Il-2 conjugates and methods of use thereof

Abstract

This document discloses compositions, kits, and methods comprising interleukin (IL) conjugates (e.g., IL-2 conjugates) for the treatment of one or more indications. This document also describes pharmaceutical compositions and kits comprising one or more of these interleukin conjugates (e.g., IL-2 conjugates).

Description

Technical Field

[0001] none Prior Technology

[0002] Different T cell populations regulate the immune system to maintain immune homeostasis and tolerance. For example, regulatory T (Treg) cells prevent inappropriate immune responses by preventing pathological autoreactivity, while cytotoxic T cells target and destroy infected cells and / or cancer cells. In some cases, the regulation of different T cell populations provides an option for treating diseases or indications. Summary of the Invention

[0003] This article describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is subjected to a structural substitution of formula (I): Equation (I); where: Z is CH2 and Y is Y represents CH2 and Z represents Z is CH2 and Y is ;or Y is CH2 and Z is W represents 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; and X has the following structure: ; 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... The PEG group, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is selected from the 5 kDa, 10 kDa, 20 kDa, and 30 kDa examples of the PEG group. In some embodiments of the IL-2 conjugate described herein, the average molecular weight of the PEG group is 5 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugate described herein, the average molecular weight of the PEG group is 10 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugate described herein, the average molecular weight of the PEG group is 15 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugate described herein, the average molecular weight of the PEG group is 20 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the average molecular weight of the PEG group is 25 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the average molecular weight of the PEG group is 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the average molecular weight of the PEG group is 35 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the average molecular weight of the PEG group is 40 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the average molecular weight of the PEG group is 45 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the average molecular weight of the PEG group is 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 refers 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 refers 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 refers 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 structure of formula (I) is located at position F42 in the amino acid sequence of the IL-2 conjugate, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate refers 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 structure of formula (I) is located at position F44 in the amino acid sequence of the IL-2 conjugate, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate refers 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 structure of formula (I) is located at position K43 in the amino acid sequence of the IL-2 conjugate, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate refers 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 structure of formula (I) is located at position E62 in the amino acid sequence of the IL-2 conjugate, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate refers 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 structure of formula (I) is located at position P65 in the amino acid sequence of the IL-2 conjugate, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate refers 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 structure of formula (I) is located at position R38 in the amino acid sequence of the IL-2 conjugate, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate refers 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 structure of formula (I) is located at position T41 in the amino acid sequence of the IL-2 conjugate, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate refers 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 structure of formula (I) is located at position E68 in the amino acid sequence of the IL-2 conjugate, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate refers 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 structure of formula (I) is located at position Y45 in the amino acid sequence of the IL-2 conjugate, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate refers 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 structure of formula (I) is located at position V69 in the amino acid sequence of the IL-2 conjugate, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate refers 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 structure of formula (I) is located at position L72 in the amino acid sequence of the IL-2 conjugate, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate refers to the position in SEQ ID NO: 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0004] This article describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 4, wherein at least one amino acid residue in the IL-2 conjugate is subjected to a structural substitution of formula (I): Equation (I); where: Z is CH2 and Y is Y represents CH2 and Z represents Z is CH2 and Y is ;or Y is CH2 and Z is W represents 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; and X has the following structure: ; 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... The PEG group, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is selected from the 5 kDa, 10 kDa, 20 kDa, and 30 kDa examples of the PEG group. In some embodiments of the IL-2 conjugate described herein, the average molecular weight of the PEG group is 5 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugate described herein, the average molecular weight of the PEG group is 10 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugate described herein, the average molecular weight of the PEG group is 15 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugate described herein, the average molecular weight of the PEG group is 20 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the average molecular weight of the PEG group is 25 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the average molecular weight of the PEG group is 30 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the average molecular weight of the PEG group is 35 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the average molecular weight of the PEG group is 40 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the average molecular weight of the PEG group is 45 kDa, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, the average molecular weight of the PEG group is 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 refers 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 refers 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 refers 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 structure of formula (I) is located at position F42 in the amino acid sequence of the IL-2 conjugate, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate refers 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 structure of formula (I) is located at position F44 in the amino acid sequence of the IL-2 conjugate, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate refers 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 structure of formula (I) is located at position K43 in the amino acid sequence of the IL-2 conjugate, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate refers 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 structure of formula (I) is located at position E62 in the amino acid sequence of the IL-2 conjugate, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate refers 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 structure of formula (I) is located at position P65 in the amino acid sequence of the IL-2 conjugate, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate refers 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 structure of formula (I) is located at position R38 in the amino acid sequence of the IL-2 conjugate, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate refers 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 structure of formula (I) is located at position T41 in the amino acid sequence of the IL-2 conjugate, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate refers 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 structure of formula (I) is located at position E68 in the amino acid sequence of the IL-2 conjugate, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate refers 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 structure of formula (I) is located at position Y45 in the amino acid sequence of the IL-2 conjugate, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate refers 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 structure of formula (I) is located at position V69 in the amino acid sequence of the IL-2 conjugate, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate refers 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 structure of formula (I) is located at position L72 in the amino acid sequence of the IL-2 conjugate, wherein the position of the structure of formula (I) in the amino acid sequence of the IL-2 conjugate refers to the position in SEQ ID NO: 1, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0005] This document describes IL-2 conjugates comprising the amino acid sequences of any one of SEQ ID NO: 15 to 19, wherein [AzK_PEG] has the structure of formula (II) or (III), or a mixture of formulas (II) and (III): Equation (II); Formula (III); where: W is 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; and X has the following structure: ; or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, [AzK_PEG] is a mixture of formulas (II) and (III), or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, [AzK_PEG] has the structure of formula (II):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 an amino acid sequence 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 the following: 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 an amino acid sequence 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 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 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 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 an amino acid sequence 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 an amino acid sequence 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 the structure of formula (III). 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 an amino acid sequence 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 an amino acid sequence 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 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 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 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 an amino acid sequence 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 an amino acid sequence 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 the methoxy PEG group is illustrated in the mPEG-DBCO structure of process 1 in Example 2.

[0006] In some embodiments of the IL-2 conjugate described herein having an amino acid sequence selected from any of SEQ ID NO: 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 conjugate described herein having an amino acid sequence selected from any of SEQ ID NO: 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 conjugate described herein having an amino acid sequence selected from any of SEQ ID NO: 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 conjugate described herein having an amino acid sequence selected from any of SEQ ID NO: 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 conjugate described herein having an amino acid sequence selected from any of SEQ ID NO: 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 conjugate described herein having an amino acid sequence selected from any of SEQ ID NO: 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 conjugate described herein having an amino acid sequence selected from any of SEQ ID NO: 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 conjugate described herein having an amino acid sequence selected from any of SEQ ID NO: 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 conjugate described herein having an amino acid sequence selected from any of SEQ ID NO: 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 of SEQ ID NO: 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 conjugate described herein having an amino acid sequence selected from any of SEQ ID NO: 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 conjugate described herein having an amino acid sequence selected from any of SEQ ID NO: 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 of SEQ ID NO: 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 straight-chain methoxy PEG group, or a branched-chain methoxy PEG group.

[0007] This document describes IL-2 conjugates comprising the amino acid sequences of any one of SEQ ID NO: 20 to 24, wherein [AzK_PEG5kD] has the structure of formula (II) or (III), or a mixture of formulas (II) and (III): Equation (II); Formula (III); where: W is a PEG group with an average molecular weight of 5 kDa; and X has the following structure: 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 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 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 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 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 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). 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 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 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 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 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 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). 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 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 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 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 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 SEQ ID NO: 24, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0008] This document describes IL-2 conjugates comprising the amino acid sequences of any one of SEQ ID NO: 25 to 29, wherein [AzK_PEG30kD] has a structure of formula (II) or (III), or a mixture of the structures of formula (II) and (III): Equation (II); Formula (III); where: W is a PEG group with an average molecular weight of 30 kDa; and X has the following structure: 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 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 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 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 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 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): 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 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 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 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 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 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). 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 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 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 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 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 SEQ ID NO: 29, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0009] This article describes IL-2 conjugates containing the amino acid sequences of any one of SEQ ID NO: 15 to 19, wherein [AzK_PEG] is a mixture of structures of formula (II) and formula (III): Equation (II); Formula (III); where: W is 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; and X has the following structure: ; 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) containing the total amount of [AzK_PEG] in the IL-2 conjugate to the amount of the structure of formula (III) is about 1:1. In some embodiments of the IL-2 conjugates described herein, the ratio of the amount of the structure of formula (II) containing the total amount of [AzK_PEG] in the IL-2 conjugate to the amount of the structure of formula (III) is greater than 1:1. In some embodiments of the IL-2 conjugates described herein, the ratio of the amount of the structure of formula (II) containing the total amount of [AzK_PEG] in the IL-2 conjugate to the amount of the structure of formula (III) is less than 1:1. In some embodiments of the IL-2 conjugates described herein, W is a straight-chain or branched-chain 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.

[0010] This document describes IL-2 conjugates containing the amino acid sequences of any one of SEQ ID NO: 20 to 24, wherein [AzK_PEG5kD] is a mixture of structures of formula (II) and formula (III): Equation (II); Formula (III); where: W is a PEG group with an average molecular weight of 5 kDa; and X has the following structure: ; 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) containing the total amount of [AzK_PEG5kD] in the IL-2 conjugate to the amount of the structure of formula (III) is approximately 1:1. In some embodiments of the IL-2 conjugates described herein, the ratio of the amount of the structure of formula (II) containing the total amount of [AzK_PEG5kD] in the IL-2 conjugate to the amount of the structure of formula (III) is greater than 1:1. In some embodiments of the IL-2 conjugates described herein, the ratio of the amount of the structure of formula (II) containing the total amount of [AzK_PEG5kD] in the IL-2 conjugate to the amount of the structure of formula (III) is less than 1:1.

[0011] This article describes IL-2 conjugates containing the amino acid sequences of any one of SEQ ID NO: 25 to 29, wherein [AzK_PEG30kD] is a mixture of structures of formula (II) and formula (III): Equation (II); Formula (III); where: W is a PEG group with an average molecular weight of 30 kDa; and X has the following structure: ; 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) containing the total amount of [AzK_PEG30kD] in the IL-2 conjugate to the amount of the structure of formula (III) is approximately 1:1. In some embodiments of the IL-2 conjugates described herein, the ratio of the amount of the structure of formula (II) containing the total amount of [AzK_PEG30kD] in the IL-2 conjugate to the amount of the structure of formula (III) is greater than 1:1. In some embodiments of the IL-2 conjugates described herein, the ratio of the amount of the structure of formula (II) containing the total amount of [AzK_PEG30kD] in the IL-2 conjugate to the amount of the structure of formula (III) is less than 1:1.

[0012] This document describes IL-2 conjugates comprising the amino acid sequences of any one of SEQ ID NO: 40 to 44, wherein [AzK_L1_PEG] has the structure of formula (IV) or (V), or a mixture of formulas (IV) and (V): Formula (IV); Formula (V); where: W is 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; and X has the following structure: 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 formulas (IV) and (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): 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 an amino acid sequence 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 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 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 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 an amino acid sequence 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 an amino acid sequence 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 the structure of formula (V).

[0013] 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 an amino acid sequence 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 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 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 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 an amino acid sequence 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 an amino acid sequence 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 conjugate described herein having an amino acid sequence selected from any of SEQ ID NO: 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. In some embodiments of the IL-2 conjugate described herein having an amino acid sequence selected from any of SEQ ID NO: 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 conjugate described herein having an amino acid sequence selected from any of SEQ ID NO: 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 conjugate described herein having an amino acid sequence selected from any of SEQ ID NO: 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 conjugate described herein having an amino acid sequence selected from any of SEQ ID NO: 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 conjugate described herein having an amino acid sequence selected from any of SEQ ID NO: 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 conjugate described herein having an amino acid sequence selected from any of SEQ ID NO: 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 conjugate described herein having an amino acid sequence selected from any of SEQ ID NO: 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 conjugate described herein having an amino acid sequence selected from any of SEQ ID NO: 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 conjugate described herein having an amino acid sequence selected from any of SEQ ID NO: 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 conjugate described herein having an amino acid sequence selected from any of SEQ ID NO: 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 conjugate described herein having an amino acid sequence selected from any of SEQ ID NO: 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 of SEQ ID NO: 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 straight-chain methoxy PEG group, or a branched-chain methoxy PEG group.

[0014] This document describes IL-2 conjugates comprising the amino acid sequences of any one of SEQ ID NO: 45 to 49, wherein [AzK_L1_PEG5kD] has the structure of formula (IV) or (V), or a mixture of formulas (IV) and (V): Formula (IV); Formula (V); where: W is a PEG group with an average molecular weight of 5 kDa; and X has the following structure: 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 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 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 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 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 SEQ ID NO: 49, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, [AzK_L1_PEG5kD] has the structure of formula (IV). 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 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 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 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 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 SEQ ID NO: 49, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, [AzK_L1_PEG5kD] has the structure of formula (V). 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 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 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 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 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 SEQ ID NO: 49, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0015] This document describes IL-2 conjugates comprising the amino acid sequences of any one of SEQ ID NO: 50 to 54, wherein [AzK_L1_PEG30kD] has the structure of formula (IV) or formula (V), or a mixture of the structures of formula (IV) and formula (V): Formula (IV); Formula (V); where: W is a PEG group with an average molecular weight of 30 kDa; and X has the following structure: 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 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 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 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 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 SEQ ID NO: 54, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, [AzK_L1_PEG30kD] has the structure of formula (IV): 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 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 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 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 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 SEQ ID NO: 54, or a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments of the IL-2 conjugates described herein, [AzK_L1_PEG30kD] has the structure of formula (V). 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 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 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 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 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 SEQ ID NO: 54, or a pharmaceutically acceptable salt, solvate, or hydrate thereof.

[0016] This document describes IL-2 conjugates containing the amino acid sequences of any one of SEQ ID NO: 40 to 44, wherein [Azk_L1_PEG] is a mixture of structures of formula (IV) and formula (V): Formula (IV); Formula (V); where: W is 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; and X has the following structure: 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) containing the total amount of [AzK_L1_PEG] in the IL-2 conjugate to the amount of the structure of formula (V) is about 1:1. In some embodiments of the IL-2 conjugates described herein, the ratio of the amount of the structure of formula (IV) containing the total amount of [AzK_L1_PEG] in the IL-2 conjugate to the amount of the structure of formula (V) is greater than 1:1. In some embodiments of the IL-2 conjugates described herein, the ratio of the amount of the structure of formula (IV) containing the total amount of [AzK_L1_PEG] in the IL-2 conjugate to the amount of the structure of formula (V) is less than 1:1. In some embodiments of the IL-2 conjugates described herein, W is a straight-chain or branched-chain 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.

[0017] This document describes IL-2 conjugates containing the amino acid sequences of any one of SEQ ID NO: 45 to 49, wherein [AzK_L1_PEG5kD] is a mixture of structures of formula (IV) and formula (V): Formula (IV); Formula (V); where: W is a PEG group with an average molecular weight of 5 kDa; and X has the following structure: ; 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) containing the total amount of [AzK_L1_PEG5kD] in the IL-2 conjugate to the amount of the structure of formula (V) is approximately 1:1. In some embodiments of the IL-2 conjugates described herein, the ratio of the amount of the structure of formula (IV) containing the total amount of [AzK_L1_PEG5kD] in the IL-2 conjugate to the amount of the structure of formula (V) is greater than 1:1. In some embodiments of the IL-2 conjugates described herein, the ratio of the amount of the structure of formula (IV) containing the total amount of [AzK_L1_PEG5kD] in the IL-2 conjugate to the amount of the structure of formula (V) is less than 1:1.

[0018] This document describes IL-2 conjugates containing the amino acid sequences of any of SEQ ID NO: 50 to 54, wherein [AzK_L1_PEG30kD] is a mixture of structures of formula (IV) and formula (V): Formula (IV); Formula (V); where: W is a PEG group with an average molecular weight of 30 kDa; and X has the following structure: ; 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) containing the total amount of [AzK_L1_PEG30kD] in the IL-2 conjugate to the amount of the structure of formula (V) is approximately 1:1. In some embodiments of the IL-2 conjugates described herein, the ratio of the amount of the structure of formula (IV) containing the total amount of [AzK_L1_PEG30kD] in the IL-2 conjugate to the amount of the structure of formula (V) is greater than 1:1. In some embodiments of the IL-2 conjugates described herein, the ratio of the amount of the structure of formula (IV) containing the total amount of [AzK_L1_PEG30kD] in the IL-2 conjugate to the amount of the structure of formula (V) is less than 1:1.

[0019] This article describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted with a structure of formula (VI) or (VII) or a mixture of (VI) and (VII): Formula (VI) Equation (VII) Where: n is an integer in the range of approximately 2 to approximately 5000; and X has the following 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 formulas (VI) and (VII) is in the following ranges: 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 175 0, 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 formulas (VI) and (VII) is an integer selected from the following: 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, 13 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 positions of structures of formulas (VI) and (VII), or mixtures of formulas (VI) and (VII), in the amino acid sequence of the IL-2 conjugate are selected from K34, F41, F43, K42, E61, P64, R37, T40, E67, Y44, V68, and L71, wherein the position of structure (I) in the amino acid sequence of the IL-2 conjugate is referenced to the position in SEQ ID NO: 3. In some embodiments of the IL-2 conjugates described herein, the positions of structures of formulas (VI) and (VII), or mixtures of formulas (VI) and (VII), in the amino acid sequence of the IL-2 conjugate in SEQ ID NO: 3 are 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 structure of formula (VI) or (VII), or a mixture of formulas (VI) and (VII), is located at position K34 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) or (VII), or a mixture of formulas (VI) and (VII), is located at position F41 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) or (VII), or a mixture of formulas (VI) and (VII), is located at position F43 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 formulas (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 formulas (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 formulas (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 formulas (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 formulas (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 formulas (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 formulas (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 formulas (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 structures of formulas (VI) and (VII), or mixtures of formulas (VI) and (VII), are located at position L71 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 ratio of the amount of the structure of formula (VI) comprising the total amount of the IL-2 conjugate to the amount of the structure of formula (VII) is approximately 1:1. In some embodiments of the IL-2 conjugates described herein, the ratio of the amount of the structure of formula (VI) comprising the total amount of the IL-2 conjugate to the amount of the structure of formula (VII) 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) containing the total amount of IL-2 conjugate to the amount of the structure of formula (VII) is less than 1:1.

[0020] In some embodiments, this document describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted with a structure of formula (VI) or (VII) or a mixture of (VI) and (VII), wherein the substituted 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 of the following: 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 68 2. 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 1 250, 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 formulas (VI) and (VII) is an integer selected from the following: 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, 13 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.

[0021] In some embodiments, this document describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted with a structure of formula (VI) or (VII) or a mixture of (VI) and (VII), wherein the substituted amino acid residue in SEQ ID NO: 3 is selected from F41, F43, K42, E61 and P64, and wherein n is an integer of about 450 to about 800, or about 454 to about 796, or about 454 to about 682, or about 568 to about 909. In some embodiments of the IL-2 conjugates described herein, n in the compounds of formulas (VI) and (VII) is an integer selected from the following: 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, 1137, and 1249.

[0022] In some embodiments, this document describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted with a structure of formula (VI) or (VII) or a mixture of (VI) and (VII), wherein the substituted 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 formulas (VI) and (VII) is an integer selected from the following: 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910.

[0023] In some embodiments, this document describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted with a structure of formula (VI) or (VII) or a mixture of (VI) and (VII), wherein the substituted 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 conjugate described herein, n in the compounds of formulas (VI) and (VII) is an integer selected from the following: 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.

[0024] In some embodiments, this document describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted with a structure of formula (VI) or (VII) or a mixture of (VI) and (VII), wherein the substituted 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 conjugate described herein, n in the compounds of formulas (VI) and (VII) is an integer selected from the following: 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.

[0025] This document describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted with a structure of formula (VI) or (VII) or a mixture of (VI) and (VII), wherein n is an integer such that the molecular weight of the PEG moiety is in the following ranges: 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. or approximately 8,000 Daltons to approximately 70,000 Daltons, or approximately 5,000 Daltons to approximately 70,000 Daltons, or approximately 5,000 Daltons to approximately 65,000 Daltons, or approximately 5,000 Daltons to approximately 60,000 Daltons, or approximately 5,000 Daltons to approximately 50,000 Daltons, or approximately 6,000 Daltons to approximately 50,000 Daltons, or approximately 7,000 Daltons to approximately 50,000 Daltons, or approximately 7,000 Daltons to approximately 45,000 Daltons, or approximately 7,000 Daltons to approximately 40,000 Daltons, or approximately 8,000 Daltons to approximately 40,000 Daltons, or approximately 8,500 Daltons to approximately 40,000 Daltons, or Approximately 8,500 Daltons to approximately 35,000 Daltons, or approximately 9,000 Daltons to approximately 50,000 Daltons, or approximately 9,000 Daltons to approximately 45,000 Daltons, or approximately 9,000 Daltons to approximately 40,000 Daltons, or approximately 9,000 Daltons to approximately 35,000 Daltons, or approximately 9,000 Daltons to approximately 30,000 Daltons, or approximately 9,500 Daltons to approximately 35,000 Daltons, or approximately 9,500 Daltons to approximately 30,000 Daltons, or approximately 10,000 Daltons to approximately 50,000 Daltons, or approximately 10,000 Daltons to approximately 45,000 Daltons, or approximately 10,000 Daltons to approximately 40,000 Daltons, or Approximately 10,000 Daltons to approximately 35,000 Daltons, or approximately 10,000 Daltons to approximately 30,000 Daltons, or approximately 15,000 Daltons to approximately 50,000 Daltons, or approximately 15,000 Daltons to approximately 45,000 Daltons, or approximately 15,000 Daltons to approximately 40,000 Daltons, or approximately 15,000 Daltons to approximately 35,000 Daltons, or approximately 15,000 Daltons to approximately 30,000 Daltons, or approximately 20,000 Daltons to approximately 50,000 Daltons, or approximately 20,000 Daltons to approximately 45,000 Daltons, or approximately 20,000 Daltons to approximately 40,000 Daltons, or approximately 20,000 Daltons to approximately 35,000 Daltons.000 Daltons, or about 20,000 Daltons to about 30,000 Daltons. This article describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted with a structure of formula (VI) or (VII) or a mixture of (VI) and (VII), wherein n is an integer such that the molecular weight of the PEG moiety is an integer of the following: 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 20,000 Daltons to about 30,000 Daltons. 00 Daltons, approximately 35,000 Daltons, approximately 40,000 Daltons, approximately 45,000 Daltons, approximately 50,000 Daltons, approximately 60,000 Daltons, approximately 70,000 Daltons, approximately 80,000 Daltons, approximately 90,000 Daltons, approximately 100,000 Daltons, approximately 125,000 Daltons, approximately 150,000 Daltons, approximately 175,000 Daltons, or approximately 200,000 Daltons. This document describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted with a structure of formula (VI) or (VII) or a mixture of (VI) and (VII), wherein n is an integer such that the molecular weight of the PEG moiety is an integer of the following: 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.

[0026] This article describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted with a structure of formula (VIII) or (IX) or a mixture of (VIII) and (IX): Formula (VIII) Equation (IX) where: n is an integer in the range of approximately 2 to approximately 5000; and X has the following 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 formulas (VIII) and (IX) is in the following ranges: 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 formulas (VIII) and (IX) is an integer selected from the following: 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, 13 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 positions of the structures of formulas (VIII), (IX), or mixtures of formulas (VIII) and (IX) in the amino acid sequence of the IL-2 conjugate are 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 referenced to the position in SEQ ID NO: 3. In some embodiments of the IL-2 conjugates described herein, the positions of the structures of formulas (VIII), (IX), or mixtures of formulas (VIII) and (IX) in the amino acid sequence of the IL-2 conjugate in SEQ ID NO: 3 are 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 structure of formula (VIII), formula (IX), or a mixture of formulas (VIII) and (IX) is located at position K34 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 formulas (VIII) and (IX) is located at position F41 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 formulas (VIII) and (IX) is located at position F43 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 formulas (VIII) and (IX) 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 (VIII), formula (IX), or a mixture of formulas (VIII) and (IX) 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 (VIII), formula (IX), or a mixture of formulas (VIII) and (IX) 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 (VIII), formula (IX), or a mixture of formulas (VIII) and (IX) 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 (VIII), formula (IX), or a mixture of formulas (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 formulas (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 formulas (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 formulas (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 structure of formula (VIII), formula (IX), or a mixture of formulas (VIII) and (IX) is located at position L71 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 ratio of the amount of the structure of formula (VIII) comprising the total amount of the IL-2 conjugate to the amount of the structure of formula (IX) is approximately 1:1. In some embodiments of the IL-2 conjugates described herein, the ratio of the amount of the structure of formula (VIII) containing the total amount of IL-2 conjugates to the amount of the structure of formula (IX) 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) containing the total amount of IL-2 conjugate to the amount of the structure of formula (IX) is less than 1:1.

[0027] In some embodiments, this document describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted with a structure of formula (VIII) or (IX), or a mixture of (VIII) and (IX), wherein the substituted 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 of the following: 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 68 2. 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 1 250, 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 formulas (VIII) and (IX) is an integer selected from the following: 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, 13 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.

[0028] In some embodiments, this document describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted with a structure of formula (VIII) or (IX), or a mixture of (VIII) and (IX), wherein the substituted 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 formulas (VIII) and (IX) is an integer selected from the following: 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, 1137, and 1249.

[0029] In some embodiments, this document describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted with a structure of formula (VIII) or (IX), or a mixture of (VIII) and (IX), wherein the substituted 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 formulas (VIII) and (IX) is an integer selected from the following: 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910.

[0030] In some embodiments, this document describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted with a structure of formula (VIII) or (IX), or a mixture of (VIII) and (IX), wherein the substituted 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 conjugate described herein, n in the compounds of formulas (VIII) and (IX) is an integer selected from the following: 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 approximately 681.

[0031] In some embodiments, this document describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted with a structure of formula (VIII) or (IX), or a mixture of (VIII) and (IX), wherein the substituted amino acid residue in SEQ ID NO: 3 is P64, and wherein n is an integer from about 450 to about 800, or about 454 to about 796, or about 454 to about 682, or about 568 to about 909. In some embodiments of the IL-2 conjugate described herein, n in the compounds of formulas (VIII) and (IX) is an integer selected from the following: 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 approximately 681.

[0032] This document describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted 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 following ranges: 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. 0.00 Daltons, or approximately 8,000 Daltons to approximately 70,000 Daltons, or approximately 5,000 Daltons to approximately 70,000 Daltons, or approximately 5,000 Daltons to approximately 65,000 Daltons, or approximately 5,000 Daltons to approximately 60,000 Daltons, or approximately 5,000 Daltons to approximately 50,000 Daltons, or approximately 6,000 Daltons to approximately 50,000 Daltons, or approximately 7,000 Daltons to approximately 50,000 Daltons, or approximately 7,000 Daltons to approximately 45,000 Daltons, or approximately 7,000 Daltons to approximately 40,000 Daltons, or approximately 8,000 Daltons to approximately 40,000 Daltons, or approximately 8,500 Daltons to approximately 40,000 Daltons. 0 Daltons, or approximately 8,500 Daltons to approximately 35,000 Daltons, or approximately 9,000 Daltons to approximately 50,000 Daltons, or approximately 9,000 Daltons to approximately 45,000 Daltons, or approximately 9,000 Daltons to approximately 40,000 Daltons, or approximately 9,000 Daltons to approximately 35,000 Daltons, or approximately 9,000 Daltons to approximately 30,000 Daltons, or approximately 9,500 Daltons to approximately 35,000 Daltons, or approximately 9,500 Daltons to approximately 30,000 Daltons, or approximately 10,000 Daltons to approximately 50,000 Daltons, or approximately 10,000 Daltons to approximately 45,000 Daltons, or approximately 10,000 Daltons to approximately 40,000 Daltons. ,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 40,000 Daltons, or about 20,000 Daltons to about 40,000 Daltons, or about 20,000 Daltons to about 40,000 Daltons, or about 20,000 Daltons to about 45 ...From about 35,000 Daltons to about 20,000 Daltons, or from about 20,000 Daltons to about 30,000 Daltons. This document describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted 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 an integer of the following: 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 30,000 Daltons. 000 Daltons, approximately 35,000 Daltons, approximately 40,000 Daltons, approximately 45,000 Daltons, approximately 50,000 Daltons, approximately 60,000 Daltons, approximately 70,000 Daltons, approximately 80,000 Daltons, approximately 90,000 Daltons, approximately 100,000 Daltons, approximately 125,000 Daltons, approximately 150,000 Daltons, approximately 175,000 Daltons, or approximately 200,000 Daltons. This document describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted 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 an integer of the following: 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.

[0033] This article describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted with a structure of formula (X) or (XI) or a mixture of (X) and (XI): Formula (X) Formula (XI) Where: n is an integer in the range of about 2 to about 5000; and the wavy line represents a covalent bond with an unsubstituted amino acid residue in SEQ ID NO: 3, or a medically acceptable salt, solvate or hydrate thereof.

[0034] In some embodiments, the stereochemistry of the antipallic centers in formulas (X) and (XI) is racemic, enriched (R), enriched (S), substantially (R), substantially (S), (R), or (S). In some embodiments, the stereochemistry of the antipallic centers in formulas (X) and (XI) is racemic. In some embodiments, the stereochemistry of the antipallic centers in formulas (X) and (XI) is enriched (R). In some embodiments, the stereochemistry of the antipallic centers in formulas (X) and (XI) is enriched (S). In some embodiments, the stereochemistry of the antipallic centers in formulas (X) and (XI) is substantially (R). In some embodiments, the stereochemistry of the antipallic centers in formulas (X) and (XI) is substantially (S). In some embodiments, the stereochemistry of the antipallic centers in formulas (X) and (XI) is (R). In some embodiments, the stereochemistry of the antipallic centers in formulas (X) and (XI) is (S).

[0035] In some embodiments of the IL-2 conjugates described herein, n in the compounds of formulas (X) and (XI) is in the following ranges: 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 formulas (X) and (XI) is an integer selected from the following: 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, 136 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 positions of structures of formulas (X) and (XI) or mixtures of formulas (X) and (XI) in the amino acid sequence of the IL-2 conjugate are selected from K34, F41, F43, K42, E61, P64, R37, T40, E67, Y44, V68, and L71, wherein the position of structure (I) in the amino acid sequence of the IL-2 conjugate is referenced to the position in SEQ ID NO: 3. In some embodiments of the IL-2 conjugates described herein, the positions of structures of formulas (X) and (XI) or mixtures of formulas (X) and (XI) in the amino acid sequence of the IL-2 conjugate in SEQ ID NO: 3 are 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 structure of formulas (X) and (XI) or a mixture of formulas (X) and (XI) is located at position K34 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 formulas (X) and (XI) or a mixture of formulas (X) and (XI) is located at position F41 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 formulas (X) and (XI) or a mixture of formulas (X) and (XI) is located at position F43 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 formulas (X) and (XI) or a mixture of formulas (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 formulas (X) and (XI) or a mixture of formulas (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 formulas (X) and (XI) or a mixture of formulas (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 formulas (X) and (XI) or a mixture of formulas (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 formulas (X) and (XI) or a mixture of formulas (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 formulas (X) and (XI) or a mixture of formulas (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 formulas (X) and (XI) or a mixture of formulas (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 formulas (X) and (XI) or a mixture of formulas (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 structures of formulas (X) and (XI), or mixtures of formulas (X) and (XI), are positioned at position L71 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 ratio of the amount of structure of formula (X) comprising the total amount of the IL-2 conjugate to the amount of structure of formula (XI) is approximately 1:1. In some embodiments of the IL-2 conjugates described herein, the ratio of the amount of structure of formula (X) comprising the total amount of the IL-2 conjugate to the amount of structure of formula (XI) is greater than 1:1. In some embodiments of the IL-2 conjugates described herein, the ratio of the amount of structure of formula (X) comprising the total amount of the IL-2 conjugate to the amount of structure of formula (XI) is less than 1:1.

[0036] In some embodiments, this document describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted with a structure of formula (X) or (XI), or a mixture of (X) and (XI), wherein the substituted 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 of the following: 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 68 2. 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 1 250, 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 formulas (VI) and (VII) is an integer selected from the following: 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, 13 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.

[0037] In some embodiments, this document describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted with a structure of formula (X) or (XI), or a mixture of (X) and (XI), wherein the substituted 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 formulas (X) and (XI) is an integer selected from the following: 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, 1137, and 1249.

[0038] In some embodiments, this document describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted with a structure of formula (X) or (XI), or a mixture of (X) and (XI), wherein the substituted 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 formulas (X) and (XI) is an integer selected from the following: 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910.

[0039] In some embodiments, this document describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted with a structure of formula (X) or (XI), or a mixture of (X) and (XI), wherein the substituted 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 conjugate described herein, n in the compounds of formulas (X) and (XI) is an integer selected from the following: 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.

[0040] In some embodiments, this document describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted with a structure of formula (X) or (XI), or a mixture of (X) and (XI), wherein the substituted 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 conjugate described herein, n in the compounds of formulas (X) and (XI) is an integer selected from the following: 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.

[0041] This document describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted 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 following ranges: 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, or Approximately 8,000 Daltons to approximately 70,000 Daltons, or approximately 5,000 Daltons to approximately 70,000 Daltons, or approximately 5,000 Daltons to approximately 65,000 Daltons, or approximately 5,000 Daltons to approximately 60,000 Daltons, or approximately 5,000 Daltons to approximately 50,000 Daltons, or approximately 6,000 Daltons to approximately 50,000 Daltons, or approximately 7,000 Daltons to approximately 50,000 Daltons, or approximately 7,000 Daltons to approximately 45,000 Daltons, or approximately 7,000 Daltons to approximately 40,000 Daltons, or approximately 8,000 Daltons to approximately 40,000 Daltons, or approximately 8,500 Daltons to approximately 40,000 Daltons, or approximately 8 ,500 Daltons to approximately 35,000 Daltons, or approximately 9,000 Daltons to approximately 50,000 Daltons, or approximately 9,000 Daltons to approximately 45,000 Daltons, or approximately 9,000 Daltons to approximately 40,000 Daltons, or approximately 9,000 Daltons to approximately 35,000 Daltons, or approximately 9,000 Daltons to approximately 30,000 Daltons, or approximately 9,500 Daltons to approximately 35,000 Daltons, or approximately 9,500 Daltons to approximately 30,000 Daltons, or approximately 10,000 Daltons to approximately 50,000 Daltons, or approximately 10,000 Daltons to approximately 45,000 Daltons, or approximately 10,000 Daltons to approximately 40,000 Daltons, or approximately 10,000 Daltons to approximately 35,000 Daltons, or approximately 10,000 Daltons to approximately 30,000 Daltons, or approximately 15,000 Daltons to approximately 50,000 Daltons, or approximately 15,000 Daltons to approximately 45,000 Daltons, or approximately 15,000 Daltons to approximately 40,000 Daltons, or approximately 15,000 Daltons to approximately 35,000 Daltons, or approximately 15,000 Daltons to approximately 30,000 Daltons, or approximately 20,000 Daltons to approximately 50,000 Daltons, or approximately 20,000 Daltons to approximately 45,000 Daltons, or approximately 20,000 Daltons to approximately 40,000 Daltons, or approximately 20,000 Daltons to approximately 35,000 Daltons.000 Daltons, or about 20,000 Daltons to about 30,000 Daltons. This article describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted 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 an integer of the following: 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. Daltons, approximately 35,000 Daltons, approximately 40,000 Daltons, approximately 45,000 Daltons, approximately 50,000 Daltons, approximately 60,000 Daltons, approximately 70,000 Daltons, approximately 80,000 Daltons, approximately 90,000 Daltons, approximately 100,000 Daltons, approximately 125,000 Daltons, approximately 150,000 Daltons, approximately 175,000 Daltons, or approximately 200,000 Daltons. This document describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted 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 an integer of the following: 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.

[0042] This article describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted with a structure of formula (XII) or (XIII) or a mixture of (XII) and (XIII): Formula (XII) Formula (XIII) Where: n is an integer in the range of about 2 to about 5000; and the wavy line represents a covalent bond with an unsubstituted amino acid residue in SEQ ID NO: 3, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[0043] In some embodiments, the stereochemistry of the antipallic centers in formulas (XII) and (XIII) is racemic, enriched (R), enriched (S), substantially (R), substantially (S), (R), or (S). In some embodiments, the stereochemistry of the antipallic centers in formulas (XII) and (XIII) is racemic. In some embodiments, the stereochemistry of the antipallic centers in formulas (XII) and (XIII) is enriched (R). In some embodiments, the stereochemistry of the antipallic centers in formulas (XII) and (XIII) is enriched (S). In some embodiments, the stereochemistry of the antipallic centers in formulas (XII) and (XIII) is substantially (R). In some embodiments, the stereochemistry of the antipallic centers in formulas (XII) and (XIII) is substantially (S). In some embodiments, the stereochemistry of the antipallic centers in formulas (XII) and (XIII) is (R). In some embodiments, the stereochemistry of the palmar centers in formulas (XII) and (XIII) is (S).

[0044] In some embodiments of the IL-2 conjugates described herein, n in the compounds of formulas (XII) and (XIII) is in the following ranges: 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 formulas (XII) and (XIII) is an integer selected from the following: 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 positions of structures of formulas (XII) and (XIII) or mixtures of formulas (XII) and (XIII) in the amino acid sequence of the IL-2 conjugate are selected from K34, F41, F43, K42, E61, P64, R37, T40, E67, Y44, V68, and L71, wherein the position of structure (I) in the amino acid sequence of the IL-2 conjugate is referenced to the position in SEQ ID NO: 3. In some embodiments of the IL-2 conjugates described herein, the positions of structures of formulas (XII) and (XIII) or mixtures of formulas (XII) and (XIII) in the amino acid sequence of the IL-2 conjugate in SEQ ID NO: 3 are 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 structure of formulas (XII) and (XIII) or a mixture of formulas (XII) and (XIII) is located at position K34 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 formulas (XII) and (XIII) or a mixture of formulas (XII) and (XIII) is located at position F41 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 formulas (XII) and (XIII) or a mixture of formulas (XII) and (XIII) is located at position F43 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 formulas (XII) and (XIII) or a mixture of formulas (XII) and (XIII) 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 formulas (XII) and (XIII) or a mixture of formulas (XII) and (XIII) 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 formulas (XII) and (XIII) or a mixture of formulas (XII) and (XIII) 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 formulas (XII) and (XIII) or a mixture of formulas (XII) and (XIII) 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 formulas (XII) and (XIII) or a mixture of formulas (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 formulas (XII) and (XIII) or a mixture of formulas (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 formulas (XII) and (XIII) or a mixture of formulas (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 formulas (XII) and (XIII) or a mixture of formulas (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 structure of formulas (XII) and (XIII) or a mixture of formulas (XII) and (XIII) is located at position L71 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 ratio of the amount of the structure of formula (XII) comprising the total amount of the IL-2 conjugate to the amount of the structure of formula (XIII) is approximately 1:1. In some embodiments of the IL-2 conjugates described herein, the ratio of the amount of the structure of formula (XII) containing the total amount of the IL-2 conjugate to the amount of the structure of formula (XIII) 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) containing the total amount of the IL-2 conjugate to the amount of the structure of formula (XIII) is less than 1:1.

[0045] In some embodiments, this document describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted with a structure of formula (XII) or (XIII), or a mixture of (XII) and (XIII), wherein the substituted 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 of the following: 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 68 2. 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 1 250, 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 formulas (XII) and (XIII) is an integer selected from the following: 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.

[0046] In some embodiments, this document describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted with a structure of formula (XII) or (XIII), or a mixture of (XII) and (XIII), wherein the substituted 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 formulas (XII) and (XIII) is an integer selected from the following: 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, 1137, and 1249.

[0047] In some embodiments, this document describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted with a structure of formula (XII) or (XIII), or a mixture of (XII) and (XIII), wherein the substituted 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 following: 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910.

[0048] In some embodiments, this document describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted with a structure of formula (XII) or (XIII), or a mixture of (XII) and (XIII), wherein the substituted 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 conjugate described herein, n in the compounds of formula (XII) and (XIII) is an integer selected from the following: 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 approximately 681.

[0049] In some embodiments, this document describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted with a structure of formula (XII) or (XIII), or a mixture of (XII) and (XIII), wherein the substituted 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 conjugate described herein, n in the compounds of formula (XII) and (XIII) is an integer selected from the following: 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 approximately 681.

[0050] This document describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted 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 following ranges: 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. 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. 00 Daltons, or approximately 8,500 Daltons to approximately 35,000 Daltons, or approximately 9,000 Daltons to approximately 50,000 Daltons, or approximately 9,000 Daltons to approximately 45,000 Daltons, or approximately 9,000 Daltons to approximately 40,000 Daltons, or approximately 9,000 Daltons to approximately 35,000 Daltons, or approximately 9,000 Daltons to approximately 30,000 Daltons, or approximately 9,500 Daltons to approximately 35,000 Daltons, or approximately 9,500 Daltons to approximately 30,000 Daltons, or approximately 10,000 Daltons to approximately 50,000 Daltons, or approximately 10,000 Daltons to approximately 45,000 Daltons, or approximately 10,000 Daltons to approximately 40,000 Daltons. ,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 40,000 Daltons, or about 20,000 Daltons to about 40,000 Daltons, or about 20,000 Daltons to about 40,000 Daltons, or about 20,000 Daltons to about 45 ...From about 35,000 Daltons to about 20,000 Daltons, or from about 20,000 Daltons to about 30,000 Daltons. This document describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted 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 an integer of the following: 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 30,000 Daltons. ,000 Daltons, approximately 35,000 Daltons, approximately 40,000 Daltons, approximately 45,000 Daltons, approximately 50,000 Daltons, approximately 60,000 Daltons, approximately 70,000 Daltons, approximately 80,000 Daltons, approximately 90,000 Daltons, approximately 100,000 Daltons, approximately 125,000 Daltons, approximately 150,000 Daltons, approximately 175,000 Daltons, or approximately 200,000 Daltons. This document describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted 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 an integer of the following: 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.

[0051] This article describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted with a structure of formula (XIV) or (XV) or a mixture of (XIV) and (XV): Formula (XIV) Formula (XV) where: m is an integer from 0 to 20; p is an integer from 0 to 20; n is an integer in the range of about 2 to about 5000; and the wavy line represents a covalent bond with an unsubstituted amino acid residue in SEQ ID NO: 3, or a pharmaceutically acceptable salt, solvate or hydrate thereof.

[0052] In some embodiments, the stereochemistry of the antipallic centers in formulas (XIV) and (XV) is racemic, enriched (R), enriched (S), substantially (R), substantially (S), (R), or (S). In some embodiments, the stereochemistry of the antipallic centers in formulas (XIV) and (XV) is racemic. In some embodiments, the stereochemistry of the antipallic centers in formulas (XIV) and (XV) is enriched (R). In some embodiments, the stereochemistry of the antipallic centers in formulas (XIV) and (XV) is enriched (S). In some embodiments, the stereochemistry of the antipallic centers in formulas (XIV) and (XV) is substantially (R). In some embodiments, the stereochemistry of the antipallic centers in formulas (XIV) and (XV) is substantially (S). In some embodiments, the stereochemistry of the antipallic centers in formulas (XIV) and (XV) is (R). In some embodiments, the stereochemistry of the palmar centers in formulas (XIV) and (XV) is (S).

[0053] In some embodiments of the IL-2 conjugates described herein, m in the compounds of formulas (XIV) and (XV) is 0 to 20, or 0 to 18, or 0 to 16, or 0 to 14, or 0 to 12, or 0 to 10, or 0 to 9, or 0 to 8, or 0 to 7, or 0 to 6, or 0 to 5, or 0 to 4, or 0 to 3, or 0 to 2. In some embodiments of the IL-2 conjugates described herein, m in the compounds of formulas (XIV) and (XV) is 0. In some embodiments of the IL-2 conjugates described herein, m in the compounds of formulas (XIV) and (XV) is 1. In some embodiments of the IL-2 conjugates described herein, m in the compounds of formulas (XIV) and (XV) is 2. In some embodiments of the IL-2 conjugates described herein, m in the compounds of formulas (XIV) and (XV) is 3. In some embodiments of the IL-2 conjugates described herein, m is 4 in compounds of formulas (XIV) and (XV). In some embodiments of the IL-2 conjugates described herein, m is 5 in compounds of formulas (XIV) and (XV). In some embodiments of the IL-2 conjugates described herein, m is 6 in compounds of formulas (XIV) and (XV). In some embodiments of the IL-2 conjugates described herein, m is 7 in compounds of formulas (XIV) and (XV). In some embodiments of the IL-2 conjugates described herein, m is 8 in compounds of formulas (XIV) and (XV). In some embodiments of the IL-2 conjugates described herein, m is 9 in compounds of formulas (XIV) and (XV). In some embodiments of the IL-2 conjugates described herein, m is 10 in compounds of formulas (XIV) and (XV). In some embodiments of the IL-2 conjugates described herein, m is 11 in compounds of formulas (XIV) and (XV). In some embodiments of the IL-2 conjugates described herein, m in compounds of formulas (XIV) and (XV) is 12. In some embodiments of the IL-2 conjugates described herein, m in compounds of formulas (XIV) and (XV) is 13. In some embodiments of the IL-2 conjugates described herein, m in compounds of formulas (XIV) and (XV) is 14. In some embodiments of the IL-2 conjugates described herein, m in compounds of formulas (XIV) and (XV) is 15. In some embodiments of the IL-2 conjugates described herein, m in compounds of formulas (XIV) and (XV) is 16. In some embodiments of the IL-2 conjugates described herein, m in compounds of formulas (XIV) and (XV) is 17. In some embodiments of the IL-2 conjugates described herein, m in compounds of formulas (XIV) and (XV) is 18. In some embodiments of the IL-2 conjugates described herein, m in the compounds of formulas (XIV) and (XV) is 19.In some embodiments of the IL-2 conjugates described herein, m in compounds of formulas (XIV) and (XV) is 20.

[0054] In some embodiments of the IL-2 conjugates described herein, p in the compounds of formulas (XIV) and (XV) is 0 to 20, or 0 to 18, or 0 to 16, or 0 to 14, or 0 to 12, or 0 to 10, or 0 to 9, or 0 to 8, or 0 to 7, or 0 to 6, or 0 to 5, or 0 to 4, or 0 to 3, or 0 to 2. In some embodiments of the IL-2 conjugates described herein, p in the compounds of formulas (XIV) and (XV) is 0. In some embodiments of the IL-2 conjugates described herein, p in the compounds of formulas (XIV) and (XV) is 1. In some embodiments of the IL-2 conjugates described herein, p in the compounds of formulas (XIV) and (XV) is 2. In some embodiments of the IL-2 conjugates described herein, p in the compounds of formulas (XIV) and (XV) is 3. In some embodiments of the IL-2 conjugates described herein, p is 4 in compounds of formulas (XIV) and (XV). In some embodiments of the IL-2 conjugates described herein, p is 5 in compounds of formulas (XIV) and (XV). In some embodiments of the IL-2 conjugates described herein, p is 6 in compounds of formulas (XIV) and (XV). In some embodiments of the IL-2 conjugates described herein, p is 7 in compounds of formulas (XIV) and (XV). In some embodiments of the IL-2 conjugates described herein, p is 8 in compounds of formulas (XIV) and (XV). In some embodiments of the IL-2 conjugates described herein, p is 9 in compounds of formulas (XIV) and (XV). In some embodiments of the IL-2 conjugates described herein, p is 10 in compounds of formulas (XIV) and (XV). In some embodiments of the IL-2 conjugates described herein, p is 11 in compounds of formulas (XIV) and (XV). In some embodiments of the IL-2 conjugates described herein, p is 12 in compounds of formulas (XIV) and (XV). In some embodiments of the IL-2 conjugates described herein, p is 13 in compounds of formulas (XIV) and (XV). In some embodiments of the IL-2 conjugates described herein, p is 14 in compounds of formulas (XIV) and (XV). In some embodiments of the IL-2 conjugates described herein, p is 15 in compounds of formulas (XIV) and (XV). In some embodiments of the IL-2 conjugates described herein, m is 16 in compounds of formulas (XIV) and (XV). In some embodiments of the IL-2 conjugates described herein, p is 17 in compounds of formulas (XIV) and (XV). In some embodiments of the IL-2 conjugates described herein, p is 18 in compounds of formulas (XIV) and (XV). In some embodiments of the IL-2 conjugates described herein, p is 19 in compounds of formulas (XIV) and (XV).In some embodiments of the IL-2 conjugates described herein, p is 20 in compounds of formulas (XIV) and (XV).

[0055] In some embodiments of the IL-2 conjugates described herein, n in the compounds of formulas (XIV) and (XV) is in the following ranges: 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 175 0, 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.

[0056] In some embodiments of the IL-2 conjugates described herein in compounds of formulas (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 following: 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 formulas (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 following: 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 formulas (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 following: 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 formulas (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 following: 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 formulas (XIV) and (XV), m is 1, p is 2, and n is an integer selected from the following: 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 formulas (XIV) and (XV), m is 2, p is 2, and n is an integer selected from the following: 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 formulas (XIV) and (XV), m is 3, p is 2, and n is an integer selected from the following: 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 formulas (XIV) and (XV), m is 4, p is 2, and n is an integer selected from the following: 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 formulas (XIV) and (XV), m is 5, p is 2, and n is an integer selected from the following: 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 formulas (XIV) and (XV), m is 6, p is 2, and n is an integer selected from the following: 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 formulas (XIV) and (XV), m is 7, p is 2, and n is an integer selected from the following: 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 formulas (XIV) and (XV), m is 8, p is 2, and n is an integer selected from the following: 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 formulas (XIV) and (XV), m is 9, p is 2, and n is an integer selected from the following: 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 formulas (XIV) and (XV), m is 10, p is 2, and n is an integer selected from the following: 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 formulas (XIV) and (XV), m is 11, p is 2, and n is an integer selected from the following: 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 formulas (XIV) and (XV), m is 11, p is 2, and n is an integer selected from the following: 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 formulas (XIV) and (XV), m is 2, p is 2, and n is an integer selected from the following: 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137.

[0057] In some embodiments of the IL-2 conjugates described herein, n in compounds of formulas (XIV) and (XV) is an integer selected from the following: 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, 13 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 positions of structures of formulas (XIV) and (XV) or mixtures of formulas (XIV) and (XV) in the amino acid sequence of the IL-2 conjugate are selected from K34, F41, F43, K42, E61, P64, R37, T40, E67, Y44, V68, and L71, wherein the position of structure (I) in the amino acid sequence of the IL-2 conjugate is referenced to the position in SEQ ID NO: 3. In some embodiments of the IL-2 conjugates described herein, the positions of structures of formulas (XIV) and (XV) or mixtures of formulas (XIV) and (XV) in the amino acid sequence of the IL-2 conjugate in SEQ ID NO: 3 are 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 structure of formulas (XIV) and (XV) or a mixture of formulas (XIV) and (XV) is located at position K34 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 formulas (XIV) and (XV) or a mixture of formulas (XIV) and (XV) is located at position F41 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 formulas (XIV) and (XV) or a mixture of formulas (XIV) and (XV) is located at position F43 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 formulas (XIV) and (XV) or a mixture of formulas (XIV) and (XV) 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 formulas (XIV) and (XV) or a mixture of formulas (XIV) and (XV) 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 formulas (XIV) and (XV) or a mixture of formulas (XIV) and (XV) 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 formulas (XIV) and (XV) or a mixture of formulas (XIV) and (XV) 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 formulas (XIV) and (XV) or a mixture of formulas (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 formulas (XIV) and (XV) or a mixture of formulas (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 formulas (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 formulas (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 structure of formula (XIV) and (XV) or a mixture of formulas (XIV) and (XV) is located at position L71 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 ratio of the amount of the structure of formula (XIV) comprising the total amount of the IL-2 conjugate to the amount of the structure of formula (XV) is approximately 1:1. In some embodiments of the IL-2 conjugates described herein, the ratio of the amount of the structure of formula (XIV) containing the total amount of the IL-2 conjugate to the amount of the structure of formula (XV) 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) containing the total amount of IL-2 conjugate to the amount of the structure of formula (XV) is less than 1:1.

[0058] In some embodiments, this document describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted with a structure of formula (XIV) or (XV), or a mixture of (XIV) and (XV), wherein the substituted 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 of the following: 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 68 2. 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 1 250, 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 compounds of formulas (XIV) and (XV) is an integer selected from the following: 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, 13 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.

[0059] In some embodiments, this document describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted with a structure of formula (XIV) or (XV), or a mixture of (XIV) and (XV), wherein the substituted 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 formulas (XIV) and (XV) is an integer selected from the following: 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, 1137, and 1249.

[0060] In some embodiments, this document describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted with a structure of formula (XIV) or (XV), or a mixture of (XIV) and (XV), wherein the substituted 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 following: 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910.

[0061] In some embodiments, this document describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted with a structure of formula (XIV) or (XV), or a mixture of (XIV) and (XV), wherein the substituted 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 conjugate described herein, n in the compounds of formula (XIV) and (XV) is an integer selected from the following: 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 approximately 681.

[0062] In some embodiments, this document describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted with a structure of formula (XIV) or (XV), or a mixture of (XIV) and (XV), wherein the substituted amino acid residue in SEQ ID NO: 3 is P64, and wherein n is an integer from about 450 to about 800, or about 454 to about 796, or about 454 to about 682, or 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 following: 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 approximately 681.

[0063] This document describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted 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 following ranges: 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. or approximately 8,000 Daltons to approximately 70,000 Daltons, or approximately 5,000 Daltons to approximately 70,000 Daltons, or approximately 5,000 Daltons to approximately 65,000 Daltons, or approximately 5,000 Daltons to approximately 60,000 Daltons, or approximately 5,000 Daltons to approximately 50,000 Daltons, or approximately 6,000 Daltons to approximately 50,000 Daltons, or approximately 7,000 Daltons to approximately 50,000 Daltons, or approximately 7,000 Daltons to approximately 45,000 Daltons, or approximately 7,000 Daltons to approximately 40,000 Daltons, or approximately 8,000 Daltons to approximately 40,000 Daltons, or approximately 8,500 Daltons to approximately 40,000 Daltons, or Approximately 8,500 Daltons to approximately 35,000 Daltons, or approximately 9,000 Daltons to approximately 50,000 Daltons, or approximately 9,000 Daltons to approximately 45,000 Daltons, or approximately 9,000 Daltons to approximately 40,000 Daltons, or approximately 9,000 Daltons to approximately 35,000 Daltons, or approximately 9,000 Daltons to approximately 30,000 Daltons, or approximately 9,500 Daltons to approximately 35,000 Daltons, or approximately 9,500 Daltons to approximately 30,000 Daltons, or approximately 10,000 Daltons to approximately 50,000 Daltons, or approximately 10,000 Daltons to approximately 45,000 Daltons, or approximately 10,000 Daltons to approximately 40,000 Daltons, or Approximately 10,000 Daltons to approximately 35,000 Daltons, or approximately 10,000 Daltons to approximately 30,000 Daltons, or approximately 15,000 Daltons to approximately 50,000 Daltons, or approximately 15,000 Daltons to approximately 45,000 Daltons, or approximately 15,000 Daltons to approximately 40,000 Daltons, or approximately 15,000 Daltons to approximately 35,000 Daltons, or approximately 15,000 Daltons to approximately 30,000 Daltons, or approximately 20,000 Daltons to approximately 50,000 Daltons, or approximately 20,000 Daltons to approximately 45,000 Daltons, or approximately 20,000 Daltons to approximately 40,000 Daltons, or approximately 20,000 Daltons to approximately 35,000 Daltons.000 Daltons, or about 20,000 Daltons to about 30,000 Daltons. This article describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted 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 an integer of the following: 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 20,000 Daltons to about 30,000 Daltons. 00 Daltons, approximately 35,000 Daltons, approximately 40,000 Daltons, approximately 45,000 Daltons, approximately 50,000 Daltons, approximately 60,000 Daltons, approximately 70,000 Daltons, approximately 80,000 Daltons, approximately 90,000 Daltons, approximately 100,000 Daltons, approximately 125,000 Daltons, approximately 150,000 Daltons, approximately 175,000 Daltons, or approximately 200,000 Daltons. This document describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted 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 an integer of the following: 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.

[0064] In some embodiments, this document describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted with a structure of formula (XIV) or (XV), or a mixture of (XIV) and (XV), wherein the substituted 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 of about 450 to about 800, or about 454 to about 796, or about 454 to about 682, or about 568 to about 909. In some embodiments of the IL-2 conjugates described herein in compounds of formulas (XIV) and (XV), m is 2, p is 2, and n is an integer selected from the following: 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, 1137, and 1249.

[0065] In some embodiments, this document describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted with a structure of formula (XIV) or (XV), or a mixture of (XIV) and (XV), wherein the substituted 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 selected from about 450 to about 800, or about 454 to about 796, or about 454 to about 682, or about 568 to about 909. In some embodiments of the IL-2 conjugate described herein in compounds of formula (XIV) and (XV), m is 2, p is 2, and n is an integer selected from the following: 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910.

[0066] In some embodiments, this document describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted with a structure of formula (XIV) or (XV), or a mixture of (XIV) and (XV), wherein the substituted 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 of about 450 to about 800, or about 454 to about 796, or about 454 to about 682, or about 568 to about 909. In some embodiments of the IL-2 conjugate described herein in compounds of formula (XIV) and (XV), m is 2, p is 2, and n is an integer selected from the following: 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910. In some embodiments, n is about 500 to about 1000. In some embodiments, n is about 550 to about 800. In some embodiments, n is about 681.

[0067] In some embodiments, this document describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted with a structure of formula (XIV) or (XV), or a mixture of (XIV) and (XV), wherein the substituted 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 of about 450 to about 800, or about 454 to about 796, or about 454 to about 682, or about 568 to about 909. In some embodiments of the IL-2 conjugate described herein in compounds of formula (XIV) and (XV), m is 2, p is 2, and n is an integer selected from the following: 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910. In some embodiments, n is about 500 to about 1000. In some embodiments, n is about 550 to about 800. In some embodiments, n is about 681.

[0068] This article describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted with a structure of formula (XVI) or (XVII) or a mixture of (XVI) and (XVII): Formula (XVI) Formula (XVII) Where: m is an integer from 0 to 20; n is an integer in the range of about 2 to about 5000; and the wavy line represents a covalent bond with an unsubstituted amino acid residue in SEQ ID NO: 3, or a medically acceptable salt, solvate or hydrate thereof.

[0069] In some embodiments, the stereochemistry of the antipallic centers in formulas (XVI) and (XVII) is racemic, enriched (R), enriched (S), substantially (R), substantially (S), (R), or (S). In some embodiments, the stereochemistry of the antipallic centers in formulas (XVI) and (XVII) is racemic. In some embodiments, the stereochemistry of the antipallic centers in formulas (XVI) and (XVII) is enriched (R). In some embodiments, the stereochemistry of the antipallic centers in formulas (XVI) and (XVII) is enriched (S). In some embodiments, the stereochemistry of the antipallic centers in formulas (XVI) and (XVII) is substantially (R). In some embodiments, the stereochemistry of the antipallic centers in formulas (XVI) and (XVII) is substantially (S). In some embodiments, the stereochemistry of the antipallic centers in formulas (XVI) and (XVII) is (R). In some embodiments, the stereochemistry of the palmar centers in formulas (XVI) and (XVII) is (S).

[0070] In some embodiments of the IL-2 conjugates described herein, m in the compounds of formulas (XVI) and (XVII) is 0 to 20, or 0 to 18, or 0 to 16, or 0 to 14, or 0 to 12, or 0 to 10, or 0 to 9, or 0 to 8, or 0 to 7, or 0 to 6, or 0 to 5, or 0 to 4, or 0 to 3, or 0 to 2. In some embodiments of the IL-2 conjugates described herein, m in the compounds of formulas (XVI) and (XVII) is 0. In some embodiments of the IL-2 conjugates described herein, m in the compounds of formulas (XVI) and (XVII) is 1. In some embodiments of the IL-2 conjugates described herein, m in the compounds of formulas (XVI) and (XVII) is 2. In some embodiments of the IL-2 conjugates described herein, m in the compounds of formulas (XVI) and (XVII) is 3. In some embodiments of the IL-2 conjugates described herein, m is 4 in compounds of formulas (XVI) and (XVII). In some embodiments of the IL-2 conjugates described herein, m is 5 in compounds of formulas (XVI) and (XVII). In some embodiments of the IL-2 conjugates described herein, m is 6 in compounds of formulas (XVI) and (XVII). In some embodiments of the IL-2 conjugates described herein, m is 7 in compounds of formulas (XVI) and (XVII). In some embodiments of the IL-2 conjugates described herein, m is 8 in compounds of formulas (XVI) and (XVII). In some embodiments of the IL-2 conjugates described herein, m is 9 in compounds of formulas (XVI) and (XVII). In some embodiments of the IL-2 conjugates described herein, m is 10 in compounds of formulas (XVI) and (XVII). In some embodiments of the IL-2 conjugates described herein, m is 11 in compounds of formulas (XVI) and (XVII). In some embodiments of the IL-2 conjugates described herein, m in compounds of formulas (XVI) and (XVII) is 12. In some embodiments of the IL-2 conjugates described herein, m in compounds of formulas (XVI) and (XVII) is 13. In some embodiments of the IL-2 conjugates described herein, m in compounds of formulas (XVI) and (XVII) is 14. In some embodiments of the IL-2 conjugates described herein, m in compounds of formulas (XVI) and (XVII) is 15. In some embodiments of the IL-2 conjugates described herein, m in compounds of formulas (XVI) and (XVII) is 16. In some embodiments of the IL-2 conjugates described herein, m in compounds of formulas (XVI) and (XVII) is 17. In some embodiments of the IL-2 conjugates described herein, m in compounds of formulas (XVI) and (XVII) is 18.In some embodiments of the IL-2 conjugates described herein, m is 19 in compounds of formulas (XVI) and (XVII). In some embodiments of the IL-2 conjugates described herein, m is 20 in compounds of formulas (XVI) and (XVII).

[0071] In some embodiments of the IL-2 conjugates described herein, n in the compounds of formulas (XVI) and (XVII) is in the following ranges: 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.

[0072] In some embodiments of the IL-2 conjugates described herein in the compounds of formulas (XVI) and (XVII), m is an integer from 0 to 6, and n is an integer selected from the following: 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 formulas (XVI) and (XVII), m is an integer from 1 to 6, and n is an integer selected from the following: 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 formulas (XVI) and (XVII), m is an integer from 2 to 6, and n is an integer selected from the following: 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 formulas (XVI) and (XVII), m is an integer from 2 to 4, and n is an integer selected from the following: 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 formulas (XVI) and (XVII), m is 1, and n is an integer selected from the following: 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 formulas (XVI) and (XVII), m is 2, and n is an integer selected from the following: 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 formulas (XVI) and (XVII), m is 3, and n is an integer selected from the following: 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 formulas (XVI) and (XVII), m is 4, and n is an integer selected from the following: 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 formulas (XVI) and (XVII), m is 5, and n is an integer selected from the following: 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 formulas (XVI) and (XVII), m is 6, and n is an integer selected from the following: 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 formulas (XVI) and (XVII), m is 7, and n is an integer selected from the following: 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 formulas (XVI) and (XVII), m is 8, and n is an integer selected from the following: 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 formulas (XVI) and (XVII), m is 9, and n is an integer selected from the following: 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 formulas (XVI) and (XVII), m is 10, and n is an integer selected from the following: 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 formulas (XVI) and (XVII), m is 11, and n is an integer selected from the following: 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 formulas (XVI) and (XVII), m is 12, and n is an integer selected from the following: 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 formulas (XVI) and (XVII), m is 2, and n is an integer selected from the following: 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137.

[0073] In some embodiments of the IL-2 conjugates described herein, n in the compounds of formulas (XVI) and (XVII) is an integer selected from the following: 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 positions of structures of formulas (XVI) and (XVII) or mixtures of formulas (XVI) and (XVII) in the amino acid sequence of the IL-2 conjugate are selected from K34, F41, F43, K42, E61, P64, R37, T40, E67, Y44, V68, and L71, wherein the position of structure (I) in the amino acid sequence of the IL-2 conjugate is referenced to the position in SEQ ID NO: 3. In some embodiments of the IL-2 conjugates described herein, the positions of structures of formulas (XVI) and (XVII) or mixtures of formulas (XVI) and (XVII) in the amino acid sequence of the IL-2 conjugate in SEQ ID NO: 3 are 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 structure of formulas (XVI) and (XVII) or a mixture of formulas (XVI) and (XVII) is located at position K34 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 formulas (XVI) and (XVII) or a mixture of formulas (XVI) and (XVII) is located at position F41 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 formulas (XVI) and (XVII) or a mixture of formulas (XVI) and (XVII) is located at position F43 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 formulas (XVI) and (XVII) or a mixture of formulas (XVI) and (XVII) 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 formulas (XVI) and (XVII) or a mixture of formulas (XVI) and (XVII) 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 formulas (XVI) and (XVII) or a mixture of formulas (XVI) and (XVII) 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 formulas (XVI) and (XVII) or a mixture of formulas (XVI) and (XVII) 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 formulas (XVI) and (XVII) or a mixture of formulas (XVI) and (XVII) 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 formulas (XVI) and (XVII) or a mixture of formulas (XVI) and (XVII) 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 formulas (XVI) and (XVII) or a mixture of formulas (XVI) and (XVII) 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 formulas (XVI) and (XVII) or a mixture of formulas (XVI) and (XVII) 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 structure of formulas (XVI) and (XVII) or a mixture of formulas (XVI) and (XVII) is located at position L71 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 ratio of the amount of the structure of formula (XVI) to the amount of the structure of formula (XVII) comprising the total amount of the IL-2 conjugate is approximately 1:1. In some embodiments of the IL-2 conjugates described herein, the ratio of the amount of the structure of formula (XVI) containing the total amount of the IL-2 conjugate to the amount of the structure of formula (XVII) 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) containing the total amount of the IL-2 conjugate to the amount of the structure of formula (XVII) is less than 1:1.

[0074] In some embodiments, this document describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted with a structure of formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), wherein the substituted 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 of the following: 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 68 2. 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 1 250, 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 formulas (XVI) and (XVII) is an integer selected from the following: 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.

[0075] In some embodiments, this document describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted with a structure of formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), wherein the substituted 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 formulas (XVI) and (XVII) is an integer selected from the following: 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, 1137, and 1249.

[0076] In some embodiments, this document describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted with a structure of formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), wherein the substituted 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 formulas (XVI) and (XVII) is an integer selected from the following: 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910.

[0077] In some embodiments, this document describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted with a structure of formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), wherein the substituted 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 conjugate described herein, n in the compounds of formulas (XVI) and (XVII) is an integer selected from the following: 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 approximately 681.

[0078] In some embodiments, this document describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted with a structure of formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), wherein the substituted 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 conjugate described herein, n in the compounds of formulas (XVI) and (XVII) is an integer selected from the following: 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 approximately 681.

[0079] This document describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted 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 following ranges: 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. 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. 00 Daltons, or approximately 8,500 Daltons to approximately 35,000 Daltons, or approximately 9,000 Daltons to approximately 50,000 Daltons, or approximately 9,000 Daltons to approximately 45,000 Daltons, or approximately 9,000 Daltons to approximately 40,000 Daltons, or approximately 9,000 Daltons to approximately 35,000 Daltons, or approximately 9,000 Daltons to approximately 30,000 Daltons, or approximately 9,500 Daltons to approximately 35,000 Daltons, or approximately 9,500 Daltons to approximately 30,000 Daltons, or approximately 10,000 Daltons to approximately 50,000 Daltons, or approximately 10,000 Daltons to approximately 45,000 Daltons, or approximately 10,000 Daltons to approximately 40,000 Daltons. ,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 40,000 Daltons, or about 20,000 Daltons to about 40,000 Daltons, or about 20,000 Daltons to about 40,000 Daltons, or about 20,000 Daltons to about 45 ...From about 1,000 Daltons to about 35,000 Daltons, or from about 20,000 Daltons to about 30,000 Daltons. This document describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted 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 an integer of the following: 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 30,000 Daltons. ,000 Daltons, approximately 35,000 Daltons, approximately 40,000 Daltons, approximately 45,000 Daltons, approximately 50,000 Daltons, approximately 60,000 Daltons, approximately 70,000 Daltons, approximately 80,000 Daltons, approximately 90,000 Daltons, approximately 100,000 Daltons, approximately 125,000 Daltons, approximately 150,000 Daltons, approximately 175,000 Daltons, or approximately 200,000 Daltons. This document describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted 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 an integer of the following: 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.

[0080] In some embodiments, this document describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted with a structure of formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), wherein the substituted 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 of about 450 to about 800, or about 454 to about 796, or about 454 to about 682, or about 568 to about 909. In some embodiments of the IL-2 conjugates described herein in the compounds of formulas (XVI) and (XVII), m is 2, and n is an integer selected from the following: 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, 1137, and 1249.

[0081] In some embodiments, this document describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted with a structure of formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), wherein the substituted 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 selected from: about 450 to about 800, or about 454 to about 796, or about 454 to about 682, or about 568 to about 909. In some embodiments of the IL-2 conjugate described herein in compounds of formulas (XVI) and (XVII), m is 2, and n is an integer selected from: 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910.

[0082] In some embodiments, this document describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted with a structure of formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), wherein the substituted 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 selected from: about 450 to about 800, or about 454 to about 796, or about 454 to about 682, or about 568 to about 909. In some embodiments of the IL-2 conjugates described herein in compounds of formulas (XVI) and (XVII), m is 2, and n is an integer selected from: 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910. In some embodiments, n is about 500 to about 1000. In some embodiments, n is about 550 to about 800. In some embodiments, n is about 681.

[0083] In some embodiments, this document describes an IL-2 conjugate comprising the amino acid sequence SEQ ID NO: 3, wherein at least one amino acid residue in the IL-2 conjugate is substituted with a structure of formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), wherein the substituted 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 selected from: about 450 to about 800, or about 454 to about 796, or about 454 to about 682, or about 568 to about 909. In some embodiments of the IL-2 conjugates described herein in compounds of formulas (XVI) and (XVII), m is 2, and n is an integer selected from: 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910. In some embodiments, n is about 500 to about 1000. In some embodiments, n is about 550 to about 800. In some embodiments, n is about 681.

[0084] This article describes a pharmaceutical composition comprising an effective amount of the IL-2 conjugate described herein and one or more pharmaceutically acceptable excipients.

[0085] This article describes a method for treating cancer in an individual, comprising administering an effective amount of the IL-2 conjugate described herein to an individual in need. In some embodiments of the method for treating cancer described herein, the individual'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 cancer, microsatellite stable cancer, gastric cancer, cervical cancer, hepatocellular carcinoma (HCC), Merkel cell carcinoma (MCC), melanoma, small cell lung cancer (SCLC), esophageal cancer, and glioblastoma. Cellular tumors, mesotheliomas, breast cancer, triple-negative breast cancer, prostate cancer, castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, metastatic castration-resistant prostate cancer with DNA damage response (DDR) deficiency, bladder cancer, ovarian cancer, tumors with moderate to low mutation burden, squamous cell carcinoma of the skin (CSCC), squamous cell skin carcinoma (SCSC), tumors with low to no PD-L1 expression, tumors that have spread systemically to the liver and beyond the primary anatomical origin of the CNS, and diffuse large B-cell lymphoma. This article describes a method of treating an individual's cancer, comprising administering an effective amount of the IL-2 conjugate described herein to an individual in need. In some embodiments of the method of treating the cancer described herein, the individual's cancer is cholangiocarcinoma. In some embodiments of the method of treating cancer described herein, the individual's cancer is selected from renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), urothelial carcinoma, and melanoma. In some embodiments of the methods for treating cancer described herein, individuals in need are administered IL-2 conjugates once every two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, or eight weeks. In some embodiments of the methods for treating cancer described herein, individuals in need are administered IL-2 conjugates once a week or every two weeks. In some embodiments of the methods for treating cancer described herein, individuals in need are administered IL-2 conjugates once a week. In some embodiments of the methods for treating cancer described herein, individuals in need are administered IL-2 conjugates once every two weeks. In some embodiments of the methods for treating cancer described herein, administration of an effective amount of IL-2 conjugates to an individual does not cause vascular leakage syndrome in the individual. In some embodiments of the methods for treating cancer described herein, administration of an effective amount of IL-2 conjugates to an individual does not cause grade 2, 3, or 4 vascular leakage syndrome in the individual. In some embodiments of the methods for treating cancer described herein, administration of an effective amount of the IL-2 conjugate to an individual does not induce grade 2 vascular leakage syndrome in that individual. In some embodiments of the methods for treating cancer described herein, administration of an effective amount of the IL-2 conjugate to an individual does not induce grade 3 vascular leakage syndrome in that individual.In some embodiments of the methods for treating cancer described herein, administration of an effective amount of IL-2 conjugate to an individual does not induce grade 4 vascular leakage syndrome. In some embodiments of the methods for treating cancer described herein, administration of an effective amount of IL-2 conjugate to an individual does not induce loss of vascular tone. In some embodiments of the methods for treating cancer described herein, administration of an effective amount of IL-2 conjugate to an individual does not induce extravasation of plasma proteins and fluids into the extravascular space. In some embodiments of the methods for treating cancer described herein, administration of an effective amount of IL-2 conjugate to an individual does not induce hypotension or decreased organ perfusion. In some embodiments of the methods for treating cancer described herein, administration of an effective amount of IL-2 conjugate to an individual does not induce decreased neutrophil function. In some embodiments of the methods for treating cancer described herein, administration of an effective amount of IL-2 conjugate to an individual does not induce decreased chemotaxis. In some embodiments of the methods for treating cancer described herein, administration of an effective amount of IL-2 conjugate to an individual is not associated with an increased risk of disseminated infection. In some embodiments of the methods for treating cancer described herein, the disseminated infection is sepsis or bacterial endocarditis. In some embodiments of the methods for treating cancer described herein, the disseminated infection is sepsis. In some embodiments of the methods for treating cancer described herein, the disseminated infection is bacterial endocarditis. In some embodiments of the methods for treating cancer described herein, any pre-existing bacterial infection in the individual is treated before administration of the IL-2 conjugate. In some embodiments of the methods for treating cancer described herein, the individual is treated with an antibacterial agent selected from oxacillin, nafcillin, ciprofloxacin, and vancomycin before administration of the IL-2 conjugate. In some embodiments of the methods for treating cancer described herein, administration of an effective amount of the IL-2 conjugate to the individual does not exacerbate any pre-existing or initial manifestations of autoimmune disease or inflammatory conditions in the individual. In some embodiments of the methods for treating cancer described herein, administration of an effective amount of IL-2 conjugate to an individual does not exacerbate the pre-existing or initial manifestations of an individual's autoimmune disease. In some embodiments of the methods for treating cancer described herein, administration of an effective amount of IL-2 conjugate to an individual does not exacerbate the pre-existing or initial manifestations of an individual's inflammatory condition. In some embodiments of the methods for treating cancer described herein, the individual's autoimmune disease or inflammatory condition 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 for treating cancer described herein, the individual's autoimmune disease or inflammatory condition is Crohn's disease. In some embodiments of the methods for treating cancer described herein, the individual's autoimmune disease or inflammatory condition is scleroderma. In some embodiments of the methods for treating cancer described herein, the individual's autoimmune disease or inflammatory condition is thyroiditis. In some embodiments of the methods for treating cancer described herein, the individual's autoimmune disease or inflammatory condition is inflammatory arthritis. In some embodiments of the methods for treating cancer described herein, the individual's autoimmune disease or inflammatory condition is diabetes. In some embodiments of the methods for treating cancer described herein, the individual's autoimmune disease or inflammatory condition is ocular myasthenia gravis. In some embodiments of the methods for treating cancer described herein, the individual's autoimmune disease or inflammatory condition is crescentic IgA glomerulonephritis. In some embodiments of the methods for treating cancer described herein, the individual's autoimmune disease or inflammatory condition is cholecystitis. In some embodiments of the methods for treating cancer described herein, the individual's autoimmune disease or inflammatory condition is cerebral vasculitis. In some embodiments of the methods for treating cancer described herein, the individual's autoimmune disease or inflammatory condition is Stephens-Johnson syndrome. In some embodiments of the methods for treating cancer described herein, the individual's autoimmune disease or inflammatory condition is bullous pemphigoid. In some embodiments of the methods for treating cancer described herein, administration of an effective amount of IL-2 conjugate to the individual does not cause changes in the individual's mental state, speech difficulties, cortical blindness, limb or gait incoordination, hallucinations, agitation, slowed reflexes, or coma. In some embodiments of the methods for treating cancer described herein, administration of an effective amount of IL-2 conjugate to the individual does not cause epilepsy. In some embodiments of the methods for treating cancer described herein, administration of an effective amount of IL-2 conjugate to the individual is not prohibited in individuals with known epilepsy. In some embodiments of the methods for treating cancer described herein, administration of an effective amount of IL-2 conjugate to the individual does not cause capillary leakage syndrome. In some embodiments of the methods for treating cancer described herein, administration of an effective amount of IL-2 conjugate to an individual does not induce grade 2, 3, or 4 capillary leakage syndrome in that individual. In some embodiments of the methods for treating cancer described herein, administration of an effective amount of IL-2 conjugate to an individual does not induce grade 2 capillary leakage syndrome in that individual. In some embodiments of the methods for treating cancer described herein, administration of an effective amount of IL-2 conjugate to an individual does not induce grade 3 capillary leakage syndrome in that individual. In some embodiments of the methods for treating cancer described herein, administration of an effective amount of IL-2 conjugate to an individual does not induce grade 4 capillary leakage syndrome in that individual.In some embodiments of the methods for treating cancer described herein, administration of an effective amount of IL-2 conjugate to an individual does not cause a decrease in the individual's mean arterial blood pressure. In some embodiments of the methods for treating cancer described herein, administration of an effective amount of IL-2 conjugate to an individual does not cause hypotension. In some embodiments of the methods for treating cancer described herein, administration of an effective amount of IL-2 conjugate to an individual does not cause the individual to experience systolic blood pressure below 90 mmHg or a decrease in systolic blood pressure of 20 mmHg from baseline. In some embodiments of the methods for treating cancer described herein, administration of an effective amount of IL-2 conjugate to an individual does not cause edema. In some embodiments of the methods for treating cancer described herein, administration of an effective amount of IL-2 conjugate to an individual does not cause impaired kidney or liver function. In some embodiments of the methods for treating cancer described herein, administration of an effective amount of IL-2 conjugate to an individual does not cause an increase in eosinophil count in the individual after administration of the IL-2 conjugate. In some embodiments of the methods for treating cancer described herein, administration of an effective amount of IL-2 conjugate to an individual does not cause an eosinophil count in the peripheral blood of the individual after administration of the IL-2 conjugate to exceed 500 cells / μl. In some embodiments of the methods for treating cancer described herein, administration of an effective amount of IL-2 conjugate to an individual does not cause an eosinophil count in the peripheral blood of the individual after administration of the IL-2 conjugate to exceed 500 to 1500 cells / μl. In some embodiments of the methods for treating cancer described herein, administration of an effective amount of IL-2 conjugate to an individual does not cause an eosinophil count in the peripheral blood of the individual after administration of the IL-2 conjugate to exceed 1500 to 5000 cells / μl. In some embodiments of the methods for treating cancer described herein, administration of an effective amount of the IL-2 conjugate to an individual does not result in an eosinophil count in the individual's peripheral blood exceeding 5000 cells / μL after administration of the IL-2 conjugate. In some embodiments of the methods for treating cancer described herein, administration of an effective amount of the IL-2 conjugate to an individual under existing psychotropic drug therapy is not prohibited.

[0086] In some embodiments of the methods for treating cancer described herein, administration of an effective amount of IL-2 conjugates is not prohibited in individuals receiving existing therapies for nephrotoxicity, myelotoxicity, cardiotoxicity, or hepatotoxicity. In some embodiments of the methods for treating cancer described herein, administration of an effective amount of IL-2 conjugates is not prohibited in individuals receiving existing therapies for aminoglycosides, cytotoxic chemotherapy, cranberry, methotrexate, or aspartate aminotransferase. In some embodiments of the methods for treating cancer described herein, administration of an effective amount of IL-2 conjugates is not prohibited in individuals receiving a combination regimen containing an antitumor agent. In some embodiments of the methods for treating cancer described herein, the antitumor agent is selected from dacarbazine, cisplatinum, tamoxifen, and interferon-alpha. In some embodiments of the methods for treating cancer described herein, administration of an effective amount of IL-2 conjugates does not cause one or more grade 4 adverse events in the individual following administration of the IL-2 conjugates. In some embodiments of the methods for treating cancer described herein, one or more grade 4 adverse events are selected from: hypothermia; shock; bradycardia; ventricular premature contractions; myocardial ischemia; syncope; hemorrhage; atrial arrhythmia; phlebitis; second-degree AV blockage; endocarditis; pericardial effusion; peripheral gangrene; thrombosis; coronary artery disease; stomatitis; nausea and vomiting; abnormal liver function tests; gastrointestinal bleeding; hematemesis; hemorrhagic diarrhea; gastrointestinal disorders; intestinal perforation; Pancreatitis; anemia; leukopenia; leukocytosis; hypocalcemia; increased alkaline phosphatase; increased blood urea nitrogen (BUN); hyperuricemia; increased non-protein nitrogen (NPN); respiratory acidosis; somnolence; agitation; neurosis; paranoid reactions; convulsions; lacrimal tetany; delirium; asthma; pulmonary edema; hyperventilation; hypoxia; hemoptysis; hypoventilation; pneumothorax; mydriasis; pupillary disorders; renal dysfunction; renal failure; and acute tubular necrosis. In some embodiments of the methods for treating cancer described herein, administration of an effective amount of the IL-2 conjugate to an individual did not cause one or more grade 4 adverse events in more than 1% of individuals following administration of the IL-2 conjugate.In some embodiments of the methods for treating cancer described herein, one or more grade 4 adverse events are selected from: hypothermia; shock; bradycardia; ventricular premature contractions; myocardial ischemia; syncope; hemorrhage; atrial arrhythmia; phlebitis; second-degree AV blockage; endocarditis; pericardial effusion; peripheral gangrene; thrombosis; coronary artery disease; stomatitis; nausea and vomiting; abnormal liver function tests; gastrointestinal bleeding; hematemesis; hemorrhagic diarrhea; gastrointestinal disorders; intestinal perforation; Pancreatitis; anemia; leukopenia; leukocytosis; hypocalcemia; increased alkaline phosphatase; increased blood urea nitrogen (BUN); hyperuricemia; increased non-protein nitrogen (NPN); respiratory acidosis; somnolence; agitation; neurosis; paranoid reactions; convulsions; lacrimal tetany; delirium; asthma; pulmonary edema; hyperventilation; hypoxia; hemoptysis; hypoventilation; pneumothorax; dilated pupils; pupillary disorders; renal dysfunction; renal failure; and acute vascular necrosis. In some embodiments of the methods for treating cancer described herein, administration of an effective amount of the IL-2 conjugate to an individual does not cause one or more adverse events in more than 1% of individuals after administration of the IL-2 conjugate, wherein one or more adverse events are selected from duodenal ulcer; intestinal necrosis; myocarditis; supraventricular tachycardia; permanent or transient blindness secondary to optic neuritis; transient ischemic attack; meningitis; cerebral edema; pericarditis; allergic interstitial nephritis; and tracheoesophageal fistula. In some embodiments of the methods for treating cancer described herein, administration of an effective amount of the IL-2 conjugate to an individual does not cause one or more adverse events in more than 1% of individuals after administration of the IL-2 conjugate, wherein one or more adverse events are selected from malignant hypertension; cardiac arrest; myocardial infarction; pulmonary embolism; stroke; intestinal perforation; liver or kidney failure; suicide due to severe depression; pulmonary edema; respiratory arrest; respiratory failure. In some embodiments of the methods for treating cancer described herein, administering an effective amount of IL-2 conjugate to an individual does not produce neutralizing antibodies against the IL-2 conjugate. In some embodiments of the methods for treating cancer described herein, administering an IL-2 conjugate to an individual increases the number of peripheral CD8+ T and NK cells without increasing the number of peripheral CD4+ regulatory T cells. In some embodiments of the methods for treating cancer described herein, administering an IL-2 conjugate to an individual increases the number of peripheral CD8+ T and NK cells without increasing the number of peripheral eosinophils. In some embodiments of the methods for treating cancer described herein, administering an IL-2 conjugate to an individual increases the number of intratumoral CD8+ T and NK cells without increasing the number of intratumoral CD4+ regulatory T cells. In some embodiments of the methods for treating cancer described herein, administering an effective amount of IL-2 conjugate to an individual does not require intensive care facilities or a skilled specialist in cardiopulmonary or intensive care medicine. In some embodiments of the methods for treating cancer described herein, administering an effective amount of IL-2 conjugate to an individual does not require intensive care facilities.In some embodiments of the cancer treatment methods described herein, administering an effective amount of IL-2 conjugate to an individual does not require a skilled specialist in cardiopulmonary or intensive care medicine. Simple Explanation of the Diagram

[0087] The novel features of this invention are set forth in detail in the appended claims. A better understanding of the features and advantages of this invention will be obtained by referring to the following detailed description of illustrative embodiments utilizing the principles of the invention and their accompanying drawings:

[0088] [picture] [1] Exemplary non-natural amino acids are shown. This figure is adapted from Figure 2 by Young et al., "Beyond the canonical 20 amino acids: expanding the genetic lexicon," J. of Biological Chemistry.

[0285] (15): 11039-11044 (2010).

[0089] [picture] [2A] [To the image] [2B] Explains illustrative non-natural amino acids. [picture] [2A] Explains illustrative lysine derivatives. [picture] [2B] Explanation of illustrative phenylalanine derivatives.

[0090] [picture] [3A] [To the image] [3D] Explains illustrative non-natural amino acids. These non-natural amino acids (UAA) are genetically encoded in proteins. [picture] [3A]-UAA 1-42; [picture] [3B]-UAA 43-89; [picture] [3C]-UAA 90-128; [picture] [3D]-UAA 129-167). Image [3A] [to] [3D] Adapted from Table 1 of Dumas et al., Chemical Science 2015, 6, 50-69.

[0091] [picture] [4A] [To the image] [4C] Surface plasma resonance (SPR) analysis of native IL-2, P65_30kD, P65_5kD, E62_30kD, E62_5kD and F42_30kD PEG conjugates. [picture] [4A] Presents SPR analysis of IL-2 variants bound to fixed IL-2 Rα. [picture] [4B] Presents SPR analysis of IL-2 variants bound to fixed IL-2 Rβ. [picture] [4C] SPR analysis of recombinant IL-2 and IL-2 variant F42_30kD bound to fixed IL-2 Rα and IL-2 Rβ.

[0092] [picture] [5A] [to] [picture] [5F] shows an exemplary dose-response curve of an IL-2 variant in the primary cell population of human LRS, illustrating pSTAT5 signaling. [picture] [5A]: Native IL-2; [picture] [5B]:P65_30kD; [picture] [5C]:K64_30kD; [picture] [5D]:K43_30kD; [picture] [5E]:K35_30kD, and [picture] [5F]:F42_30kD.

[0093] [picture] [6A] [to] [C] Demonstrates the α-nonpharmacology of PEG and residue substitution-induced IL-2 variants. [picture] [6A]: Native IL-2; [picture] [6B]:E62K; [picture] [6C]:E62_30kD.

[0094] [picture] [7] Demonstrates that the α-pharmacology of IL-2 variants is PEG size-independent.

[0095] [picture] [8] The mean (±SD) plasma concentrations relative to time profiles following a single intravenous rapid administration of aldesleukin (IL-2), E62_5, E62_30 and P65_30 to C57BL / 6 mice.

[0096] [picture] [9] Shows the percentage of pSTAT5+CD8+ T cells in peripheral blood relative to time units after a single intravenous rapid administration of P65_30 or interleukin to C57BL / 6 mice.

[0097] [picture] [10A] [to] [picture] [10C] Demonstrates the reduction of CD8+ T cells in the PBMC population after a single intravenous rapid administration of P65_30 or interleukin (IL-2). [picture] [10A]), NK cells ( [picture] [10B]) and CD4+ Treg cells ( [picture] [10C]) percentage. Blood was drawn via cardiac puncture at the indicated time points, and the immune cell population was assessed by flow cytometry. Each data point represents the mean ± SEM of three copies at each time point.

[0098] [picture] [11A] [To the image] [11B] This study demonstrates the difference between P65_30 and IL-2 (aldeleukin) in the proliferation of memory CD8+CD44+ T cells in a stimulated CD3+ population following a single intravenous rapid administration of P65_30 or interleukin (IL-2). Blood was aspirated via cardiac puncture at indicated time points, and the immune cell population was assessed by flow cytometry. Data were analyzed using unpaired Student's t-tests. ***Indicates P < 0.001. [picture] [11A] Demonstrates the proliferation of memory CD8+CD44+ T cells at 72, 96 and 120 hours. [picture] [11B] Demonstrates flow cytometry analysis of the cells at a 120-hour time point.

[0099] [picture] [12A] [to] [picture] [12B] Demonstrates an increase in tumor-infiltrating lymphocytes (TILs) over time in C57Bl6 mice with syngeneic B16F10 tumors following a single intravenous rapid administration of P65_30. [picture] [12A] shows the percentage of NK, CD8+ T and CD4+ Treg cells in P65_30 treated animals relative to untreated (mediator) animals on day 5 of treatment. [picture] [12B] Presents the CD8+ / CD4+ Treg cell ratio in P65_30 treated and control (mediator) animals. Data were analyzed using unpaired Student's t-test. ***Indicates P-value < 0.001.

[0100] [picture] [13A] [to] [picture] [13B] Plasma levels of IL-2, TNF-α, IFNγ, IL-5, and IL-6 in mice following a single intravenous rapid administration of escalating doses (0.01–5 mg / kg) of P65_30 or interleukin (IL-2). Plasma concentrations of the interleukins were determined by ELISA (Abcam, Cambridge, UK). For each dose group, N=3 mice were used and samples were collected at 4, 34, and 72 h post-administration. [picture] [13A] Demonstrates the interleukin content in animals treated with aldehyde and [picture] [13B] Shows the cytokine content in animals that were given P65_30.

[0101] [picture]

[14] White blood cell, lymphocyte and eosinophil counts (mean ± SD) after a single intravenous administration of P65_30kD to male cynomolgus monkeys.

[0102] [picture] [15A] [to] [picture] [15B] Dose-response curves of an exemplary IL-2 variant in pSTAT5 signaling of primary human LRS cells ( [picture] [15A]) Proliferative response of mouse CTLL-2 population ( [picture] [15B]).

[0103] [picture] [16A] [to] [picture] [16B] Demonstrates that, compared with a normal IL-2 control, the PEG IL-2 compound can specifically expand the immune cell population in vitro in primary lymphocytes. [picture] [16A] Demonstrates the expansion of immune cells after treatment with IL-2 (control). [picture] [16B] Demonstrates the expansion of immune cells after treatment with P65_30kD.

[0104] [picture] [17A] [to] [picture] [17B] rhIL-2 (recombinant human interleukin-2) is displayed on the surface of IL-2Rα. [picture] [17A]) and the synthetic conjugate IL-2_P65[AzK_L1_PEG30kD]-1 ( [picture] [17B]) Sensor spectrum of the binding reaction. Under these conditions, no significant binding reaction was detected in IL-2_P65[AzK_L1_PEG30kD]-1.

[0105] [picture] [17C] [and] [picture] [17D] Demonstrates rhIL-2 (recombinant human interleukin-2) bound to the surface of IL-2R β. [picture] [17C]) and the synthetic conjugate IL-2_P65[AzK_L1_PEG30kD]-1 ( [picture] [17D]) Sensor spectrum of the sample.

[0106] [picture]

[18] The gating strategy for Treg cell sorting by flow cytometry is demonstrated. First, cells are gated to a single peak using FSC-A via FSC-H to exclude any aggregates or doublets (single-peak gate, group 1). Within this gate, cells are gated to the center-high forward scatter (FSC-A) and side scatter (SSC-A) to exclude erythrocytes, debris, and granulocytes (lymphocyte gate, group 2). T cells are then gated into a CD3+, CD56 / 16 negative population, group 3. NK cells are identified as a CD3-negative, CD56 / 16-high population, group 3. T cells are then separated into CD4+ T cells and CD8+ T cells (group 4). Tregs are then gated from CD4+ T cells into a CD25hi×C127lo population, group 5.

[0107] [picture]

[19] The stability of three concentrations of the compound IL-2_P65[AzK_L1_PEG30kD]-1 in human serum up to 168 hours is shown as described in Example 15. Implementation

[0108] [Cross-reference] []

[0109] This application claims the rights 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 herein by reference in their entirety. [Sequence List] []

[0110] This application contains a sequence list, which has been submitted electronically in ASCII format and whose full text is incorporated herein by reference. The ASCII copy created on February 4, 2020, is named 46085-729_851_SL.txt and is 124,806 bytes in size.

[0111] Cytokines comprise a family of cell signaling proteins, such as chemokines, interferons, interleukins, lymphotransmitters, tumor necrosis factor, 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, mast cells, endothelial cells, fibroblasts, and various stromal cells. In some cases, cytokines regulate the balance between humoral and cellular immune responses.

[0112] Interleukin is a signal transduction protein that regulates the development and differentiation of T and B lymphocytes, monocytes of the monocyte lineage, neutrophils, basophils, eosinophils, megakaryocytes, and hematopoietic cells. Interleukin is produced by helper CD4 T and B lymphocytes, monocytes, macrophages, endothelial cells, and other tissue resident organisms.

[0113] Interleukin-2 (IL-2) is a pleiotropic type I cytokine with a 15.5 kDa four-α helical bundle. The precursor form of IL-2 is 153 amino acid residues long, with the first 20 amino acids forming the signal peptide and residues 21 to 153 forming the mature form. IL-2 is primarily produced by CD4+ T cells after antigen stimulation, and to a lesser extent by CD8+ cells, natural killer (NK) cells and natural killer T (NKT) cells, activated dendritic cells (DCs), and mast cells. IL-2 signaling occurs through specific interactions with the IL-2 receptor (IL-2R) subunit, IL-2Rα (also known as CD25), IL-2Rβ (also known as CD122), and IL-2Rγ (also known as CD132). The interaction between IL-2 and IL-2Rα forms a "low-affinity" IL-2 receptor complex with approximately 10⁻⁸ M kDa. The interaction of IL-2 with -2Rβ and IL-2Rγ forms an "intermediate affinity" IL-2 receptor complex with a Kd of approximately 10⁻⁹ M. The interaction of IL-2 with all three subunits, IL-2Rα, IL-2Rβ, and IL-2Rγ, forms a "high affinity" IL-2 receptor complex with a Kd of approximately >10⁻¹¹ M.

[0114] In some cases, the activation and proliferation of regulatory T cells are regulated via IL-2 signaling through the high-affinity IL-2Rαβγ complex. Regulatory T cells, or CD4+CD25+Foxp3+ regulatory T (Treg) cells, maintain immune homeostasis by suppressing effector cells such as CD4+ T cells, CD8+ T cells, B cells, NK cells, and NKT cells. In some cases, Treg cells are produced by the thymus (tTreg cells) or induced by peripheral natural T cells (pTreg cells). In some cases, Treg cells are considered mediators with peripheral tolerance. In fact, in one study, the metastasis of peripheral CD4+ T cells lacking CD25 induced various autoimmune diseases in nude mice; however, co-metastasis of CD4+CD25+ T cells suppressed autoimmune manifestation (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)). The expansion of the Treg cell population downregulates effector T cell proliferation and suppresses autoimmunity and T cell antitumor responses.

[0115] The activation and proliferation of CD8+ effector T (Teff) cells, NK cells, and NKT cells are regulated by IL-2 signaling via the "intermediate affinity" IL-2Rβγ complex. CD8+ Teff cells (also known as cytotoxic T cells, Tc cells, cytotoxic T lymphocytes, CTLs, T killer cells, lysogenic 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 cell lines are lymphocyte types similar to CD8+ Teff cells, target cancer cells, and cells infected by pathogens.

[0116] In some cases, IL-2 signaling is used to regulate T cell responses and subsequently for cancer treatment. For example, high doses of IL-2 are administered to induce Teff cell population expansion for cancer treatment. However, high doses of IL-2 further lead to the stimulation of Treg cells, which exhibit a weakened anti-tumor immune response. High doses of IL-2 also induce toxic adverse events mediated by the binding of IL-2Rα chain-expressing cells in the blood vessels (including type 2 innate immune cells (ILC-2), eosinophils, and endothelial cells). This results in eosinophilia, capillary leakage, and vascular leakage syndrome (VLS).

[0117] Receptor cell therapy enables physicians to effectively utilize a patient's own immune cells to fight diseases such as proliferative disorders (e.g., cancer) and infectious diseases. In one non-limiting example, T lymphocytes can be collected from a patient, reengineered to target specific antigens on the surface of malignant cells, and then reintroduced into the patient's body to specifically target the malignant cells. Furthermore, recipient cell therapy provides a sustained response in the body through signal transduction to immune cells, allowing the reengineered cells to grow and divide long-term after being reintroduced into the patient's immune system.

[0118] In some embodiments, this document discloses a method for selectively upregulating different populations of lymphocytes (e.g., CD4+ helper cells, CD8+ effector natural and memory cells, NK cells, or NKT cells) via interleukin / interleukin receptor signaling. In some cases, the interleukin comprises interleukin, interferon, or tumor necrosis factor. In some cases, the interleukin is a cytokine conjugate, such as an interleukin conjugate, interferon conjugate, or tumor necrosis factor conjugate. In additional cases, this document describes kits comprising pharmaceutical compositions and kits comprising one or more of the cytokine conjugates described herein.

[0119] In some embodiments, this document also describes a method for selectively upregulating populations of CD4+ helper cells, CD8+ effector natural and memory cells, NK cells, and / or NKT cells via IL-2 / IL-2R signaling. In some cases, IL-2 is an IL-2 conjugate that interacts with a "moderate affinity" IL-2Rβγ complex, having potency similar to the IL-2Rαβγ complex, and exhibiting attenuated IL-2Rα interaction relative to wild-type IL-2. In some embodiments, this document further describes methods for treating cancer using the IL-2 conjugates described herein. In additional embodiments, this document describes pharmaceutical compositions and kits comprising one or more of the IL-2 conjugates described herein. In some embodiments, the IL-2 conjugate includes a binding moiety (e.g., PEG) that helps increase or decrease an individual's "clearance" or plasma half-life without affecting pharmacokinetics, including desired interleukin-receptor interactions and immune cell expansion.

[0120] In some embodiments, this document discloses reagents for developing recipient cell therapies comprising cells engineered to express modified cytokines, such cells enabling selective cytokine-receptor interactions and immune cell proliferation. In some embodiments, the reagents comprise nucleic acid constructs encoding the aforementioned IL-2 conjugates. Recipient cell therapies comprising the aforementioned IL-2 conjugates, applicable to the treatment of the proliferative or infectious diseases described herein, are also disclosed.

[0121] In some embodiments, compositions for inducing selective interleukin-receptor interactions and immune cell proliferation are disclosed herein. In some embodiments, the reagent comprises a nucleic acid construct encoding the aforementioned IL-2 conjugate. Pharmaceutical compositions comprising the aforementioned IL-2 conjugate, suitable for treating the proliferative or infectious diseases described herein, are also disclosed. [Cytoin conjugates] []

[0122] In some embodiments, cytokine conjugates are described herein. In some cases, cytokines comprise interleukins, tumor necrosis factor, interferons, chemokines, lymphokines, or growth factors. In some cases, the cytokine is an interleukin. In some cases, the cytokine is an interferon. In additional cases, the cytokine is a tumor necrosis factor. In other cases, the cytokine is a growth factor.

[0123] In some embodiments, an interleukin conjugate is described herein. Exemplary interleukins include, but are not limited to, interleukin-2 (IL-2). IL-2 conjugate

[0124] This article describes [surface] The polypeptide shown in

[20] . In some embodiments, the IL-2 conjugates described herein are exemplified in [surface]

[20] in.

[0125] [surface]

[20] [name] [sequence] [SEQ ID NO:] IL-2 (Homo sapiens) (mature form) APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT 1 IL-2 (Homo sapiens) (precursor) NCBI Register Number: AAB46883.1 MYRMQLLSCIALSLALVTNSAPTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT 2 Aldesleukin PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 3 IL-2_C125S APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLPRRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 4 IL-2_P65X APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELK [ , X , ]LEEVLNLLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 5 IL-2_E62X APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEE [ , X , ]LKPLEEVLNLAQSKNFHLRPRDLISNINNVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 6 IL-2_F42X APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLT [ , X , ]KFYMPKKATELKHLQCLEEELKPLEEVLNLLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 7 IL-2_K43 [ , X , ]FYMPKKATELKHLQCLEEELKPLEEVLNLLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 8 IL-2_K35X APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNP [ , X , ]LTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 9 IL-2_P65[AzK] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELK [ , [AzK], ]LEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 10 IL-2_E62[AzK] APTSSSTKKTQLQLEHLLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEE[ [ , AzK] , ]LKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 11 IL-2_F42[AzK] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLT[ [ , AzK] , ]KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 12 IL-2_K43[AzK] APTSSSTKKTQLQLEHLLLLDLQMILNGINNYKNPKLTRMLTF[ [ , AzK] , ]FYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 13 IL-2_K35[AzK] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNP[ [ , AzK] , ]LTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 14 IL-2_P65[AzK_PEG] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELK [ , [AzK_PEG], ]LEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 15 IL-2_E62[AzK_PEG] APTSSSTKKTQLQLEHLLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEE [[, AzK_PEG] , ]LKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 16 IL-2_F42[AzK_PEG] APTSSSTKKTQLQLEHLLLLDLQMILNGINNYKNPKLTRMLT [[, AzK_PEG] , ]KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 17 IL-2_K43[AzK_PEG] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF [[, AzK_PEG] , ]FYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 18 IL-2_K35[AzK_PEG] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNP [[, AzK_PEG] , ]LTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 19 IL-2_P65[AzK_PEG5kD] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELK [ , [AzK_PEG5kD], ]LEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 20 IL-2_E62[AzK_PEG5kD] APTSSSTKKTQLQLEHLLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEE [[, AzK_PEG5kD] , ]LKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 21 IL-2_F42[AzK_PEG5kD] APTSSSTKKTQLQLEHLLLLDLQMILNGINNYKNPKLTRMLT [[, AzK_PEG5kD] , ]KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 22 IL-2_K43[AzK_PEG5kD] APTSSSTKKTQLQLEHLLLLDLQMILNGINNYKNPKLTRMLTF [[, AzK_PEG5kD] , ]FYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 23 IL-2_K35[AzK_PEG5kD] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNP [[, AzK_PEG5kD] , ]LTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 24 IL-2_P65[AzK_PEG30kD] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELK [ , [AzK_PEG30kD], ]LEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 25 IL-2_E62[AzK_PEG30kD] APTSSSTKKTQLQLEHLLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEE [[, AzK_PEG30kD] , ]LKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 26 IL-2_F42[AzK_PEG30kD] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLT [[, AzK_PEG30kD] , ]KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 27 IL-2_K43[AzK_PEG30kD] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF [[, AzK_PEG30kD] , ]FYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 28 IL-2_K35[AzK_PEG30kD] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNP [[, AzK_PEG30kD] . [ , X, ]LEEVLNLLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 30 IL-2_E62X-1 PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEE [ , X , ]LKPLEEVLNLAQSKNFHLRPRDLISNINNVIVLELELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 31 IL-2_F42X-1 PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLT [ , X ... [ , X , ]FYMPKKATELKHLQCLEEELKPLEEVLNLLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 33 IL-2_K35X-1 PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNP [ , X , ]LTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 34 IL-2_P65[AzK]-1 PTSSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELK [ , [AzK], ]LEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 35 IL-2_E62[AzK]-1 PTSSSTKKTQLQLEHLLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEE[ [ , AzK] , ]LKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 36 IL-2_F42[AzK]-1 PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLT[ [ , AzK] , ]KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 37 IL-2_K43[AzK]-1 PTSSSTKKTQLQLEHLLLLDLQMILNGINNYKNPKLTRMLTF[ [ , AzK] , ]FYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 38 IL-2_K35[AzK]-1 PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNP[ [ , AzK] , ]LTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 39 IL-2_P65[AzK_L1_PEG]-1 PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELK [ , [AzK_L1_PEG], ]LEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 40 IL-2_E62[AzK_ L1_PEG]-1 PTSSSTKKTQLQLEHLLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEE [[, AzK_L1_PEG] , ]LKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 41 IL-2_F42[AzK_ L1_PEG]-1 PTSSSTKKTQLQLEHLLLDLQMINLGINNYKNPKLTRMLT [[, AzK_L1_PEG] , ]KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 42 IL-2_K43[AzK_ L1_PEG]-1 PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF [[, AzK_L1_PEG] , ]FYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 43 IL-2_K35[AzK_ L1_PEG]-1 PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNP [[, AzK_L1_PEG] , ]LTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 44 IL-2_P65[AzK_ L1_PEG5kD]-1 PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELK [ , [AzK_L1_PEG5kD], ]LEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 45 IL-2_E62[AzK_ L1_PEG5kD]-1 PTSSSTKKTQLQLEHLLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEE [[, AzK_L1_PEG5kD] , ]LKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 46 IL-2_F42[AzK_ L1_PEG5kD]-1 PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLT [[, AzK_L1_PEG5kD] , ]KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 47 IL-2_K43[AzK_ L1_PEG5kD]-1 PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF [[, AzK_L1_PEG5kD] , ]FYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 48 IL-2_K35[AzK_ L1_PEG5kD]-1 PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNP [[, AzK_L1_PEG5kD] , ]LTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 49 IL-2_P65[AzK_ L1_PEG30kD]-1 PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELK [ , [AzK_L1_PEG30kD], ]LEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 50 IL-2_E62[AzK_ L1_PEG30kD]-1 PTSSSTKKTQLQLEHLLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEE [[, AzK_L1_PEG30kD] , ]LKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 51 IL-2_F42[AzK_ L1_PEG30kD]-1 PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLT [[, AzK_L1_PEG30kD] , ]KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 52 IL-2_K43[AzK_ L1_PEG30kD]-1 PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF [[, AzK_L1_PEG30kD] , ]FYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 53 IL-2_K35[AzK_ L1_PEG30kD]-1 PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNP [[, AzK_L1_PEG30kD] , ]LTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 54 IL-2_P65[AzK_L1_PEG]-2 APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELK [ , [AzK_L1_PEG], ]LEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 55 IL-2_E62[AzK_ L1_PEG]-2 APTSSSTKKTQLQLEHLLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEE [[, AzK_L1_PEG] , ]LKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 56 IL-2_F42[AzK_ L1_PEG]-2 APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLT [[, AzK_L1_PEG] , ]KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 57 IL-2_K43[AzK_ L1_PEG]-2 APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF [[, AzK_L1_PEG] , ]FYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 58 IL-2_K35[AzK_ L1_PEG]-2 APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNP [[, AzK_L1_PEG] , ]LTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 59 IL-2_P65[AzK_ L1_PEG5kD]-2 APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELK [ , [AzK_L1_PEG5kD], ]LEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 60 IL-2_E62[AzK_ L1_PEG5kD]-2 APTSSSTKKTQLQLEHLLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEE [[, AzK_L1_PEG5kD] , ]LKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 61 IL-2_F42[AzK_ L1_PEG5kD]-2 APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLT [[, AzK_L1_PEG5kD] , ]KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 62 IL-2_K43[AzK_ L1_PEG5kD]-2 APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF [[, AzK_L1_PEG5kD] , ]FYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 63 IL-2_K35[AzK_ L1_PEG5kD]-2 APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNP [[, AzK_L1_PEG5kD] , ]LTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 64 IL-2_P65[AzK_ L1_PEG30kD]-2 APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELK [ , [AzK_L1_PEG30kD], ]LEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 65 IL-2_E62[AzK_ L1_PEG30kD]-2 APTSSSTKKTQLQLEHLLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEE [[, AzK_L1_PEG30kD] , ]LKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 66 IL-2_F42[AzK_ L1_PEG30kD]-2 APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLT [[, AzK_L1_PEG30kD] , ]KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 67 IL-2_K43[AzK_ L1_PEG30kD]-2 APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF [[, AzK_L1_PEG30kD] , ]FYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 68 IL-2_K35[AzK_ L1_PEG30kD]-2 APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNP [[, AzK_L1_PEG30kD] , ]LTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 69 IL-2_P65[AzK_PEG]-1 PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELK [ , [AzK_PEG], ]LEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 70 IL-2_E62[AzK_ PEG]-1 PTSSSTKKTQLQLEHLLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEE [[, AzK_PEG] , ]LKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 71 IL-2_F42[AzK_ PEG]-1 PTSSSTKKTQLQLEHLLLDLQMINLGINNYKNPKLTRMLT [[, AzK_PEG] , ]KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 72 IL-2_K43[AzK_ PEG]-1 PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF [[, AzK_PEG] , ]FYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 73 IL-2_K35[AzK_ PEG]-1 PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNP [[, AzK_PEG] , ]LTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 74 IL-2_P65[AzK_ PEG5kD]-1 PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELK [ , [[ID=, ]LEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 75 IL-2_E62[AzK_PEG5kD]-1 PTSSSTKKTQLQLEHLLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEE [[, ​ , ]LKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 76 IL-2_F42[AzK_PEG5kD]-1 PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLT [[, ​ , ]KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 77 IL-2_K43[AzK_PEG5kD]-1 PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF [[, ​ , ]FYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 78 IL-2_K35[AzK_PEG5kD]-1 PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNP [[, ​ , ]LTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 79 IL-2_P65[AzK_PEG30kD]-1 PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELK [ , ​, ]LEEVLNLAQSKNFHLPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 80 IL-2_E62[AzK_PEG30kD]-1 PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEE [[, ​ , ]LKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 81 IL-2_F42[AzK_PEG30kD]-1 PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLT [[, ​ , ]KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 82 IL-2_K43[AzK_PEG30kD]-1 PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF [[, ​ , ]FYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 83 IL-2_K35[AzK_PEG30kD]-1 PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNP [[, ​ , ]LTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 84 [X] = Sites containing non-natural amino acids. [[] [AzK] []]=N6-((2-azidoethoxy)-carbonyl)-L-lysine (its structure is shown as compound 90 in Figure 3C). The compound has Chemical Abstracts Service number 1167421-25-1. [[AzK_PEG]] = N6-((2-azidoethoxy)-carbonyl)-L-lysine is bound to PEG via DBCO-mediated click chemistry to form a compound comprising a structure of formula (II) or (III). For example, if specified, PEG5kD represents a methoxy-terminated linear polyethylene glycol chain with an average molecular weight of 5 kilodaltons. The ratio of regioisomers generated by the click reaction is about 1:1 or greater than 1:1. The term "DBCO" means a chemical moiety including a dibenzocyclooctylene group, such as the mPEG-DBCO compound illustrated in process 1 of Example 2. An illustrative structure of the methoxy PEG group is illustrated in the mPEG-DBCO structure of process 1 of Example 2. [[AzK_L1_PEG]] = N6-((2-azidoethoxy)-carbonyl)-L-lysine is bound to PEG via DBCO-mediated click chemistry to form a compound containing a structure of formula (IV) or (V). For example, if specified, PEG5kD represents a methoxy-terminated linear polyethylene glycol chain with an average molecular weight of 5 kilodaltons. The ratio of regioisomers generated by the click reaction is about 1:1 or greater than 1:1. The term "DBCO" means a chemical moiety including a dibenzocyclooctylene group, such as the mPEG-DBCO compound described in process 1 of Example 2.

[0126] In some embodiments, IL-2 conjugates modified at amino acid positions are described herein. In some cases, the modification relates to a native amino acid. In some cases, the modification relates to a non-native amino acid. In some cases, an isolated and modified IL-2 polypeptide comprising at least one non-native amino acid is described herein. In some cases, the IL-2 polypeptide is an isolated and purified mammalian IL-2, such as 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% of the sequence of SEQ ID NO: 1. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 1. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 1. In additional cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% of the sequence of SEQ ID NO: 2. In additional cases, the IL-2 polypeptide comprises the sequence SEQ ID NO: 2. In additional cases, the IL-2 polypeptide consists of the sequence SEQ ID NO: 2. In some cases, the IL-2 polypeptide comprises approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 3. In some cases, the IL-2 polypeptide comprises the sequence SEQ ID NO: 3. In some cases, the IL-2 polypeptide consists of the sequence SEQ ID NO: 3. In additional cases, the IL-2 polypeptide comprises approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 4. In additional cases, the IL-2 polypeptide comprises the sequence SEQ ID NO: 4. In additional cases, the IL-2 polypeptide consists of the sequence SEQ ID NO: 4. In some cases, the IL-2 polypeptide comprises approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 5. In some cases, the IL-2 polypeptide comprises the sequence SEQ ID NO: 5. In some cases, the IL-2 polypeptide consists entirely of the sequence SEQ ID NO: 5. In additional cases, the IL-2 polypeptide comprises approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identical to SEQ ID NO: 6. In additional cases, the IL-2 polypeptide comprises the sequence SEQ ID NO: 6. In additional cases, the IL-2 polypeptide consists entirely of the sequence SEQ ID NO: 6.In some cases, the IL-2 peptide contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 7. In some cases, the IL-2 peptide contains the sequence SEQ ID NO: 7. In some cases, the IL-2 peptide consists entirely of the sequence SEQ ID NO: 7. In additional cases, the IL-2 peptide contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 8. In additional cases, the IL-2 peptide contains the sequence SEQ ID NO: 8. In additional cases, the IL-2 peptide consists entirely of the sequence SEQ ID NO: 8. In some cases, the IL-2 peptide contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 9. In some cases, the IL-2 peptide contains the sequence SEQ ID NO: 9. In some cases, the IL-2 peptide consists entirely of the sequence SEQ ID NO: 9. In some cases, the IL-2 peptide contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 10. In some cases, the IL-2 peptide contains the sequence SEQ ID NO: 10. In some cases, the IL-2 peptide consists entirely of the sequence SEQ ID NO: 10. In some cases, the IL-2 peptide contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 11. In some cases, the IL-2 peptide contains the sequence SEQ ID NO: 11. In some cases, the IL-2 peptide consists entirely of the sequence SEQ ID NO: 11. In some cases, the IL-2 peptide contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 12. In some cases, the IL-2 peptide contains the sequence SEQ ID NO: 12. In some cases, the IL-2 polypeptide consists of the sequence SEQ ID NO: 12. In some cases, the IL-2 polypeptide contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 13. In some cases, the IL-2 polypeptide contains the sequence SEQ ID NO: 13. In some cases, the IL-2 polypeptide consists of the sequence SEQ ID NO: 13. In some cases, the IL-2 polypeptide contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 14.In some cases, the IL-2 polypeptide comprises the sequence SEQ ID NO: 14. In some cases, the IL-2 polypeptide consists of the sequence SEQ ID NO: 14. In some cases, the IL-2 polypeptide comprises approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 15. In some cases, the IL-2 polypeptide comprises the sequence SEQ ID NO: 15. In some cases, the IL-2 polypeptide comprises approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 16. In some cases, the IL-2 polypeptide comprises the sequence SEQ ID NO: 16. In some cases, the IL-2 polypeptide consists of the sequence SEQ ID NO: 16. In some cases, the IL-2 peptide contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 17. In some cases, the IL-2 peptide contains the sequence SEQ ID NO: 17. In some cases, the IL-2 peptide consists entirely of the sequence SEQ ID NO: 17. In some cases, the IL-2 peptide contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 18. In some cases, the IL-2 peptide consists entirely of the sequence SEQ ID NO: 18. In some cases, the IL-2 peptide contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 19. In some cases, the IL-2 peptide contains the sequence SEQ ID NO: 19. In some cases, the IL-2 polypeptide consists of the sequence SEQ ID NO: 19. In some cases, the IL-2 polypeptide contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 20. In some cases, the IL-2 polypeptide contains the sequence SEQ ID NO: 20. In some cases, the IL-2 polypeptide consists of the sequence SEQ ID NO: 20. In some cases, the IL-2 polypeptide contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 21. In some cases, the IL-2 polypeptide contains the sequence SEQ ID NO: 21. In some cases, the IL-2 polypeptide consists of the sequence SEQ ID NO: 21.In some cases, the IL-2 peptide contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 22. In some cases, the IL-2 peptide contains the sequence SEQ ID NO: 22. In some cases, the IL-2 peptide consists entirely of the sequence SEQ ID NO: 22. In some cases, the IL-2 peptide contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 23. In some cases, the IL-2 peptide contains the sequence SEQ ID NO: 23. In some cases, the IL-2 peptide consists entirely of the sequence SEQ ID NO: 23. In some cases, the IL-2 peptide contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 24. In some cases, the IL-2 peptide contains the sequence SEQ ID NO: 24. In some cases, the IL-2 polypeptide comprises the sequence SEQ ID NO: 24. In additional cases, the IL-2 polypeptide contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 25. In additional cases, the IL-2 polypeptide comprises the sequence SEQ ID NO: 25. In additional cases, the IL-2 polypeptide comprises the sequence SEQ ID NO: 25. In some cases, the IL-2 polypeptide contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 26. In some cases, the IL-2 polypeptide comprises the sequence SEQ ID NO: 26. In some cases, the IL-2 polypeptide comprises the sequence SEQ ID NO: 26. In additional cases, the IL-2 polypeptide contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 27. In additional cases, the IL-2 polypeptide comprises the sequence SEQ ID NO: 27. In additional cases, the IL-2 polypeptide consists of the sequence SEQ ID NO: 27. In some cases, the IL-2 polypeptide comprises approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 28. In some cases, the IL-2 polypeptide comprises the sequence SEQ ID NO: 28. In some cases, the IL-2 polypeptide consists of the sequence SEQ ID NO: 28. In additional cases, the IL-2 polypeptide comprises approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 29.In some cases, the IL-2 polypeptide comprises the sequence SEQ ID NO: 29. In some cases, the IL-2 polypeptide consists of the sequence SEQ ID NO: 29. In some cases, the IL-2 polypeptide comprises approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 30. In some cases, the IL-2 polypeptide comprises the sequence SEQ ID NO: 30. In some cases, the IL-2 polypeptide comprises approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 31. In some cases, the IL-2 polypeptide comprises the sequence SEQ ID NO: 31. In some cases, the IL-2 polypeptide consists of the sequence SEQ ID NO: 31. In additional cases, the IL-2 peptide comprises approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 32. In additional cases, the IL-2 peptide comprises the sequence SEQ ID NO: 32. In additional cases, the IL-2 peptide consists of the sequence SEQ ID NO: 32. In some cases, the IL-2 peptide comprises approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 33. In some cases, the IL-2 peptide comprises the sequence SEQ ID NO: 33. In some cases, the IL-2 peptide consists of the sequence SEQ ID NO: 33. In additional cases, the IL-2 peptide comprises approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 34. In additional cases, the IL-2 peptide comprises the sequence SEQ ID NO: 34. In some cases, the IL-2 polypeptide consists of the sequence SEQ ID NO: 34. In some cases, the IL-2 polypeptide contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 35. In some cases, the IL-2 polypeptide contains the sequence SEQ ID NO: 35. In some cases, the IL-2 polypeptide consists of the sequence SEQ ID NO: 35. In some cases, the IL-2 polypeptide contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 36. In some cases, the IL-2 polypeptide contains the sequence SEQ ID NO: 36. In some cases, the IL-2 polypeptide consists of the sequence SEQ ID NO: 36.In some cases, the IL-2 peptide contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 37. In some cases, the IL-2 peptide contains the sequence SEQ ID NO: 37. In some cases, the IL-2 peptide consists entirely of the sequence SEQ ID NO: 37. In additional cases, the IL-2 peptide contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 38. In additional cases, the IL-2 peptide contains the sequence SEQ ID NO: 38. In additional cases, the IL-2 peptide consists entirely of the sequence SEQ ID NO: 38. In some cases, the IL-2 peptide contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 39. In some cases, the IL-2 peptide contains the sequence SEQ ID NO: 39. In some cases, the IL-2 polypeptide consists of the sequence SEQ ID NO: 39. In some cases, the IL-2 polypeptide contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 40. In some cases, the IL-2 polypeptide contains the sequence SEQ ID NO: 40. In some cases, the IL-2 polypeptide consists of the sequence SEQ ID NO: 40. In some cases, the IL-2 polypeptide contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 41. In some cases, the IL-2 polypeptide contains the sequence SEQ ID NO: 41. In some cases, the IL-2 polypeptide consists of the sequence SEQ ID NO: 41. In some cases, the IL-2 polypeptide contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 42. In some cases, the IL-2 polypeptide comprises the sequence SEQ ID NO: 42. In some cases, the IL-2 polypeptide consists of the sequence SEQ ID NO: 42. In some cases, the IL-2 polypeptide comprises approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 43. In some cases, the IL-2 polypeptide comprises the sequence SEQ ID NO: 43. In some cases, the IL-2 polypeptide comprises approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 44.In some cases, the IL-2 polypeptide comprises the sequence SEQ ID NO: 44. In some cases, the IL-2 polypeptide consists of the sequence SEQ ID NO: 44. In some cases, the IL-2 polypeptide comprises approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 45. In some cases, the IL-2 polypeptide comprises the sequence SEQ ID NO: 45. In some cases, the IL-2 polypeptide comprises approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 46. In some cases, the IL-2 polypeptide comprises the sequence SEQ ID NO: 46. In some cases, the IL-2 polypeptide consists of the sequence SEQ ID NO: 46. In some cases, the IL-2 peptide contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 47. In some cases, the IL-2 peptide contains the sequence SEQ ID NO: 47. In some cases, the IL-2 peptide consists entirely of the sequence SEQ ID NO: 47. In some cases, the IL-2 peptide contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 48. In some cases, the IL-2 peptide consists entirely of the sequence SEQ ID NO: 48. In some cases, the IL-2 peptide contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 49. In some cases, the IL-2 peptide contains the sequence SEQ ID NO: 49. In some cases, the IL-2 polypeptide consists of the sequence SEQ ID NO: 49. In some cases, the IL-2 polypeptide contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 50. In some cases, the IL-2 polypeptide contains the sequence SEQ ID NO: 50. In some cases, the IL-2 polypeptide consists of the sequence SEQ ID NO: 50. In some cases, the IL-2 polypeptide contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 51. In some cases, the IL-2 polypeptide contains the sequence SEQ ID NO: 51. In some cases, the IL-2 polypeptide consists of the sequence SEQ ID NO: 51.In some cases, the IL-2 peptide contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 52. In some cases, the IL-2 peptide contains the sequence SEQ ID NO: 52. In some cases, the IL-2 peptide consists entirely of the sequence SEQ ID NO: 52. In some cases, the IL-2 peptide contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 53. In some cases, the IL-2 peptide contains the sequence SEQ ID NO: 53. In some cases, the IL-2 peptide consists entirely of the sequence SEQ ID NO: 53. In some cases, the IL-2 peptide contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 54. In some cases, the IL-2 peptide contains the sequence SEQ ID NO: 54. In some cases, the IL-2 polypeptide comprises the sequence SEQ ID NO: 54. In additional cases, the IL-2 polypeptide contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 55. In additional cases, the IL-2 polypeptide comprises the sequence SEQ ID NO: 55. In additional cases, the IL-2 polypeptide comprises the sequence SEQ ID NO: 55. In some cases, the IL-2 polypeptide contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 56. In some cases, the IL-2 polypeptide comprises the sequence SEQ ID NO: 56. In some cases, the IL-2 polypeptide comprises the sequence SEQ ID NO: 56. In additional cases, the IL-2 polypeptide contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 57. In additional cases, the IL-2 polypeptide comprises the sequence SEQ ID NO: 57. In additional cases, the IL-2 polypeptide consists of the sequence SEQ ID NO: 57. In some cases, the IL-2 polypeptide comprises approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 58. In some cases, the IL-2 polypeptide comprises the sequence SEQ ID NO: 58. In some cases, the IL-2 polypeptide consists of the sequence SEQ ID NO: 58. In additional cases, the IL-2 polypeptide comprises approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 59.In some cases, the IL-2 polypeptide comprises the sequence SEQ ID NO: 59. In some cases, the IL-2 polypeptide consists of the sequence SEQ ID NO: 59. In some cases, the IL-2 polypeptide comprises approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 60. In some cases, the IL-2 polypeptide comprises the sequence SEQ ID NO: 60. In some cases, the IL-2 polypeptide comprises approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 61. In some cases, the IL-2 polypeptide comprises the sequence SEQ ID NO: 61. In some cases, the IL-2 polypeptide consists of the sequence SEQ ID NO: 61. In additional cases, the IL-2 polypeptide comprises approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 62. In additional cases, the IL-2 polypeptide comprises the sequence SEQ ID NO: 62. In additional cases, the IL-2 polypeptide consists of the sequence SEQ ID NO: 62. In some cases, the IL-2 polypeptide comprises approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 63. In some cases, the IL-2 polypeptide comprises the sequence SEQ ID NO: 63. In some cases, the IL-2 polypeptide consists of the sequence SEQ ID NO: 63. In additional cases, the IL-2 polypeptide comprises approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 64. In additional cases, the IL-2 polypeptide comprises the sequence SEQ ID NO: 64. In some cases, the IL-2 polypeptide consists of the sequence SEQ ID NO: 64. In some cases, the IL-2 polypeptide contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 65. In some cases, the IL-2 polypeptide contains the sequence SEQ ID NO: 65. In some cases, the IL-2 polypeptide consists of the sequence SEQ ID NO: 65. In some cases, the IL-2 polypeptide contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 66. In some cases, the IL-2 polypeptide contains the sequence SEQ ID NO: 66. In some cases, the IL-2 polypeptide consists of the sequence SEQ ID NO: 66.In some cases, the IL-2 peptide contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 67. In some cases, the IL-2 peptide contains the sequence SEQ ID NO: 67. In some cases, the IL-2 peptide consists entirely of the sequence SEQ ID NO: 67. In additional cases, the IL-2 peptide contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 68. In additional cases, the IL-2 peptide consists entirely of the sequence SEQ ID NO: 68. In some cases, the IL-2 peptide contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 69. In some cases, the IL-2 peptide contains the sequence SEQ ID NO: 69. In some cases, the IL-2 polypeptide consists of the sequence SEQ ID NO: 69. In some cases, the IL-2 polypeptide contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 70. In some cases, the IL-2 polypeptide contains the sequence SEQ ID NO: 70. In some cases, the IL-2 polypeptide consists of the sequence SEQ ID NO: 70. In some cases, the IL-2 polypeptide contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 71. In some cases, the IL-2 polypeptide contains the sequence SEQ ID NO: 71. In some cases, the IL-2 polypeptide consists of the sequence SEQ ID NO: 71. In some cases, the IL-2 polypeptide contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 72. In some cases, the IL-2 polypeptide comprises the sequence SEQ ID NO: 72. In some cases, the IL-2 polypeptide consists of the sequence SEQ ID NO: 72. In some cases, the IL-2 polypeptide comprises approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 73. In some cases, the IL-2 polypeptide comprises the sequence SEQ ID NO: 73. In some cases, the IL-2 polypeptide comprises approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 74.In some cases, the IL-2 polypeptide comprises the sequence SEQ ID NO: 74. In some cases, the IL-2 polypeptide consists of the sequence SEQ ID NO: 74. In some cases, the IL-2 polypeptide comprises approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 75. In some cases, the IL-2 polypeptide comprises the sequence SEQ ID NO: 75. In some cases, the IL-2 polypeptide comprises approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 76. In some cases, the IL-2 polypeptide comprises the sequence SEQ ID NO: 76. In some cases, the IL-2 polypeptide consists of the sequence SEQ ID NO: 76. In some cases, the IL-2 peptide contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 77. In some cases, the IL-2 peptide contains the sequence SEQ ID NO: 77. In some cases, the IL-2 peptide consists entirely of the sequence SEQ ID NO: 77. In some cases, the IL-2 peptide contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 78. In some cases, the IL-2 peptide consists entirely of the sequence SEQ ID NO: 78. In some cases, the IL-2 peptide contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 79. In some cases, the IL-2 peptide contains the sequence SEQ ID NO: 79. In some cases, the IL-2 polypeptide consists of the sequence SEQ ID NO: 79. In some cases, the IL-2 polypeptide contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 80. In some cases, the IL-2 polypeptide contains the sequence SEQ ID NO: 80. In some cases, the IL-2 polypeptide consists of the sequence SEQ ID NO: 80. In some cases, the IL-2 polypeptide contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 81. In some cases, the IL-2 polypeptide contains the sequence SEQ ID NO: 81. In some cases, the IL-2 polypeptide consists of the sequence SEQ ID NO: 81.In some cases, the IL-2 peptide contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 82. In some cases, the IL-2 peptide contains the sequence SEQ ID NO: 82. In some cases, the IL-2 peptide consists entirely of the sequence SEQ ID NO: 82. In some cases, the IL-2 peptide contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 83. In some cases, the IL-2 peptide contains the sequence SEQ ID NO: 83. In some cases, the IL-2 peptide consists entirely of the sequence SEQ ID NO: 83. In some cases, the IL-2 peptide contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 84. In some cases, the IL-2 peptide contains the sequence SEQ ID NO: 84. In some cases, the IL-2 polypeptide consists of the sequence SEQ ID NO: 84.

[0127] In some cases, the IL-2 peptide is a truncated variant. In some cases, the truncation is an N-terminal deletion. In some cases, the truncation is a C-terminal deletion. In additional cases, the truncation includes both N-terminal and C-terminal deletions. For example, truncation may be the 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, C-terminus, or both ends. In some cases, the IL-2 peptide contains 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 peptide contains 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 peptide contains an N-terminal deletion of at least or about 2 residues. In some cases, the IL-2 peptide contains an N-terminal deletion of at least or about 3 residues. In some cases, the IL-2 peptide contains an N-terminal deletion of at least or about 4 residues. In some cases, the IL-2 peptide contains an N-terminal deletion of at least or about 5 residues. In some cases, the IL-2 peptide contains an N-terminal deletion of at least or about 6 residues. In some cases, the IL-2 peptide contains an N-terminal deletion of at least or about 7 residues. In some cases, the IL-2 peptide contains an N-terminal deletion of at least or about 8 residues. In some cases, the IL-2 peptide contains an N-terminal deletion of at least or about 9 residues. In some cases, the IL-2 peptide contains an N-terminal deletion of at least or about 10 residues.

[0128] In some embodiments, the IL-2 polypeptide is a functionally active fragment. In some cases, the functionally active fragment comprises IL-2 regions 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 those in SEQ ID NO: 1. In some cases, the functionally active fragment comprises IL-2 regions 10-133, wherein the residue positions are referenced to those in SEQ ID NO: 1. In some cases, the functionally active fragment comprises IL-2 regions 20-133, wherein the residue positions are referenced to those in SEQ ID NO: 1. In some cases, the functionally active fragment comprises IL-2 regions 30-133, wherein the residue positions are referenced to those in SEQ ID NO: 1. In some cases, the functionally active fragment comprises IL-2 regions 10-125, wherein the residue positions are referenced to those in SEQ ID NO: 1. In some cases, the functionally active fragment comprises IL-2 regions 20-125, wherein the residue positions are referenced to those in SEQ ID NO: 1. In some cases, the functionally active fragment comprises IL-2 regions 1-130, wherein the residue positions are referenced to those in SEQ ID NO: 1. In some cases, the functionally active fragment comprises IL-2 regions 1-125, wherein the residue positions are referenced to those in SEQ ID NO: 1.

[0129] In some embodiments, an IL-2 conjugate is described herein comprising an isolated, purified, and modified IL-2 polypeptide and a binding moiety. In some cases, the IL-2 conjugate exhibits reduced affinity for the IL-2 receptor α (IL-2Rα) subunit relative to the wild-type IL-2 polypeptide. In some cases, the binding 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 binding moiety binds to an amino acid residue near the IL-2 / IL-2Rα interface (e.g., about 5 Å, about 10 Å, about 15 Å, or about 20 Å away from the IL-2 / IL-2Rα interface). As used herein, residues associated with 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.

[0130] In some cases, the binding portion binds to an amino acid residue selected from the following amino acid positions: Y31, K32, N33, P34, K35, T37, R38, T41, F42, K43, F44, Y45, P47, K48, Q57, E60, E61, E62, L63, K64, P65, E68, V69, N71, L72, Q74, S75, K76, N77, M104, C105, E106, Y107, A108, D109, E110, T111, or A112, wherein the amino acid residue number corresponds to SEQ ID NO: 1. In some cases, the amino acid positions are selected from Y31, K32, N33, P34, K35, T37, R38, T41, F42, K43, F44, Y45, P47, K48, E61, E62, E68, K64, P65, V69, L72, Q74, S75, K76, N77, M104, C105, E106, Y107, A108, D109, E110, T111, and A112. In some cases, the amino acid position is selected from N33, P34, K35, T37, R38, M39, T41, F42, K43, F44, Y45, Q57, E60, E61, E62, L63, K64, P65, E68, V69, N71, L72, M104, C105, E106, Y107, A108, D109, E110, T111, and A112. In other cases, the amino acid position is selected from 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 is located at R38. In some cases, the amino acid is located at T41. In some cases, the amino acid is located at F42. In some cases, the amino acid is located at K43. In some cases, the amino acid is located at F44. In some cases, the amino acid is located at Y45. In some cases, the amino acid is located at E61.In some cases, the amino acid is located at E62. In some cases, the amino acid is located at K64. In some cases, the amino acid is located at E68. In some cases, the amino acid is located at P65. In some cases, the amino acid is located at V69. In some cases, the amino acid is located at L72. In some cases, the amino acid is located at Y107. In some cases, the amino acid is located at L72. In some cases, the amino acid is located at D109.

[0131] In some cases, the IL-2 conjugate further contains additional mutations. In some cases, the additional mutation is at a position selected from the following amino acids: K35, T37, R38, T41, F42, K43, F44, Y45, E61, E62, E68, K64, P65, V69, L72, and Y107. In such cases, the amino acid binds to the additional binding site to increase serum half-life, stability, or a combination thereof. Alternatively, the amino acid may first be mutated to a native amino acid such as lysine, cysteine, histamine, arginine, aspartic acid, glutamic acid, serine, threonine, or tyrosine before binding to the additional binding site; or mutated to a non-native amino acid.

[0132] In some embodiments, the affinity of the modified IL-2 peptide for the IL-2 receptor α (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 non-natural amino acid-modified wild-type IL-2 peptide (e.g., wild-type IL-2 peptide). 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 approximately 100%.

[0133] In some embodiments, the modified IL-2 peptide exhibits a reduced affinity for the IL-2 receptor α (IL-2Rα) subunit by approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 30, 50, 100, 200, 300, 400, 500, 1,000, or higher compared to an equivalent IL-2 peptide without non-natural amino acid modifications (e.g., a wild-type IL-2 peptide). In some cases, the reduced affinity is approximately 1. In some cases, the reduced affinity is approximately 2. In some cases, the reduced affinity is approximately 4. In some cases, the reduced affinity is approximately 5. In some cases, the reduced affinity is approximately 6. In some cases, the reduced affinity is approximately 8. In some cases, the reduced affinity is approximately 10. In some cases, the reduced affinity is approximately 30. In some cases, the affinity reduction is approximately 50-fold. In some cases, the affinity reduction is approximately 100-fold. In some cases, the affinity reduction is approximately 300-fold. In some cases, the affinity reduction is approximately 500-fold. In some cases, the affinity reduction is approximately 1000-fold. In some cases, the affinity reduction exceeds 1000-fold.

[0134] In some cases, the modified IL-2 peptide does not interact with IL-2Rα. In other cases, the modified IL-2 peptide further binds to the binding moiety. In still other cases, the IL-2 conjugate does not interact with IL-2Rα.

[0135] In some embodiments, the modified IL-2 peptide exhibits first receptor signaling activity with the IL-2βγ signaling complex and second receptor signaling activity with the IL-2αβγ signaling complex, wherein the difference between the first receptor signaling activity and the second receptor signaling activity is less than 10-fold. In some embodiments, the modified IL-2 peptide exhibits first receptor signaling activity with the IL-2βγ signaling complex and second receptor signaling activity with the IL-2αβγ signaling complex, wherein the difference between the first receptor signaling activity and the second receptor signaling activity 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 peptide is a partial agonist, such as an activator of receptors (e.g., the IL-2βγ signaling complex or the IL-2αβγ signaling complex), but an agonist that has only partial efficacy against the receptor compared to a full agonist. In some cases, modified IL-2 peptides are complete agonists, such as agonists that activate receptors (e.g., IL-2βγ signaling complex or IL-2αβγ signaling complex) with maximum response.

[0136] In some cases, receptor signaling efficacy is measured using EC50 values. In some cases, a modified IL-2 peptide provides a first EC50 value for activating the IL-2βγ signaling complex and a second EC50 value for activating the IL-2αβγ signaling complex, wherein the difference between the first and second EC50 values ​​is less than 10-fold. In some cases, a modified IL-2 peptide provides a first EC50 value for activating the IL-2βγ signaling complex and a second EC50 value for activating the IL-2αβγ signaling complex, wherein the difference between the first and second EC50 values ​​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.

[0137] In some cases, receptor signaling efficacy is measured using the ED50 value. In some cases, a modified IL-2 peptide provides a first ED50 value for activating the IL-2βγ signaling complex and a second ED50 value for activating the IL-2αβγ signaling complex, wherein the difference between the first and second ED50 values ​​is less than 10-fold. In some cases, a modified IL-2 peptide provides a first ED50 value for activating the IL-2βγ signaling complex and a second ED50 value for activating the IL-2αβγ signaling complex, wherein the difference between the first and second ED50 values ​​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.

[0138] In some embodiments, the binding 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 binding moiety (e.g., a polymer, protein, or peptide) is fused to the IL-2 gene at the N-terminus or C-terminus of IL-2, directly or indirectly via a linker peptide. In some cases, the binding moiety is linked to an N-terminal or C-terminal amino acid residue. In some cases, the binding moiety is linked to a reactive group that binds to an N-terminal or C-terminal amino acid residue.

[0139] In some embodiments, IL-2 conjugates with reduced affinity for IL-2Rα can amplify populations of CD4+ helper cells, CD8+ effector natural and memory T cells, natural killer (NK) cells, or natural killer T (NKT) cells. In some cases, the binding motif weakens or blocks the binding of IL-2 to IL-2Rα.

[0140] In some cases, CD4+ helper cells, CD8+ effector innate and memory cells, natural killer (NK) cells, or natural killer T (NKT) cell populations maintain significant activation efficacy relative to wild-type IL-2 peptides via activation by the IL-2Rβγ complex with modified IL-2 peptides. In some cases, activation with modified IL-2 peptides is equivalent to activation with wild-type IL-2 peptides. In other cases, activation with modified IL-2 peptides is superior to activation with wild-type IL-2 peptides. In some cases, the receptor signaling efficacy of the modified IL-2 peptide and IL-2Rβγ complex is higher than that of the wild-type IL-2 peptide and IL-2Rβγ complex. In some cases, the receptor signaling efficacy of modified IL-2 peptides is at least 1 times higher than the corresponding efficacy of wild-type IL-2 peptides. In some cases, the receptor signaling efficacy of modified IL-2 peptides is approximately or at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 300, 400, 500, 1,000, or higher compared to that of wild-type IL-2 peptides. In such cases, the dose or concentration of the modified IL-2 peptide used to achieve similar activation levels in CD4+ helper cells, CD8+ effector natural and memory cells, natural killer (NK) cells, or natural killer T (NKT) cell populations as that of wild-type IL-2 peptides is lower than that used with wild-type IL-2 peptides.

[0141] In some embodiments, populations of CD4+ helper cells, CD8+ effector natural and memory cells, natural killer (NK) cells, or natural killer T (NKT) cells maintain the significant activation efficacy of wild-type IL-2 peptides through activation by the modified IL-2 peptide via the IL-2Rβγ complex. In some cases, the receptor signaling efficacy of the modified IL-2 peptide IL-2Rβγ complex is lower than that of the wild-type IL-2 peptide IL-2Rβγ complex. In some cases, the receptor signaling efficacy of the modified IL-2 peptide is about or at least 1, 2, 3, 4, 5, 10, 20, or 50 times lower than that of the wild-type IL-2 peptide.

[0142] In some embodiments, the modified IL-2 peptide exhibits signal transduction efficacy with both the first receptor of IL-2Rβγ and the second receptor of IL-2Rαβγ. In some cases, the signal transduction efficacy with the first receptor of IL-2Rβγ is improved relative to the wild-type IL-2 peptide. In some cases, the signal transduction efficacy with the first receptor of IL-2Rβγ is weakened relative to the wild-type IL-2 peptide. In some embodiments, the modified IL-2 peptide exhibits signal transduction efficacy with both the first receptor of IL-2Rβγ and the second receptor of IL-2Rαβγ, wherein the signal transduction efficacy with the first receptor is at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 50, 100, 500, 1000, or higher compared to the signal transduction efficacy with the second receptor. In some cases, the efficacy of the first receptor signaling pathway is at least 1-fold or greater than that of the second receptor signaling pathway. In some cases, the efficacy of the first receptor signaling pathway is at least 2-fold or greater than that of the second receptor signaling pathway. In some cases, the efficacy of the first receptor signaling pathway is at least 5-fold or greater than that of the second receptor signaling pathway. In some cases, the efficacy of the first receptor signaling pathway is at least 10-fold or greater than that of the second receptor signaling pathway. In some cases, the efficacy of the first receptor signaling pathway is at least 20-fold or greater than that of the second receptor signaling pathway. In some cases, the efficacy of the first receptor signaling pathway is at least 50-fold or greater than that of the second receptor signaling pathway. In some cases, the efficacy of the first receptor signaling pathway is at least 100-fold or greater than that of the second receptor signaling pathway. In some cases, the efficacy of the first receptor signaling pathway is at least 500-fold or greater than that of the second receptor signaling pathway. In some cases, the efficacy of the first receptor signaling pathway is at least 1000-fold or greater than that of the second receptor signaling pathway. In some cases, the modified IL-2 peptide exhibits higher first-receptor signaling efficacy than the wild-type IL-2 peptide and IL-2Rβγ, while its second-receptor signaling efficacy is lower than that of the wild-type IL-2 peptide and IL-2Rαβγ. In other cases, both receptor signaling efficiencies are lower than their corresponding efficiencies with the wild-type IL-2 peptide. In still other cases, both receptor signaling efficiencies are higher than their corresponding efficiencies with the wild-type IL-2 peptide.

[0143] In some embodiments, IL-2 conjugates reduce adverse toxicity events in individuals administered the IL-2 conjugates. Exemplary adverse toxicity events include eosinophilia, capillary leakage, and vascular leakage syndrome (VLS). In some cases, IL-2 conjugates reduce the incidence of adverse toxicity events by approximately 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or approximately 100% compared to administration of a second individual of wild-type IL-2 or aldehyde. In some cases, IL-2 conjugates reduce the severity of adverse toxicity events by approximately 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or approximately 100% compared to administration of a second individual of wild-type IL-2 or aldehyde.

[0144] In some cases, the adverse toxicity event is eosinophilia. In some cases, IL-2 conjugates reduced the incidence of eosinophil...

Claims

1. An IL-2 conjugate comprising: (i) an amino acid sequence having 80% sequence identity with the amino acid sequence of SEQ ID NO: 3 and (ii) a modified amino acid, not proline, at position 64 of SEQ ID NO: 3, wherein the modified amino acid has the structure of formula (XII) or formula (XIII): (XII) (XIII) Wherein: n is an integer, and the PEG having the -(OCH2CH2)n-OCH3 structure has a molecular weight of about 30 kDa; and the wavy line indicates the covalent bond connecting the amino acid residue at position 63 and the amino acid residue at position 65 in SEQ ID NO: 3, respectively.

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

3.

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

3.

4. The IL-2 conjugate of claim 1, which consists of the amino acid sequence of SEQ ID NO: 3, wherein the modified amino acid sequence of the structure of formula (XII) or (XIII) in SEQ ID NO: 3 is located at position 64 of SEQ ID NO: 3 and is not proline.

5. An IL-2 conjugate comprising an amino acid sequence (i) being at least 97% identical to the amino acid sequence of SEQ ID NO: 30 and (ii) including X at position 64 of SEQ ID NO: 30, wherein X is a lysine analog comprising an azide group having a molecular weight of about 30 kDa covalently linked to a binding moiety containing a dibenzocyclooctynyl group.

6. The IL-2 conjugate of claim 5, wherein the lysine analog containing an azide group is N6-((2-azidoethoxy)-carbonyl)-L-lysine (AzK).

7. The IL-2 conjugate of claim 5 or 6, wherein the lysine analogue covalently linked to the PEG group via the binding moiety is entirely represented by the structure of formula (XII) or formula (XIII): (XII) (XIII) Wherein: n is an integer, and the PEG having the -(OCH2CH2)n-OCH3 structure has a molecular weight of about 30 kDa; and the wavy lines indicate the covalent bonds connecting the first amino acid residue X and the last amino acid residue X in SEQ ID NO: 30, respectively.

8. An IL-2 conjugate comprising an amino acid sequence (i) being at least 98% identical to the amino acid sequence of SEQ ID NO: 30 and (ii) including X at position 64 of SEQ ID NO: 30, wherein X is a lysine analog comprising an azide group having a molecular weight of about 30 kDa covalently linked to a binding moiety containing a dibenzocyclooctynyl group.

9. The IL-2 conjugate of claim 8, wherein the lysine analog containing an azide group is N6-((2-azidoethoxy)-carbonyl)-L-lysine (AzK).

10. The IL-2 conjugate of claim 8 or 9, wherein the lysine analogue covalently linked to the PEG group via the binding moiety is entirely represented by the structure of formula (XII) or formula (XIII): (XII) (XIII) Wherein: n is an integer, and the PEG having the -(OCH2CH2)n-OCH3 structure has a molecular weight of about 30 kDa; and the wavy lines indicate the covalent bonds connecting the first amino acid residue X and the last amino acid residue X in SEQ ID NO: 30, respectively.

11. An IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 30, wherein the X-series lysine analog of SEQ ID NO: 30 comprises an azide group having a molecular weight of about 30 kDa covalently linked to a binding moiety containing a dibenzocyclooctynyl group.

12. The IL-2 conjugate of claim 11, wherein the lysine analog containing an azide group is N6-((2-azidoethoxy)-carbonyl)-L-lysine (AzK).

13. The IL-2 conjugate of claim 11 or 12, wherein the lysine analogue covalently linked to the PEG group via the binding moiety is entirely represented by the structure of formula (XII) or formula (XIII): (XII) (XIII) Wherein: n is an integer, and the PEG having the -(OCH2CH2)n-OCH3 structure has a molecular weight of about 30 kDa; and the wavy lines indicate the covalent bonds connecting the first amino acid residue X and the last amino acid residue X in SEQ ID NO: 30, respectively.

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

15. A pharmaceutical composition comprising an IL-2 conjugate as claimed in claims 1 to 6, 8, 9, 11, and 12.

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

17. The pharmaceutical composition of claim 14 or 15 further comprises sorbitol.

18. The pharmaceutical composition of claim 14 or 15, further comprising polysorbate-20.

19. A dispenser device comprising a pharmaceutical composition as claimed in claim 14 or 15.

20. A syringe comprising a pharmaceutical composition as claimed in claim 14 or 15.

21. A vial containing a pharmaceutical composition as claimed in claim 14 or 15.

22. A method for manufacturing an IL-2 conjugate, comprising: reacting an IL-2 polypeptide, a pharmaceutically acceptable salt thereof, a solvate or a hydrate thereof, with mPEG-DBCO of the following formula, wherein the IL-2 polypeptide comprises a non-natural amino acid having the following structure, wherein the IL-2 polypeptide comprises an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 3, wherein the amino acid residue at position X is replaced by the non-natural amino acid, wherein position X is located at position P64 corresponding to the amino acid position in reference SEQ ID NO: 3, position X-1 indicates the position of the preceding amino acid residue, position X+1 indicates the position of the following amino acid residue, and the wavy line indicates the covalent bond connecting the preceding and following amino acid residues in SEQ ID NO: 3, respectively, wherein n is an integer, and such that mPEG-DBCO comprises mPEG having a molecular weight of about 30 kDa. To form an IL-2 conjugate, wherein the IL-2 conjugate comprises the structure of formula (XII) or formula (XIII): (XII) (XIII).

23. The method of claim 22, wherein the IL-2 polypeptide comprises an amino acid sequence having at least 95% sequence identity with the amino acid sequence of SEQ ID NO:

3.

24. The method of claim 22, wherein the IL-2 polypeptide comprises an amino acid sequence having at least 97% sequence identity with the amino acid sequence of SEQ ID NO:

3.

25. The method of claim 22, wherein the IL-2 polypeptide comprises SEQ ID NO: 3, wherein the non-natural amino acid is located at the position corresponding to P64 of the amino acid position in reference SEQ ID NO:

3.

26. Use of an IL-2 conjugate as claimed in any one of claims 1 to 13 or a pharmaceutical composition as claimed in any one of claims 14 to 18 for the preparation of a medicament for increasing the number of Teff cells and / or NK cells in an individual in need.

27. As claimed in claim 26, wherein the Teff cell comprises CD4+ helper cells, CD8+ effector cells, CD8+ natural cells, CD8+ memory cells, natural killer (NK) cells, natural killer T (NKT) cells, or any combination thereof.

28. For the purposes of claim 26, wherein the individual has cancer.

29. Use of an IL-2 conjugate as claimed in claims 1 to 13 or a pharmaceutical composition as claimed in claims 14 to 18 for the preparation of a medicament for the treatment of cancer in an individual in need.

30. As claimed in paragraphs 28 or 29, wherein the cancer is a solid tumor.

31. As claimed in claim 30, wherein the solid tumor is bladder cancer, bone cancer, brain cancer, breast cancer, colorectal cancer, esophageal cancer, eye cancer, head and neck cancer, kidney cancer, lung cancer, mesothelioma, skin cancer, ovarian cancer, pancreatic cancer, or prostate cancer.

32. As requested in paragraphs 28 or 29, wherein the cancer is a malignant hematologic disease.

33. As claimed in claim 32, wherein the malignant hematologic disease is lymphoma.

34. As claimed in claim 33, wherein the lymphoma is classical Hodgkin lymphoma (cHL) or B-cell lymphoma.

35. As claimed in paragraphs 28 or 29, wherein the IL-2 conjugate is used in combination with an additional therapeutic agent.

36. As claimed in claim 35, wherein the IL-2 conjugate system and the additional therapeutic agent combination are administered sequentially.

37. As claimed in claim 35, wherein the IL-2 conjugate system is administered simultaneously with the additional therapeutic agent combination.

38. As claimed in claims 28 or 29, wherein the IL-2 conjugate is administered in combination with a recipient-mediated T-cell delivery therapy.

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