjugates described herein, the position of the structure of Formula (VI), Formula (VII), or a mixture of Formulas (VI) and (VII) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position E61. In some embodiments of the IL-2 conjugates described herein, the position of the structure of Formula (VI), Formula (VII), or a mixture of Formulas (VI) and (VII) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position P64. In some embodiments of the IL-2 conjugates described herein, the position of the structure of formula (VI), formula (VII), or a mixture of formulas (VI) and (VII) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position R37.In some embodiments of the IL-2 conjugates described herein, the location of the structure of Formula (VI), Formula (VII), or a mixture of Formulas (VI) and (VII) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position T40. In some embodiments of the IL-2 conjugates described herein, the location of the structure of Formula (VI), Formula (VII), or a mixture of Formulas (VI) and (VII) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3. is at position E67. In some embodiments of the IL-2 conjugates described herein, the position of the structure of Formula (VI), Formula (VII), or a mixture of Formulas (VI) and (VII) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position Y44. In some embodiments of the IL-2 conjugates described herein, the position of the structure of Formula (VI), Formula (VII), or a mixture of Formulas (VI) and (VII) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position V68. In some embodiments of the IL-2 conjugates described herein, the position of the structure of Formula (VI), Formula (VII), or a mixture of Formulas (VI) and (VII) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position L71. In some embodiments of the IL-2 conjugates described herein, the ratio of the amount of the structure of Formula (VI) to the amount of the structure of Formula (VII), including the total amount of the IL-2 conjugate, is about 1:1. In some embodiments of the IL-2 conjugates described herein, the ratio of the amount of the structure of formula (VI) to the amount of the structure of formula (VII), including the total amount of the IL-2 conjugate, is greater than 1: 1. In some embodiments of the IL-2 conjugates described herein, the ratio of the amount of the structure of formula (VI) to the amount of the structure of formula (VII), including the total amount of the IL-2 conjugate, is less than 1: 1.

[0034] In some embodiments, described herein is an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is replaced with a structure of formula (VI) or (VII), or a mixture of (VI) and (VII), and the replaced amino acid residues in SEQ ID NO: 3 are K34, F41, F43, K42, E61, P64, R37, T40, E67, Y44, V68, and and L71, where n is selected from 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 1 250, 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-2 conjugates described herein, n in the compounds of formula (VI) and (VII) 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, 1 is an integer selected from 476, 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.

[0035] In some embodiments, described herein is an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid in the IL-2 conjugate is wherein the amino acid residue in SEQ ID NO: 3 is replaced with a structure of formula (VI) or (VII), or a mixture of (VI) and (VII), and the replaced amino acid residue in SEQ ID NO: 3 is selected from F41, F43, K42, E61, and P64, 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-2 conjugates described herein, n in the compounds of formula (VI) and (VII) 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.

[0036] In some embodiments, described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is replaced with a structure of formula (VI) or (VII), or a mixture of (VI) and (VII), wherein the replaced amino acid residue in SEQ ID NO: 3 is selected from E61 and P64, 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-2 conjugates described herein, n in the compounds of formula (VI) and (VII) is an integer selected from 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910.

[0037] In some embodiments, described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is replaced with a structure of formula (VI) or (VII), or a mixture of (VI) and (VII), where the replaced amino acid residue in SEQ ID NO: 3 is E61, 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-2 conjugates described herein, n in the compounds of formula (VI) and (VII) 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.

[0038] In some embodiments, described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is replaced with a structure of formula (VI) or (VII), or a mixture of (VI) and (VII), wherein the replaced amino acid residue in SEQ ID NO: 3 is P64, 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-2 conjugates described herein, n in the compounds of formulas (VI) and (VII) 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.

[0039] Described herein is an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is replaced with a structure of formula (VI) or (VII), or a mixture of (VI) and (VII), 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, or from 5,000 daltons to 100,000 daltons, or from 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 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 15,000 Daltons to about 45,000 Daltons 1,000 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 is an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is replaced with a structure of formula (VI) or (VII), or a mixture of (VI) and (VII), and n is a number that indicates 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 40,000 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 120,000 daltons, about 140,000 daltons, about 160,000 daltons, about 180,000 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, about 50,000 daltons, about 55,000 daltons, about 55,000 daltons, about 60,000 daltons, about 65,000 daltons, about 65,000 daltons, about 70,000 daltons, about 75,000 daltons, about 80 The amino acid sequence is an integer such that the amino acid sequence is about 1,000 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 is an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is replaced with a structure of formula (VI) or (VII), or a mixture of (VI) and (VII), 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.

[0040] Described herein is an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 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;

[0041] X is [ka] or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, n in compounds of formula (VIII) and (IX) 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 from about 100 to about 1650, or from about 100 to about 1500, or from about 100 to about 1400, or from about 100 to about 1300, or from about 100 to about 1250, or 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 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 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. In some embodiments of the IL-2 conjugates described herein, n in the compounds of formula (VIII) and (IX) 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. In some embodiments of the IL-2 conjugates described herein, the position of the structure of Formula (VIII), Formula (IX), or a mixture of Formulas (VIII) and (IX) in the amino acid sequence of the IL-2 conjugate is selected from K34, F41, F43, K42, E61, P64, R37, T40, E67, Y44, V68, and L71, and the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is relative to the position in SEQ ID NO:3.In some embodiments of the IL-2 conjugates described herein, the position of the structure of Formula (VIII), Formula (IX), or a mixture of Formulas (VIII) and (IX) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is selected from K34, F41, F43, K42, E61, P64, R37, T40, E67, Y44, V68, and L71. In some embodiments of the IL-2 conjugates described herein, the position of the structure of Formula (VIII), Formula (IX), or a mixture of Formulas (VIII) and (IX) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is K34. In some embodiments of the IL-2 conjugates described herein, the position of the structure of Formula (VIII), Formula (IX), or a mixture of Formulas (VIII) and (IX) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is F41. In some embodiments of the IL-2 conjugates described herein, the position of the structure of Formula (VIII), Formula (IX), or a mixture of Formulas (VIII) and (IX) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position F43. In some embodiments of the IL-2 conjugates described herein, the position of the structure of Formula (VIII), Formula (IX), or a mixture of Formulas (VIII) and (IX) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position K42. In some embodiments of the IL-2 conjugates described herein, the position of the structure of Formula (VIII), Formula (IX), or a mixture of Formulas (VIII) and (IX) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position E61. In some embodiments of the IL-2 conjugates described herein, the position of the structure of Formula (VIII), Formula (IX), or a mixture of Formulas (VIII) and (IX) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position P64. In some embodiments of the IL-2 conjugates described herein, the position of the structure of formula (VIII), formula (IX), or a mixture of formulas (VIII) and (IX) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position R37.In some embodiments of the IL-2 conjugates described herein, the position of the structure of formula (VIII), formula (IX), or a mixture of formulas (VIII) and (IX) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position T40. In some embodiments of the IL-2 conjugates described herein, SEQ ID NO: 3. The location of the structure of Formula (VIII), Formula (IX), or a mixture of Formulas (VIII) and (IX) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position E67. In some embodiments of the IL-2 conjugates described herein, the location of the structure of Formula (VIII), Formula (IX), or a mixture of Formulas (VIII) and (IX) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position Y44. In some embodiments of the IL-2 conjugates described herein, the location of the structure of Formula (VIII), Formula (IX), or a mixture of Formulas (VIII) and (IX) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position V68. In some embodiments of the IL-2 conjugates described herein, the location of the structure of Formula (VIII), Formula (IX), or a mixture of Formulas (VIII) and (IX) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position L71. In some embodiments of the IL-2 conjugates described herein, the ratio of the amount of the structure of formula (VIII) to the amount of the structure of formula (IX), including the total amount of the IL-2 conjugate, is about 1:1. In some embodiments of the IL-2 conjugates described herein, the ratio of the amount of the structure of formula (VIII) to the amount of the structure of formula (IX), including the total amount of the IL-2 conjugate, is greater than 1:1. In some embodiments of the IL-2 conjugates described herein, the ratio of the amount of the structure of formula (VIII) to the amount of the structure of formula (IX), including the total amount of the IL-2 conjugate, is less than 1:1.

[0042] In some embodiments, described herein is an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is replaced with a structure of formula (VIII) or (IX), or a mixture of (VIII) and (IX), and the replaced amino acid residues in SEQ ID NO: 3 are K34, F41, F43, K42, E61, P64, R37, T40, E67, Y44, V68, and L71, wherein n is selected from 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 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-2 conjugates described herein, n in the compounds of formula (VIII) and (IX) 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.

[0043] In some embodiments, described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is replaced with a structure of formula (VIII) or (IX), or a mixture of (VIII) and (IX), wherein the replaced amino acid residue in SEQ ID NO: 3 is selected from F41, F43, K42, E61, and P64, 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-2 conjugates described herein, n in the compounds of formula (VIII) and (IX) 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.

[0044] In some embodiments, described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is replaced with a structure of formula (VIII) or (IX), or a mixture of (VIII) and (IX), wherein the replaced amino acid residue in SEQ ID NO: 3 is selected from E61 and P64, 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-2 conjugates described herein, n in the compounds of Formulas (VIII) and (IX) is an integer selected from 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910.

[0045] In some embodiments, described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is replaced with a structure of formula (VIII) or (IX), or a mixture of (VIII) and (IX), where the replaced amino acid residue in SEQ ID NO: 3 is E61, 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-2 conjugates described herein, n in the compounds of Formulas (VIII) and (IX) 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.

[0046] In some embodiments, described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is replaced with a structure of formula (VIII) or (IX), or a mixture of (VIII) and (IX), wherein the replaced amino acid residue in SEQ ID NO: 3 is P64, 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-2 conjugates described herein, n in the compounds of formula (VIII) and (IX) 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.

[0047] Described herein is an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is replaced with a structure of formula (VIII) or (IX), or a mixture of (VIII) and (IX), and n is a number representing the molecular weight of the PEG moiety between about 1,000 daltons and about 200,000 daltons. or about 2,000 daltons to about 150,000 daltons, or about 3,000 daltons to about 125,000 daltons, or 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 1000 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 15,000 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.2,000 daltons, or about 20,000 daltons to about 35,000 daltons, or about 20,000 daltons to about 30,000 daltons. Described herein is an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is replaced with a structure of formula (VIII) or (IX), or a mixture of (VIII) and (IX), 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, or about 35,000 daltons. and an integer such as 5,000 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 is an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is replaced with a structure of formula (VIII) or (XI), or a mixture of (VIII) and (IX), 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.

[0048] Described herein is an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 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 amino acid residue in SEQ ID NO: 3 that is not replaced), or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0049] 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).

[0050] In some embodiments of the IL-2 conjugates described herein, n in compounds of formula (X) and (XI) 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 about 100 to about 2000, or about 100 to about 1900, or about 100 to about 1850, or 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 10 0 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 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. In some embodiments of the IL-2 conjugates described herein, n in the compounds of formula (X) and (XI) 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, 14 , 3976, 3977, 3978, 4544, 4545, and 4546.In some embodiments of the IL-2 conjugates described herein, the position of the structures of Formula (X) and (XI), or a mixture of Formula (X) and (XI), in the amino acid sequence of the IL-2 conjugate is selected from K34, F41, F43, K42, E61, P64, R37, T40, E67, Y44, V68, and L71, and the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is relative to the position of SEQ ID NO: 3. In some embodiments of the IL-2 conjugates described herein, the position of the structures of Formula (X) and (XI), or a mixture of Formula (X) and (XI), in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is selected from K34, F41, F43, K42, E61, P64, R37, T40, E67, Y44, V68, and L71. In some embodiments of the IL-2 conjugates described herein, the location of the structure of Formula (X) and (XI), or a mixture of Formulas (X) and (XI), in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position K34. In some embodiments of the IL-2 conjugates described herein, the location of the structure of Formula (X) and (XI), or a mixture of Formulas (X) and (XI), in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position F41. In some embodiments of the IL-2 conjugates described herein, the location of the structure of Formula (X) and (XI), or a mixture of Formulas (X) and (XI), in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position F43. In some embodiments of the IL-2 conjugates described herein, the location of the structure of Formula (X) and (XI), or a mixture of Formulas (X) and (XI), in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position K42. In some embodiments of the IL-2 conjugates described herein, the location of the structure of formula (X) and (XI), or a mixture of formulas (X) and (XI), in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position E61. In some embodiments of the IL-2 conjugates described herein, the location of the structure of formula (X) and (XI), or a mixture of formulas (X) and (XI), in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position P64.In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate of SEQ ID NO:3. The location of the structure of Formula (X) and (XI), or a mixture of Formulas (X) and (XI), in the amino acid sequence of the gate is position R37. In some embodiments of the IL-2 conjugates described herein, the location of the structure of Formula (X) and (XI), or a mixture of Formulas (X) and (XI), in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position T40. In some embodiments of the IL-2 conjugates described herein, the location of the structure of Formula (X) and (XI), or a mixture of Formulas (X) and (XI), in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position E67. In some embodiments of the IL-2 conjugates described herein, the location of the structure of Formula (X) and (XI), or a mixture of Formulas (X) and (XI), in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position Y44. In some embodiments of the IL-2 conjugates described herein, the position of the structure of Formula (X) and (XI), or a mixture of Formulas (X) and (XI), in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position V68. In some embodiments of the IL-2 conjugates described herein, the position of the structure of Formula (X) and (XI), or a mixture of Formulas (X) and (XI), in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position L71. In some embodiments of the IL-2 conjugates described herein, the ratio of the amount of the structure of Formula (X) to the amount of the structure of Formula (XI), including the total amount of the IL-2 conjugate, is about 1:1. In some embodiments of the IL-2 conjugates described herein, the ratio of the amount of the structure of Formula (X) to the amount of the structure of Formula (XI), including the total amount of the IL-2 conjugate, is greater than 1:1. In some embodiments of the IL-2 conjugates described herein, the ratio of the amount of the structure of formula (X) to the amount of the structure of formula (XI), including the total amount of the IL-2 conjugate, is less than 1:1.

[0051] In some embodiments, described herein is an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is replaced with a structure of formula (X) or (XI), or a mixture of (X) and (XI), and the replaced amino acid residues in SEQ ID NO: 3 are K34, F41, F43, K42, E61, P64, R37, T40, E67, Y44, V68, and L69. 71, where n is selected 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 100 to about 350, or from about 100 to about 275, or from about 100 to about 230, or from 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 12 50, 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-2 conjugates described herein, n in the compounds of formula (VI) and (VII) 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. is an integer selected from the group consisting of 40, 2841, 2953, 2954, 2955, 3408, 3409, 3410, 3976, 3977, 3978, 4544, 4545, and 4546.

[0052] In some embodiments, described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is replaced with a structure of formula (X) or (XI), or a mixture of (X) and (XI), wherein the replaced amino acid residue in SEQ ID NO: 3 is selected from F41, F43, K42, E61, and P64, 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-2 conjugates described herein, n in the compounds of formula (X) and (XI) 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.

[0053] In some embodiments, described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is replaced with a structure of formula (X) or (XI), or a mixture of (X) and (XI), wherein the replaced amino acid residue in SEQ ID NO: 3 is selected from E61 and P64, 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-2 conjugates described herein, n in the compounds of Formulas (X) and (XI) is an integer selected from 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910.

[0054] In some embodiments, described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is replaced with a structure of formula (X) or (XI), or a mixture of (X) and (XI), where the replaced amino acid residue in SEQ ID NO: 3 is E61, 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-2 conjugates described herein, n in the compounds of formula (X) and (XI) 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.

[0055] In some embodiments, described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is replaced with a structure of formula (X) or (XI), or a mixture of (X) and (XI), where the replaced amino acid residue in SEQ ID NO: 3 is P64, 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-2 conjugates described herein, n in the compounds of formula (X) and (XI) 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.

[0056] Described herein is an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO:3. wherein at least one amino acid residue in the IL-2 conjugate is replaced with a structure of formula (X) or (XI), or a mixture of (X) and (XI), and n is a number representing the molecular weight of the PEG moiety 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 from about 5,000 daltons to about 100,000 daltons, or from 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 15,000 daltons to about 45,000 daltons, or about 15,000 daltons to about 40,000 daltons, or about 15,The integer is in the range of about 1,000 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 is an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is replaced with a structure of formula (X) or (XI), or a mixture of (X) and (XI), and n is a number ranging from 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 40,000 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 120,000 daltons, about 140,000 daltons, about 160,000 daltons, about 180,000 daltons, about 190,000 daltons, about 210,000 daltons, about 220,000 daltons, about 230,000 daltons, about 240,000 daltons, about 250,000 daltons, about 260,000 daltons, about 270,000 daltons, about 280,000 daltons, about 290,000 daltons, about 300,000 daltons, about 310,000 daltons, about 320,000 daltons, about 330,000 daltons, about 3 00 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 is an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is replaced with a structure of formula (X) or (XI), or a mixture of (X) and (XI), 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.

[0057] Described herein is an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is represented by the formula (XI Structure of I) 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 amino acid residue in SEQ ID NO: 3 that is not replaced), or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0058] 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).

[0059] In some embodiments of the IL-2 conjugates described herein, n in compounds of formula (XII) and (XIII) 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, is about 100 to about 1900, or about 100 to about 1850, or 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, is 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 46 ... It is in the range of 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 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. In some embodiments of the IL-2 conjugates described herein, n in the compounds of formula (XII) and (XIII) 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.In some embodiments of the IL-2 conjugates described herein, the position of the structures of Formula (XII) and (XIII) or a mixture of Formulas (XII) and (XIII) in the amino acid sequence of the IL-2 conjugate is selected from K34, F41, F43, K42, E61, P64, R37, T40, E67, Y44, V68, and L71, and the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is relative to the position of SEQ ID NO: 3. In some embodiments of the IL-2 conjugates described herein, the position of the structures of Formula (XII) and (XIII) or a mixture of Formulas (XII) and (XIII) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is selected from K34, F41, F43, K42, E61, P64, R37, T40, E67, Y44, V68, and L71. In some embodiments of the IL-2 conjugates described herein, the location of the structure of Formula (XII) and (XIII) or a mixture of Formulas (XII) and (XIII) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position K34. In some embodiments of the IL-2 conjugates described herein, the location of the structure of Formula (XII) and (XIII) or a mixture of Formulas (XII) and (XIII) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position F41. In some embodiments of the IL-2 conjugates described herein, the location of the structure of Formula (XII) and (XIII) or a mixture of Formulas (XII) and (XIII) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position F43. In some embodiments of the IL-2 conjugates described herein, the location of the structure of Formula (XII) and (XIII) or a mixture of Formulas (XII) and (XIII) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position K42. In some embodiments of the IL-2 conjugates described herein, the location of the structures of formula (XII) and (XIII) or a mixture of formula (XII) and (XIII) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position E61.In some embodiments of the IL-2 conjugates described herein, the position of the structures of formulas (XII) and (XIII) or a mixture of formulas (XII) and (XIII) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position P64 of the IL-2 conjugates described herein. In some embodiments, the position of the structure of Formula (XII) and (XIII) or a mixture of Formulas (XII) and (XIII) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position R37. In some embodiments of the IL-2 conjugates described herein, the position of the structure of Formula (XII) and (XIII) or a mixture of Formulas (XII) and (XIII) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position T40. In some embodiments of the IL-2 conjugates described herein, the position of the structure of Formula (XII) and (XIII) or a mixture of Formulas (XII) and (XIII) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position E67. In some embodiments of the IL-2 conjugates described herein, the position of the structure of Formula (XII) and (XIII) or a mixture of Formulas (XII) and (XIII) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position Y44. In some embodiments of the IL-2 conjugates described herein, the position of the structure of Formula (XII) and (XIII) or a mixture of Formulas (XII) and (XIII) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position V68. In some embodiments of the IL-2 conjugates described herein, the position of the structure of Formula (XII) and (XIII) or a mixture of Formulas (XII) and (XIII) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position L71. In some embodiments of the IL-2 conjugates described herein, the ratio of the amount of the structure of Formula (XII) to the amount of the structure of Formula (XIII), including the total amount of the IL-2 conjugate, is about 1:1. In some embodiments of the IL-2 conjugates described herein, the ratio of the amount of the structure of Formula (XII) to the amount of the structure of Formula (XIII), including the total amount of the IL-2 conjugate, is greater than 1:1. In some embodiments of the IL-2 conjugates described herein, the ratio of the amount of the structure of formula (XII) to the amount of the structure of formula (XIII), including the total amount of the IL-2 conjugate, is less than 1:1.

[0060] In some embodiments, described herein is an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is replaced with a structure of formula (XII) or (XIII), or a mixture of (XII) and (XIII), and the replaced amino acid residues in SEQ ID NO: 3 are K34, F41, F43, K42, E61, P64, R37, T40, E67, Y44, V6 8, and L71, and n is selected from 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 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-2 conjugates described herein, n in the compounds of formula (XII) and (XIII) 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, 1716, 1718, 1719, 1720, 1721, 1722, 1723, 1724, 1725, 1726, 1727, 1728, 1729, 1730, 1731, 1732, 1733, 1734, 1735, 1736, 1737, 1738, 1739, 1740, 1741, 1742, 1743, 1744, 1745, 1746, 1747, 1748, 1749, 1750, 1751, 1752, 1753, 1754, 1755, 1756, 1 04, 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.

[0061] In some embodiments, described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is replaced with a structure of formula (XII) or (XIII), or a mixture of (XII) and (XIII), wherein the replaced amino acid residue in SEQ ID NO: 3 is selected from F41, F43, K42, E61, and P64, 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-2 conjugates described herein, n in the compounds of formula (XII) and (XIII) 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.

[0062] In some embodiments, described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is replaced with a structure of formula (XII) or (XIII), or a mixture of (XII) and (XIII), wherein the replaced amino acid residue in SEQ ID NO: 3 is selected from E61 and P64, 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-2 conjugates described herein, n in the compounds of Formulas (XII) and (XIII) is an integer selected from 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910.

[0063] In some embodiments, described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is replaced with a structure of formula (XII) or (XIII), or a mixture of (XII) and (XIII), where the replaced amino acid residue in SEQ ID NO: 3 is E61, 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-2 conjugates described herein, n in the compounds of Formulas (XII) and (XIII) 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.

[0064] In some embodiments, described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is replaced with a structure of formula (XII) or (XIII), or a mixture of (XII) and (XIII), wherein the replaced amino acid residue in SEQ ID NO: 3 is P64, 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-2 conjugates described herein, n in the compounds of formula (XII) and (XIII) 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. part In this embodiment, n is about 681.

[0065] Described herein is an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is replaced with a structure of formula (XII) or (XIII), or a mixture of (XII) and (XIII), and n is an integer from 1 to 2, where n is an integer from 1 to 2, and n is an integer from 2 to 1, and n is an integer from 1 to 2 ... 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 0 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 15,000 Daltons to about 45,000 Daltons1,000 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 is an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is replaced with a structure of formula (XII) or (XIII), or a mixture of (XII) and (XIII), 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, about and an integer such as 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 is an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is replaced with a structure of formula (XII) or (XIII), or a mixture of (XII) and (XIII), 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.

[0066] Described herein is an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 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 wavy line indicates a covalent bond to the amino acid residue in SEQ ID NO: 3 that is not replaced), or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0067] 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).

[0068] In some embodiments of the IL-2 conjugates described herein, m in the compounds of formula (XIV) and (XV) is 0 to 20, or 0 to 18, or 0 to 16, or 0 to 14, or 0 to 12, or 0 to 10, or 0 to 9, or 0 to 8, or 0 to 7, or 0 to 6, or 0 to 5, or 0 to 4, or 0 to 3, or 0 to 2. In some embodiments of the IL-2 conjugates described herein, m in the compounds of formula (XIV) and (XV) is 0 to 20, or 0 to 18, or 0 to 16, or 0 to 14, or 0 to 12, or 0 to 10, or 0 to 9, or 0 to 8, or 0 to 7, or 0 to 6, or 0 to 5, or 0 to 4 In some embodiments of the IL-2 conjugates described herein, m in the compounds of Formulae (XIV) and (XV) is 0. In some embodiments of the IL-2 conjugates described herein, m in the compounds of Formulae (XIV) and (XV) is 1. In some embodiments of the IL-2 conjugates described herein, m in the compounds of Formulae (XIV) and (XV) is 2. In some embodiments of the IL-2 conjugates described herein, m in the compounds of Formulae (XIV) and (XV) is 3. In some embodiments of the IL-2 conjugates described herein, m in the compounds of Formulae (XIV) and (XV) is 4. In some embodiments of the IL-2 conjugates described herein, m in the compounds of Formulae (XIV) and (XV) is 5. In some embodiments of the IL-2 conjugates described herein, m in the compounds of Formulae (XIV) and (XV) is 6. In some embodiments of the IL-2 conjugates described herein, m in the compounds of Formula (XIV) and (XV) is 7. In some embodiments of the IL-2 conjugates described herein, m in the compounds of Formula (XIV) and (XV) is 8. In some embodiments of the IL-2 conjugates described herein, m in the compounds of Formula (XIV) and (XV) is 9. In some embodiments of the IL-2 conjugates described herein, m in the compounds of Formula (XIV) and (XV) is 10. In some embodiments of the IL-2 conjugates described herein, m in the compounds of Formula (XIV) and (XV) is 11. In some embodiments of the IL-2 conjugates described herein, m in the compounds of Formula (XIV) and (XV) is 12. In some embodiments of the IL-2 conjugates described herein, m in the compounds of Formula (XIV) and (XV) is 13. In some embodiments of the IL-2 conjugates described herein, m in the compounds of formula (XIV) and (XV) is 14. In some embodiments of the IL-2 conjugates described herein, m in the compounds of formula (XIV) and (XV) is 15.In some embodiments of the IL-2 conjugates described herein, m in the compounds of Formula (XIV) and (XV) is 16. In some embodiments of the IL-2 conjugates described herein, m in the compounds of Formula (XIV) and (XV) is 17. In some embodiments of the IL-2 conjugates described herein, m in the compounds of Formula (XIV) and (XV) is 18. In some embodiments of the IL-2 conjugates described herein, m in the compounds of Formula (XIV) and (XV) is 19. In some embodiments of the IL-2 conjugates described herein, m in the compounds of Formula (XIV) and (XV) is 20.

[0069] In some embodiments of the IL-2 conjugates described herein, p in the compounds of Formula (XIV) and (XV) is 0 to 20, or 0 to 18, or 0 to 16, or 0 to 14, or 0 to 12, or 0 to 10, or 0 to 9, or 0 to 8, or 0 to 7, or 0 to 6, or 0 to 5, or 0 to 4, or 0 to 3, or 0 to 2. In some embodiments of the IL-2 conjugates described herein, p in the compounds of Formula (XIV) and (XV) is 0. In some embodiments of the IL-2 conjugates described herein, p in the compounds of Formula (XIV) and (XV) is 1. In some embodiments of the IL-2 conjugates described herein, p in the compounds of Formula (XIV) and (XV) is 2. In some embodiments of the IL-2 conjugates described herein, p in the compounds of Formula (XIV) and (XV) is 3. In some embodiments of the IL-2 conjugates described herein, p in the compounds of formula (XIV) and (XV) is 4. In some embodiments of the IL-2 conjugates described herein, p in the compounds of formula (XIV) and (XV) is 5. In some embodiments of the IL-2 conjugates described herein, p in the compounds of formula (XIV) and (XV) is 6. In some embodiments of the IL-2 conjugates described herein, p in the compounds of formula (XIV) and (XV) is 7. In some embodiments of the IL-2 conjugates described herein, In some embodiments of the IL-2 conjugates described herein, p in the compounds of Formulae (XIV) and (XV) is 8. In some embodiments of the IL-2 conjugates described herein, p in the compounds of Formulae (XIV) and (XV) is 9. In some embodiments of the IL-2 conjugates described herein, p in the compounds of Formulae (XIV) and (XV) is 10. In some embodiments of the IL-2 conjugates described herein, p in the compounds of Formulae (XIV) and (XV) is 11. In some embodiments of the IL-2 conjugates described herein, p in the compounds of Formulae (XIV) and (XV) is 12. In some embodiments of the IL-2 conjugates described herein, p in the compounds of Formulae (XIV) and (XV) is 13. In some embodiments of the IL-2 conjugates described herein, p in the compounds of Formulae (XIV) and (XV) is 14. In some embodiments of the IL-2 conjugates described herein, p in the compounds of Formula (XIV) and (XV) is 15. In some embodiments of the IL-2 conjugates described herein, m in the compounds of Formula (XIV) and (XV) is 16. In some embodiments of the IL-2 conjugates described herein, p in the compounds of Formula (XIV) and (XV) is 17. In some embodiments of the IL-2 conjugates described herein, p in the compounds of Formula (XIV) and (XV) is 18. In some embodiments of the IL-2 conjugates described herein, p in the compounds of Formula (XIV) and (XV) is 19. In some embodiments of the IL-2 conjugates described herein, p in the compounds of Formula (XIV) and (XV) is 20.

[0070] In some embodiments of the IL-2 conjugates described herein, n in 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.

[0071] In some embodiments of the IL-2 conjugates described herein, in the compounds of formula (XIV) and (XV), m is an integer from 0 to 6, p is an integer from 0 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-2 conjugates described herein, in the compounds of formula (XIV), In compounds of formulas (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-2 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-2 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-2 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-2 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-2 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-2 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-2 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-2 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-2 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-2 conjugates described herein, in the compounds of formula (XIV) and (XV), m is 8, p is 2, and n is 113, 114, 227, 228,. is an integer selected from 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-2 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-2 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-2 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-2 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-2 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.

[0072] In some embodiments of the IL-2 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, 1 is an integer selected from 476, 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. In some embodiments of the IL-2 conjugates described herein, the position of the structures of Formula (XIV) and (XV), or a mixture of Formulas (XIV) and (XV), in the amino acid sequence of the IL-2 conjugate is selected from K34, F41, F43, K42, E61, P64, R37, T40, E67, Y44, V68, and L71, and the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is relative to the position of SEQ ID NO: 3. In some embodiments of the IL-2 conjugates described herein, the position of the structures of Formula (XIV) and (XV), or a mixture of Formulas (XIV) and (XV), in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is selected from K34, F41, F43, K42, E61, P64, R37, T40, E67, Y44, V68, and L71. In some embodiments of the IL-2 conjugates described herein, the position of the structure of formula (XIV) and (XV), or a mixture of formula (XIV) and (XV), in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position K34. In some embodiments of the IL-2 conjugates described herein, the location of the structure of Formula (XIV) and (XV), or a mixture of Formulas (XIV) and (XV), in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position F41. In some embodiments of the IL-2 conjugates described herein, the location of the structure of Formula (XIV) and (XV), or a mixture of Formulas (XIV) and (XV), in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position F43. In some embodiments of the IL-2 conjugates described herein, the location of the structure of Formula (XIV) and (XV), or a mixture of Formulas (XIV) and (XV), in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position K42. In some embodiments of the IL-2 conjugates described herein, the location of the structure of Formula (XIV) and (XV), or a mixture of Formulas (XIV) and (XV), in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position E61. In some embodiments of the IL-2 conjugates described herein, the location of the structure of Formula (XIV) and (XV), or a mixture of Formulas (XIV) and (XV), in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position P64. In some embodiments of the IL-2 conjugates described herein, the location of the structure of Formula (XIV) and (XV), or a mixture of Formulas (XIV) and (XV), in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position R37. In some embodiments of the IL-2 conjugates described herein, the location of the structure of Formula (XIV) and (XV), or a mixture of Formulas (XIV) and (XV), in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position T40. In some embodiments of the IL-2 conjugates described herein, the location of the structure of Formula (XIV) and (XV), or a mixture of Formulas (XIV) and (XV), in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position E67. In some embodiments of the IL-2 conjugates described herein, the location of the structures of formula (XIV) and (XV), or a mixture of formula (XIV) and (XV), in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position Y44.In some embodiments of the IL-2 conjugates described herein, 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-2 conjugate of SEQ ID NO: 3 is position V68. In some embodiments of the IL-2 conjugates described herein, 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-2 conjugate of SEQ ID NO: 3 is position L71. In some embodiments of the IL-2 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 of the IL-2 conjugate, is about 1:1. In some embodiments of the IL-2 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 of the IL-2 conjugate, is greater than 1:1. In some embodiments of the IL-2 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 of the IL-2 conjugate, is less than 1:1.

[0073] In some embodiments, described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 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 K34, F41, F43, K42, E61, P64, R37, T40, E67, Y44, V68, and L71; and 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 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 It is an integer of 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 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. In some embodiments of the IL-2 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, 1 is an integer selected from 476, 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.

[0074] In some embodiments, described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 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 F41, F43, K42, E61, and P64, 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-2 conjugates described herein, n in the compounds of formula (XIV) and (XV) 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.

[0075] In some embodiments, described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 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 E61 and P64, 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-2 conjugates described herein, n in the compounds of Formulas (XIV) and (XV) is an integer selected from 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910.

[0076] In some embodiments, described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is replaced with a structure of formula (XIV) or (XV), or a mixture of (XIV) and (XV), where the replaced amino acid residue in SEQ ID NO: 3 is E61, 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-2 conjugates described herein, n in the compounds of formula (XIV) and (XV) 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 In this case, n is approximately 681.

[0077] In some embodiments, described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 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 P64, 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-2 conjugates described herein, n in the compounds of formula (XIV) and (XV) 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.

[0078] Described herein is an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is replaced with a structure of formula (XIV) or (XV), or a mixture of (XIV) and (XV), and n is an integer from 1 to 2, where n is an integer from 1 to 2, and n is an integer from 2 to 1, and n is an integer from 1 to 2 ... 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 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 10,000 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 15,000 Daltons to about 45,000 Daltons1,000 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 is an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is replaced with a structure of formula (XIV) or (XV), or a mixture of (XIV) and (XV), 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, about 25,000 daltons, about 30,000 daltons, or about 40,000 daltons. 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 is an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 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.

[0079] In some embodiments, described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 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 F41, F43, K42, E61, and P64; m is an integer from 0 to 6; p is an integer from 0 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-2 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, 910, 1021, 1022, 1023, 1135, 1136, 1137, and 1249.

[0080] In some embodiments, described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 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 E61 and P64, m is an integer from 0 to 6, p is an integer from 0 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-2 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.

[0081] In some embodiments, described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 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 E61, m is an integer from 0 to 6, p is an integer from 0 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-2 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 from about 500 to about 1000. In some embodiments, n is from about 550 to about 800. In some embodiments, n is about 681.

[0082] In some embodiments, described herein is a medicament comprising the amino acid sequence of SEQ ID NO:3. An IL-2 conjugate, wherein at least one amino acid residue in the IL-2 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 P64, m is an integer from 0 to 6, p is an integer from 0 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-2 conjugate 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 from about 500 to about 1000. In some embodiments, n is about 550 to about 800. In some embodiments, n is about 681.

[0083] Described herein is an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate has the 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 amino acid residue in SEQ ID NO: 3 that is not replaced), or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0084] 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 , 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).

[0085] In some embodiments of the IL-2 conjugates described herein, m in the compounds of Formula (XVI) and (XVII) is 0 to 20, or 0 to 18, or 0 to 16, or 0 to 14, or 0 to 12, or 0 to 10, or 0 to 9, or 0 to 8, or 0 to 7, or 0 to 6, or 0 to 5, or 0 to 4, or 0 to 3, or 0 to 2. In some embodiments of the IL-2 conjugates described herein, m in the compounds of Formula (XVI) and (XVII) is 0. In some embodiments of the IL-2 conjugates described herein, m in the compounds of Formula (XVI) and (XVII) is 1. In some embodiments of the IL-2 conjugates described herein, m in the compounds of Formula (XVI) and (XVII) is 2. In some embodiments of the IL-2 conjugates described herein, m in the compounds of Formula (XVI) and (XVII) is 3. In some embodiments of the IL-2 conjugates described herein, m in the compounds of Formula (XVI) and (XVII) is 4. In some embodiments of the IL-2 conjugates described herein, m in the compounds of Formula (XVI) and (XVII) is 5. In some embodiments of the IL-2 conjugates described herein, m in the compounds of Formula (XVI) and (XVII) is 6. In some embodiments of the IL-2 conjugates described herein, m in the compounds of Formula (XVI) and (XVII) is 7. In some embodiments of the IL-2 conjugates described herein, m in the compounds of Formula (XVI) and (XVII) is 8. In some embodiments of the IL-2 conjugates described herein, m in the compounds of Formula (XVI) and (XVII) is 9. In some embodiments of the IL-2 conjugates described herein, m in the compounds of Formula (XVI) and (XVII) is 10. In some embodiments of the IL-2 conjugates described herein, m in the compounds of formula (XVI) and (XVII) is 11. In some embodiments of the IL-2 conjugates described herein, m in the compounds of formula (XVI) and (XVII) is 12.In some embodiments of the IL-2 conjugates described herein, m in the compounds of Formula (XVI) and (XVII) is 13. In some embodiments of the IL-2 conjugates described herein, m in the compounds of Formula (XVI) and (XVII) is 14. In some embodiments of the IL-2 conjugates described herein, m in the compounds of Formula (XVI) and (XVII) is 15. In some embodiments of the IL-2 conjugates described herein, m in the compounds of Formula (XVI) and (XVII) is 16. In some embodiments of the IL-2 conjugates described herein, m in the compounds of Formula (XVI) and (XVII) is 17. In some embodiments of the IL-2 conjugates described herein, m in the compounds of Formula (XVI) and (XVII) is 18. In some embodiments of the IL-2 conjugates described herein, m in the compounds of Formula (XVI) and (XVII) is 19. In some embodiments of the IL-2 conjugates described herein, m is 20 in the compounds of formula (XVI) and (XVII).

[0086] In some embodiments of the IL-2 conjugates described herein, n in 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 1750, or from about 100 to about 1650, or about 10 0 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 is 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 about 225 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.

[0087] In some embodiments of the IL-2 conjugates described herein, in the compounds of formula (XVI) and (XVII), m is an integer from 0 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-2 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-2 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-2 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-2 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-2 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-2 conjugates described herein, in the compounds of formula (XVI) and (XVII), m is 3 and n is 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-2 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-2 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-2 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-2 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-2 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-2 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-2 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-2 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-2 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-2 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.

[0088] In some embodiments of the IL-2 conjugates described herein, n in the compounds of formula (XVI) and (XVII) is 2, 5, 10, 11, 22, 23, 113, 1 14, 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. In some embodiments of the IL-2 conjugates described herein, the position of the structures of Formula (XVI) and (XVII), or a mixture of Formulas (XVI) and (XVII), in the amino acid sequence of the IL-2 conjugate is selected from K34, F41, F43, K42, E61, P64, R37, T40, E67, Y44, V68, and L71, and the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is relative to the position of SEQ ID NO: 3. In some embodiments of the IL-2 conjugates described herein, the position of the structures of Formula (XVI) and (XVII), or a mixture of Formulas (XVI) and (XVII), in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is selected from K34, F41, F43, K42, E61, P64, R37, T40, E67, Y44, V68, and L71. In some embodiments of the IL-2 conjugates described herein, the location of the structure of Formula (XVI) and (XVII), or a mixture of Formulas (XVI) and (XVII), in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position K34. In some embodiments of the IL-2 conjugates described herein, the location of the structure of Formula (XVI) and (XVII), or a mixture of Formulas (XVI) and (XVII), in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position F41.In some embodiments of the IL-2 conjugates described herein, the location of the structure of Formula (XVI) and (XVII) or a mixture of Formulas (XVI) and (XVII) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position F43. In some embodiments of the IL-2 conjugates described herein, the location of the structure of Formula (XVI) and (XVII) or a mixture of Formulas (XVI) and (XVII) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position K42. In some embodiments of the IL-2 conjugates described herein, the location of the structure of Formula (XVI) and (XVII) or a mixture of Formulas (XVI) and (XVII) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position E61. In some embodiments of the IL-2 conjugates described herein, the location of the structure of Formula (XVI) and (XVII) or a mixture of Formulas (XVI) and (XVII) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position P64. In some embodiments of the IL-2 conjugates described herein, the location of the structure of Formula (XVI) and (XVII) or a mixture of Formulas (XVI) and (XVII) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position R37. In some embodiments of the IL-2 conjugates described herein, the location of the structure of Formula (XVI) and (XVII) or a mixture of Formulas (XVI) and (XVII) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position T40. In some embodiments of the IL-2 conjugates described herein, the location of the structure of Formula (XVI) and (XVII), or a mixture of Formulas (XVI) and (XVII), in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position E67. In some embodiments of the IL-2 conjugates described herein, the location of the structure of Formula (XVI) and (XVII), or a mixture of Formulas (XVI) and (XVII), in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position Y44.In some embodiments of the IL-2 conjugates described herein, the position of the structures of formulae (XVI) and (XVII) or a mixture of formulae (XVI) and (XVII) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position V68. In some embodiments of the IL-2 conjugates described herein, the position of the structures of formulae (XVI) and (XVII) or a mixture of formulae (XVI) and (XVII) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is position V68. The position of the structure of formula (XVI) and (XVII) or a mixture of formula (XVI) and (XVII) in the amino acid sequence of the gate is position L71. In some embodiments of the IL-2 conjugates described herein, the ratio of the amount of the structure of formula (XVI) to the amount of the structure of formula (XVII), including the total amount of the IL-2 conjugate, is about 1:1. In some embodiments of the IL-2 conjugates described herein, the ratio of the amount of the structure of formula (XVI) to the amount of the structure of formula (XVII), including the total amount of the IL-2 conjugate, is greater than 1:1. In some embodiments of the IL-2 conjugates described herein, the ratio of the amount of the structure of formula (XVI) to the amount of the structure of formula (XVII), including the total amount of the IL-2 conjugate, is less than 1:1.

[0089] In some embodiments, described herein is an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is replaced with a structure of formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), and the replaced amino acid residues in SEQ ID NO: 3 are K34, F41, F43, K42, E61, P64, R37, T40, E67, Y44, V6 8, and L71, and n is selected from 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 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-2 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, 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.

[0090] In some embodiments, described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is replaced with a structure of formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), and the replaced amino acid residue in SEQ ID NO: 3 is selected from F41, F43, K42, E61, and P64, 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-2 conjugates described herein, n in the compounds of formula (XVI) and (XVII) is 454, 455, 568, 569, 68 is an integer selected from 0, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, 1137, and 1249.

[0091] In some embodiments, described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 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 selected from E61 and P64, 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-2 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.

[0092] In some embodiments, described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is replaced with a structure of formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), where the replaced amino acid residue in SEQ ID NO: 3 is E61, 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-2 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.

[0093] In some embodiments, described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 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 P64, 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-2 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.

[0094] Described herein is an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is replaced with a structure of formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), and n is a number representing the molecular weight of the PEG moiety 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. 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 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 50,000 daltons 0 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 15,000 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 is an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 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, about and an integer such as 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 is an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 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.

[0095] In some embodiments, described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 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 selected from F41, F43, K42, E61, and P64, m is an integer from 0 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-2 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.

[0096] In some embodiments, described herein is a medicament comprising the amino acid sequence of SEQ ID NO:3. An IL-2 conjugate, wherein at least one amino acid residue in the IL-2 conjugate is replaced with a structure of formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), and the replaced amino acid residue in SEQ ID NO: 3 is selected from E61 and P64, m is an integer from 0 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-2 conjugate 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.

[0097] In some embodiments, described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 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 E61, m is an integer from 0 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-2 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 from about 500 to about 1000. In some embodiments, n is from about 550 to about 800. In some embodiments, n is about 681.

[0098] In some embodiments, described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 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 P64, m is an integer from 0 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-2 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 from about 500 to about 1000. In some embodiments, n is from about 550 to about 800. In some embodiments, n is about 681.

[0099] Described herein are pharmaceutical compositions comprising an effective amount of an IL-conjugate described herein and one or more pharmaceutically acceptable excipients.

[0100] Described herein are methods of treating cancer in a subject, comprising administering to a subject in need thereof an effective amount of an IL-2 conjugate described herein. In some embodiments of the methods of treating cancer described herein, the cancer in the subject is selected from the group consisting of 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 carcinoma, microsatellite stable carcinoma, gastric cancer, cervix, hepatocellular carcinoma (HCC), Merkel cell carcinoma (MCC), melanoma, small cell lung cancer (SCLC), esophageal cancer, glial cancer, and glioma. Blastoma, mesothelioma, breast cancer, triple-negative breast cancer, prostate cancer, castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, metastatic castration-resistant prostate cancer with DNA damage response (DDR) deficiency, bladder cancer, ovarian cancer, tumors with moderate to low mutated tumor 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 cell type B and lymphoma. Described herein are methods of treating cancer in a subject, comprising administering an effective amount of an IL-2 conjugate described herein to a subject in need thereof. In some embodiments of the methods of treating cancer described herein, the cancer in the subject is cholangiocarcinoma. In some embodiments of the methods of treating cancer described herein, the cancer in the subject is selected from renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), urothelial carcinoma, and melanoma. In some embodiments of the methods of treating cancer described herein, the IL-2 conjugate is administered to a subject in need thereof once 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 of the methods of treating cancer described herein, the IL-2 conjugate is administered to a subject in need thereof once per week or once every two weeks. In some embodiments of the methods of treating cancer described herein, the IL-2 conjugate is administered to a subject in need thereof once per week. In some embodiments of the methods of treating cancer described herein, the IL-2 conjugate is administered to a subject in need thereof once every two weeks. In some embodiments of the methods of treating cancer described herein, administering an effective amount of the IL-2 conjugate to a subject does not cause vascular leak syndrome in the subject. In some embodiments of the methods of treating cancer described herein, administering an effective amount of an IL-2 conjugate to a subject does not cause grade 2, grade 3, or grade 4 vascular leak syndrome in the subject. In some embodiments of the methods of treating cancer described herein, administering an effective amount of an IL-2 conjugate to a subject does not cause grade 2 vascular leak syndrome in the subject. In some embodiments of the methods of treating cancer described herein, administering an effective amount of an IL-2 conjugate to a subject does not cause grade 3 vascular leak syndrome in the subject. In some embodiments of the methods of treating cancer described herein, administering an effective amount of an IL-2 conjugate to a subject does not cause grade 4 vascular leak syndrome in the subject. In some embodiments of the methods of treating cancer described herein, administering an effective amount of an IL-2 conjugate to a subject does not cause a lack of vascular tone in the subject. In some embodiments of the methods of treating cancer described herein, administering an effective amount of an IL-2 conjugate to a subject does not cause extravasation of plasma proteins and fluid into the extravascular space in the subject. In some embodiments of the methods of treating cancer described herein, administering an effective amount of an IL-2 conjugate to a subject does not cause hypotension and decreased organ perfusion in the subject. In some embodiments of the methods of treating cancer described herein, administering an effective amount of an IL-2 conjugate to a subject does not cause neutrophil dysfunction in the subject. In some embodiments of the methods of treating cancer described herein, administering an effective amount of an IL-2 conjugate to a subject does not cause decreased chemotaxis in the subject. In some embodiments of the methods of treating cancer described herein, administering an effective amount of an IL-2 conjugate to a subject is not associated with an increased risk of disseminated infection in the subject. In some embodiments of the methods of treating cancer described herein, the disseminated infection is sepsis or bacterial endocarditis. In some embodiments of the methods of treating cancer described herein, the disseminated infection is sepsis. In some embodiments of the methods of treating cancer described herein, the disseminated infection is bacterial endocarditis.In some embodiments of the methods of treating cancer described herein, the subject is treated for any existing bacterial infection before administering the IL-2 conjugate. In some embodiments of the methods of treating cancer described herein, the subject is treated with an antibacterial agent selected from oxacillin, nafcillin, ciprofloxacin, and vancomycin before administering the IL-2 conjugate. In some embodiments of the methods of treating cancer described herein, administering an effective amount of an IL-2 conjugate to a subject does not exacerbate an existing or initial manifestation of an autoimmune disease or inflammatory disorder in the subject. In some embodiments of the methods of treating cancer described herein, administering an effective amount of an IL-2 conjugate to a subject does not exacerbate an existing or initial manifestation of an autoimmune disease in the subject. In some embodiments of the methods of treating cancer described herein, administering an effective amount of an IL-2 conjugate to a subject does not exacerbate an existing or initial manifestation of an inflammatory disorder in the subject. or does not worsen the initial presentation. In some embodiments of the methods of treating cancer described herein, the autoimmune disease or inflammatory disorder in the subject is selected from Crohn's disease, scleroderma, thyroiditis, inflammatory arthritis, diabetes mellitus, oculo-bulbar myasthenia gravis, crescentic IgA glomerulonephritis, cholecystitis, cerebral vasculitis, Stevens-Johnson syndrome, and pemphigoid. In some embodiments of the methods of treating cancer described herein, the autoimmune disease or inflammatory disorder in the subject is Crohn's disease. In some embodiments of the methods of treating cancer described herein, the autoimmune disease or inflammatory disorder in the subject is scleroderma. In some embodiments of the methods of treating cancer described herein, the autoimmune disease or inflammatory disorder in the subject is thyroiditis. In some embodiments of the methods of treating cancer described herein, the autoimmune disease or inflammatory disorder in the subject is inflammatory arthritis. In some embodiments of the methods for treating cancer described herein, the autoimmune disease or inflammatory disorder in the subject is diabetes mellitus.In some embodiments of the methods for treating cancer described herein, the autoimmune disease or inflammatory disorder in the subject is ocular myasthenia gravis.In some embodiments of the methods for treating cancer described herein, the autoimmune disease or inflammatory disorder in the subject is crescentic IgA glomerulonephritis. In some embodiments of the methods of treating cancer described herein, the autoimmune disease or inflammatory disorder in the subject is cholecystitis. In some embodiments of the methods of treating cancer described herein, the autoimmune disease or inflammatory disorder in the subject is cerebral vasculitis. In some embodiments of the methods of treating cancer described herein, the autoimmune disease or inflammatory disorder in the subject is Stevens-Johnson syndrome. In some embodiments of the methods of treating cancer described herein, the autoimmune disease or inflammatory disorder in the subject is pemphigoid. In some embodiments of the methods of treating cancer described herein, administration of an effective amount of an IL-2 conjugate to a subject does not cause the subject to experience altered mental status, speech impairment, cortical blindness, limb or gait ataxia, hallucinations, agitation, relaxation, or coma. In some embodiments of the methods of treating cancer described herein, administration of an effective amount of an IL-2 conjugate to a subject does not cause the subject to experience seizures. In some embodiments of the methods of treating cancer described herein, administration of an effective amount of an IL-2 conjugate to a subject is not contraindicated in subjects with known seizure disorders. In some embodiments of the methods of treating cancer described herein, administration of an effective amount of an IL-2 conjugate to a subject does not cause capillary leak syndrome in the subject. In some embodiments of the methods of treating cancer described herein, administration of an effective amount of an IL-2 conjugate to a subject does not cause grade 2, grade 3, or grade 4 capillary leak syndrome in the subject. In some embodiments of the methods of treating cancer described herein, administration of an effective amount of an IL-2 conjugate to a subject does not cause grade 2 capillary leak syndrome in the subject. In some embodiments of the methods of treating cancer described herein, administration of an effective amount of an IL-2 conjugate to a subject does not cause grade 3 capillary leak syndrome in the subject. In some embodiments of the methods of treating cancer described herein, administration of an effective amount of an IL-2 conjugate to a subject does not cause grade 4 capillary leak syndrome in the subject.In some embodiments of the methods of treating cancer described herein, administering an effective amount of an IL-2 conjugate to a subject does not cause a decrease in mean arterial pressure in the subject after administration of the IL-2 conjugate to the subject. In some embodiments of the methods of treating cancer described herein, administering an effective amount of an IL-2 conjugate to a subject does not cause hypotension in the subject after administration of the IL-2 conjugate to the subject. In some embodiments of the methods of treating cancer described herein, administering an effective amount of an IL-2 conjugate to a subject does not cause the subject to experience a decrease in systolic blood pressure from baseline systolic blood pressure of less than 90 mmHg or 20 mmHg after administration of the IL-2 conjugate to the subject. In some embodiments of the methods of treating cancer described herein, administering an effective amount of an IL-2 conjugate to a subject does not cause edema in the subject after administration of the IL-2 conjugate to the subject. In some embodiments of the methods of treating cancer described herein, an effective amount of IL-2 conjugate to a subject is administered. Administration of an IL-2 conjugate to a subject does not cause impairment of kidney or liver function in the subject after administration of the IL-2 conjugate to the subject. In some embodiments of the methods of treating cancer described herein, administration of an effective amount of an IL-2 conjugate to a subject does not cause eosinophilia in the subject after administration of the IL-2 conjugate to the subject. In some embodiments of the methods of treating cancer described herein, administration of an effective amount of an IL-2 conjugate to a subject does not cause an eosinophil count in the subject's peripheral blood to exceed 500 per μL after administration of the IL-2 conjugate to the subject. In some embodiments of the methods of treating cancer described herein, administration of an effective amount of an IL-2 conjugate to a subject does not cause an eosinophil count in the subject's peripheral blood to exceed 500 to 1500 per μL after administration of the IL-2 conjugate to the subject. In some embodiments of the methods of treating cancer described herein, administering an effective amount of an IL-2 conjugate to a subject does not cause the subject's peripheral blood eosinophil count to exceed 1500 per μL to 5000 per μL after administration of the IL-2 conjugate to the subject. In some embodiments of the methods of treating cancer described herein, administering an effective amount of an IL-2 conjugate to a subject does not cause the subject's peripheral blood eosinophil count to exceed 5000 per μL after administration of the IL-2 conjugate to the subject. In some embodiments of the methods of treating cancer described herein, administering an effective amount of an IL-2 conjugate to a subject is not contraindicated in the subject's current regimen of psychotropic medications.

[0101] In some embodiments of the methods for treating cancer described herein, the administration of an effective amount of an IL-2 conjugate to a subject is not contraindicated in the subject's current regimen of nephrotoxic, myelotoxic, cardiotoxic, or hepatotoxic drugs. In some embodiments of the methods for treating cancer described herein, the administration of an effective amount of an IL-2 conjugate to a subject is not contraindicated in the subject's current regimen of aminoglycosides, cytotoxic chemotherapy, doxorubicin, methotrexate, or asparaginase. In some embodiments of the methods for treating cancer described herein, the administration of an effective amount of an IL-2 conjugate to a subject is not contraindicated in the subject's current regimen of an anti-neoplastic agent. In some embodiments of the methods for treating cancer described herein, the anti-neoplastic agent is selected from dacarbazine, cis-platinum, tamoxifen, and interferon-alpha. In some embodiments of the methods of treating cancer described herein, administering an effective amount of an IL-2 conjugate to a subject does not cause one or more grade 4 adverse events in the subject following administration of the IL-2 conjugate to the subject. In some embodiments of the methods of treating cancer described herein, the one or more Grade 4 adverse events include hypothermia; shock; bradycardia; ventricular extrasystoles; myocardial ischemia; syncope; bleeding; atrial arrhythmia; phlebitis; second-degree atrioventricular block; endocarditis; pericardial effusion; peripheral gangrene; thrombosis; coronary artery disease; stomatitis; nausea and vomiting; abnormal liver function tests; gastrointestinal bleeding; hematemesis; bloody diarrhea; gastrointestinal disorders; intestinal perforation; pancreatitis; anemia; leukopenia; leukocytosis; hypocalcemia; increased alkaline phosphatase; increased blood urea nitrogen (BUN); hyperuricemia; increased non-protein nitrogen (NPN); respiratory acidosis; somnolence; agitation; neuropathy; paranoid reaction; convulsions; grand mal seizures convulsion); delirium; asthma, pulmonary edema; hyperventilation; hypoxia; hemoptysis; hypoventilation; pneumothorax; mydriasis; pupillary obstruction; abnormal renal function; renal failure; and acute renal tubular necrosis. In some embodiments of the methods of treating cancer described herein, administering an effective amount of an IL-2 conjugate to a group of subjects does not cause one or more Grade 4 adverse events in more than 1% of the subjects after administration of the IL-2 conjugate to the subjects.In some embodiments of the methods of treating cancer described herein, the one or more grade 4 adverse events include hypothermia; shock; bradycardia; ventricular extrasystoles; myocardial ischemia; syncope; bleeding; atrial arrhythmia; phlebitis; second-degree atrioventricular block; endocarditis; pericardial effusion; peripheral gangrene; thrombosis; coronary artery disease; stomatitis; nausea and vomiting; abnormal liver function tests; gastrointestinal bleeding; hematemesis; bloody diarrhea; gastrointestinal disorders; intestinal perforation; pancreatitis; anemia; leukopenia; leukocytosis; hypocalcemia; increased alkaline phosphatase; increased blood urea nitrogen (BUN); hyperuricemia; increased non-protein nitrogen (NPN); respiratory acidosis; somnolence; agitation; neuropathy; paranoid reaction; convulsions; grand mal seizures; delirium; asthma, pulmonary edema, or hypercalcemia. In some embodiments of the methods of treating cancer described herein, the adverse events are selected from: gas; hypoxia; hemoptysis; hypoventilation; pneumothorax; mydriasis; pupillary obstruction; abnormal renal function; renal failure; and acute renal tubular necrosis. In some embodiments of the methods of treating cancer described herein, administering an effective amount of an IL-2 conjugate to a group of subjects does not cause one or more adverse events in more than 1% of the subjects after administration of the IL-2 conjugate, wherein the one or more adverse events are selected from: duodenal ulcer; intestinal necrosis; myocarditis; supraventricular tachycardia; permanent or transient blindness secondary to optic neuritis; transient ischemic attack; meningitis; cerebral edema; pericarditis; allergic interstitial nephritis; and tracheoesophageal fistula. In some embodiments of the methods of treating cancer described herein, administering an effective amount of an IL-2 conjugate to a group of subjects does not cause one or more adverse events in more than 1% of the subjects after administration of the IL-2 conjugate, wherein the one or more adverse events are selected from malignant hyperthermia; cardiac arrest; myocardial infarction; pulmonary embolism; stroke; intestinal perforation; liver or kidney failure; severe depression leading to suicide; pulmonary edema; respiratory arrest; and respiratory failure. In some embodiments of the methods of treating cancer described herein, administering an effective amount of an IL-2 conjugate to a subject does not result in the production of neutralizing antibodies against the IL-2 conjugate. In some embodiments of the methods of treating cancer described herein, administering an IL-2 conjugate to a subject increases the number of peripheral CD8+ T and NK cells in the subject, but does not increase the number of peripheral CD4+ regulatory T cells in the subject. In some embodiments of the methods of treating cancer described herein, administering an IL-2 conjugate to a subject increases the number of peripheral CD8+ T and NK cells in the subject, without increasing the number of peripheral eosinophils in the subject. In some embodiments of the methods of treating cancer described herein, administering an IL-2 conjugate to a subject increases the number of intratumoral CD8+ T and NK cells in the subject, without increasing the number of intratumoral CD4+ regulatory T cells in the subject. In some embodiments of the methods of treating cancer described herein, administering an effective amount of an IL-2 conjugate to a subject does not require the availability of an intensive care facility or a skilled specialist in cardiopulmonary or critical care medicine.In some embodiments of the methods of treating cancer described herein, administering an effective amount of an IL-2 conjugate to a subject does not require the availability of an intensive care facility. In some embodiments of the methods of treating cancer described herein, administering an effective amount of an IL-2 conjugate to a subject does not require the availability of a skilled specialist in cardiopulmonary or intensive care medicine.

[0102] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings. [Brief explanation of the drawings]

[0103] [Figure 1] Exemplary unnatural amino acids are shown. This figure is adapted from Figure 2 in Young et al., "Beyond the canonical 20 amino acids: expanding the genetic lexicon," J. of Biological Chemistry 285(15):11039-11044 (2010). [Figure 2-1] Figures 2A-2B show exemplary unnatural amino acids: Figure 2A shows exemplary lysine derivatives; and Figure 2B shows exemplary phenylalanine derivatives. [Figure 2-2] Continued from Figure 2-1. [Figure 2-3] Continued from Figure 2-2. [Figure 3-1] Figures 3A-3D show exemplary unnatural amino acids. These unnatural amino acids (UAAs) are genetically encoded in proteins (Figure 3A - UAAs #1-42; Figure 3B - UAAs #43-89; Figure 3C - UAAs #90-128; Figure 3D - UAAs #129-167). Figures 3A-3D are adapted from Table 1 in Dumas et al., Chemical Science 2015, 6, 50-69. [Figure 3-2] Continued from Figure 3-1. [Figure 3-3]Continued from Figure 3-2. [Figure 3-4] Continued from Figure 3-3. [Figure 3-5] Continued from Figure 3-4. [Figure 3-6] Continued from Figure 3-5. [Figure 3-7] Continued from Figure 3-6. [Figure 4-1] Figures 4A-4C show surface plasmon resonance (SPR) analyses of native IL-2, P65_30kD, P65_5kD, E62_30kD, E62_5kD, and F42_30kD PEG conjugates. Figure 4A shows SPR analyses of IL-2 variant binding to immobilized IL-2Rα. Figure 4B shows SPR analyses of IL-2 variant binding to immobilized IL-2Rβ. Figure 4C shows SPR analyses of recombinant IL-2 and IL-2 variant F42_30kD binding to immobilized IL-2Rα and IL-2Rβ. [Figure 4-2] Continued from Figure 4-1. [Figure 4-3] Continued from Figure 4-2. [Figure 4-4] Continued from Figure 4-3. [Figure 4-5] Continued from Figure 4-4. [Figure 4-6] Continued from Figure 4-5. [Figure 5-1] Figures 5A-5F show exemplary IL-2 variant dose-response curves for pSTAT5 signaling in human LRS primary cell populations: Figure 5A: native IL-2; Figure 5B: P65_30kD; Figure 5C: K64_30kD; Figure 5D: K43_30kD; Figure 5E: K35_30kD, and Figure 5F: F42_30kD. [Figure 5-2] Continued from Figure 5-1. [Figure 5-3] Continued from Figure 5-2. [Figure 6-1] Figures 6A-6C show that PEG and residue substitutions contribute to the non-alpha pharmacology of IL-2 variants: Figure 6A: native IL-2; Figure 6B: E62K; Figure 6C: E62_30kD. [Figure 6-2] Continued from Figure 6-1. [Figure 7]Figure 1 shows that the non-alpha pharmacology of IL-2 variants is independent of PEG size. [Figure 8] 1 shows the mean (±SD) plasma concentration versus time profiles following a single IV bolus dose of aldesleukin (IL-2), E62_5, E62_30, and P65_30 in C57BL / 6 mice. [Figure 9] 1 shows the percentage of pSTAT5+ CD8+ T cells versus time in peripheral blood after treatment of C57BL / 6 mice with a single IV bolus dose of P65_30 or aldesleukin. [Figure 10-1] Figures 10A-10C show the percentage of CD8+ T cells (Figure 10A), NK cells (Figure 10B), and CD4+ Treg cells (Figure 10C) in PBMC populations after treatment with a single IV bolus dose of P65_30 or aldesleukin (IL-2). Blood was collected by cardiac puncture at the indicated time points, and immune cell populations were assessed by flow cytometry. Each data point represents the mean ± SEM from triplicates at each time point. [Figure 10-2] Continued from Figure 10-1. [Figure 11A] Figure 11A shows the difference between P65_30 and aldesleukin (IL-2) in stimulating memory CD8+CD44+ T cell proliferation within the CD3+ population after treatment with a single IV bolus dose of P65_30 or aldesleukin (IL-2). Blood was collected by cardiac puncture at the indicated time points, and immune cell populations were assessed by flow cytometry. Data were analyzed using an unpaired Student's t-test. *** indicates a p-value <0.001. Figure 11B shows memory CD8+CD44+ T cell proliferation at 72, 96, and 120 hours. [Figure 11B]Figure 11B shows the difference between P65_30 and aldesleukin (IL-2) in stimulating memory CD8+CD44+ T cell proliferation within the CD3+ population after treatment with a single IV bolus dose of P65_30 or aldesleukin (IL-2). Blood was collected by cardiac puncture at the indicated time points, and immune cell populations were assessed by flow cytometry. Data were analyzed using an unpaired Student's t-test. *** indicates a p-value <0.001. Figure 11B shows flow cytometry analysis of the cells at 120 hours. [Figure 12] Figures 12A and 12B show the increase in tumor-infiltrating lymphocytes (TILs) over time in C57B16 mice bearing syngeneic B16F10 tumors after treatment with a single IV bolus dose of P65_30. Figure 12A shows the percentage of NK, CD8+ T, and CD4+ Treg cells in P65_30-treated versus untreated (vehicle) animals on day 5 of treatment. Figure 12B shows the ratio of CD8+ / CD4+ Treg cells in P65_30-treated and control (vehicle) animals. Data were analyzed using an unpaired Student's t-test. *** indicates a p-value <0.001. [Figure 13] Figures 13A and 13B show plasma levels of IL-2, TNF-α, IFN-γ, IL-5, and IL-6 in mice after treatment with a single IV bolus dose of increasing levels (0.01-5 mg / kg) of P65_30 or aldesleukin (IL-2). Plasma concentrations of each cytokine were determined by ELISA (Abcam, Cambridge, UK). For each dose group, N=3 mice and samples were collected at 4, 34, and 72 hours post-dose. Figure 13A shows cytokine levels for aldesleukin-treated animals, and Figure 13B shows cytokine levels for P65_30-treated animals. [Figure 14] Leukocyte, lymphocyte, and eosinophil counts (mean±SD) are shown following a single IV dose of P65_30kD to male cynomolgus monkeys. [Figure 15]Figures 15A and 15B show dose response curves of exemplary IL-2 variants on pSTAT5 signaling in human LRS primary cells (Figure 15A), and the proliferative response in murine CTLL-2 populations (Figure 15B). [Figure 16] Figures 16A and 16B show that PEG IL-2 compounds can specifically expand immune cell populations ex vivo in primary lymphocytes compared to normal IL-2 controls. Figure 16A shows immune cell proliferation after treatment with IL-2 (control). Figure 16B shows immune cell proliferation after treatment with P65_30kD. [Figure 17-1] Figures 17A and 17B show sensorgrams of the binding response for rhIL-2 (recombinant human interleukin-2, Figure 17A) and the synthetic conjugate IL-2_P65[AzK_L1_PEG30kD]-1 (Figure 17B) on the IL-2R alpha surface. Under these conditions, no significant binding response was detected for IL-2_P65[AzK_L1_PEG30kD]-1. [Figure 17-2] Figures 17C and 17D show sensorgrams of binding of rhIL-2 (recombinant human interleukin-2, Figure 17C) and synthetic conjugate IL-2_P65[AzK_L1_PEG30kD]-1 samples (Figure 17D) to the IL-2R beta surface. [Figure 18]The gating strategy for flow cytometry cell sorting of Tregs is shown. First, cells were gated on singlets using FSC-A by FSC-H to exclude any aggregates or doublets (singlet gate, first panel). Within this gate, cells were gated on medium-to-high forward scatter (FSC-A) and side scatter (SSC-A) to exclude erythrocytes, debris, and granulocytes (lymphocyte gate, second panel). T cells were then gated as a CD3+, CD56 / 16-negative population (third panel). NK cells were identified as a CD3-negative, CD56 / 16-high population (third panel). T cells were then sorted into CD4+ and CD8+ T cells (fourth panel). Tregs were then gated from CD4+ T cells as a CD25hi×C127lo population (fifth panel). [Figure 19] 1 shows the stability of compound IL-2_P65[AzK_L1_PEG30kD]-1 in human serum at three concentrations for up to 168 hours, as described in Example 15. DETAILED DESCRIPTION OF THE INVENTION

[0104] Cytokines include a family of cell signaling proteins, such as chemokines, interferons, interleukins, lymphokines, tumor necrosis factors, and other growth factors that play a role in innate and adaptive immune cell homeostasis. 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 instances, cytokines regulate the balance between humoral and cellular immune responses.

[0105] Interleukins are signaling proteins that regulate the development and differentiation of T and B lymphocytes, cells of the monocyte lineage, neutrophils, basophils, eosinophils, megakaryocytes, and hematopoietic cells. Interleukins are produced by CD4 T and B lymphocytes, monocytes, macrophages, endothelial cells, and other tissue residents.

[0106] Interleukin-2 (IL-2) is a pleiotropic type-1 cytokine whose structure contains a four-α-helical bundle of 15.5 kDa. The precursor of IL-2 is 153 amino acid residues in length, with the first 20 amino acids forming a signal peptide and the remaining 21–153 amino acids forming the mature form. IL-2 is produced primarily by CD4+ T cells after antigen stimulation, and to a lesser extent by CD8+ cells, natural killer (NK) cells, and natural killer T (NKT) cells, activated dendritic cells (DCs), and mast cells. IL-2 signaling occurs through interaction with a specific combination of IL-2 receptor (IL-2R) subunits, IL-2Rα (also known as CD25), IL-2Rβ (also known as CD122), and IL-2Rγ (also known as CD132). The interaction of IL-2 with IL-2Rα is approximately 10 -8 K of M d The interaction of IL-2 with IL-2Rβ and IL-2Rγ occurs at approximately 10 -9 K of M d The interaction of IL-2 with all three subunits, IL-2Rα, IL-2Rβ, and IL-2Rγ, occurs at approximately >10 -11 K of M d form a "high affinity" IL-2 receptor complex.

[0107] In some instances, IL-2 signaling through the "high affinity" IL-2Rαβγ complex regulates the activation and proliferation of regulatory T cells, or CD4 + CD25 + Foxp3 + Regulatory T (Treg) cells are effector cells, e.g., CD4 + T cells, CD8 +They mediate the maintenance of immune homeostasis by suppressing T cells, B cells, NK cells, and NKT cells. In some instances, Treg cells arise from the thymus (tTreg cells) or are derived from naive T cells in the periphery (pTreg cells). In some cases, Treg cells are considered mediators of peripheral tolerance. Indeed, one study showed that CD25-depleted peripheral CD4 + T cell transplantation induces various autoimmune diseases in nude mice, while CD4 + CD25 + Cotransplantation of T cells suppressed the development of autoimmunity (Sakaguchi, et al., "Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25)," J. Immunol. 155(3):1151-1164 (1995)). Expansion of the Treg cell population down-regulates effector T cell proliferation and suppresses autoimmunity and T cell antitumor responses.

[0108] IL-2 signaling through the "intermediate affinity" IL-2Rβγ complex mediates CD8 + Regulates the activation and proliferation of effector T (Teff) cells, NK cells, and NKT cells. CD8 + Teff cells (also known as cytotoxic T cells, Tc cells, cytotoxic T lymphocytes, CTLs, T killer cells, cytolytic T cells, Tcon, or killer T cells) are T lymphocytes that recognize and kill damaged, cancerous, and pathogen-infected cells. NK and NKT cells are CD8 + Teff cells are a type of lymphocyte that resemble target cancerous cells and pathogen-infected cells.

[0109] In some cases, IL-2 signaling regulates T cell responses and is subsequently utilized in cancer treatment. For example, IL-2 is administered at high doses to induce the expansion of Teff cell populations for cancer treatment. However, high-dose IL-2 also leads to the concomitant stimulation of Treg cells, which blunts anti-tumor immune responses. High-dose IL-2 also induces toxic adverse events mediated by the involvement of IL-2R alpha chain-expressing cells in the vasculature, including type 2 innate immune cells (ILC-2), eosinophils, and endothelial cells. This results in eosinophilia, capillary leakage, and vascular leak syndrome (VLS).

[0110] Adoptive cell therapy allows physicians to effectively utilize a patient's own immune cells to fight disease, such as proliferative diseases (e.g., cancer) as well as infectious diseases. In one non-limiting example, T lymphocytes are removed from a patient, re-engineered to target specific antigens on the surface of malignant cells, and re-introduced into the patient's body to specifically target the malignant cells. In addition, adoptive cell therapy provides a sustained response throughout the body by signaling immune cells, causing them to grow and divide, long after the re-engineered cells are re-introduced into the patient's immune system.

[0111] Described herein, in certain embodiments, are methods for selectively upregulating distinct populations of lymphocytes (e.g., CD4+ helper cells, CD8+ effector naive and memory cells, NK cells, or NKT cells) via cytokine / cytokine receptor signaling. In some examples, the cytokine comprises an interleukin, an interferon, or a tumor necrosis factor. In some cases, the cytokine is a cytokine conjugate, such as an interleukin conjugate, an interferon conjugate, or a tumor necrosis factor conjugate. Additionally, included herein are pharmaceutical compositions and kits comprising one or more cytokine conjugates described herein.

[0112] Also described herein in some embodiments are methods of selectively upregulating CD4+ helper cells, CD8+ effector naive and memory cells, NK cells, and / or NKT cell populations via IL-2 / IL-2R signaling. In some examples, the IL-2 is an IL-2 conjugate that interacts with the "intermediate affinity" IL-2Rβγ complex, optionally with potency similar to the IL-2Rαβγ complex and with weaker IL-2Rα interaction compared to wild-type IL-2. Further described herein in some embodiments are methods of treating cancer using the IL-2 conjugates described herein. In additional embodiments, described herein are pharmaceutical compositions and kits comprising one or more IL-2 conjugates described herein. In some embodiments, the IL-2 conjugates include a conjugated moiety (e.g., PEG) that contributes to an increased or decreased "clearance rate" or plasma half-life in a subject without affecting pharmacokinetics, including desired cytokine-receptor interaction and immune cell expansion.

[0113] Described herein are reagents used in some embodiments to develop adoptive cell therapies comprising cells engineered to express modified cytokines that result in selective cytokine-receptor interactions and immune cell expansion. In some embodiments, the reagents comprise a nucleic acid construct encoding the IL-2 conjugates described above. Also disclosed are adoptive cell therapies comprising the IL-2 conjugates described above that are useful for treating proliferative or infectious diseases described herein.

[0114] Described herein, in some embodiments, are compositions that provide selective cytokine-receptor interaction and immune cell expansion. In some embodiments, the reagent comprises a nucleic acid construct encoding the IL-2 conjugate described above. Also disclosed are pharmaceutical compositions comprising the IL-2 conjugate described above that are useful for treating the proliferative or infectious diseases described herein.

[0115] Cytokine Conjugates In some embodiments, described herein are cytokine conjugates. In some instances, the cytokine comprises an interleukin, tumor necrosis factor, interferon, chemokine, lymphokine, or growth factor. In some instances, the cytokine is an interleukin. In some instances, the cytokine is an interferon. In additional instances, the cytokine is a tumor necrosis factor. In further instances, the cytokine is a growth factor.

[0116] In some embodiments, described herein are interleukin conjugates. Exemplary interleukins include, but are not limited to, interleukin 2 (IL-2).

[0117] IL-2 conjugates Described herein are the polypeptides set forth in Table 20. In some embodiments, the IL-2 conjugates described herein are exemplified in Table 20.

[0118] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7]

[0119] In some embodiments, the present specification describes IL-2 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-2 polypeptides comprising at least one non-natural amino acid. In some examples, the IL-2 polypeptide is isolated and purified mammalian IL-2, e.g., rodent IL-2 protein, or human IL-2 protein. In some cases, the IL-2 polypeptide is a human IL-2 protein. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 1. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 1. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 1. In additional cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:2. In additional cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO:2. In additional cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO:2. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:3. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO:3. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO:3. In additional cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:4. In additional cases, the IL-2 polypeptide In additional instances, the IL-2 polypeptide comprises the sequence of SEQ ID NO:4. In additional instances, the IL-2 polypeptide consists of the sequence of SEQ ID NO:4. In some instances, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:5. In some instances, the IL-2 polypeptide comprises the sequence of SEQ ID NO:5. In some instances, the IL-2 polypeptide consists of the sequence of SEQ ID NO:5. In additional instances, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:6. In additional instances, the IL-2 polypeptide comprises the sequence of SEQ ID NO:6. In additional instances, the IL-2 polypeptide consists of the sequence of SEQ ID NO:6. In some instances, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:7. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 7. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 7. In additional cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 8. In additional cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 8. In additional cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 8. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 9. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 9. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 9. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 10. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 10. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 10. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 11. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 11.In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 11. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 12. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 12. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 13. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 13. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 14. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 14. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 14. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 15. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 15. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 15. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 16. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 16. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 16. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 17. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 17. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 17. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 18. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 18.Optionally, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 18. Optionally, the IL-2 polypeptide. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 19. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 19. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 19. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 20. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 20. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 20. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 21. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 21. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO:21. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:22. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO:22. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:23. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO:23. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:24. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 24. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 24. In additional cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 25. In additional cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 25. In additional cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 25.In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 26. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 26. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 26. In additional cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 27. In additional cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 27. In additional cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 27. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 28. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 28. In some instances, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 28. In additional instances, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 29. In additional instances, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 29. In additional instances, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 29. In some instances, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 30. In some instances, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 30. In some instances, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 31. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 31. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 31. In additional cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 32. In additional cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 32. In additional cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 32.In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:33. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO:33. In some instances, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 33. In additional instances, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 34. In additional instances, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 34. In additional instances, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 34. In some instances, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 35. In some instances, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 35. In additional instances, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 36. In additional instances, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 36. In additional instances, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 36. In some instances, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 37. In some instances, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 37. In some instances, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 37. In additional instances, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 38. In additional instances, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 38. In additional instances, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 38. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 39. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 39. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 39. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 40. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 40.In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 40. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 41. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 41. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 41. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 42. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 42. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 43. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 43. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 43. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 44. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 44. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 45. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 45. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 45. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 46. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 46. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 46. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 47. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 47. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to ... The peptide consists of the sequence of SEQ ID NO: 47. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 48. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 48. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 49. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 49. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 50. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 50. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 50. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 51. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 51. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 51. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 52. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 52. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 52. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 53. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 53. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 53. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 54. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 54. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 54.In additional cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 55. In additional cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 55. In additional cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 55. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 56. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 56. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 56. In additional cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 57. In additional cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 57. In additional instances, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 57. In some instances, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 58. In some instances, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 58. In some instances, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 59. In additional instances, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 59. In additional instances, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 59. In some instances, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 60. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 60. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 60. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 61. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 61. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 61.In additional instances, the IL-2 polypeptide is about 80% identical to SEQ ID NO:62, 85. In additional instances, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:63. In additional instances, the IL-2 polypeptide comprises the sequence of SEQ ID NO:63. In additional instances, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:64. In additional instances, the IL-2 polypeptide comprises the sequence of SEQ ID NO:64. In additional instances, the IL-2 polypeptide consists of the sequence of SEQ ID NO:64. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 65. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 65. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 65. In additional cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 66. In additional cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 66. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 67. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 67. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 67. In additional cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 68. In additional cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 68. In additional cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 68. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 69. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 69. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 70. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 70. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 70. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 71. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 71. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 71. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 72. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 72. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 72. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 73. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 73. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 73. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 74. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 74. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 74. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 75.In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 75. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 75. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 76. In some cases, The IL-2 polypeptide comprises the sequence of SEQ ID NO: 76. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 76. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 77. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 77. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 77. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 78. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 78. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 78. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 79. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 79. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 79. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 80. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 80. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 80. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 81. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 81. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 81. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 82. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 82. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 82. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 83. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 83.In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 83. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 84. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 84. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 84.

[0120] In some examples, the IL-2 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 IL-2 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 IL-2 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 IL-2 polypeptide includes an N-terminal deletion of at least or about 2 residues. In some cases, the IL-2 polypeptide comprises an N-terminal deletion of at least or about 3 residues. In some cases, the IL-2 polypeptide comprises an N-terminal deletion of at least or about 4 residues. In some cases, the IL-2 polypeptide comprises an N-terminal deletion of at least or about 5 residues. In some cases, the IL-2 polypeptide comprises an N-terminal deletion of at least or about 6 residues. In some cases, the IL-2 polypeptide comprises an N-terminal deletion of at least or about 7 residues. In some cases, the IL-2 polypeptide comprises an N-terminal deletion of at least or about 8 residues. In some cases, the IL-2 polypeptide comprises an N-terminal deletion of at least or about 9 residues. In some cases, the IL-2 polypeptide comprises an N-terminal deletion of at least or about 10 residues.

[0121] In some embodiments, the IL-2 polypeptide is a functionally active fragment. In some embodiments, the functionally active fragment comprises IL-2 region 10-133, 20-133, 30-133, 10-130, 20-130, 30-130, 10-125, 20-125, 30-125, 1-130, or 1-125, where the residue positions are relative to the positions in SEQ ID NO:1. In some embodiments, the functionally active fragment comprises IL-2 region 10-133, where the residue positions are relative to the positions in SEQ ID NO:1. In some embodiments, the functionally active fragment comprises IL-2 region 20-133, where the residue positions are relative to the positions in SEQ ID NO:1. In some embodiments, the functionally active fragment comprises IL-2 region 30-133, where the residue positions are relative to the positions in SEQ ID NO:1. In some cases, the functionally active fragment comprises IL-2 region 10-125, with the residue positions being relative to the positions in SEQ ID NO: 1. In some cases, the functionally active fragment comprises IL-2 region 20-125, with the residue positions being relative to the positions in SEQ ID NO: 1. In some cases, the functionally active fragment comprises IL-2 region 1-130, with the residue positions being relative to the positions in SEQ ID NO: 1. In some cases, the functionally active fragment comprises IL-2 region 1-125, with the residue positions being relative to the positions in SEQ ID NO: 1.

[0122] In some embodiments, described herein are IL-2 conjugates, including isolated, purified, and modified IL-2 polypeptides and conjugating moieties. In some examples, the IL-2 conjugates have reduced affinity for the IL-2 receptor alpha (IL-2Rα) subunit compared to wild-type IL-2 polypeptides. In some cases, the conjugating moiety binds to an amino acid residue that interacts with IL-2Rα (e.g., at the IL-2 / IL-2Rα interface). In some cases, the conjugating moiety binds to an amino acid residue proximal to the IL-2 / IL-2Rα interface (e.g., about 5 Å, about 10 Å, about 15 Å, or about 20 Å away from the IL-2 / IL-2Rα interface). As used herein, residues involved in the IL-2 / IL-2Rα interface include IL-2 residues that form hydrophobic interactions, hydrogen bonds, or ionic interactions with residues from the IL-2Rα subunit.

[0123] In some examples, the conjugating moiety is attached to an amino acid residue selected from amino acid positions Y31, K32, N33, P34, K35, T37, R38, T41, F42, K43, F44, Y45, P47, K48, Q57, E60, E61, E62, L63, K64, P65, E68, V69, N71, L72, Q74, S75, K76, N77, M104, C105, E106, Y107, A108, D109, E110, T111, or A112, where the numbering of the amino acid residues corresponds to SEQ ID NO: 1. In some examples, the amino acid positions are selected from Y31, K32, N33, P34, K35, T37, R38, T41, F42, K43, F44, Y45, P47, K48, E61, E62, E68, K64, P65, V69, L72, Q74, S75, K76, N77, M104, C105, E106, Y107, A108, D109, E110, T111, and A112. In some examples, the amino acid positions are selected from N33, P34, K35, T37, R38, M39, T41, F42, K43, F44, Y45, Q57, E60, E61, E62, L63, K64, P65, E68, V69, N71, L72, M104, C105, E106, Y107, A108, D109, E110, T111, and A112. In some examples, the amino acid positions are selected from K35, T37, R38, T41, F42, K43, F44, Y45, E61, E62, E68, K64, P65, V69, L72, and Y107. In some examples, the amino acid positions are selected from T37, R38, T41, F42, F44, Y45, E61, E62, E68, K64, P65, V69, L72, and Y107. In some examples, the amino acid positions are selected from T37, R38, T41, F42, F44, Y45, E61, E62, E68, P65, V69, L72, and Y107. In some examples, the amino acid positions are selected from T37, T41, F42, F44, Y In some examples, the amino acid position is selected from R38 and K64. In some examples, the amino acid position is selected from E61, E62, and E68. Optionally, the amino acid position is at K35. Optionally, the amino acid position is at T37. Optionally, the amino acid position is at R38. Optionally, the amino acid position is at T41. Optionally, the amino acid position is at F42. Optionally, the amino acid position is at K43. Optionally, the amino acid position is at F44. Optionally, the amino acid position is at Y45. Optionally, the amino acid position is at E61. Optionally, the amino acid position is at E62. Optionally, the amino acid position is at K64. Optionally, the amino acid position is at E68. Optionally, the amino acid position is at P65. Optionally, the amino acid position is at V69. Optionally, the amino acid position is at L72. Optionally, the amino acid position is at Y107. Optionally, the amino acid position is L72. Optionally, the amino acid position is D109.

[0124] In some examples, the IL-2 conjugate further comprises an additional mutation. In some cases, the additional mutation is at an amino acid position selected from K35, T37, R38, T41, F42, K43, F44, Y45, E61, E62, E68, K64, P65, V69, L72, and Y107. In such cases, the amino acid is conjugated to an additional conjugation moiety for increased serum half-life, stability, or a combination thereof. Alternatively, the amino acid is first mutated to a natural amino acid, such as lysine, cysteine, histidine, arginine, aspartic acid, glutamic acid, serine, threonine, or tyrosine; or to a non-natural amino acid before being attached to the additional conjugation moiety.

[0125] In some embodiments, the reduced affinity of the modified IL-2 polypeptide for the IL-2 receptor alpha (IL-2Rα) subunit is about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99%, or more than 99%, compared to a wild-type IL-2 polypeptide (e.g., a wild-type IL-2 polypeptide) without the non-natural amino acid modification. In some embodiments, the reduced affinity is about 10%. In some cases, the reduced affinity is about 20%. In some cases, the reduced affinity is about 40%. In some cases, the reduced affinity is about 50%. In some cases, the reduced affinity is about 60%. In some cases, the reduced affinity is about 80%. In some cases, the reduced affinity is about 90%. In some cases, the reduced affinity is about 99%. In some cases, the reduced affinity is more than about 99%. In some cases, the reduced affinity is about 80%. In some cases, the reduced affinity is about 100%.

[0126] In some embodiments, the modified IL-2 polypeptide has about a 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 30-fold, 50-fold, 100-fold, 200-fold, 300-fold, 400-fold, 500-fold, 1,000-fold, or more decreased affinity for the IL-2 receptor alpha (IL-2Rα) subunit compared to an equivalent IL-2 polypeptide (e.g., a wild-type IL-2 polypeptide) without the non-natural amino acid modification. In some embodiments, the decreased affinity is about 1-fold. In some cases, the decreased affinity is about 2-fold. In some cases, the decreased affinity is about 4-fold. In some cases, the decreased affinity is about 5-fold. In some cases, the decreased affinity is about 6-fold. In some cases, the decreased affinity is about 8-fold. In some cases, the decreased affinity is about 10-fold. In some cases, the decreased affinity is about 30-fold. In some cases, the reduced affinity is about 50-fold. In some cases, the reduced affinity is about 100-fold. In some cases, the reduced affinity is about 300-fold. In some cases, the reduced affinity is about 500-fold. In some cases, the reduced affinity is about 1000-fold. In some cases, the reduced affinity is about 1000-fold. In this case, the reduced affinity is more than 1,000-fold.

[0127] In some cases, the modified IL-2 polypeptide does not interact with IL-2Rα. In some examples, the modified IL-2 polypeptide is further conjugated to a conjugating moiety. In some cases, the IL-2 conjugate does not interact with IL-2Rα.

[0128] In some embodiments, the modified IL-2 polypeptide exhibits a first receptor signaling potency for the IL-2βγ signaling complex and a second receptor signaling potency for the IL-2αβγ signaling complex, wherein the difference between the first and second receptor signaling potencies is less than 10-fold. In some embodiments, the modified IL-2 polypeptide exhibits a first receptor signaling potency for the IL-2βγ signaling complex and a second receptor signaling potency for the IL-2αβγ signaling complex, wherein the difference between the first and second receptor signaling potencies is less than 5-fold. In some examples, the difference is less than 9-fold, less than 8-fold, less than 7-fold, less than 6-fold, less than 5-fold, less than 4-fold, less than 3-fold, less than 2-fold, or less than 1-fold. In some examples, the modified IL-2 polypeptide is a partial agonist, e.g., an agonist that activates a receptor (e.g., the IL-2βγ signaling complex or the IL-2αβγ signaling complex), but has only partial efficacy at the receptor compared to a full agonist. In some examples, the modified IL-2 polypeptide is a full agonist, e.g., an agonist that activates a receptor (e.g., the IL-2βγ signaling complex or the IL-2αβγ signaling complex) with a maximal response.

[0129] In some examples, receptor signaling potency is measured by EC50 value. In some examples, the modified IL-2 polypeptide provides a first EC50 value for activating the IL-2βγ signaling complex and a second EC50 value for activating the IL-2αβγ signaling complex, and the difference between the first EC50 value and the second EC50 value is less than 10-fold. In some examples, the modified IL-2 polypeptide provides a first EC50 value for activating the IL-2βγ signaling complex and a second EC50 value for activating the IL-2αβγ signaling complex, and the difference between the first EC50 value and the second EC50 value is less than 5-fold. In some cases, the difference is less than 9-fold, less than 8-fold, less than 7-fold, less than 6-fold, less than 5-fold, less than 4-fold, less than 3-fold, less than 2-fold, or less than 1-fold.

[0130] In some cases, receptor signaling potency is measured by ED50 value. In some cases, the modified IL-2 polypeptide provides a first ED50 value for activating the IL-2βγ signaling complex and a second ED50 value for activating the IL-2αβγ signaling complex, and the difference between the first ED50 value and the second ED50 value is less than 10-fold. In some cases, the modified IL-2 polypeptide provides a first ED50 value for activating the IL-2βγ signaling complex and a second ED50 value for activating the IL-2αβγ signaling complex, and the difference between the first ED50 value and the second ED50 value is less than 5-fold. In some cases, the difference is less than 9-fold, less than 8-fold, less than 7-fold, less than 6-fold, less than 5-fold, less than 4-fold, less than 3-fold, less than 2-fold, or less than 1-fold.

[0131] In some embodiments, the conjugation moiety is linked to the N-terminus or C-terminus of the IL-2 polypeptide, either directly or indirectly via a linker peptide. In some cases, the conjugation moiety (e.g., a polymer, protein, or peptide) is genetically fused to the N-terminus or C-terminus of IL-2, either directly or indirectly via a linker peptide. In some examples, the conjugation moiety is linked to the N-terminus or C-terminal amino acid residue. In some examples, the conjugation moiety is linked to a reactive group that binds to the N-terminus or C-terminal amino acid residue.

[0132] In some embodiments, IL-2 conjugates with reduced binding affinity to IL-2Rα can expand CD4+ helper cell, CD8+ effector naive and memory T cell, natural killer (NK) cell, or natural killer T (NKT) cell populations. In some cases, the conjugated moiety impairs or blocks binding of IL-2 to IL-2Rα.

[0133] In some cases, activation of CD4+ helper cells, CD8+ effector naive and memory cells, natural killer (NK) cells, or natural killer T (NKT) cell populations via the IL-2Rβγ complex by the modified IL-2 polypeptide retains significant potency of activation of the cell populations compared to wild-type IL-2 polypeptide. In some cases, activation by the modified IL-2 polypeptide is equivalent to that of the wild-type IL-2 polypeptide. In other cases, activation by the modified IL-2 polypeptide is greater than that of the wild-type IL-2 polypeptide. In some cases, the receptor signaling potency of the modified IL-2 polypeptide at the IL-2Rβγ complex is greater than that of the wild-type IL-2 polypeptide. In some cases, the receptor signaling potency of the modified IL-2 polypeptide is at least one-fold greater than that of the wild-type IL-2 polypeptide. In some cases, the receptor signaling potency of the modified IL-2 polypeptide is about or at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 300-fold, 400-fold, 500-fold, 1,000-fold, or more than the respective potency of the wild-type IL-2 polypeptide. In such cases, the dose or concentration of the modified IL-2 polypeptide used to achieve similar levels of activation of CD4+ helper cells, CD8+ effector naive and memory cells, natural killer (NK) cells, or natural killer T (NKT) cell populations as the wild-type IL-2 polypeptide is lower than the dose or concentration used for the wild-type IL-2 polypeptide.

[0134] In some embodiments, activation of CD4+ helper cells, CD8+ effector naive and memory cells, natural killer (NK) cells, or natural killer T (NKT) cell populations via the IL-2Rβγ complex by a modified IL-2 polypeptide retains substantial potency of activation of said cell populations by a wild-type IL-2 polypeptide. In some cases, the receptor signaling potency of the modified IL-2 polypeptide at the IL-2Rβγ complex is lower than the receptor signaling potency of the wild-type IL-2 polypeptide at the IL-2Rβγ complex. In some cases, the receptor signaling potency of the modified IL-2 polypeptide is about or at least 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 20-fold, or 50-fold lower than the respective potencies of the wild-type IL-2 polypeptide.

[0135] In some embodiments, the modified IL-2 polypeptide exhibits a first receptor signaling potency for IL-2βγ and a second receptor signaling potency for IL-2αβγ. In some examples, the first receptor signaling potency for IL-2Rβγ is improved potency compared to the wild-type IL-2 polypeptide. In some examples, the second receptor signaling potency for IL-2Rαβγ is impaired potency compared to the wild-type IL-2 polypeptide. In some embodiments, the modified IL-2 polypeptide exhibits a first receptor signaling potency for IL-2βγ and a second receptor signaling potency for IL-2αβγ, wherein the first receptor signaling potency is at least 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 30-fold, 50-fold, 100-fold, 500-fold, 1000-fold, or more, greater than the second receptor signaling potency. In some examples, the first receptor signaling potency is at least 1-fold or more than the second receptor signaling potency. In some examples, the first receptor signaling potency is at least 2-fold or more than the second receptor signaling potency. In some examples, the first receptor signaling potency is at least 1-fold or more than the second receptor signaling potency. The first receptor signaling potency is at least 5 times or more than the second receptor signaling potency. In some examples, the first receptor signaling potency is at least 10 times or more than the second receptor signaling potency. In some examples, the first receptor signaling potency is at least 20 times or more than the second receptor signaling potency. In some examples, the first receptor signaling potency is at least 50 times or more than the second receptor signaling potency. In some examples, the first receptor signaling potency is at least 100 times or more than the second receptor signaling potency. In some examples, the first receptor signaling potency is at least 500 times or more than the second receptor signaling potency. In some examples, the first receptor signaling potency is at least 1000 times or more than the second receptor signaling potency. In some instances, the first receptor signaling potency of the modified IL-2 polypeptide is higher than the receptor signaling potency of the wild-type IL-2 polypeptide for IL-2Rβγ, and the second receptor signaling potency of the modified IL-2 polypeptide is lower than the receptor signaling potency of the wild-type IL-2 polypeptide for IL-2Rαβγ. In some instances, both receptor signaling potencies are lower than their respective potencies in the wild-type IL-2 polypeptide. In other instances, both receptor signaling potencies are higher than their respective potencies in the wild-type IL-2 polypeptide.

[0136] In some embodiments, the IL-2 conjugate reduces adverse toxic events in a subject administered the IL-2 conjugate. Exemplary adverse toxic events include eosinophilia, capillary leak, and vascular leak syndrome (VLS). In some examples, the IL-2 conjugate reduces the occurrence of adverse toxic events in a subject by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or about 100% compared to a second subject administered wild-type IL-2 or aldesleukin. In some examples, the IL-2 conjugate reduces the severity of a toxic adverse event in a subject by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or about 100% compared to a second subject administered wild-type IL-2 or aldesleukin.

[0137] In some cases, the toxic adverse event is eosinophilia.In some cases, the IL-2 conjugate reduces the occurrence of eosinophilia in the subject by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99% or about 100% compared to the second subject administered wild-type IL-2 or aldesleukin.In some cases, the IL-2 conjugate reduces the severity of eosinophilia in the subject by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99% or about 100% compared to the second subject administered wild-type IL-2 or aldesleukin.

[0138] In some cases, the toxic adverse event is capillary leakage.In some cases, the IL-2 conjugate reduces the occurrence of capillary leakage in the subject by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99% or about 100% compared to the second subject administered with wild-type IL-2 or aldesleukin.In some cases, the IL-2 conjugate reduces the severity of capillary leakage in the subject by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99% or about 100% compared to the second subject administered with wild-type IL-2 or aldesleukin.

[0139] In some instances, the toxic adverse event is VLS. In some instances, the IL-2 conjugate exhibits a reduction in VLS of about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% of the IL-2 conjugate compared to a second subject administered wild-type IL-2 or aldesleukin. In some cases, the IL-2 conjugate reduces the severity of VLS in a subject by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or about 100% compared to a second subject administered wild-type IL-2 or aldesleukin.

[0140] In some embodiments, the IL-2 conjugate comprises a plasma half-life of greater than 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 18 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or more. In some embodiments, the IL-2 conjugate comprises a plasma half-life of greater than 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, or more. In some embodiments, the IL-2 conjugate comprises a plasma half-life of greater than 1 hour. In some embodiments, the IL-2 conjugate comprises a plasma half-life of greater than 2 hours. In some embodiments, the IL-2 conjugate comprises a plasma half-life of greater than 3 hours. In some embodiments, the IL-2 conjugate comprises a plasma half-life of greater than 4 hours. In some embodiments, the IL-2 conjugate comprises a plasma half-life of greater than 5 hours. In some embodiments, the IL-2 conjugate comprises a plasma half-life of greater than 6 hours. In some embodiments, the IL-2 conjugate comprises a plasma half-life of greater than 7 hours. In some embodiments, the IL-2 conjugate comprises a plasma half-life of greater than 8 hours. In some embodiments, the IL-2 conjugate comprises a plasma half-life of greater than 9 hours. In some embodiments, the IL-2 conjugate comprises a plasma half-life of greater than 10 hours. In some embodiments, the IL-2 conjugate comprises a plasma half-life of greater than 12 hours. In some embodiments, the IL-2 conjugate comprises a plasma half-life of greater than 18 hours. In some embodiments, the IL-2 conjugate comprises a plasma half-life of greater than 24 hours.

[0141] In some embodiments, the IL-2 conjugate comprises a plasma half-life of at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 15 hours, 18 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or more. In some embodiments, the IL-2 conjugate comprises a plasma half-life of at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 15 hours, 18 hours, 24 hours, or more. In some embodiments, the IL-2 conjugate comprises a plasma half-life of at least 1 hour. In some embodiments, the IL-2 conjugate comprises a plasma half-life of at least 2 hours. In some embodiments, the IL-2 conjugate comprises a plasma half-life of at least 3 hours. In some embodiments, the IL-2 conjugate comprises a plasma half-life of at least 4 hours. In some embodiments, the IL-2 conjugate comprises a plasma half-life of at least 5 hours. In some embodiments, the IL-2 conjugate comprises a plasma half-life of at least 6 hours. In some embodiments, the IL-2 conjugate comprises a plasma half-life of at least 7 hours. In some embodiments, the IL-2 conjugate comprises a plasma half-life of at least 8 hours. In some embodiments, the IL-2 conjugate comprises a plasma half-life of at least 9 hours. In some embodiments, the IL-2 conjugate comprises a plasma half-life of at least 10 hours. In some embodiments, the IL-2 conjugate comprises a plasma half-life of at least 12 hours. In some embodiments, the IL-2 conjugate comprises a plasma half-life of at least 18 hours. In some embodiments, the IL-2 conjugate comprises a plasma half-life of at least 24 hours.

[0142] In some embodiments, the IL-2 conjugate comprises a plasma half-life of about 1 hour to about 7 days, about 12 hours to about 7 days, about 18 hours to about 7 days, about 24 hours to about 7 days, about 1 hour to about 5 days, about 12 hours to about 5 days, about 24 hours to about 5 days, about 2 days to about 5 days, or about 2 days to about 3 days.

[0143] In some embodiments, the IL-2 conjugate comprises a plasma half-life of about 1 hour to about 18 hours, about 1 hour to about 12 hours, about 2 hours to about 10 hours, about 2 hours to about 8 hours, about 4 hours to about 18 hours, about 4 hours to about 12 hours, about 4 hours to about 10 hours, about 4 hours to about 8 hours, about 6 hours to about 18 hours, about 6 hours to about 12 hours, about 6 hours to about 10 hours, about 6 hours to about 8 hours, about 8 hours to about 18 hours, about 8 hours to about 12 hours, or about 8 hours to about 10 hours.

[0144] In some embodiments, the IL-2 conjugate comprises a plasma half-life that allows proliferation and / or expansion of CD4+ helper cells, CD8+ effector naive and memory T cells, NK cells, NKT cells, or combinations thereof, but does not exert deleterious effects such as apoptosis.

[0145] In some embodiments, the IL-2 conjugate comprises an increased plasma half-life, e.g., by at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 15 hours, 18 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or more, compared to wild-type IL-2. In some embodiments, the IL-2 conjugate comprises an increased plasma half-life, e.g., by at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 15 hours, 18 hours, 24 hours, or more, compared to wild-type IL-2.

[0146] In some embodiments, the IL-2 conjugate comprises an extended plasma half-life of, for example, about 1 hour to about 18 hours, about 1 hour to about 12 hours, about 2 hours to about 10 hours, about 2 hours to about 8 hours, about 4 hours to about 18 hours, about 4 hours to about 12 hours, about 4 hours to about 10 hours, about 4 hours to about 8 hours, about 6 hours to about 18 hours, about 6 hours to about 12 hours, about 6 hours to about 10 hours, about 6 hours to about 8 hours, about 8 hours to about 18 hours, about 8 hours to about 12 hours, or about 8 hours to about 10 hours, compared to wild-type IL-2.

[0147] In some embodiments, the IL-2 conjugate comprises an extended plasma half-life of at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 15 hours, 18 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or more, compared to, for example, aldesleukin. In some embodiments, the IL-2 conjugate comprises an extended plasma half-life of at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 15 hours, 18 hours, 24 hours, or more, compared to, for example, aldesleukin.

[0148] In some embodiments, the IL-2 conjugate comprises an extended plasma half-life of, for example, about 1 hour to about 18 hours, about 1 hour to about 12 hours, about 2 hours to about 10 hours, about 2 hours to about 8 hours, about 4 hours to about 18 hours, about 4 hours to about 12 hours, about 4 hours to about 10 hours, about 4 hours to about 8 hours, about 6 hours to about 18 hours, about 6 hours to about 12 hours, about 6 hours to about 10 hours, about 6 hours to about 8 hours, about 8 hours to about 18 hours, about 8 hours to about 12 hours, or about 8 hours to about 10 hours, compared to aldesleukin.

[0149] In some embodiments, the IL-2 conjugate comprises an extended plasma half-life and reduced toxicity. In some examples, the IL-2 conjugate comprises an extended plasma half-life of at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 15 hours, 18 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or more, resulting in reduced toxicity. In some examples, the IL-2 conjugate comprises an extended plasma half-life of at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 15 hours, 18 hours, 24 hours, or more. In some examples, the IL-2 conjugate comprises an extended plasma half-life of about 1 hour to about 18 hours, about 1 hour to about 12 hours, about 2 hours to about 10 hours, about 2 hours to about 8 hours, about 4 hours to about 18 hours, about 4 hours to about 12 hours, about 4 hours to about 10 hours, about 4 hours to about 8 hours, about 6 hours to about 18 hours, about 6 hours to about 12 hours, about 6 hours to about 10 hours, about 6 hours to about 8 hours, about 8 hours to about 18 hours, about 8 hours to about 12 hours, or about 8 hours to about 10 hours, resulting in reduced toxicity. In some cases, the reduced toxicity is at least 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 30-fold, 50-fold, 100-fold, or more, compared to wild-type IL2. In some cases, the reduced toxicity is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500% or more compared to wild-type IL-2.

[0150] In some embodiments, the IL-2 conjugate comprises an extended plasma half-life and has reduced toxicity. In some examples, the IL-2 conjugate comprises an extended plasma half-life of at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 15 hours, 18 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or more, and has reduced toxicity. In some examples, the IL-2 conjugate comprises an extended plasma half-life of at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 15 hours, 18 hours, 24 hours, or more, and has reduced toxicity. In some examples, the IL-2 conjugate comprises an extended plasma half-life of about 1 hour to about 18 hours, about 1 hour to about 12 hours, about 2 hours to about 10 hours, about 2 hours to about 8 hours, about 4 hours to about 18 hours, about 4 hours to about 12 hours, about 4 hours to about 10 hours, about 4 hours to about 8 hours, about 6 hours to about 18 hours, about 6 hours to about 12 hours, about 6 hours to about 10 hours, about 6 hours to about 8 hours, about 8 hours to about 18 hours, about 8 hours to about 12 hours, or about 8 hours to about 10 hours, and exhibits reduced toxicity. In some cases, the reduced toxicity is at least 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 30-fold, 50-fold, 100-fold, or more, compared to aldesleukin. In some cases, the reduced toxicity is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500% or more compared to aldesleukin.

[0151] In some embodiments, the IL-2 conjugate comprises a conjugating moiety, and the size (e.g., volume or length) of the conjugating moiety increases plasma stability but does not decrease potency. In some examples, the size of the conjugating moiety extends plasma half-life by at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 15 hours, 18 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or more. In some examples, the size of the conjugating moiety extends plasma half-life by at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 15 hours, 18 hours, 24 hours, or more. In some examples, the size of the conjugated moiety increases the plasma half-life by about 1 hour to about 18 hours, about 1 hour to about 12 hours, about 2 hours to about 10 hours, about 2 hours to about 8 hours, about 4 hours to about 18 hours, about 4 hours to about 12 hours, about 4 hours to about 10 hours, about 4 hours to about 8 hours, about 6 hours to about 18 hours, about 6 hours to about 12 hours, about 6 hours to about 10 hours, about 6 hours to about 8 hours, about 8 hours to about 18 hours, about 8 hours to about 12 hours, or about 8 hours to about 10 hours. In some examples, the size of the conjugated moiety reduces potency by less than 5%, 4%, 3%, 2%, 1%, or more compared to aldesleukin.

[0152] In some embodiments, the IL-2 conjugate comprises a conjugating moiety, and the size (e.g., volume or length) of the conjugating moiety increases plasma stability and potency. In some examples, the size of the conjugating moiety increases plasma stability and potency for at least 1 hour, 2 hours, 3 hours, or 4 hours. In some examples, the size of the conjugated moiety increases the plasma half-life by at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 15 hours, 18 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or more. In some examples, the size of the conjugated moiety increases the plasma half-life by at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 15 hours, 18 hours, 24 hours, or more. In some examples, the size of the conjugated moiety increases the plasma half-life by about 1 hour to about 18 hours, about 1 hour to about 12 hours, about 2 hours to about 10 hours, about 2 hours to about 8 hours, about 4 hours to about 18 hours, about 4 hours to about 12 hours, about 4 hours to about 10 hours, about 4 hours to about 8 hours, about 6 hours to about 18 hours, about 6 hours to about 12 hours, about 6 hours to about 10 hours, about 6 hours to about 8 hours, about 8 hours to about 18 hours, about 8 hours to about 12 hours, or about 8 hours to about 10 hours. In some examples, the size of the conjugated moiety further increases potency by more than 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200% or more compared to aldesleukin.

[0153] In some embodiments, described herein are IL-2 conjugates that include a non-natural amino acid covalently attached to a conjugating moiety, wherein the non-natural amino acid is located in region 35-107, which region 35-107 corresponds to residues K35-Y107 of SEQ ID NO:1.

[0154] In some embodiments, described herein are interleukin-2 beta gamma receptor (IL-2Rβγ) binding proteins, wherein the binding affinity of the binding protein to interleukin-2 alpha receptor (IL-2Rα) is less than that of wild-type human IL-2 (hIL-2), and wherein the binding affinity of the binding protein to interleukin-2 alpha receptor (IL-2Rα) is less than that of wild-type human IL-2 (hIL-2). In some embodiments, described herein are interleukin-2 beta gamma receptor (IL-2Rβγ) binding proteins, wherein the binding affinity of the binding protei...

Claims

1. 1. A container comprising an IL-2 conjugate comprising: (i) an amino acid sequence having at least 90% sequence identity with the amino acid sequence of SEQ ID NO: 3; and (ii) an amino acid modified to replace proline at a position corresponding to position 64 of SEQ ID NO: 3, wherein the modified amino acid has the structure of formula (XII) or formula (XIII): 【Chemical 1】 and During the ceremony, n is -(OCH 2 CH 2 ) n -OCH 3 The PEG group having the structure are integers such that The wavy lines indicate covalent bonds to the amino acid residues at positions 63 and 65, respectively, in SEQ ID NO:

3. The container.

2. The container of claim 1 , wherein the amino acid sequence of (i) has at least 95% sequence identity with the amino acid sequence of SEQ ID NO:

3.

3. 2. The container of claim 1, wherein the amino acid sequence of (i) has at least 97% sequence identity with the amino acid sequence of SEQ ID NO:

3.

4. 2. The container of claim 1, wherein the IL-2 conjugate consists of the amino acid sequence of SEQ ID NO: 3, wherein the modified amino acid of the structure of formula (XII) or formula (XIII) is located at position 64 of SEQ ID NO: 3 in place of a proline.

5. 1. A container comprising an IL-2 conjugate comprising: (i) an amino acid sequence that is at least 97% identical to the amino acid sequence of SEQ ID NO: 30; and (ii) an amino acid sequence that comprises X at a position corresponding to position 64 of SEQ ID NO: 30, wherein X is a lysine analog containing an azide group covalently attached to a PEG group having a molecular weight of about 30 kDa through a conjugation moiety that comprises a dibenzocyclooctyne group.

6. 6. The container according to claim 5, wherein the lysine analog containing an azide group is N6-(2-azidoethoxy)-carbonyl-L-lysine (Azk).

7. The lysine analogs covalently attached to a PEG group through the conjugation moiety collectively have the structure of formula (XII) or formula (XIII): 【Chemistry 2】 is represented by During the ceremony, n is -(OCH 2 CH 2 ) n -OCH 3 The PEG group having the structure are integers such that The wavy lines indicate covalent bonds to the amino acid residues immediately preceding and immediately following X in SEQ ID NO: 30, respectively.

7. A container according to claim 5 or 6.

8. 1. A container comprising an IL-2 conjugate comprising: (i) an amino acid sequence that is at least 98% identical to the amino acid sequence of SEQ ID NO: 30; and (ii) an amino acid sequence that comprises X at a position corresponding to position 64 of SEQ ID NO: 30, wherein X is a lysine analog containing an azide group covalently attached to a PEG group having a molecular weight of about 30 kDa through a conjugation moiety that comprises a dibenzocyclooctyne group.

9. 9. The container according to claim 8, wherein the lysine analog containing an azide group is N6-(2-azidoethoxy)-carbonyl-L-lysine (Azk).

10. The lysine analogs covalently attached to a PEG group through the conjugation moiety collectively have the structure of formula (XII) or formula (XIII): 【Chemistry 3】 is represented by During the ceremony, n is -(OCH 2 CH 2 ) n -OCH 3 is an integer such that the PEG group having the structure has a molecular weight of about 30 kDa, The wavy lines indicate covalent bonds to the amino acid residues immediately preceding and immediately following X in SEQ ID NO: 30, respectively.

10. A container according to claim 8 or 9.

11. A container comprising an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO:30, wherein X in SEQ ID NO:30 is a lysine analog comprising an azide group covalently attached to a PEG group having a molecular weight of approximately 30 kDa through a conjugating moiety comprising a dibenzocyclooctyne group.

12. 12. The container according to claim 11, wherein the lysine analog containing an azide group is N6-(2-azidoethoxy)-carbonyl-L-lysine (Azk).

13. The lysine analogs covalently attached to a PEG group through the conjugation moiety collectively have the structure of formula (XII) or formula (XIII): 【Chemistry 4】 is represented by During the ceremony, n is -(OCH 2 CH 2 ) n -OCH 3 is an integer such that the PEG group having the structure has a molecular weight of about 30 kDa, The wavy lines indicate covalent bonds to the amino acid residues immediately preceding and immediately following X in SEQ ID NO: 30, respectively. Container according to claim 11 or 12.

14. A container containing a pharmaceutical composition comprising a mixture of IL-2 conjugates according to any one of claims 1 to 4, 7, 10 and 13, wherein the mixture comprises (i) an IL-2 conjugate having the structure of formula (XII) and (ii) an IL-2 conjugate having the structure of formula (XIII).

15. A container containing a pharmaceutical composition comprising the IL-2 conjugate of any one of claims 5, 6, 8, 9, 11 and 12.

16. 16. The container of claim 14 or 15, further comprising a diluent, a buffer, a stabilizer, a surfactant, or any combination thereof.

17. 16. The container of claim 14 or 15, further comprising sorbitol.

18. 16. The container of claim 14 or 15, further comprising polysorbate-20.

19. 16. The container of claim 14 or 15, wherein the container comprises a dispenser device.

20. 16. The container of claim 14 or 15, wherein the container comprises a syringe.

21. 16. The container of claim 14 or 15, wherein the container comprises a vial.

22. 1. A method for producing an IL-2 conjugate, comprising: The following structure: 【Chemistry 5】 or a pharmaceutically acceptable salt, solvate, or hydrate thereof, comprising an IL-2 polypeptide having an unnatural amino acid having the formula: 【Chemistry 6】 wherein n is an integer such that the mPEG-DBCO comprises an mPEG having a molecular weight of about 30 kDa to form a compound having the structure of formula (XII) or formula (XIII): 【Chemistry 7】 forming an IL-2 conjugate having

23. 23. The method of claim 22, wherein the IL-2 polypeptide has at least 97% sequence identity with the amino acid sequence of SEQ ID NO: 3, and consists of an amino acid sequence in which the amino acid residue at position P64 in SEQ ID NO: 3 is replaced with the unnatural amino acid.

24. 23. The method of claim 22, wherein the IL-2 polypeptide has at least 98% sequence identity with the amino acid sequence of SEQ ID NO: 3, wherein the amino acid residue at position P64 in SEQ ID NO: 3 is replaced with the unnatural amino acid.

25. 23. The method of claim 22, wherein the IL-2 polypeptide consists of the amino acid sequence of SEQ ID NO: 3, with the amino acid residue at position P64, with reference to amino acid positions within SEQ ID NO: 3, replaced by the unnatural amino acid.

26. 23. The method of claim 22, wherein the method further comprises a purification step, and wherein the IL-2 polypeptide consists of the amino acid sequence of SEQ ID NO: 3, with the amino acid residue at position P64, referenced to the amino acid position in SEQ ID NO: 3, replaced by the unnatural amino acid.

27. 22. A container according to any one of claims 1 to 21 for use in expanding Teff cells and / or NK cells in a subject in need thereof.

28. The Teff cells are CD4 + Helper cells, CD8 + Effector cells, CD8 + Naive cells, CD8 + 28. The container of claim 27, comprising memory cells, natural killer (NK) cells, natural killer T (NKT) cells, or any combination thereof.

29. 28. The container of claim 27, wherein the subject has cancer.

30. 22. A container according to any one of claims 1 to 21 for use in treating cancer in a subject in need thereof.

31. 31. The container of claim 30, wherein the cancer is a solid tumor.

32. 32. The container of claim 31 , wherein the solid tumor is bladder cancer, bone cancer, brain cancer, breast cancer, colorectal cancer, esophageal cancer, eye cancer, head and neck cancer, kidney cancer, lung cancer, mesothelioma, skin cancer, ovarian cancer, pancreatic cancer, or prostate cancer.

33. 31. The container of claim 30, wherein the cancer is a hematological malignancy.

34. 34. The container of claim 33, wherein the hematological malignancy is lymphoma.

35. 35. The container of claim 34, wherein the lymphoma is classical Hodgkin's lymphoma (cHL) or B-cell lymphoma.

36. 31. The container of claim 30, wherein the IL-2 conjugate is for use in combination with an additional therapeutic agent.

37. 37. The container of claim 36, wherein the additional therapeutic agent comprises an immune checkpoint inhibitor.

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