IL-2 conjugates and methods of use thereof

Abstract

Disclosed herein are compositions, kits, and methods comprising interleukin (IL) conjugates (e.g., IL-2 conjugates) that can be used to treat one or more indications. Also described herein are pharmaceutical compositions and kits comprising one or more interleukin conjugates (e.g., IL-2 conjugates).

Description

[0001] This application is a divisional application of the Chinese patent application with application number 202080027006.1 (application date: February 5, 2020, invention name: IL-2 conjugate and method of use thereof).

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] 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, all of which are incorporated by reference in their entireties.

[0004] Sequence Listing

[0005] [0001.1] This application contains a sequence listing submitted electronically in ASCII format and hereby incorporated by reference in its entirety. The ASCII copy created on February 4, 2020 is named 46085-729_601_SL.txt and is 124,806 bytes in size. Background Art

[0006] Different populations of T cells regulate the immune system to maintain immune homeostasis and tolerance. For example, regulatory T (Treg) cells prevent inappropriate responses of the immune system by preventing pathological self-reactivity, while cytotoxic T cells target and destroy infected cells and / or cancer cells. In some cases, the regulation of different T cell populations provides options for the treatment of diseases or indications. Summary of the Invention

[0007] 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 (I):

[0008]

[0009]

[0010] in:

[0011] Z is CH2 and Y is

[0012] Y is CH2 and Z is

[0013] Z is CH2 and Y is or

[0014] Y is CH2 and Z is

[0015] W is a PEG group having an average molecular weight selected from the group consisting of 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, 45 kDa, 50 kDa, and 60 kDa; and

[0016] X has the following structure:

[0017]

[0018] or a pharmaceutically acceptable salt, solvate or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, Z is CH2 and Y is or a pharmaceutically acceptable salt, solvate or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, Y is CH2 and Z is or a pharmaceutically acceptable salt, solvate or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, Z is CH2 and Y is or a pharmaceutically acceptable salt, solvate or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, Z is CH2 and Y is or a pharmaceutically acceptable salt, solvate or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, Y is CH2 and Z is or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the PEG group has an average molecular weight selected from 5 kDa, 10 kDa, 20 kDa, and 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the PEG group has an average molecular weight of 5 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the PEG group has an average molecular weight of 10 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the PEG group has an average molecular weight of 15 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the PEG group has an average molecular weight of 20 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the PEG group has an average molecular weight of 25 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the PEG group has an average molecular weight of 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the PEG group has an average molecular weight of 35 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the PEG group has an average molecular weight of 40 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the PEG group has an average molecular weight of 45 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the PEG group has an average molecular weight of 50 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the PEG group has an average molecular weight of 60 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates 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, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is with reference to the position in SEQ ID NO: 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof.In some embodiments of the IL-2 conjugates 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, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is with reference to the position in SEQ ID NO: 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is K35, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is with reference to the position in SEQ ID NO: 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is F42, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is with reference to the position in SEQ ID NO: 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is F44, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is with reference to the position in SEQ ID NO: 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is K43, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is with reference to the position in SEQ ID NO: 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is E62, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is with reference to the position in SEQ ID NO: 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is P65, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is with reference to the position in SEQ ID NO: 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is R38, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is with reference to the position in SEQ ID NO: 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.In some embodiments of the IL-2 conjugates described herein, the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is T41, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is with reference to the position in SEQ ID NO: 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is E68, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is with reference to the position in SEQ ID NO: 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is Y45, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is with reference to the position in SEQ ID NO: 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is V69, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is with reference to the position in SEQ ID NO: 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is L72, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is with reference to the position in SEQ ID NO: 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0019] Described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 4, wherein at least one amino acid residue in the IL-2 conjugate is replaced with a structure of formula (I):

[0020]

[0021] in:

[0022] Z is CH2 and Y is

[0023] Y is CH2 and Z is

[0024] Z is CH2 and Y is or

[0025] Y is CH2 and Z is

[0026] W is a PEG group having an average molecular weight selected from the group consisting of 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, 45 kDa, 50 kDa, and 60 kDa; and

[0027] X has the following structure:

[0028]

[0029] or a pharmaceutically acceptable salt, solvate or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, Z is CH2 and Y is or a pharmaceutically acceptable salt, solvate or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, Y is CH2 and Z is or a pharmaceutically acceptable salt, solvate or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, Z is CH2 and Y is or a pharmaceutically acceptable salt, solvate or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, Z is CH2 and Y is or a pharmaceutically acceptable salt, solvate or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, Y is CH2 and Z is or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the PEG group has an average molecular weight selected from 5 kDa, 10 kDa, 20 kDa, and 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the PEG group has an average molecular weight of 5 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the PEG group has an average molecular weight of 10 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the PEG group has an average molecular weight of 15 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the PEG group has an average molecular weight of 20 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the PEG group has an average molecular weight of 25 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the PEG group has an average molecular weight of 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the PEG group has an average molecular weight of 35 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the PEG group has an average molecular weight of 40 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the PEG group has an average molecular weight of 45 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the PEG group has an average molecular weight of 50 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the PEG group has an average molecular weight of 60 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates 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, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is with reference to the position in SEQ ID NO: 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof.In some embodiments of the IL-2 conjugates 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, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is with reference to the position in SEQ ID NO: 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is K35, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is with reference to the position in SEQ ID NO: 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is F42, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is with reference to the position in SEQ ID NO: 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is F44, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is with reference to the position in SEQ ID NO: 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is K43, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is with reference to the position in SEQ ID NO: 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is E62, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is with reference to the position in SEQ ID NO: 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is P65, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is with reference to the position in SEQ ID NO: 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is R38, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is with reference to the position in SEQ ID NO: 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.In some embodiments of the IL-2 conjugates described herein, the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is T41, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is with reference to the position in SEQ ID NO: 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is E68, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is with reference to the position in SEQ ID NO: 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is Y45, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is with reference to the position in SEQ ID NO: 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is V69, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is with reference to the position in SEQ ID NO: 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is L72, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is with reference to the position in SEQ ID NO: 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0030] Described herein are IL-2 conjugates comprising the amino acid sequence of any one of SEQ ID NOs: 15-19, wherein [AzK_PEG] has a structure of Formula (II) or Formula (III), or a mixture of Formula (II) and Formula (III):

[0031]

[0032] in:

[0033] W is a PEG group having an average molecular weight selected from the group consisting of 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, 45 kDa, 50 kDa, and 60 kDa; and

[0034] X has the following structure:

[0035] or a pharmaceutically acceptable salt, solvate or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the [AzK_PEG] is a mixture of formula (II) and formula (III), or a pharmaceutically acceptable salt, solvate or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the [AzK_PEG] has a structure of formula (II):

[0036]

[0037] Formula (II); or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 15, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, and 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight selected from 5 kDa and 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight of 5 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight of 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 16, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, 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, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group having an average molecular weight selected from 5 kDa and 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group having an average molecular weight of 5 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group having an average molecular weight of 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 17, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, 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, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group having an average molecular weight selected from 5 kDa and 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight of 5 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight of 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 18, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, and 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight selected from 5 kDa and 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight of 5 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight of 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 19, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, and 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight selected from 5 kDa and 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight of 5 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight of 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, [AzK_PEG] has a structure of formula (III).

[0038]

[0039] Formula (III); or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 15, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, and 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight selected from 5 kDa and 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight of 5 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight of 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 16, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, 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, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group having an average molecular weight selected from 5 kDa and 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group having an average molecular weight of 5 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group having an average molecular weight of 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 17, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, 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, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group having an average molecular weight selected from 5 kDa and 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight of 5 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight of 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 18, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, and 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight selected from 5 kDa and 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight of 5 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight of 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 19, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, and 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight selected from 5 kDa and 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight of 5 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight of 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a linear or branched PEG group, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a linear PEG group, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a branched PEG group, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.In some embodiments of the IL-2 conjugates described herein, W is a methoxy PEG group, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the methoxy PEG group is linear or branched, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the methoxy PEG group is linear, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the methoxy PEG group is branched, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. An exemplary structure of a methoxy PEG group is shown in the mPEG-DBCO structure in Scheme 1 of Example 2.

[0040] 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 with 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 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 with an average molecular weight of 5 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 with an average molecular weight of 10 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 with an average molecular weight of 15 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 with an average molecular weight of 20 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 with an average molecular weight of 25 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 with 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 with an average molecular weight of 35 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 with an average molecular weight of 40 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 with an average molecular weight of 45 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 with an average molecular weight of 50 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 with an average molecular weight of 60 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 with 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, wherein the PEG group is a methoxy PEG group, a linear methoxy PEG group, or a branched methoxy PEG group.

[0041] Described herein are IL-2 conjugates comprising the amino acid sequence of any one of SEQ ID NOs: 20-24, wherein [AzK_PEG5kD] has a structure of Formula (II) or Formula (III), or a mixture of Formula (II) and Formula (III):

[0042]

[0043] in:

[0044] W is a PEG group with an average molecular weight of 5 kDa; and

[0045] X has the following structure:

[0046] or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 20, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 21, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 22, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 23, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 24, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, [AzK_PEG5kD] has the structure of formula (II)

[0047]

[0048] or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 20, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 21, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 22, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 23, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 24, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, [AzK_PEG5kD] has the structure of formula (III)

[0049]

[0050] Formula (III); or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 20, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 21, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 22, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 23, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 24, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0051] Described herein are IL-2 conjugates comprising the amino acid sequence of any one of SEQ ID NOs: 25-29, wherein [AzK_PEG30kD] has the structure of Formula (II) or Formula (III), or is a mixture of the structures of Formula (II) and Formula (III):

[0052]

[0053] in:

[0054] W is a PEG group having an average molecular weight of 30 kDa; and

[0055] X has the following structure:

[0056] or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 25, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 26, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 27, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 28, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 29, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, [AzK_PEG30kD] has the structure of Formula (II):

[0057]

[0058] Formula (II); or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 25, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 26, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 27, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 28, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 29, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, [AzK_PEG30kD] has the structure of formula (III)

[0059]

[0060] Formula (III); or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 25, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 26, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 27, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 28, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 29, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0061] Described herein are IL-2 conjugates comprising the amino acid sequence of any one of SEQ ID NOs: 15-19, wherein [AzK_PEG] is a mixture of structures of Formula (II) and Formula (III):

[0062]

[0063] in:

[0064] W is a PEG group having an average molecular weight selected from the group consisting of 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, 45 kDa, 50 kDa, and 60 kDa; and

[0065] X has the following structure:

[0066] 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) to the amount of the structure of formula (III) constituting the total amount of [AzK_PEG] in 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 (II) to the amount of the structure of formula (III) constituting the total amount of [AzK_PEG] in 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 (II) to the amount of the structure of formula (III) constituting the total amount of [AzK_PEG] in the IL-2 conjugate is less than 1:1. In some embodiments of the IL-2 conjugates described herein, W is a linear or branched PEG group, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a linear PEG group, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a branched PEG group, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a methoxy PEG group, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the methoxy PEG group is linear or branched, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the methoxy PEG group is linear, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the methoxy PEG group is branched, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0067] Described herein are IL-2 conjugates comprising the amino acid sequence of any one of SEQ ID NOs: 20 to 24, wherein [AzK_PEG5kD] is a mixture of structures of formula (II) and formula (III):

[0068]

[0069]

[0070] in:

[0071] W is a PEG group with an average molecular weight of 5 kDa; and

[0072] X has the following structure:

[0073] 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) to the amount of the structure of formula (III) constituting the total amount of [AzK_PEG5kD] in 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 (II) to the amount of the structure of formula (III) constituting the total amount of [AzK_PEG5kD] in 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 (II) to the amount of the structure of formula (III) constituting the total amount of [AzK_PEG5kD] in the IL-2 conjugate is less than 1:1.

[0074] 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):

[0075]

[0076] in:

[0077] W is a PEG group having an average molecular weight of 30 kDa; and

[0078] X has the following structure:

[0079] 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) to the amount of the structure of formula (III) constituting the total amount of [AzK_PEG30kD] in 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 (II) to the amount of the structure of formula (III) constituting the total amount of [AzK_PEG30kD] in 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 (II) to the amount of the structure of formula (III) constituting the total amount of [AzK_PEG30kD] in the IL-2 conjugate is less than 1:1.

[0080] 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 a structure of Formula (IV) or Formula (V), or a mixture of Formula (IV) and Formula (V):

[0081]

[0082] in:

[0083] W is a PEG group having an average molecular weight selected from the group consisting of 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, 45 kDa, 50 kDa, and 60 kDa; and

[0084] X has the following structure:

[0085] or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, [AzK_L1_PEG] is a mixture of Formula (IV) and Formula (V), or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, [AzK_L1_PEG] has the structure of Formula (IV):

[0086]

[0087] Formula (IV); or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 40, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, and 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight selected from 5 kDa and 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight of 5 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight of 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 41, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, and 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight selected from 5 kDa and 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight of 5 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight of 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 42, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, 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, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group having an average molecular weight selected from 5 kDa and 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight of 5 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight of 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 43, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, and 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight selected from 5 kDa and 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight of 5 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight of 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 44, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, and 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight selected from 5 kDa and 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight of 5 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight of 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, [AzK_L1_PEG] has a structure of Formula (V).

[0088]

[0089] Formula (V); or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 40, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, and 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight selected from 5 kDa and 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight of 5 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight of 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 41, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, and 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight selected from 5 kDa and 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight of 5 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight of 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 42, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, 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, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group having an average molecular weight selected from 5 kDa and 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight of 5 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight of 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 43, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, and 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight selected from 5 kDa and 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight of 5 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight of 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 44, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight selected from 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, and 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight selected from 5 kDa and 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight of 5 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a PEG group with an average molecular weight of 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a linear or branched PEG group, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a linear PEG group, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a branched PEG group, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.In some embodiments of the IL-2 conjugates described herein, W is a methoxy PEG group, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the methoxy PEG group is linear or branched, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the methoxy PEG group is linear, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the methoxy PEG group is branched, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. 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 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 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 with an average molecular weight of 5 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 with an average molecular weight of 10 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 with an average molecular weight of 15 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 with an average molecular weight of 20 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 with an average molecular weight of 25 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 with 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 with an average molecular weight of 35 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 with an average molecular weight of 40 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 with an average molecular weight of 45 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 with an average molecular weight of 50 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 with an average molecular weight of 60 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 with 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, wherein the PEG group is a methoxy PEG group, a linear methoxy PEG group, or a branched methoxy PEG group.

[0090] 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 a structure of Formula (IV) or Formula (V), or a mixture of Formula (IV) and Formula (V):

[0091]

[0092]

[0093] in:

[0094] W is a PEG group with an average molecular weight of 5 kDa; and

[0095] X has the following structure:

[0096] or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 45, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 46, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 47, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 48, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 49, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the [AzK_L1_PEG5kD] has the structure of formula (IV)

[0097]

[0098] Formula (IV); or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 45, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 46, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 47, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 48, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 49, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the [AzK_L1_PEG5kD] has the structure of formula (V)

[0099]

[0100] Formula (V); or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 45, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 46, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 47, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 48, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 49, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0101] Described herein are IL-2 conjugates comprising the amino acid sequence of any one of SEQ ID NOs: 50-54, wherein [AzK_L1_PEG30kD] has a structure of Formula (IV) or Formula (V), or is a mixture of the structures of Formula (IV) and Formula (V):

[0102]

[0103]

[0104] in:

[0105] W is a PEG group having an average molecular weight of 30 kDa; and

[0106] X has the following structure:

[0107] or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 50, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 51, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 52, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 53, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 54, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the [AzK_L1_PEG30kD] has the structure of Formula (IV):

[0108]

[0109] Formula (IV); or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 50, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 51, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 52, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 53, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 54, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the [AzK_L1_PEG30kD] has the structure of formula (V)

[0110]

[0111] Formula (V); or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 50, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 51, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 52, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 53, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 54, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0112] 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):

[0113]

[0114]

[0115] in:

[0116] W is a PEG group having an average molecular weight selected from the group consisting of 5 kDa, 10 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, 45 kDa, 50 kDa, and 60 kDa; and

[0117] X has the following structure:

[0118] 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) to the amount of the structure of formula (V) constituting the total amount of [AzK_L1_PEG] in 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 (IV) to the amount of the structure of formula (V) constituting the total amount of [AzK_L1_PEG] in 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 (IV) to the amount of the structure of formula (V) constituting the total amount of [AzK_L1_PEG] in the IL-2 conjugate is less than 1:1. In some embodiments of the IL-2 conjugates described herein, W is a linear or branched PEG group, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a linear PEG group, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a branched PEG group, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, W is a methoxy PEG group, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the methoxy PEG group is linear or branched, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the methoxy PEG group is linear, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the methoxy PEG group is branched, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0119] Described herein are IL-2 conjugates comprising the amino acid sequence of any one of SEQ ID NOs: 45 to 49, wherein [AzK_L1_PEG5kD] is a mixture of structures of Formula (IV) and Formula (V):

[0120]

[0121] in:

[0122] W is a PEG group with an average molecular weight of 5 kDa; and

[0123] X has the following structure:

[0124] 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) to the amount of the structure of formula (V) constituting the total amount of [AzK_L1_PEG5kD] in 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 (IV) to the amount of the structure of formula (V) constituting the total amount of [AzK_L1_PEG5kD] in 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 (IV) to the amount of the structure of formula (V) constituting the total amount of [AzK_L1_PEG5kD] in the IL-2 conjugate is less than 1:1.

[0125] Described herein are IL-2 conjugates comprising the amino acid sequence of any one of SEQ ID NOs: 50-54, wherein [AzK_L1_PEG30kD] is a mixture of structures of Formula (IV) and Formula (V):

[0126]

[0127]

[0128] in:

[0129] W is a PEG group having an average molecular weight of 30 kDa; and

[0130] X has the following structure:

[0131] 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) to the amount of the structure of formula (V) constituting the total amount of [AzK_L1_PEG30kD] in 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 (IV) to the amount of the structure of formula (V) constituting the total amount of [AzK_L1_PEG30kD] in 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 (IV) to the amount of the structure of formula (V) constituting the total amount of [AzK_L1_PEG30kD] in the IL-2 conjugate is less than 1:1.

[0132] 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 Formula (VI) and Formula (VII):

[0133]

[0134] in:

[0135] n is an integer in the range of about 2 to about 5000; and

[0136] X has the structure: 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 in the range of about 5 to about 4600, or about 10 to about 4000, or about 20 to about 3000, or about 100 to about 3000, or about 100 to about 2900, or about 150 to about 2900, or about 125 to about 2900, or 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 17 50, or about 100 to about 1650, or about 100 to about 1500, or about 100 to about 1400, or about 100 to about 1300, or about 100 to about 1250, or about 100 to about 1150, or about 100 to about 1100, or about 100 to about 1000, or about 100 to about 900, or about 100 to about 750, or about 100 to about 700, or about 100 to about 600, or about 100 to about 575, or about 100 to about 500, or about 100 to about 450, or about 100 to about 3 50, 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 an integer selected from the group consisting of: 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, 1365, 1366, 1367, 1368, 1369, 1370, 1371, 1372, 1373, 1374, 1375, 1376, 1377, 1378, 1379, 1371, 1377, 1379, 1371 64, 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 structure of formula (VI), formula (VII), or a mixture of formula (VI) and (VII) is present at a position in the amino acid sequence of the IL-2 conjugate selected from the group consisting of K34, F41, F43, K42, E61, P64, R37, T40, E67, Y44, V68, and L71, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is with reference to the position in SEQ ID NO: 3. In some embodiments of the IL-2 conjugates described herein, the structure of formula (VI), formula (VII), or a mixture of formula (VI) and (VII) is present at a position in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 selected from the group consisting of 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 Formula (VI) and (VII) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is at position 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 Formula (VI) and (VII) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is at position 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 Formula (VI) and (VII) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is at position F43.In some embodiments of the IL-2 conjugates described herein, the structure of Formula (VI), Formula (VII), or a mixture of Formula (VI) and (VII) is located at position K42 in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3. In some embodiments of the IL-2 conjugates described herein, the structure of Formula (VI), Formula (VII), or a mixture of Formula (VI) and (VII) is located at position E61 in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3. In some embodiments of the IL-2 conjugates described herein, the structure of Formula (VI), Formula (VII), or a mixture of Formula (VI) and (VII) is located at position P64 in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3. In some embodiments of the IL-2 conjugates described herein, the structure of Formula (VI), Formula (VII), or a mixture of Formula (VI) and (VII) is located at position R37 in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3. In some embodiments of the IL-2 conjugates described herein, the structure of Formula (VI), Formula (VII), or a mixture of Formula (VI) and (VII) is located at position T40 in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3. In some embodiments of the IL-2 conjugates described herein, the structure of Formula (VI), Formula (VII), or a mixture of Formula (VI) and (VII) is located at position E67 in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3. In some embodiments of the IL-2 conjugates described herein, the structure of Formula (VI), Formula (VII), or a mixture of Formula (VI) and (VII) is located at position Y44 in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3. In some embodiments of the IL-2 conjugates described herein, the structure of Formula (VI), Formula (VII), or a mixture of Formula (VI) and (VII) is located at position V68 in the amino acid sequence of the IL-2 conjugate of 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 formula (VI) and (VII) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is at 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) constituting 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) constituting 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) making up the total amount of the IL-2 conjugate is less than 1:1.

[0137] In some embodiments described herein, an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3 is provided, wherein at least one amino acid residue in the IL-2 conjugate is replaced by a structure of Formula (VI) or (VII), or a mixture of Formula (VI) and Formula (VII), 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 wherein n is an integer 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 750. 00, 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 an integer selected from the group consisting of: 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, 1365, 1366, 1367, 1368, 1369, 1370, 1371, 1372, 1373, 1374, 1375, 1376, 1377, 1378, 1379, 1371, 1377, 1379, 1371 64, 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.

[0138] In some embodiments described herein, an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3 is provided, 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 Formula (VI) and Formula (VII), wherein the replaced amino acid residue in SEQ ID NO: 3 is selected from F41, F43, K42, E61, and P64, and wherein 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 the group consisting of: 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, 1137, and 1249.

[0139] In some embodiments described herein, an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3 is provided, 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 Formula (VI) and Formula (VII), wherein the replaced amino acid residue in SEQ ID NO: 3 is selected from E61 and P64, and wherein 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, n in the compounds of Formula (VI) and (VII) is an integer selected from the group consisting of: 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910.

[0140] In some embodiments described herein, an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3 is provided, 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 Formula (VI) and Formula (VII), wherein the replaced amino acid residue in SEQ ID NO: 3 is E61, and wherein 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 the group consisting of: 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.

[0141] In some embodiments described herein, an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3 is provided, 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 Formula (VI) and Formula (VII), wherein the replaced amino acid residue in SEQ ID NO: 3 is P64, and wherein 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 the group consisting of: 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.

[0142] 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 Formula (VI) and Formula (VII), wherein n is an integer such that the molecular weight of the PEG moiety is in the range of about 1,000 Daltons to 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 90,000 Daltons. 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 15,000 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. IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 3 are described herein, 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 Formula (VI) and Formula (VII), wherein 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 40,000 Daltons, about 50,000 Daltons, about 60,000 Daltons, about 75,000 Daltons, about 80,000 Daltons, about 90,000 Daltons, about 100,000 Daltons, about 150,000 Daltons, about 160,000 Daltons, about 170,000 Daltons, about 180,000 Daltons, about 200,000 Daltons, about 250,000 Daltons, about 300,000 Daltons, about 350,000 Daltons, about 350,000 Daltons, about 400,000 Daltons, about 500,000 Daltons, about 600,000 Daltons, about 750,000 Daltons, about 800,000 Daltons, about 800,000 Daltons, about 900,000 Daltons, about 180, About 30,000 Daltons, about 35,000 Daltons, about 40,000 Daltons, about 45,000 Daltons, about 50,000 Daltons, about 60,000 Daltons, about 70,000 Daltons, about 80,000 Daltons, about 90,000 Daltons, about 100,000 Daltons, about 125,000 Daltons, about 150,000 Daltons, about 175,000 Daltons, or about 200,000 Daltons. Described herein are IL-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 Formula (VI) and Formula (VII), wherein 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.

[0143] 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):

[0144]

[0145] in:

[0146] n is an integer in the range of about 2 to about 5000; and

[0147] X has the structure: 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 (VIII) and (IX) is in the range of about 5 to about 4600, or about 10 to about 4000, or about 20 to about 3000, or about 100 to about 3000, or about 100 to about 2900, or about 150 to about 2900, or about 125 to about 2900, or 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 1 750, 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 (VIII) and (IX) is an integer selected from the group consisting of 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, 1 364, 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 structure of formula (VIII), formula (IX), or a mixture of formula (VIII) and (IX) is present at a position in the amino acid sequence of the IL-2 conjugate selected from the group consisting of K34, F41, F43, K42, E61, P64, R37, T40, E67, Y44, V68, and L71, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is with reference to the position in SEQ ID NO: 3. In some embodiments of the IL-2 conjugates described herein, the structure of formula (VIII), formula (IX), or a mixture of formula (VIII) and (IX) is present at a position in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 selected from the group consisting of 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 Formula (VIII) and (IX) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is at position 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 Formula (VIII) and (IX) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is at position 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 Formula (VIII) and (IX) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is at 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 formula (VIII) and (IX) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is at 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 formula (VIII) and (IX) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is at 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 formula (VIII) and (IX) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is at 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 formula (VIII) and (IX) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is at position R37. In some embodiments of the IL-2 conjugates described herein, the structure of formula (VIII), formula (IX), or a mixture of formula (VIII) and (IX) is located at position T40 in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3. In some embodiments of the IL-2 conjugates described herein, the structure of formula (VIII), formula (IX), or a mixture of formula (VIII) and (IX) is located at position E67 in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3. In some embodiments of the IL-2 conjugates described herein, the structure of formula (VIII), formula (IX), or a mixture of formula (VIII) and (IX) is located at position Y44 in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3. In some embodiments of the IL-2 conjugates described herein, the structure of formula (VIII), formula (IX), or a mixture of formula (VIII) and (IX) is located at position V68 in the amino acid sequence of the IL-2 conjugate of 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 formula (VIII) and (IX) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is at 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) constituting 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) constituting 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) making up the total amount of the IL-2 conjugate is less than 1:1.

[0148] In some embodiments described herein, an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3 is provided, wherein at least one amino acid residue in the IL-2 conjugate is replaced by 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 K34, F41, F43, K42, E61, P64, R37, T40, E67, Y44, V68, and L71, and wherein n is an integer 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 750. 00, 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 (VIII) and (IX) is an integer selected from the group consisting of 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, 1 364, 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.

[0149] In some embodiments described herein, an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3 is provided, wherein at least one amino acid residue in the IL-2 conjugate is replaced by 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 wherein 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 the group consisting of: 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, 1137, and 1249.

[0150] In some embodiments described herein, an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3 is provided, 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 wherein 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, n in the compounds of formula (VIII) and (IX) is an integer selected from the group consisting of: 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910.

[0151] In some embodiments described herein, an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3 is provided, 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 E61, and wherein 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 the group consisting of: 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.

[0152] In some embodiments described herein, an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3 is provided, 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 wherein 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 the group consisting of: 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.

[0153] 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 n is an integer such that the molecular weight of the PEG moiety is in the range of about 1,000 daltons to 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 90,000 daltons. 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 15,000 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. IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 3 are described herein, wherein at least one amino acid residue in the IL-2 conjugate is replaced by a structure of formula (VIII) or (IX), or a mixture of (VIII) and (IX), wherein 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, or about 30,000 daltons. About 30,000 Daltons, about 35,000 Daltons, about 40,000 Daltons, about 45,000 Daltons, about 50,000 Daltons, about 60,000 Daltons, about 70,000 Daltons, about 80,000 Daltons, about 90,000 Daltons, about 100,000 Daltons, about 125,000 Daltons, about 150,000 Daltons, about 175,000 Daltons, or about 200,000 Daltons. Described herein are IL-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 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.

[0154] 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):

[0155]

[0156] in:

[0157] n is an integer in the range of about 2 to about 5000; and

[0158] The wavy line indicates a covalent bond to the unsubstituted amino acid residue in SEQ ID NO: 3, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[0159] In some embodiments, the stereochemistry of the chiral centers within Formula (X) and Formula (XI) is racemic, is (R)-rich, is (S)-rich, is substantially (R), is substantially (S), is (R) or is (S). In some embodiments, the stereochemistry of the chiral centers within Formula (X) and Formula (XI) is racemic. In some embodiments, the stereochemistry of the chiral centers within Formula (X) and Formula (XI) is (R)-rich. In some embodiments, the stereochemistry of the chiral centers within Formula (X) and Formula (XI) is (S)-rich. In some embodiments, the stereochemistry of the chiral centers within Formula (X) and Formula (XI) is substantially (R). In some embodiments, the stereochemistry of the chiral centers within Formula (X) and Formula (XI) is substantially (S). In some embodiments, the stereochemistry of the chiral centers within Formula (X) and Formula (XI) is (R). In some embodiments, the stereochemistry of the chiral centers within Formula (X) and Formula (XI) is (S).

[0160] In some embodiments of the IL-2 conjugates described herein, n in the compounds of formula (X) and (XI) is in the range of about 5 to about 4600, or about 10 to about 4000, or about 20 to about 3000, or about 100 to about 3000, or about 100 to about 2900, or about 150 to about 2900, or about 125 to about 2900, or 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 35 0, 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 an integer selected from the group consisting of: 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, 1365, 1366, 1367, 1368, 1369, 1369, 1361 ...1, 1369, 1361, 1369, 1361, 1361, 1369, 1361, 1361, 1369, 1361, 1361 4, 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 structure of formula (X) and (XI), or a mixture of formula (X) and (XI), is present at a position in the amino acid sequence of the IL-2 conjugate selected from the group consisting of K34, F41, F43, K42, E61, P64, R37, T40, E67, Y44, V68, and L71, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is with reference to the position in SEQ ID NO: 3. In some embodiments of the IL-2 conjugates described herein, the structure of formula (X) and (XI), or a mixture of formula (X) and (XI), is present at a position in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 selected from the group consisting of 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 (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 at position K34. In some embodiments of the IL-2 conjugates described herein, the position of the structure 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 at position F41. In some embodiments of the IL-2 conjugates described herein, the position of the structure 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 at position F43.In some embodiments of the IL-2 conjugates described herein, the structure of formula (X) and (XI) or a mixture of formula (X) and (XI) is located at position K42 in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3. In some embodiments of the IL-2 conjugates described herein, the structure of formula (X) and (XI) or a mixture of formula (X) and (XI) is located at position E61 in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3. In some embodiments of the IL-2 conjugates described herein, the structure of formula (X) and (XI) or a mixture of formula (X) and (XI) is located at position P64 in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3. In some embodiments of the IL-2 conjugates described herein, the structure of formula (X) and (XI) or a mixture of formula (X) and (XI) is located at position R37 in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3. In some embodiments of the IL-2 conjugates described herein, the structure of formula (X) and (XI) or a mixture of formula (X) and (XI) is located at position T40 in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3. In some embodiments of the IL-2 conjugates described herein, the structure of formula (X) and (XI) or a mixture of formula (X) and (XI) is located at position E67 in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3. In some embodiments of the IL-2 conjugates described herein, the structure of formula (X) and (XI) or a mixture of formula (X) and (XI) is located at position Y44 in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3. In some embodiments of the IL-2 conjugates described herein, the structure of formula (X) and (XI) or a mixture of formula (X) and (XI) is located at position V68 in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3. In some embodiments of the IL-2 conjugates described herein, the position of the structure 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 at 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) constituting 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) constituting 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) constituting the total amount of the IL-2 conjugate is less than 1:1.

[0161] In some embodiments described herein, an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3 is provided, wherein at least one amino acid residue in the IL-2 conjugate is replaced by 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 K34, F41, F43, K42, E61, P64, R37, T40, E67, Y44, V68, and L71, and wherein n is an integer 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 7 00, 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 an integer selected from the group consisting of: 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, 1365, 1366, 1367, 1368, 1369, 1370, 1371, 1372, 1373, 1374, 1375, 1376, 1377, 1378, 1379, 1371, 1377, 1379, 1371 64, 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.

[0162] In some embodiments described herein, an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3 is provided, 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 wherein 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 the group consisting of 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, 1137, and 1249.

[0163] In some embodiments described herein, an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3 is provided, 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 wherein 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, n in the compounds of formula (X) and (XI) is an integer selected from the group consisting of 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910.

[0164] In some embodiments described herein, an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3 is provided, 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 E61, and wherein 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 the group consisting of: 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.

[0165] In some embodiments described herein, an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3 is provided, 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 P64, and wherein 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 the group consisting of 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.

[0166] 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 n is an integer such that the molecular weight of the PEG moiety is in the range of about 1,000 daltons to 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. 00 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 Daltons, or about 8,500 to about 35,000 Daltons, or about 9,000 to about 50,000 Daltons, or about 9,000 to about 45,000 Daltons, or about 9,000 to about 40,000 Daltons, or about 9,000 to about 35,000 Daltons, or about 9,000 to about 30,000 Daltons, or about 9,500 to about 35,000 Daltons, or about 9,500 to about 30,000 Daltons, or about 10,000 to about 50,000 Daltons, or about 10,000 to about 45,000 Daltons, or about 10,000 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 daltonsDescribed 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 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 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 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 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.

[0167] 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):

[0168]

[0169] in:

[0170] n is an integer in the range of about 2 to about 5000; and

[0171] The wavy line indicates a covalent bond to the unsubstituted amino acid residue in SEQ ID NO: 3, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[0172] In some embodiments, the stereochemistry of the chiral centers within Formula (XII) and Formula (XIII) is racemic, is (R)-rich, is (S)-rich, is substantially (R), is substantially (S), is (R) or is (S). In some embodiments, the stereochemistry of the chiral centers within Formula (XII) and Formula (XIII) is racemic. In some embodiments, the stereochemistry of the chiral centers within Formula (XII) and Formula (XIII) is (R)-rich. In some embodiments, the stereochemistry of the chiral centers within Formula (XII) and Formula (XIII) is (S)-rich. In some embodiments, the stereochemistry of the chiral centers within Formula (XII) and Formula (XIII) is substantially (R). In some embodiments, the stereochemistry of the chiral centers within Formula (XII) and Formula (XIII) is substantially (S). In some embodiments, the stereochemistry of the chiral centers within Formula (XII) and Formula (XIII) is (R). In some embodiments, the stereochemistry of the chiral centers within Formula (XII) and Formula (XIII) is (S).

[0173] In some embodiments of the IL-2 conjugates described herein, n in the compounds of Formula (XII) and (XIII) is in the range of about 5 to about 4600, or about 10 to about 4000, or about 20 to about 3000, or about 100 to about 3000, or about 100 to about 2900, or about 150 to about 2900, or about 125 to about 2900, or 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 1 750, 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 (XII) and (XIII) is an integer selected from the group consisting of 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, 1 364, 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 structure of formula (XII) and (XIII) or a mixture of formula (XII) and (XIII) is at a position in the amino acid sequence of the IL-2 conjugate selected from K34, F41, F43, K42, E61, P64, R37, T40, E67, Y44, V68, and L71, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is with reference to the position in SEQ ID NO: 3. In some embodiments of the IL-2 conjugates described herein, the structure of formula (XII) and (XIII) or a mixture of formula (XII) and (XIII) is at a position in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 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 (XII) and (XIII) or the mixture of formula (XII) and (XIII) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is at position K34. In some embodiments of the IL-2 conjugates described herein, the position of the structure of formula (XII) and (XIII) or the mixture of formula (XII) and (XIII) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is at position F41. In some embodiments of the IL-2 conjugates described herein, the position of the structure of formula (XII) and (XIII) or the mixture of formula (XII) and (XIII) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is at position F43.In some embodiments of the IL-2 conjugates described herein, the position of the structure of formula (XII) and (XIII) or the mixture of formula (XII) and (XIII) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is at position K42. In some embodiments of the IL-2 conjugates described herein, the position of the structure of formula (XII) and (XIII) or the mixture of formula (XII) and (XIII) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is at position E61. In some embodiments of the IL-2 conjugates described herein, the position of the structure of formula (XII) and (XIII) or the mixture of formula (XII) and (XIII) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is at position P64. In some embodiments of the IL-2 conjugates described herein, the position of the structure of formula (XII) and (XIII) or the mixture of formula (XII) and (XIII) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is at position R37. In some embodiments of the IL-2 conjugates described herein, the structure of formula (XII) and (XIII) or a mixture of formula (XII) and (XIII) is located at position T40 in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3. In some embodiments of the IL-2 conjugates described herein, the structure of formula (XII) and (XIII) or a mixture of formula (XII) and (XIII) is located at position E67 in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3. In some embodiments of the IL-2 conjugates described herein, the structure of formula (XII) and (XIII) or a mixture of formula (XII) and (XIII) is located at position Y44 in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3. In some embodiments of the IL-2 conjugates described herein, the structure of formula (XII) and (XIII) or a mixture of formula (XII) and (XIII) is located at position V68 in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3. In some embodiments of the IL-2 conjugates described herein, the position of the structure 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 at 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) constituting 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) constituting 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) constituting the total amount of the IL-2 conjugate is less than 1:1.

[0174] In some embodiments described herein, an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3 is provided, wherein at least one amino acid residue in the IL-2 conjugate is replaced by 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 K34, F41, F43, K42, E61, P64, R37, T40, E67, Y44, V68, and L71, and wherein n is an integer 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 7 00, 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 (XII) and (XIII) is an integer selected from the group consisting of 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, 1 364, 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.

[0175] In some embodiments described herein, an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3 is provided, 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 wherein 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 the group consisting of 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, 1137, and 1249.

[0176] In some embodiments described herein, an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3 is provided, 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 wherein 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, n in the compounds of formula (XII) and (XIII) is an integer selected from the group consisting of 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910.

[0177] In some embodiments described herein, an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3 is provided, 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 E61, and wherein 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 the group consisting of: 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.

[0178] In some embodiments described herein, an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3 is provided, 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 wherein 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 the group consisting of: 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.

[0179] 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 n is an integer such that the molecular weight of the PEG moiety is in the range of about 1,000 daltons to 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 90,000 daltons. 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 10,000 Daltons. 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 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. IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 3 are described herein, 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 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, or about 30,000 Daltons. , about 30,000 Daltons, about 35,000 Daltons, about 40,000 Daltons, about 45,000 Daltons, about 50,000 Daltons, about 60,000 Daltons, about 70,000 Daltons, about 80,000 Daltons, about 90,000 Daltons, about 100,000 Daltons, about 125,000 Daltons, about 150,000 Daltons, about 175,000 Daltons, or about 200,000 Daltons. Described herein are IL-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 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.

[0180] 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):

[0181]

[0182] in:

[0183] m is an integer from 0 to 20;

[0184] p is an integer from 0 to 20;

[0185] n is an integer in the range of about 2 to about 5000; and

[0186] The wavy line indicates a covalent bond to the unsubstituted amino acid residue in SEQ ID NO: 3, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[0187] In some embodiments, the stereochemistry of the chiral centers within Formula (XIV) and Formula (XV) is racemic, is (R)-rich, is (S)-rich, is substantially (R), is substantially (S), is (R) or is (S). In some embodiments, the stereochemistry of the chiral centers within Formula (XIV) and Formula (XV) is racemic. In some embodiments, the stereochemistry of the chiral centers within Formula (XIV) and Formula (XV) is (R)-rich. In some embodiments, the stereochemistry of the chiral centers within Formula (XIV) and Formula (XV) is (S)-rich. In some embodiments, the stereochemistry of the chiral centers within Formula (XIV) and Formula (XV) is substantially (R). In some embodiments, the stereochemistry of the chiral centers within Formula (XIV) and Formula (XV) is substantially (S). In some embodiments, the stereochemistry of the chiral centers within Formula (XIV) and Formula (XV) is (R). In some embodiments, the stereochemistry of the chiral center within Formula (XIV) and Formula (XV) is (S).

[0188] In some embodiments of the IL-2 conjugates described herein, m in the compound 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 compound of formula (XIV) and (XV) is 0. In some embodiments of the IL-2 conjugates described herein, m in the compound of formula (XIV) and (XV) is 1. In some embodiments of the IL-2 conjugates described herein, m in the compound of formula (XIV) and (XV) is 2. In some embodiments of the IL-2 conjugates described herein, m in the compound of formula (XIV) and (XV) is 3. In some embodiments of the IL-2 conjugates described herein, m in the compound of formula (XIV) and (XV) is 4. In some embodiments of the IL-2 conjugates described herein, m in the compound of formula (XIV) and (XV) is 5. In some embodiments of the IL-2 conjugates described herein, m in the compound of formula (XIV) and (XV) is 6. In some embodiments of the IL-2 conjugates described herein, m in the compound of formula (XIV) and (XV) is 7. In some embodiments of the IL-2 conjugates described herein, m in the compound of formula (XIV) and (XV) is 8. In some embodiments of the IL-2 conjugates described herein, m in the compound of formula (XIV) and (XV) is 9. In some embodiments of the IL-2 conjugates described herein, m in the compound of formula (XIV) and (XV) is 10. In some embodiments of the IL-2 conjugates described herein, m in the compound of formula (XIV) and (XV) is 11. In some embodiments of the IL-2 conjugates described herein, m in the compound of formula (XIV) and (XV) is 12. In some embodiments of the IL-2 conjugates described herein, m in the compound of formula (XIV) and (XV) is 13. In some embodiments of the IL-2 conjugates described herein, m in the compound of formula (XIV) and (XV) is 14. In some embodiments of the IL-2 conjugates described herein, m in the compound of formula (XIV) and (XV) is 15. In some embodiments of the IL-2 conjugates described herein, m in the compound of formula (XIV) and (XV) is 16. In some embodiments of the IL-2 conjugates described herein, m in the compound of formula (XIV) and (XV) is 17. In some embodiments of the IL-2 conjugates described herein, m in the compound of formula (XIV) and (XV) is 18. In some embodiments of the IL-2 conjugates described herein, m in the compound 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.

[0189] In some embodiments of the IL-2 conjugates described herein, p in the compound 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 compound of formula (XIV) and (XV) is 0. In some embodiments of the IL-2 conjugates described herein, p in the compound of formula (XIV) and (XV) is 1. In some embodiments of the IL-2 conjugates described herein, p in the compound of formula (XIV) and (XV) is 2. In some embodiments of the IL-2 conjugates described herein, p in the compound of formula (XIV) and (XV) is 3. In some embodiments of the IL-2 conjugates described herein, p in the compound of formula (XIV) and (XV) is 4. In some embodiments of the IL-2 conjugates described herein, p in the compound of formula (XIV) and (XV) is 5. In some embodiments of the IL-2 conjugates described herein, p in the compound of formula (XIV) and (XV) is 6. In some embodiments of the IL-2 conjugates described herein, p in the compound of formula (XIV) and (XV) is 7. In some embodiments of the IL-2 conjugates described herein, p in the compound of formula (XIV) and (XV) is 8. In some embodiments of the IL-2 conjugates described herein, p in the compound of formula (XIV) and (XV) is 9. In some embodiments of the IL-2 conjugates described herein, p in the compound of formula (XIV) and (XV) is 10. In some embodiments of the IL-2 conjugates described herein, p in the compound of formula (XIV) and (XV) is 11. In some embodiments of the IL-2 conjugates described herein, p in the compound of formula (XIV) and (XV) is 12. In some embodiments of the IL-2 conjugates described herein, p in the compound of formula (XIV) and (XV) is 13. In some embodiments of the IL-2 conjugates described herein, p in the compound of formula (XIV) and (XV) is 14. In some embodiments of the IL-2 conjugates described herein, p in the compound of formula (XIV) and (XV) is 15. In some embodiments of the IL-2 conjugates described herein, m in the compound of formula (XIV) and (XV) is 16. In some embodiments of the IL-2 conjugates described herein, p in the compound of formula (XIV) and (XV) is 17. In some embodiments of the IL-2 conjugates described herein, p in the compound of formula (XIV) and (XV) is 18. In some embodiments of the IL-2 conjugates described herein, p in the compound 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.

[0190] In some embodiments of the IL-2 conjugates described herein, n in the compounds of Formula (XIV) and (XV) is in the range of about 5 to about 4600, or about 10 to about 4000, or about 20 to about 3000, or about 100 to about 3000, or about 100 to about 2900, or about 150 to about 2900, or about 125 to about 2900, or 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 17 50, or about 100 to about 1650, or about 100 to about 1500, or about 100 to about 1400, or about 100 to about 1300, or about 100 to about 1250, or about 100 to about 1150, or about 100 to about 1100, or about 100 to about 1000, or about 100 to about 900, or about 100 to about 750, or about 100 to about 700, or about 100 to about 600, or about 100 to about 575, or about 100 to about 500, or about 100 to about 450, or about 100 to about 3 50, 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.

[0191] 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 the group consisting of 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 1 to 6, p is an integer from 1 to 6, and n is an integer selected from the group consisting of 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 the group consisting of 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 the group consisting of 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 the group consisting of 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 the group consisting of 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 the group consisting of 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 the group consisting of 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 the group consisting of 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 the group consisting of 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 the group consisting of 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 an integer selected from the group consisting of 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 9, p is 2, and n is an integer selected from the group consisting of 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 the group consisting of 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 the group consisting of 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 the group consisting of 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 compounds of Formula (XIV) and (XV), m is 2, p is 2, and n is an integer selected from the group consisting of 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137.

[0192] In some embodiments of the IL-2 conjugates described herein, n in the compounds of formula (XIV) and (XV) is an integer selected from the group consisting of 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, 1365, 1366, 1367, 1368, 1369, 1370, 1371, 1372, 1373, 1374, 1375, 1376, 1377, 1378, 1379, 1371, 1377, 1379, 1371 64, 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 structure of formula (XIV) and (XV) or a mixture of formula (XIV) and (XV) is at a position in the amino acid sequence of the IL-2 conjugate selected from K34, F41, F43, K42, E61, P64, R37, T40, E67, Y44, V68, and L71, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is with reference to the position in SEQ ID NO: 3. In some embodiments of the IL-2 conjugates described herein, the structure of formula (XIV) and (XV) or a mixture of formula (XIV) and (XV) is at a position in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 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 at position K34. 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 at position F41. 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 at position F43.In some embodiments of the IL-2 conjugates described herein, the position of the structure of formula (XIV) and (XV) or the mixture of formula (XIV) and (XV) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is at position K42. In some embodiments of the IL-2 conjugates described herein, the position of the structure of formula (XIV) and (XV) or the mixture of formula (XIV) and (XV) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is at position E61. In some embodiments of the IL-2 conjugates described herein, the position of the structure of formula (XIV) and (XV) or the mixture of formula (XIV) and (XV) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is at position P64. In some embodiments of the IL-2 conjugates described herein, the position of the structure of formula (XIV) and (XV) or the mixture of formula (XIV) and (XV) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is at position R37. In some embodiments of the IL-2 conjugates described herein, the structure of formula (XIV) and (XV) or a mixture of formula (XIV) and (XV) is located at position T40 in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3. In some embodiments of the IL-2 conjugates described herein, the structure of formula (XIV) and (XV) or a mixture of formula (XIV) and (XV) is located at position E67 in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3. In some embodiments of the IL-2 conjugates described herein, the structure of formula (XIV) and (XV) or a mixture of formula (XIV) and (XV) is located at position Y44 in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3. In some embodiments of the IL-2 conjugates described herein, the structure of formula (XIV) and (XV) or a mixture of formula (XIV) and (XV) is located at position V68 in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3. 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 at 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) constituting 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) constituting 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) constituting the total amount of the IL-2 conjugate is less than 1:1.

[0193] In some embodiments described herein, an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3 is provided, wherein at least one amino acid residue in the IL-2 conjugate is replaced by 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 wherein n is an integer 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 7 00, 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 (XIV) and (XV) is an integer selected from the group consisting of 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, 1365, 1366, 1367, 1368, 1369, 1370, 1371, 1372, 1373, 1374, 1375, 1376, 1377, 1378, 1379, 1371, 1377, 1379, 1371 64, 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.

[0194] In some embodiments described herein, an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3 is provided, 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 wherein 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 the group consisting of 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, 1137, and 1249.

[0195] In some embodiments described herein, an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3 is provided, 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 wherein 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, n in the compounds of formula (XIV) and (XV) is an integer selected from the group consisting of: 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910.

[0196] In some embodiments described herein, an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3 is provided, 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, and wherein 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 the group consisting of: 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.

[0197] In some embodiments described herein, an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3 is provided, 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 wherein 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 the group consisting of: 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.

[0198] 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 n is an integer such that the molecular weight of the PEG moiety is in the range of about 1,000 daltons to 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. or 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 4 0,000 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, or about 20,000 Daltons to about 35,000 Daltons, or about 20,000 Daltons to about 30,000 Daltons. IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 3 are described herein, 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 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, about 50,000 Daltons, about 60,000 Daltons, about 70,000 Daltons, about 80,000 Daltons, about 90,000 Daltons, about 100,000 Daltons, about 125,000 Daltons, about 150,000 Daltons, about 175,000 Daltons, or about 200,000 Daltons. Described herein are IL-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 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.

[0199] In some embodiments described herein, an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3 is provided, 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 the group consisting of: 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, 1137, and 1249.

[0200] In some embodiments described herein, an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3 is provided, 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 wherein 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 the group consisting of 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910.

[0201] In some embodiments described herein, an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3 is provided, 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, and wherein 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 the group consisting of: 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.

[0202] In some embodiments described herein, an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3 is provided, 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 wherein 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 the group consisting of: 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.

[0203] 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):

[0204]

[0205] in:

[0206] m is an integer from 0 to 20;

[0207] n is an integer in the range of about 2 to about 5000; and

[0208] The wavy line indicates a covalent bond to the unsubstituted amino acid residue in SEQ ID NO: 3, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[0209] In some embodiments, the stereochemistry of the chiral centers within Formula (XVI) and Formula (XVII) is racemic, is (R)-rich, is (S)-rich, is substantially (R), is substantially (S), is (R) or is (S). In some embodiments, the stereochemistry of the chiral centers within Formula (XVI) and Formula (XVII) is racemic. In some embodiments, the stereochemistry of the chiral centers within Formula (XVI) and Formula (XVII) is (R)-rich. In some embodiments, the stereochemistry of the chiral centers within Formula (XVI) and Formula (XVII) is (S)-rich. In some embodiments, the stereochemistry of the chiral centers within Formula (XVI) and Formula (XVII) is substantially (R). In some embodiments, the stereochemistry of the chiral centers within Formula (XVI) and Formula (XVII) is substantially (S). In some embodiments, the stereochemistry of the chiral centers within Formula (XVI) and Formula (XVII) is (R). In some embodiments, the stereochemistry of the chiral centers within Formula (XVI) and Formula (XVII) is (S).

[0210] In some embodiments of the IL-2 conjugates described herein, m in the compound 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 compound of formula (XVI) and (XVII) is 0. In some embodiments of the IL-2 conjugates described herein, m in the compound of formula (XVI) and (XVII) is 1. In some embodiments of the IL-2 conjugates described herein, m in the compound of formula (XVI) and (XVII) is 2. In some embodiments of the IL-2 conjugates described herein, m in the compound of formula (XVI) and (XVII) is 3. In some embodiments of the IL-2 conjugates described herein, m in the compound of formula (XVI) and (XVII) is 4. In some embodiments of the IL-2 conjugates described herein, m in the compound of formula (XVI) and (XVII) is 5. In some embodiments of the IL-2 conjugates described herein, m in the compound of formula (XVI) and (XVII) is 6. In some embodiments of the IL-2 conjugates described herein, m in the compound of formula (XVI) and (XVII) is 7. In some embodiments of the IL-2 conjugates described herein, m in the compound of formula (XVI) and (XVII) is 8. In some embodiments of the IL-2 conjugates described herein, m in the compound of formula (XVI) and (XVII) is 9. In some embodiments of the IL-2 conjugates described herein, m in the compound of formula (XVI) and (XVII) is 10. In some embodiments of the IL-2 conjugates described herein, m in the compound of formula (XVI) and (XVII) is 11. In some embodiments of the IL-2 conjugates described herein, m in the compound of formula (XVI) and (XVII) is 12. In some embodiments of the IL-2 conjugates described herein, m in the compound of formula (XVI) and (XVII) is 13. In some embodiments of the IL-2 conjugates described herein, m in the compound of formula (XVI) and (XVII) is 14. In some embodiments of the IL-2 conjugates described herein, m in the compound of formula (XVI) and (XVII) is 15. In some embodiments of the IL-2 conjugates described herein, m in the compound of formula (XVI) and (XVII) is 16. In some embodiments of the IL-2 conjugates described herein, m in the compound of formula (XVI) and (XVII) is 17. In some embodiments of the IL-2 conjugates described herein, m in the compound of formula (XVI) and (XVII) is 18.In some embodiments of the IL-2 conjugates described herein, m in the compound of formula (XVI) and (XVII) is 19. In some embodiments of the IL-2 conjugates described herein, m in the compound of formula (XVI) and (XVII) is 20.

[0211] In some embodiments of the IL-2 conjugates described herein, n in the compounds of Formula (XVI) and (XVII) is in the range of about 5 to about 4600, or about 10 to about 4000, or about 20 to about 3000, or about 100 to about 3000, or about 100 to about 2900, or about 150 to about 2900, or about 125 to about 2900, or 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 1 750, 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.

[0212] 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 the group consisting of 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 the group consisting of 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 the group consisting of 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 the group consisting of 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 the group consisting of 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 the group consisting of 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 an integer selected from the group consisting of 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 the group consisting of 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 the group consisting of 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 the group consisting of 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 the group consisting of 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 the group consisting of 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 the group consisting of 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 the group consisting of 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 the group consisting of 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 the group consisting of 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 the group consisting of 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137.

[0213] In some embodiments of the IL-2 conjugates described herein, n in the compounds of Formula (XVI) and (XVII) is an integer selected from the group consisting of 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, 1 364, 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 structure of formula (XVI) and (XVII) or a mixture of formula (XVI) and (XVII) is at a position in the amino acid sequence of the IL-2 conjugate selected from K34, F41, F43, K42, E61, P64, R37, T40, E67, Y44, V68, and L71, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate is with reference to the position in SEQ ID NO: 3. In some embodiments of the IL-2 conjugates described herein, the structure of formula (XVI) and (XVII) or a mixture of formula (XVI) and (XVII) is at a position in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 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 (XVI) and (XVII) or the mixture of formula (XVI) and (XVII) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is at position K34. In some embodiments of the IL-2 conjugates described herein, the position of the structure of formula (XVI) and (XVII) or the mixture of formula (XVI) and (XVII) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is at position F41. In some embodiments of the IL-2 conjugates described herein, the position of the structure of formula (XVI) and (XVII) or the mixture of formula (XVI) and (XVII) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is at position F43.In some embodiments of the IL-2 conjugates described herein, the position of the structure of formula (XVI) and (XVII) or the mixture of formula (XVI) and (XVII) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is at position K42. In some embodiments of the IL-2 conjugates described herein, the position of the structure of formula (XVI) and (XVII) or the mixture of formula (XVI) and (XVII) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is at position E61. In some embodiments of the IL-2 conjugates described herein, the position of the structure of formula (XVI) and (XVII) or the mixture of formula (XVI) and (XVII) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is at position P64. In some embodiments of the IL-2 conjugates described herein, the position of the structure of formula (XVI) and (XVII) or the mixture of formula (XVI) and (XVII) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is at position R37. In some embodiments of the IL-2 conjugates described herein, the position of the structure of formula (XVI) and (XVII) or the mixture of formula (XVI) and (XVII) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is at position T40. In some embodiments of the IL-2 conjugates described herein, the position of the structure of formula (XVI) and (XVII) or the mixture of formula (XVI) and (XVII) 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 (XVI) and (XVII) or the mixture of formula (XVI) and (XVII) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is at position Y44. In some embodiments of the IL-2 conjugates described herein, the position of the structure of formula (XVI) and (XVII) or the mixture of formula (XVI) and (XVII) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is at position V68. In some embodiments of the IL-2 conjugates described herein, 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 IL-2 conjugate of SEQ ID NO: 3 is at 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) constituting 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) constituting 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) constituting the total amount of the IL-2 conjugate is less than 1:1.

[0214] In some embodiments described herein, an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3 is provided, wherein at least one amino acid residue in the IL-2 conjugate is replaced by 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 K34, F41, F43, K42, E61, P64, R37, T40, E67, Y44, V68, and L71, and wherein n is an integer 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 7 00, 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 (XVI) and (XVII) is an integer selected from the group consisting of 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, 1 364, 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.

[0215] In some embodiments described herein, an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3 is provided, 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, and wherein 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 the group consisting of 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, 1137, and 1249.

[0216] In some embodiments described herein, an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3 is provided, 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 wherein 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, n in the compounds of formula (XVI) and (XVII) is an integer selected from the group consisting of: 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910.

[0217] In some embodiments described herein, an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3 is provided, 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, and wherein 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 the group consisting of: 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.

[0218] In some embodiments described herein, an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3 is provided, 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 wherein 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 the group consisting of: 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.

[0219] 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 n is an integer such that the molecular weight of the PEG moiety is in the range of about 1,000 daltons to 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 90,000 daltons. 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 10,000 Daltons. 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 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. IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 3 are described herein, 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 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, or about 30,000 Daltons. , about 30,000 Daltons, about 35,000 Daltons, about 40,000 Daltons, about 45,000 Daltons, about 50,000 Daltons, about 60,000 Daltons, about 70,000 Daltons, about 80,000 Daltons, about 90,000 Daltons, about 100,000 Daltons, about 125,000 Daltons, about 150,000 Daltons, about 175,000 Daltons, or about 200,000 Daltons. Described herein are IL-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 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.

[0220] In some embodiments described herein, an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3 is provided, 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 the group consisting of 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, 1137, and 1249.

[0221] In some embodiments described herein, an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3 is provided, 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 wherein 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 the group consisting of 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910.

[0222] In some embodiments described herein, an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3 is provided, 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, and wherein 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 the group consisting of 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.

[0223] In some embodiments described herein, an IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3 is provided, 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 wherein 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 the group consisting of 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.

[0224] Described herein are pharmaceutical compositions comprising an effective amount of an IL-conjugate described herein and one or more pharmaceutically acceptable excipients.

[0225] Described herein are methods for treating cancer in a subject, comprising administering to a subject in need thereof an effective amount of an IL-2 conjugate as described herein. In some embodiments of the methods for treating cancer described herein, the subject's cancer is selected from renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), classical Hodgkin lymphoma (cHL), primary mediastinal large B-cell lymphoma (PMBCL), urothelial carcinoma, microsatellite unstable carcinoma, microsatellite stable carcinoma, gastric cancer, cervical cancer, hepatocellular carcinoma (HCC), Merkel cell carcinoma (MCC), melanoma, small cell lung cancer (SCLC), esophageal cancer, glioblastoma In some embodiments, the subject is a tumor that is not expressed in the tumor, and ... 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 a 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 a 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, the effective amount of the IL-2 conjugate administered to the subject does not cause vascular leak syndrome in the subject. In some embodiments of the methods of treating cancer described herein, the effective amount of the IL-2 conjugate administered to the 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, the effective amount of the IL-2 conjugate administered to the subject does not cause grade 2 vascular leak syndrome in the subject.In some embodiments of the methods of treating cancer described herein, administration of an effective amount of the IL-2 conjugate to the subject does not cause Grade 3 vascular leak syndrome in the subject. In some embodiments of the methods of treating cancer described herein, administration of an effective amount of the IL-2 conjugate to the subject does not cause Grade 4 vascular leak syndrome in the subject. In some embodiments of the methods of treating cancer described herein, administration of an effective amount of the IL-2 conjugate to the subject does not cause loss of vascular tone in the subject. In some embodiments of the methods of treating cancer described herein, administration of an effective amount of the IL-2 conjugate to the 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, administration of an effective amount of the IL-2 conjugate to the subject does not cause hypotension and decreased organ perfusion in the subject. In some embodiments of the methods of treating cancer described herein, administration of an effective amount of the IL-2 conjugate to the subject does not cause impaired neutrophil function in the subject. In some embodiments of the methods of treating cancer described herein, administration of an effective amount of the IL-2 conjugate to the subject does not cause decreased chemotaxis in the subject. In some embodiments of the methods of treating cancer described herein, the administration of an effective amount of the IL-2 conjugate to the 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 pre-existing bacterial infection prior to administration of 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 prior to administration of the IL-2 conjugate. In some embodiments of the methods of treating cancer described herein, the administration of an effective amount of the IL-2 conjugate to the subject does not aggravate the subject's pre-existing or initially presenting autoimmune disease or inflammatory disorder. In some embodiments of the methods of treating cancer described herein, administering an effective amount of the IL-2 conjugate to the subject does not aggravate a pre-existing or newly developed autoimmune disease in the subject. In some embodiments of the methods of treating cancer described herein, administering an effective amount of the IL-2 conjugate to the subject does not aggravate a pre-existing or newly developed inflammatory disorder in the subject.In some embodiments of the methods of treating cancer described herein, the subject's autoimmune disease or inflammatory disorder is selected from Crohn's disease, scleroderma, thyroiditis, inflammatory arthritis, diabetes, ocular myasthenia gravis, crescentic IgA glomerulonephritis, cholecystitis, cerebral vasculitis, Stevens-Johnson syndrome, and bullous pemphigoid. In some embodiments of the methods of treating cancer described herein, the subject's autoimmune disease or inflammatory disorder is Crohn's disease. In some embodiments of the methods of treating cancer described herein, the subject's autoimmune disease or inflammatory disorder is scleroderma. In some embodiments of the methods of treating cancer described herein, the subject's autoimmune disease or inflammatory disorder is thyroiditis. In some embodiments of the methods of treating cancer described herein, the subject's autoimmune disease or inflammatory disorder is inflammatory arthritis. In some embodiments of the methods of treating cancer described herein, the subject's autoimmune disease or inflammatory disorder is diabetes. In some embodiments of the methods of treating cancer described herein, the subject's autoimmune disease or inflammatory disorder is ocular myasthenia gravis. In some embodiments of the methods of treating cancer described herein, the subject's autoimmune disease or inflammatory disorder is crescentic IgA glomerulonephritis. In some embodiments of the methods of treating cancer described herein, the subject's autoimmune disease or inflammatory disorder is cholecystitis. In some embodiments of the methods of treating cancer described herein, the subject's autoimmune disease or inflammatory disorder is cerebral vasculitis. In some embodiments of the methods of treating cancer described herein, the subject's autoimmune disease or inflammatory disorder is Stevens-Johnson syndrome. In some embodiments of the methods of treating cancer described herein, the subject's autoimmune disease or inflammatory disorder is bullous pemphigoid. In some embodiments of the methods of treating cancer described herein, administering an effective amount of the IL-2 conjugate to the subject does not cause changes in the subject's mental status, speech difficulties, cortical blindness, limb or gait ataxia, hallucinations, agitation, dullness, or coma. In some embodiments of the methods of treating cancer described herein, administering an effective amount of the IL-2 conjugate to the subject does not cause seizures in the subject. In some embodiments of the methods of treating cancer described herein, administering an effective amount of the IL-2 conjugate to the subject is not contraindicated in subjects with known epilepsy. In some embodiments of the methods of treating cancer described herein, administering an effective amount of the IL-2 conjugate to the subject does not cause capillary leak syndrome in the subject. In some embodiments of the methods of treating cancer described herein, administering an effective amount of the IL-2 conjugate to the 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 the IL-2 conjugate to the 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 the IL-2 conjugate to the 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 the IL-2 conjugate to the subject does not cause 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 the IL-2 conjugate to the subject does not cause a decrease in the subject's mean arterial blood pressure following 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 the IL-2 conjugate to the subject does not cause hypotension in the subject following 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 the IL-2 conjugate to the subject does not cause the subject to experience a systolic blood pressure below 90 mm Hg or a decrease of 20 mm Hg from baseline systolic blood pressure following 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 the IL-2 conjugate to the subject does not cause edema in the subject following 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 the IL-2 conjugate to the subject does not cause impaired renal or hepatic function in the subject following 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 the IL-2 conjugate to the subject does not cause eosinophilia in the subject following 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 the IL-2 conjugate to the subject does not cause an eosinophil count in the subject's peripheral blood to exceed 500 / 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 the IL-2 conjugate to the subject does not cause an eosinophil count in the subject's peripheral blood to exceed 500 / μL to 1500 / 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 the IL-2 conjugate to the subject does not cause an eosinophil count in the subject's peripheral blood to exceed 1500 / μL to 5000 / μL after administering the IL-2 conjugate to the subject. In some embodiments of the methods of treating cancer described herein, administering an effective amount of the IL-2 conjugate to the subject does not cause an eosinophil count in the subject's peripheral blood to exceed 5000 / μL after administering the IL-2 conjugate to the subject. In some embodiments of the methods of treating cancer described herein, administering an effective amount of the IL-2 conjugate to the subject is not contraindicated in subjects who are on an existing regimen of psychotropic medications.

[0226] In some embodiments of the methods of treating cancer described herein, the administration of an effective amount of the IL-2 conjugate to the subject is not contraindicated in subjects who are currently taking a nephrotoxic, myelotoxic, cardiotoxic, or hepatotoxic drug. In some embodiments of the methods of treating cancer described herein, the administration of an effective amount of the IL-2 conjugate to the subject is not contraindicated in subjects who are currently taking an aminoglycoside, cytotoxic chemotherapy, doxorubicin, methotrexate, or asparaginase. In some embodiments of the methods of treating cancer described herein, the administration of an effective amount of the IL-2 conjugate to the subject is not contraindicated in subjects who are receiving a combination regimen containing an anti-tumor agent. In some embodiments of the methods of treating cancer described herein, the anti-tumor agent is selected from dacarbazine, cisplatin, tamoxifen, and interferon-α. In some embodiments of the methods of treating cancer described herein, the administration of an effective amount of the IL-2 conjugate to the 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 are selected from the group consisting of hypothermia; shock; bradycardia; ventricular extrasystoles; myocardial ischemia; syncope; hemorrhage; atrial arrhythmias; phlebitis; second-degree atrioventricular block; endocarditis; pericardial effusion; peripheral gangrene; thrombosis; coronary artery obstruction; 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; lethargy; agitation; neuropathy; paranoid reaction; convulsions; grand mal seizures; delirium; asthma, pulmonary edema; hyperventilation; hypoxia; hemoptysis; hypoventilation; pneumothorax; mydriasis; pupillary disorders; abnormal renal function; renal failure; and acute tubular necrosis. In some embodiments of the methods of treating cancer described herein, administering an effective amount of the IL-2 conjugate to a group of subjects does not cause one or more grade 4 adverse events in greater than 1% of the subjects after administering 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 are selected from the group consisting of hypothermia; shock; bradycardia; ventricular extrasystoles; myocardial ischemia; syncope; hemorrhage; atrial arrhythmias; phlebitis; second-degree atrioventricular block; endocarditis; pericardial effusion; peripheral gangrene; thrombosis; coronary artery obstruction; stomatitis; nausea and vomiting; abnormal liver function tests; gastrointestinal bleeding; hematemesis; bloody diarrhea; gastrointestinal disorders; intestinal perforation; pancreatitis. adenitis; anemia; leukopenia; leukocytosis; hypocalcemia; increased alkaline phosphatase; increased blood urea nitrogen (BUN); hyperuricemia; increased non-protein nitrogen (NPN); respiratory acidosis; lethargy; agitation; neuropathy; paranoid reaction; convulsions; grand mal seizures; delirium; asthma, pulmonary edema; hyperventilation; hypoxia; hemoptysis; hypoventilation; pneumothorax; mydriasis; pupillary disturbances; abnormal renal function; renal failure; and acute tubular necrosis. In some embodiments of the methods of treating cancer described herein, administration of an effective amount of the IL-2 conjugate to a group of subjects does not cause one or more adverse events in greater than 1% of subjects after administration of the IL-2 conjugate to the subjects, wherein the one or more adverse events are selected from the group consisting of duodenal ulcer formation; intestinal necrosis; myocarditis; supraventricular tachycardia; permanent or temporary 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, administration of an effective amount of the IL-2 conjugate to a group of subjects does not cause one or more adverse events in greater than 1% of subjects after administration of the IL-2 conjugate to the subjects, wherein the one or more adverse events are selected from the group consisting of malignant hyperthermia; cardiac arrest; myocardial infarction; pulmonary embolism; stroke; intestinal perforation; liver or kidney failure; severe depression leading to suicide; pulmonary edema; respiratory arrest; respiratory failure. In some embodiments of the methods for treating cancer described herein, administering an effective amount of the IL-2 conjugate to the subject does not result in the production of neutralizing antibodies against the IL-2 conjugate. In some embodiments of the methods for treating cancer described herein, administering the IL-2 conjugate to the subject increases the number of peripheral CD8+T and NK cells in the subject without increasing the number of peripheral CD4+ regulatory T cells in the subject. In some embodiments of the methods for treating cancer described herein, administering the IL-2 conjugate to the 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 for treating cancer described herein, administering the IL-2 conjugate to the 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, administration of an effective amount of the IL-2 conjugate to the subject does not require the availability of an intensive care facility or a skilled specialist in cardiopulmonary or intensive care medicine. In some embodiments of the methods of treating cancer described herein, administration of an effective amount of the IL-2 conjugate to the subject does not require the availability of an intensive care facility. In some embodiments of the methods of treating cancer described herein, administration of an effective amount of the IL-2 conjugate to the subject does not require the availability of an skilled specialist in cardiopulmonary or intensive care medicine. BRIEF DESCRIPTION OF THE DRAWINGS

[0227] 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 invention will be obtained by reference to the following detailed description of illustrative embodiments utilizing the principles of the invention and the accompanying drawings, in which:

[0228] Figure 1 shows exemplary unnatural amino acids. This figure is modified from Figure 2 of Young et al., “Beyond the canonical 20 amino acids: expanding the genetic lexicon,” J. of Biological Chemistry 285(15): 11039-11044 (2010).

[0229] Figures 2A-2B illustrate exemplary unnatural amino acids. Figure 2A illustrates exemplary lysine derivatives. Figure 2B illustrates exemplary phenylalanine derivatives.

[0230] Figures 3A-3D illustrate exemplary unnatural amino acids. These unnatural amino acids (UAAs) have been genetically encoded in proteins (Figure 3A - UAA#1-42; Figure 3B - UAA#43-89; Figure 3C - UAA#90-128; Figure 3D - UAA#129-167). Figures 3A-3D are adapted from Table 1 of Dumas et al., Chemical Science 2015, 6, 50-69.

[0231] Figures 4A-4C show surface plasmon resonance (SPR) analysis of native IL-2, P65_30kD, P65_5kD, E62_30kD, E62_5kD, and F42_30kD PEG conjugates. Figure 4A shows SPR analysis of IL-2 variants bound to immobilized IL-2Rα. Figure 4B shows SPR analysis of IL-2 variants bound to immobilized IL-2Rβ. Figure 4C shows SPR analysis of recombinant IL-2 and IL-2 variant F42_30kD bound to immobilized IL-2Rα and IL-2Rβ.

[0232] Figures 5A-5F show exemplary IL-2 variant dose-response curves for pSTAT5 signaling in primary human LRS 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.

[0233] Figures 6A-6C show that PEG and residue substitutions promote no-alphapharmacology of IL-2 variants. Figure 6A: native IL-2; Figure 6B: E62K; Figure 6C: E62_30kD.

[0234] Figure 7 shows that the alpha-free pharmacology of IL-2 variants is independent of PEG size.

[0235] Figure 8 shows mean (±SD) plasma concentration versus time curves following administration of a single IV bolus dose of aldesleukin (IL-2), E62_5, E62_30, and P65_30 to C57BL / 6 mice.

[0236] FIG9 shows the percentage of pSTAT5+CD8+ T cells in peripheral blood versus time after treatment of C57BL / 6 mice with a single IV bolus dose of P65_30 or aldesleukin.

[0237] Figure 10 A-Figure 10 C is presented at after the P65-30 or aldesleukin (IL-2) treatment with single IV bolus dosage, the percentage ratio of CD8+T cell (Figure 10 A), NK cell (Figure 10 B) and CD4+Treg cell (Figure 10 C) in PBMC colony.Blood was drawn by cardiac puncture at the indicated time point, and immune cell group was assessed by flow cytometry.Each data point represents the mean ± SEM of 3 repetitions from each time point.

[0238] Figure 11A-Figure 11B are shown after treatment with P65_30 or aldesleukin (IL-2) of a single IV bolus dose, and the difference between P65_30 and IL-2 (aldesleukin) in the stimulation of memory CD8+CD44+T cell proliferation in the CD3+ population. Blood was drawn by cardiac puncture at the indicated time point, and immune cell populations were assessed by flow cytometry. Data were analyzed using unpaired Student's t-test. ***P value < 0.001 was specified. Figure 11A is shown at 72, 96, and 120 hours of memory CD8+CD44+T cell proliferation. Figure 11B is shown at the flow cytometry analysis of those cells at the 120h time point.

[0239] Figure 12 A-Figure 12 B is presented after being treated with P65_30 of single IV bolus dose, and the increase of tumor infiltrating lymphocyte (TIL) in C57B16 mice with isogenic B16F10 tumor compared to time.Figure 12 A is presented at the 5th day of treatment, the percentage of NK cell, CD8+T cell and CD4+T reg cell in P65_30 treatment and untreated (vehicle) animal.Figure 12 B shows the ratio of CD8+ / CD4+T reg cell in P65_30 treatment and control (vehicle) animal.Use unpaired Student t test to analyze data.***Specify P value<0.001.

[0240] Figure 13 A-Figure 13 B is presented at after the P65_30 or aldesleukin (IL-2) of single IV bolus dose is processed with increasing level (0.01-5mg / kg), the plasma level of mouse IL-2, TNF-α, IFNγ, IL-5 and IL-6.The concentration of each cytokine in plasma is determined by ELISA (Abcam, Cambridge, England).For each dosage group, N=3 mice and samples are collected at 4, 34 and 72h after administration.Figure 13 A shows the cytokine levels of animals given aldesleukin, and Figure 13 B shows the cytokine levels of animals given P65_30.

[0241] Figure 14 shows leukocyte, lymphocyte and eosinophil counts (mean ± SD) following administration of a single IV dose of P65_30kD to male cynomolgus monkeys.

[0242] Figures 15A-15B show dose response curves of exemplary IL-2 variants for pSTAT5 signaling in primary human LRS cells (Figure 15A) and the proliferative response in mouse CTLL-2 populations (Figure 15B).

[0243] Figures 16A-16B show that PEG IL-2 compounds can specifically expand immune cell populations in vitro in primary lymphocytes compared to normal IL-2 controls. Figure 16A shows immune cell expansion after treatment with IL-2 (control). Figure 16B shows immune cell expansion after treatment with P65-30kD.

[0244] Figures 17A-17B show sensorgrams of the binding response of rhIL-2 (recombinant human interleukin-2, Figure 17A) and the synthetic conjugate IL-2_P65[AzK_L1_PEG30kD]-1 (Figure 17B) on the IL-2Rα surface. Under these conditions, no significant binding response was detected for IL-2_P65[AzK_L1_PEG30kD]-1.

[0245] 17C-17D show sensorgrams of rhIL-2 (recombinant human interleukin-2, FIG. 17C ) and the synthetic conjugate IL-2_P65[AzK_L1_PEG30kD]-1 ( FIG. 17D ) samples bound to the IL-2Rβ surface.

[0246] Figure 18 shows the gating strategy for flow cytometry cell sorting of Treg. First, cells are gated for single state using FSC-A relative to FSC-H to exclude any aggregates or dual states (single state gate, panel 1). Within this gate, cells are gated for medium to high forward scatter (FSC-A) and side scatter (SSC-A) to exclude red blood cells, debris and granulocytes (lymphocyte gate, panel 2). T cells are then gated for CD3+, CD56 / 16 negative populations, panel 3. NK cells are identified as CD3 negative, high CD56 / 16 populations, panel 3. T cells are then divided into CD4+T cells and CD8+T cells (panel 4). Treg are then gated from CD4+T cells to CD25 hi x C127 lo Group, Panel 5.

[0247] FIG19 shows the stability of compound IL-2_P65[AzK_L1_PEG30kD]-1 in human serum at three concentrations up to 168 hours, as described in Example 15. DETAILED DESCRIPTION

[0248] 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 the homeostasis of innate and adaptive immune cells. Cytokines are produced by immune cells such as macrophages, B lymphocytes, T lymphocytes and mast cells, endothelial cells, fibroblasts, and different stromal cells. In some cases, cytokines regulate the balance between humoral and cell-based immune responses.

[0249] Interleukins are signaling proteins that regulate the development and differentiation of T and B lymphocytes, cells of the monocytic lineage, neutrophils, basophils, eosinophils, megakaryocytes, and hematopoietic cells. Interleukins are produced by helper CD4 T and B lymphocytes, monocytes, macrophages, endothelial cells, and other tissue-resident cells.

[0250] Interleukin 2 (IL-2) is a pleiotropic type 1 cytokine whose structure comprises a four α-helical bundle of 15.5 kDa. The precursor form of IL-2 is 153 amino acid residues in length, of which the first 20 amino acids form the signal peptide and residues 21-153 form the mature form. IL-2 is produced primarily by CD4+ T cells following 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 occurs at a rate of approximately 10 -8 M's K d Formation of a "low affinity" IL-2 receptor complex. IL-2 interacts with IL-2Rβ and IL-2Rγ at a rate of approximately 10 -9 M's K d Forms a "medium affinity" IL-2 receptor complex. IL-2 interacts with all three subunits IL-2Rα, IL-2Rβ, and IL-2Rγ at a rate of approximately >10 -11 M's K d Formation of a "high affinity" IL-2 receptor complex.

[0251] In certain instances, IL-2 signaling via the "high affinity" IL-2Rαβγ complex regulates the activation and proliferation of regulatory T cells. + CD25 + Foxp3 + Regulatory T (Treg) cells inhibit effector cells (such as CD4 + T cells, CD8 + T cells, B cells, NK cells and NKT cells) mediate the maintenance of immune homeostasis. In some cases, Treg cells are generated from the thymus (tTreg cells) or induced from peripheral naive T cells (pTreg cells). In some cases, Treg cells are regarded as mediators of peripheral tolerance. In fact, in one study, CD25-depleted peripheral CD4 + Transfer of T cells produces multiple autoimmune diseases in nude mice, and CD4 + CD25 +Co-transfer of T cells inhibits 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)). Increased Treg cell populations downregulate effector T cell proliferation and suppress autoimmunity and T cell anti-tumor responses.

[0252] IL-2 signaling via the "medium-affinity" IL-2Rβγ complex regulates CD8 + 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, CTL, T killer cells, cytolytic T cells, Tcon or killer T cells) are T lymphocytes that recognize and kill damaged cells, cancer cells and cells infected by pathogens. NK and NKT cells are related to CD8 + Teff cells are a similar type of lymphocyte that targets cancer cells and pathogen-infected cells.

[0253] In some cases, IL-2 signaling is used to regulate T cell responses, and is subsequently used to treat cancer. For example, IL-2 is administered in high doses to induce the amplification of Teff cell populations for treating cancer. However, high doses of IL2 further result in the accompanying stimulation of Treg cells, thereby weakening anti-tumor immune responses. High doses of IL-2 also induce toxic adverse events mediated by the engagement of IL-2R α chain expressing cells (including type 2 innate immune cells (ILC-2), eosinophils and endothelial cells) in the vasculature. This results in eosinophilia, capillary leakage and vascular leakage syndrome (VLS).

[0254] Adoptive cell therapy enables physicians to effectively utilize the patient's own immune cells to fight diseases, such as proliferative diseases (e.g., cancer) and infectious diseases. In a non-limiting example, T lymphocytes can be harvested from the patient, reengineered to target specific antigens on the surface of malignant cells, and reintroduced into the patient's body to specifically target the malignant cells. In addition, adoptive cell therapy provides a sustained response in vivo by signaling to immune cells to grow and divide over a long period of time after the reengineered cells are reintroduced into the patient's immune system.

[0255] In certain embodiments, disclosed herein is a method for selectively upregulating one or more different lymphocyte populations (e.g., CD4+ helper cells, CD8+ effector immature and memory cells, NK cells, or NKT cells) by cytokine / cytokine receptor signaling. In some cases, the cytokine comprises an interleukin, an interferon, or a tumor necrosis factor. In some cases, the cytokine is a cytokine conjugate, e.g., an interleukin conjugate, an interferon conjugate, or a tumor necrosis factor conjugate. In other cases, described herein are pharmaceutical compositions and kits comprising one or more cytokine conjugates as described herein.

[0256] In some embodiments, a method of selectively upregulating CD4+ helper cells, CD8+ effector naive and memory cells, NK cells and / or NKT cell populations by IL-2 / IL-2R signaling is also described herein. In some cases, IL-2 is an IL-2 conjugate that interacts with a "medium affinity" IL-2Rβγ complex, optionally with a potency similar to that of the IL-2Rαβγ complex, and has an IL-2Rα interaction that is weakened relative to wild-type IL-2. In some embodiments, methods of treating cancer using the IL-2 conjugates described herein are further described herein. In additional embodiments, pharmaceutical compositions and kits are described herein that comprise one or more IL-2 conjugates described herein. In some embodiments, the IL-2 conjugate comprises a conjugated portion (e.g., PEG) that promotes an increase or decrease in the "clearance rate" or plasma half-life in a subject without affecting pharmacokinetics (including desired cytokine-receptor interactions and immune cell expansion).

[0257] In some embodiments, disclosed herein are reagents that can be used to develop adoptive cell therapies comprising cells engineered to express modified cytokines, thereby resulting in selective cytokine-receptor interactions and immune cell expansion. In some embodiments, the reagent comprises a nucleic acid construct encoding the above-described IL-2 conjugate. Also disclosed are adoptive cell therapies comprising the above-described IL-2 conjugates that can be used to treat proliferative or infectious diseases described herein.

[0258] In some embodiments, compositions are disclosed herein that result in selective cytokine-receptor interactions and immune cell expansion. In some embodiments, the reagent comprises a nucleic acid construct encoding the aforementioned IL-2 conjugate. Also disclosed are pharmaceutical compositions comprising the aforementioned IL-2 conjugates that can be used to treat proliferative or infectious diseases as described herein.

[0259] Cytokine conjugates

[0260] In some embodiments, cytokine conjugates are described herein. In some cases, the cytokine comprises an interleukin, tumor necrosis factor, interferon, chemokine, lymphokine, or growth factor. In some cases, the cytokine is an interleukin. In some cases, the cytokine is an interferon. In other cases, the cytokine is a tumor necrosis factor. In other cases, the cytokine is a growth factor.

[0261] In some embodiments, interleukin conjugates are described herein.Exemplary interleukins include, but are not limited to, interleukin 2 (IL-2).

[0262] IL-2 conjugate

[0263] Described herein are the polypeptides shown in Table 20. In some embodiments, the IL-2 conjugates described herein are exemplified in Table 20.

[0264] Table 20

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277] X = site comprising an unnatural amino acid.

[0278] [AzK] = N6-((2-azidoethoxy)-carbonyl)-L-lysine (whose structure is disclosed in FIG3C as compound 90). This compound has Chemical Abstracts Service Registry Number 1167421-25-1.

[0279] [AzK_PEG] = N6-((2-azidoethoxy)-carbonyl)-L-lysine stably conjugated to PEG via DBCO-mediated click chemistry to form a compound comprising the structure of Formula (II) or Formula (III). For example, if specified, PEG5kD indicates a linear polyethylene glycol chain terminated with methoxy groups with an average molecular weight of 5 kilodaltons. The ratio of positional isomers generated from the click reaction is about 1:1 or greater than 1:1. The term "DBCO" means a chemical moiety comprising a dibenzocyclooctyne group, such as the mPEG-DBCO compound shown in Scheme 1 of Example 2. An exemplary structure of a methoxy PEG group is shown in the mPEG-DBCO structure of Scheme 1 of Example 2.

[0280] [AzK_L1_PEG] = N6-((2-azidoethoxy)-carbonyl)-L-lysine stably conjugated to PEG via DBCO-mediated click chemistry to form a compound comprising the structure of Formula (IV) or Formula (V). For example, if specified, PEG5kD indicates a linear polyethylene glycol chain terminated with methoxy groups with an average molecular weight of 5 kilodaltons. The ratio of positional isomers generated from the click reaction is about 1:1 or greater than 1:1. The term "DBCO" refers to a chemical moiety comprising a dibenzocyclooctyne group, such as the mPEG-DBCO compound shown in Scheme 1 of Example 2.

[0281] In some embodiments, described herein are IL-2 conjugates modified at amino acid positions. In some cases, the modifications are to natural amino acids. In some cases, the modifications are to non-natural amino acids. In some cases, described herein are isolated and modified IL-2 polypeptides comprising at least one non-natural amino acid. In some cases, 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 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 other instances, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 2. In other instances, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 2. In other instances, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 2. In some instances, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 3. In some instances, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 3. In some instances, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 3. In other instances, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 4. In other instances, the IL-2 polypeptide comprises the sequence of SEQ ID NO:4. In other 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 other instances, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:6. In other instances, the IL-2 polypeptide comprises the sequence of SEQ ID NO:6. In other 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 instances, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 7. In some instances, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 7. In further instances, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 8. In further instances, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 8. In further instances, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 8. In some instances, 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 consists of 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 consists of 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 instances, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 14. In some instances, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 15. In some instances, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 15. In some instances, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 15. In some instances, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 16. In some instances, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 16. In some instances, 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. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 18. 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 consists of 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 consists of 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 instances, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 24. In some instances, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 24. In other instances, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 25. In other instances, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 25. In other instances, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 25. In some instances, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 26. In some instances, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 26. In some instances, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 26. In other instances, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 27. In other instances, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 27. In other instances, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 27. In some instances, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 28. In some instances, 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 other instances, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 29.In other instances, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 29. In other 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 consists of 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 instances, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 31. In some instances, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 31. In other instances, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 32. In other instances, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 32. In other instances, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 32. In some instances, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 33. In some instances, 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 other instances, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 34. In other instances, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 34. In other 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 comprises the sequence of SEQ ID NO: 35. In some instances, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 35. In other instances, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 36. In other instances, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 36. In other 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 further instances, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 38. In further instances, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 38. In further instances, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 38. In some instances, 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 consists of 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 consists of 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 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 consists of 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 consists of 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 instances, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 54. In some instances, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 54. In other instances, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 55. In other instances, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 55. In other instances, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 55. In some instances, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 56. In some instances, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 56. In some instances, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 56. In other instances, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 57. In other instances, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 57. In other 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 consists of the sequence of SEQ ID NO: 58. In other instances, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 59.In other instances, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 59. In other 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 instances, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 60. In some instances, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 60. In some instances, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 61. In some instances, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 61. In some instances, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 61. In other instances, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 62. In other instances, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 62. In other instances, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 62. In some instances, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 63. In some instances, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 63. In some instances, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 63. In other instances, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 64. In other instances, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 64. In other instances, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 64. In some instances, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 65. In some instances, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 65. In some instances, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 65. In other instances, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 66. In other instances, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 66. In other instances, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 66.In some instances, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 67. In some instances, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 67. In some instances, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 67. In further instances, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 68. In further instances, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 68. In further instances, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 68. In some instances, 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 consists of 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.

[0282] In some cases, the IL-2 polypeptide is a truncated variant. In some cases, the truncation is an N-terminal deletion. In other cases, the truncation is a C-terminal deletion. In other cases, the truncation includes both N-terminal and C-terminal deletions. For example, the truncation can be a 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 comprises 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 comprises 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 comprises 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.

[0283] In some embodiments, the IL-2 polypeptide is a functionally active fragment. In some cases, 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, wherein the residue positions are referenced to the positions in SEQ ID NO: 1. In some cases, the functionally active fragment comprises IL-2 region 10-133, wherein the residue positions are referenced to the positions in SEQ ID NO: 1. In some cases, the functionally active fragment comprises IL-2 region 20-133, wherein the residue positions are referenced to the positions in SEQ ID NO: 1. In some cases, the functionally active fragment comprises IL-2 region 30-133, wherein the residue positions are referenced to the positions in SEQ ID NO: 1. In some cases, the functionally active fragment comprises IL-2 region 10-125, wherein the residue positions are referenced to the positions in SEQ ID NO: 1. In some cases, the functionally active fragment comprises IL-2 regions 20-125, wherein the residue positions are with reference to the positions in SEQ ID NO: 1. In some cases, the functionally active fragment comprises IL-2 regions 1-130, wherein the residue positions are with reference to the positions in SEQ ID NO: 1. In some cases, the functionally active fragment comprises IL-2 regions 1-125, wherein the residue positions are with reference to the positions in SEQ ID NO: 1.

[0284] In some embodiments, described herein are IL-2 conjugates comprising an isolated, purified, and modified IL-2 polypeptide and a conjugated moiety. In some cases, the IL-2 conjugate has a reduced affinity for the IL-2 receptor alpha (IL-2Rα) subunit relative to the wild-type IL-2 polypeptide. In some cases, the conjugated 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 conjugated 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 conjugated moiety binds to an amino acid residue that is near the IL-2 / IL-2Rα interface (e.g., about 100 μg / mL from the IL-2 / IL-2Rα interface). about about or about 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.

[0285] In some cases, the conjugate moiety is bound to an amino acid residue selected from amino acid position 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, wherein the amino acid residues are numbered corresponding to SEQ ID NO: 1. In some cases, the amino acid position is 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 cases, the amino acid position is selected from the group consisting of 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 cases, the amino acid position is selected from the group consisting of K35, T37, R38, T41, F42, K43, F44, Y45, E61, E62, E68, K64, P65, V69, L72, and Y107. In some cases, the amino acid position is selected from T37, R38, T41, F42, F44, Y45, E61, E62, E68, K64, P65, V69, L72 and Y107. In some cases, the amino acid position is selected from T37, R38, T41, F42, F44, Y45, E61, E62, E68, P65, V69, L72 and Y107. In some cases, the amino acid position is selected from T37, T41, F42, F44, Y45, P65, V69, L72 and Y107. In some cases, the amino acid position is selected from R38 and K64. In some cases, the amino acid position is selected from E61, E62 and E68. In some cases, the amino acid position is at K35. In some cases, the amino acid position is at T37. In some cases, the amino acid position is at R38. In some cases, the amino acid position is at T41. In some cases, the amino acid position is at F42. In some cases, the amino acid position is at K43. In some cases, the amino acid position is at F44. In some cases, the amino acid position is at Y45. In some cases, the amino acid position is at E61.In some cases, the amino acid position is at E62. In some cases, the amino acid position is at K64. In some cases, the amino acid position is at E68. In some cases, the amino acid position is at P65. In some cases, the amino acid position is at V69. In some cases, the amino acid position is at L72. In some cases, the amino acid position is at Y107. In some cases, the amino acid position is at L72. In some cases, the amino acid position is at D109.

[0286] In some cases, the IL-2 conjugate further comprises additional mutations. In some cases, the additional mutations are located at amino acid positions selected from the group consisting of 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 conjugated moiety to increase 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, prior to being combined with the additional conjugated moiety; or to a non-natural amino acid.

[0287] In some embodiments, the affinity of the modified IL-2 polypeptide for the IL-2 receptor alpha (IL-2Rα) subunit is reduced by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99%, or greater than 99%, relative to a wild-type IL-2 polypeptide without the non-natural amino acid modification (e.g., a wild-type IL-2 polypeptide). In some cases, 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 greater than 99%. In some cases, the reduced affinity is about 80%. In some cases, the reduced affinity is about 100%.

[0288] In some embodiments, the affinity of the modified IL-2 polypeptide for the IL-2 receptor alpha (IL-2Rα) subunit is reduced by about 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 relative to an equivalent IL-2 polypeptide without the non-natural amino acid modification (e.g., a wild-type IL-2 polypeptide). In some cases, the reduced affinity is about 1-fold. In some cases, the reduced affinity is about 2-fold. In some cases, the reduced affinity is about 4-fold. In some cases, the reduced affinity is about 5-fold. In some cases, the reduced affinity is about 6-fold. In some cases, the reduced affinity is about 8-fold. In some cases, the reduced affinity is about 10-fold. In some cases, the affinity is reduced by about 30 times. In some cases, the affinity is reduced by about 50 times. In some cases, the affinity is reduced by about 100 times. In some cases, the affinity is reduced by about 300 times. In some cases, the affinity is reduced by about 500 times. In some cases, the affinity is reduced by about 1000 times. In some cases, the affinity is reduced by more than 1,000 times.

[0289] In some cases, the modified IL-2 polypeptide does not interact with IL-2Rα. In some cases, 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.

[0290] In some embodiments, the modified IL-2 polypeptide exhibits a first receptor signaling potency for the IL-2 βγ signaling complex and a second receptor signaling potency for the IL-2 αβγ signaling complex, and wherein the difference between the first receptor signaling potency and the second receptor signaling potency is less than 10-fold. In some embodiments, the modified IL-2 polypeptide exhibits a first receptor signaling potency for the IL-2 βγ signaling complex and a second receptor signaling potency for the IL-2 αβγ signaling complex, and wherein the difference between the first receptor signaling potency and the second receptor signaling potency 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. In some cases, the modified IL-2 polypeptide is a partial agonist, for example, an agonist that activates a receptor (e.g., IL-2 βγ signaling complex or IL-2 αβγ signaling complex) but has only partial efficacy at the receptor relative to a full agonist. In some cases, the modified IL-2 polypeptide is a full agonist, e.g., an agonist that activates the receptor (e.g., the IL-2βγ signaling complex or the IL-2αβγ signaling complex) with a maximal response.

[0291] In some cases, receptor signaling potency is measured in terms of EC50 values. In some cases, the modified IL-2 polypeptide provides a first EC50 value for activating the IL-2 βγ signaling complex and a second EC50 value for activating the IL-2 αβγ signaling complex, and wherein the difference between the first EC50 value and the second EC50 value is less than 10-fold. In some cases, the modified IL-2 polypeptide provides a first EC50 value for activating the IL-2 βγ signaling complex and a second EC50 value for activating the IL-2 αβγ signaling complex, and wherein 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.

[0292] In some cases, receptor signaling efficacy is measured based on ED50 values. In some cases, the modified IL-2 polypeptide provides a first ED50 value for activating the IL-2 βγ signaling complex and a second ED50 value for activating the IL-2 αβγ signaling complex, and wherein the difference between the first ED50 value and the second ED50 value is less than 10 times. In some cases, the modified IL-2 polypeptide provides a first ED50 value for activating the IL-2 βγ signaling complex and a second ED50 value for activating the IL-2 αβγ signaling complex, and wherein the difference between the first ED50 value and the second ED50 value is less than 5 times. In some cases, the difference is less than 9 times, less than 8 times, less than 7 times, less than 6 times, less than 5 times, less than 4 times, less than 3 times, less than 2 times, or less than 1 times.

[0293] In some embodiments, the conjugate moiety is directly or indirectly linked to the N-terminus or C-terminus of the IL-2 polypeptide via a linker peptide. In some cases, the conjugate moiety (e.g., a polymer, protein, or peptide) is genetically fused to the IL-2 at the N-terminus or C-terminus of IL-2 and directly or indirectly via a linker peptide. In some cases, the conjugate moiety is linked to the N-terminal or C-terminal amino acid residue. In some cases, the conjugate moiety is linked to a reactive group that binds to the N-terminal or C-terminal amino acid residue.

[0294] In some embodiments, the IL-2 conjugate with reduced binding affinity for IL-2Rα is capable of expanding CD4+ helper cells, CD8+ effector naive and memory T cells, natural killer (NK) cells, or natural killer T (NKT) cell populations. In some cases, the conjugated moiety weakens or blocks the binding of IL-2 to IL-2Rα.

[0295] 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 to activate said cell population relative to wild-type IL-2 polypeptide. In some cases, activation by the modified IL-2 polypeptide is equivalent to activation by the wild-type IL-2 polypeptide. In other cases, activation by the modified IL-2 polypeptide is greater than activation by the wild-type IL-2 polypeptide. In some cases, the receptor signaling potency of the modified IL-2 polypeptide on the IL-2Rβγ complex is greater than the receptor signaling potency of the wild-type IL-2 polypeptide on the IL-2Rβγ complex. In some cases, the receptor signaling potency of the modified IL-2 polypeptide is at least 1-fold greater than the corresponding potency 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 greater than the corresponding 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.

[0296] 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 the modified IL-2 polypeptide retains significant potency of activation of said cell population by the wild-type IL-2 polypeptide. In some cases, the receptor signaling potency of the modified IL-2 polypeptide on the IL-2Rβγ complex is lower than the receptor signaling potency of the wild-type IL-2 polypeptide on 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 corresponding potency of the wild-type IL-2 polypeptide.

[0297] In some embodiments, the modified IL-2 polypeptide exhibits a first receptor signaling potency at IL-2Rβγ and a second receptor signaling potency at IL-2Rαβγ. In some cases, the first receptor signaling potency at IL-2Rβγ is an improved potency relative to the wild-type IL-2 polypeptide. In some cases, the second receptor signaling potency at IL-2Rαβγ is an impaired potency relative to the wild-type IL-2 polypeptide. In some embodiments, the modified IL-2 polypeptide exhibits a first receptor signaling potency at IL-2Rβγ and a second receptor signaling potency at IL-2Rαβγ, and 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 cases, the first receptor signaling potency is at least 1-fold or more greater than the second receptor signaling potency. In some cases, the first receptor signaling potency is at least 2-fold or more greater than the second receptor signaling potency. In some cases, the first receptor signaling potency is at least 5-fold or more greater than the second receptor signaling potency. In some cases, the first receptor signaling potency is at least 10-fold or more greater than the second receptor signaling potency. In some cases, the first receptor signaling potency is at least 20-fold or more greater than the second receptor signaling potency. In some cases, the first receptor signaling potency is at least 50-fold or more greater than the second receptor signaling potency. In some cases, the first receptor signaling potency is at least 100-fold or more greater than the second receptor signaling potency. In some cases, the first receptor signaling potency is at least 500-fold or more greater than the second receptor signaling potency. In some cases, the first receptor signaling potency is at least 1000-fold or more greater than the second receptor signaling potency. In some cases, the first receptor signaling potency of the modified IL-2 polypeptide is greater than the receptor signaling potency of the wild-type IL-2 polypeptide at IL-2Rβγ, and the second receptor signaling potency of the modified IL-2 polypeptide is less than the receptor signaling potency of the wild-type IL-2 polypeptide at IL-2Rαβγ. In some cases, both receptor signaling potencies are less than their corresponding potencies in the wild-type IL-2 polypeptide. In other cases, both receptor signaling potencies are greater than their corresponding potencies in the wild-type IL-2 polypeptide.

[0298] In some embodiments, IL-2 conjugates reduce the toxic adverse events of subjects to which IL-2 conjugates are administered. Exemplary toxic adverse events include eosinophilia, capillary leakage, and vascular leak syndrome (VLS). In some cases, relative to a second subject administered wild-type IL-2 or aldesleukin, IL-2 conjugates reduce the incidence of the subject's toxic adverse events by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99% or about 100%. In some cases, relative to a second subject administered wild-type IL-2 or aldesleukin, IL-2 conjugates reduce the severity of the subject's toxic adverse events by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99% or about 100%.

[0299] In some cases, the toxic adverse event is eosinophilia. In some cases, the IL-2 conjugate reduces the incidence of eosinophilia in the subject by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or about 100% relative to a 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% relative to a second subject administered wild-type IL-2 or aldesleukin.

[0300] In some cases, the toxic adverse event is capillary leakage. In some cases, the IL-2 conjugate reduces the incidence of capillary leakage in the subject by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or about 100% relative to a second subject administered 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% relative to a second subject administered wild-type IL-2 or aldesleukin.

[0301] In some cases, the toxic adverse event is VLS. In some cases, the IL-2 conjugate reduces the incidence of VLS in the subject by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99% or about 100% relative to a second subject administered wild-type IL-2 or aldesleukin. In some cases, the IL-2 conjugate reduces the severity of VLS in the subject by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99% or about 100% relative to a second subject administered wild-type IL-2 or aldesleukin.

[0302] 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.

[0303] 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.

[0304] 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.

[0305] 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.

[0306] In some embodiments, the IL-2 conjugate comprises a plasma half-life that is capable of proliferating and / or expanding CD4+ helper cells, CD8+ effector naive and memory T cells, NK cells, NKT cells, or a combination thereof, without causing deleterious effects (e.g., apoptosis).

[0307] In some embodiments, the IL-2 conjugate comprises an extended plasma half-life relative to wild-type IL-2, 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. In some embodiments, the IL-2 conjugate comprises an extended plasma half-life relative to wild-type IL-2, 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.

[0308] In some embodiments, the IL-2 conjugate comprises an extended plasma half-life relative to wild-type IL-2, e.g., 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.

[0309] In some embodiments, the IL-2 conjugate comprises an extended plasma half-life relative to aldesleukin, 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. In some embodiments, the IL-2 conjugate comprises an extended plasma half-life relative to aldesleukin, 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.

[0310] In some embodiments, the IL-2 conjugate comprises an extended plasma half-life relative to aldesleukin, e.g., 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.

[0311] In some embodiments, the IL-2 conjugate comprises an extended plasma half-life with reduced toxicity. In some cases, 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 with reduced toxicity. In some cases, 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 with reduced toxicity. In some instances, 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 with reduced toxicity. In some instances, the reduced toxicity is reduced by 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 relative to wild-type IL2. In some instances, the reduced toxicity is reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500% or more relative to wild-type IL-2.

[0312] In some embodiments, the IL-2 conjugate comprises an extended plasma half-life with reduced toxicity. In some cases, 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 with reduced toxicity. In some cases, 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 with reduced toxicity. In some instances, 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 with reduced toxicity. In some instances, the reduced toxicity is reduced by 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 relative to aldesleukin. In some instances, the reduced toxicity is reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500% or more relative to aldesleukin.

[0313] In some embodiments, the IL-2 conjugate comprises a conjugated portion, wherein the size (e.g., volume or length) of the conjugated portion enhances plasma stability without reducing efficacy. In some cases, the size of the conjugated portion extends 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 longer. In some cases, the size of the conjugated portion extends 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 longer. In some instances, the size of the conjugated moiety extends 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...

Claims

1. An IL-2 conjugate comprising: an IL-2 polypeptide comprising a lysine analog, the lysine analog comprising an azide group covalently attached to a conjugation moiety, the conjugation moiety comprising polyethylene glycol (PEG), wherein: The IL-2 polypeptide comprises: (i) the amino acid sequence of SEQ ID NO: 1, wherein With reference to the amino acid positions in SEQ ID NO: 1, the lysine analogue replaces at least one amino acid residue at position K35, F42, K43, E62 or P65 in the IL-2 polypeptide; or (ii) the amino acid sequence of SEQ ID NO: 1, wherein (A) the lysine analogue replaces at least one amino acid residue at position K35, F42, K43, E62 or P65 within the IL-2 polypeptide, with reference to the amino acid positions within SEQ ID NO: 1; and (B) the N-terminal amino acid residue of the amino acid sequence of SEQ ID NO: 1 is deleted.

2. The IL-2 conjugate of claim 1, wherein the PEG has a molecular weight of about 5 kDa, about 10 kDa, about 15 kDa, about 20 kDa, about 25 kDa, about 30 kDa, about 35 kDa, about 40 kDa, about 45 kDa or about 50 kDa.

3. The IL-2 conjugate according to claim 1 or 2, wherein the PEG has a molecular weight of about 30 kDa.

4. The IL-2 conjugate according to any one of claims 1 to 3, wherein the lysine analogue replaces the amino acid at position P65 with reference to the amino acid position within SEQ ID NO:

1.

5. The IL-2 conjugate of any one of claims 1 to 4, wherein the IL-2 polypeptide comprises the amino acid sequence of SEQ ID NO: 1, wherein (A) with reference to the amino acid positions in SEQ ID NO: 1, the lysine analogue replaces at least one amino acid residue at position K35, F42, K43, E62 or P65 in the IL-2 polypeptide; and (B) the N-terminal amino acid residue of the amino acid sequence of SEQ ID NO: 1 is deleted.

6. The IL-2 conjugate according to any one of claims 1 to 5, wherein the lysine analog is N6-(2-azidoethoxy)-carbonyl-lysine.

7. The IL-2 conjugate according to any one of claims 1 to 6, wherein the lysine analog is N6-((2-azidoethoxy)-carbonyl)-L-lysine.

8. An IL-2 conjugate comprising an IL-2 polypeptide comprising the amino acid sequence of SEQ ID NO: 3, wherein, with reference to the amino acid positions within SEQ ID NO: 3, at least one amino acid residue at an amino acid position selected from the group consisting of K34, F41, K42, E61 and P64 is replaced by a structure of formula (I): in: Z is CH2 and Y is Y is CH2 and Z is Z is CH2 and Y is or Y is CH2 and Z is W is a PEG group having a molecular weight selected from the group consisting of about 5 kDa, about 10 kDa, about 15 kDa, about 20 kDa, about 25 kDa, about 30 kDa, about 35 kDa, about 40 kDa, about 45 kDa, about 50 kDa, and about 60 kDa; and X has the following structure: X-1 indicates the point of attachment to the amino acid residue preceding X; and X+1 indicates the point of attachment to the amino acid residue following X.

9. The IL-2 conjugate according to claim 8, wherein with reference to the amino acid positions within SEQ ID NO: 3, at least one amino acid residue at position P64 is substituted by the structure of formula (I).

10. The IL-2 conjugate according to claim 8 or 9, wherein the structure of formula (I) has the structure of formula (IV) or formula (V):

11. The IL-2 conjugate according to any one of claims 8 to 10, wherein W is a PEG group having a molecular weight of about 30 kDa.

12. The IL-2 conjugate according to claim 8, wherein, with reference to the amino acid positions within SEQ ID NO: 3, at least one amino acid residue at position P64 is substituted with a structure of formula (XII) or formula (XIII): in: n is such that -(OCH2CH2) n -OCH3 structure of the PEG group has a molecular weight of about 30 kDa integer; and The wavy lines indicate covalent bonds to the first amino acid residue before and after the at least one amino acid residue at position P64 in SEQ ID NO: 3, respectively.

13. The IL-2 conjugate according to claim 8, wherein, with reference to the amino acid positions within SEQ ID NO: 3, at least one amino acid residue at position P64 is substituted by the structure of formula (XII) or formula (XIII): in: n is such that -(OCH2CH2) n The PEG group of the -OCH3 structure has an integer molecular weight of about 5 kDa, about 10 kDa, about 15 kDa, about 20 kDa, about 25 kDa, about 30 kDa, about 35 kDa, about 40 kDa, about 45 kDa, about 50 kDa or about 60 kDa; and The wavy lines indicate covalent bonds to the first amino acid residue before and after the at least one amino acid residue at position P64 in SEQ ID NO: 3, respectively. 14 . The IL-2 conjugate according to claim 1 , which is a pharmaceutically acceptable salt, solvate or hydrate.

15. A pharmaceutical composition comprising the IL-2 conjugate according to any one of claims 1 to 14 and a pharmaceutically acceptable excipient.

16. A pharmaceutical composition comprising a mixture of IL-2 conjugates according to claim 10 or 11, wherein the mixture comprises (i) an IL-2 conjugate wherein the structure of formula (I) has the structure of formula (IV) and (ii) an IL-2 conjugate wherein the structure of formula (I) has the structure of formula (V).

17. A pharmaceutical composition comprising a mixture of IL-2 conjugates according to claim 12 or 13, wherein the mixture comprises (i) an IL-2 conjugate wherein, with reference to the amino acid positions within SEQ ID NO: 3, at least one amino acid residue at position P64 is replaced by a structure of formula (XII) and (ii) an IL-2 conjugate wherein, with reference to the amino acid positions within SEQ ID NO: 3, at least one amino acid residue at position P64 is replaced by a structure of formula (XIII).

18. Use of the IL-2 conjugate according to any one of claims 1 to 14, or the pharmaceutical composition according to any one of claims 15 to 17, in the preparation of a medicament for treating cancer.

19. The method of claim 18, wherein the cancer is selected from the group consisting of renal cell carcinoma (RCC), melanoma, non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), urothelial carcinoma (UC), Merkel cell carcinoma (MCC), ovarian cancer, gastric cancer, breast cancer, bladder cancer, bone cancer, brain cancer, colorectal cancer, esophageal cancer, eye cancer, head and neck cancer, kidney cancer, lung cancer, pancreatic cancer, prostate cancer, cutaneous squamous cell carcinoma (CSCC) and classical Hodgkin lymphoma (cHL).

20. The use according to claim 18 or 19, wherein the IL-2 conjugate or the pharmaceutical composition is used in combination with other therapeutic agents.

21. Use of the IL-2 conjugate according to any one of claims 1 to 14 or the pharmaceutical composition according to any one of claims 15 to 17 in the preparation of a medicament for selectively expanding CD4+ helper T cells, CD8+ effector, naive or memory T cells, NK cells, NKT cells or a combination thereof in a subject.

22. A method for preparing the IL-2 conjugate of claim 8, comprising: The IL-2 polypeptide or its pharmaceutically acceptable salt, solvate or hydrate is combined with The mPEG-DBCO is reacted to form the IL-2 conjugate, The IL-2 polypeptide or its pharmaceutically acceptable salt, solvate or hydrate comprises the formula Unnatural amino acids, wherein the IL-2 polypeptide comprises the amino acid sequence of SEQ ID NO: 3, wherein a non-natural amino acid replaces at least one amino acid residue at position X within the amino acid sequence of SEQ ID NO: 3, wherein position X is K34, F41, K42, E61 or P64, with reference to the amino acid position within SEQ ID NO: 3, position X-1 indicates the point of attachment to the amino acid residue preceding the non-natural amino acid, and position X+1 indicates the point of attachment to the amino acid residue following the non-natural amino acid, and wherein a wavy line indicates a covalent bond to the amino acid residues at position X+1 and position X-1, respectively, within SEQ ID NO: 3, wherein n is an integer such that mPEG-DBCO comprises mPEG having a molecular weight of about 5 kDa, about 10 kDa, about 15 kDa, about 20 kDa, about 25 kDa, about 30 kDa, about 35 kDa, about 40 kDa, about 45 kDa, about 50 kDa, or about 60 kDa.

23. The method of claim 22, wherein with reference to amino acid positions within SEQ ID NO: 3, position X is P64.

24. The method of claim 22, wherein n is an integer such that mPEG-DBCO comprises mPEG having a molecular weight of about 30 kDa.

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