IL-2 conjugates and methods of use to treat autoimmune diseases

Abstract

20 26 23 40 02 16 S ep 2 02 6 A B S T R A C T O F T H E D I S C L O S U R E 2 0 2 6 2 3 4 0 0 2 1 6 S e p 2 0 2 6

Description

2026234002   16 Sep 2026

[0001] This application claims the benefit of priority to United States Provisional Application No. 62 / 898,478, filed September 10, 2019, United States Provisional Application No. 62 / 900,488, filed September 14, 2019, United States Provisional Application No. 62 / 930,987, filed November 5, 2019, United States Provisional Application No. 62 / 953,075, filed December 23, 2019, and United States Provisional Application No. 63 / 042,393, filed June 22, 2020, the contents of each of which are incorporated herein by reference in their entirety for all purposes. The entire disclosure in the complete specification of our Australian Patent Application No. 2020347154 is by this cross-reference incorporated into the present specification. SEQUENCE LISTING

[0002] The Sequence Listing provided in the electronic format of the sequence listing is incorporated herein by reference in its entirety. INTRODUCTION AND SUMMARY

[0003] Distinct populations of T cells modulate the immune system to maintain immune homeostasis and tolerance. For example, regulatory T (Treg) cells prevent inappropriate responses by the immune system by preventing pathological self-reactivity. In some instances, modulation of the different populations of T cells provides an option for treatment of a disease or indication.

[0004] Described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 3 in which at least one amino acid residue in the IL-2 conjugate is replaced by the structure of Formula (I): Formula (I); wherein: Z is CH2 and Y is     0       0 2026234002   16 Sep 2026 Y is CH2 and Z is Y is CH2 and Z is Z is CH2 and Y is W is a PEG group having an average molecular weight selected from 5kDa, lOkDa, 15kDa, 20kDa, 25kDa, 30kDa, 35kDa, 40kDa, 45kDa, 50kDa, 55 kDa, and 60kDa; and X has the structure: X-l indicates the point of attachment to the preceding amino acid residue; and X+l indicates the point of attachment to the following amino acid residue. In some embodiments, the IL-2 conjugate is a pharmaceutically acceptable salt, solvate, or hydrate thereof. Further provided H herein are IL-2 conjugates wherein Z is CEE and Y is O O                Further H provided herein are IL-2 conjugates wherein Y is CEE and Z is O O Further provided herein are IL-2 conjugates wherein Z is CEE and Y is O                            , or a pharmaceutically acceptable salt, solvate, or hydrate thereof. Further provided herein are IL-2 conjugates wherein Z is CEE and Y is N        W O                        , and W is a PEG group having an average molecular weight selected from 15kDa, 20kDa, 25kDa, 30kDa, 35kDa, 40kDa, 45kDa, 50kDa, 55 kDa, and 60kDa. Further 2026234002   16 Sep 2026 o N        W provided herein are IL-2 conjugates wherein Y is CH2 and Z is O                         . Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight selected from 5kDa, lOkDa, 20kDa, 30kDa, 40kDa, or 50kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 5kDa. Here and throughout, embodiments of Z and Y also encompass a pharmaceutically acceptable salt, solvate, or hydrate thereof. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 30kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 35kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 40kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 45kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 50kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 55kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 60kDa. Further provided herein are IL-2 conjugates wherein the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is selected from Pl, T2, S3, S4, S5, T6, K7, K8, Q10, Lil, E14, H15, L17, L18, D19, Q21, M22, N25, G26, N28, N29, Y30, K31, K34, T36, M45, P46, K47, A49, T50, E51, L52, K53, H54, Q56, E59, E66, N70, Q73, S74, K75, N76, F77, H78, R80, P81, R82, D83, S86, N87,188, V90,191, L93, E94, K96, G97, S98, E99, T100, T101, F102, Ml03, C104, E105, Y106, A107, D108, D108 in the N87R variant, E109, T110, Alli, T112, El 15, N118, RI 19, T122, F123, S124, Q125, S126, S129, T130, L131, and T132. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is selected from K8, H15, L18, D19, M22, N25, N87, V90,191, L93, E94, K96, G97, S98, E99, D108 in the N87R variant, N118, T122, S124, Q125, S126, S129, and T130. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is selected from K8, Hl 5, LI 8, D19, M22, N25, N87, V90, E99, D108 in the N87R variant, N118, T122, S124, and T130. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is K8. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is Hl 5. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is LI 8. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is D19. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (I) in the amino 2026234002   16 Sep 2026 acid sequence of the IL-2 conjugate is M22. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is N25. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is N87. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is V90. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is E99. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is D108 in the N87R variant. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is N118. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is T122. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is S124. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is T130.

[0005] Described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 4 in which at least one amino acid residue in the IL-2 conjugate is replaced by the structure of Formula (I): Formula (I); wherein: Z is CEE and Y is 6 O Y is CEL and Z is O O 2026234002   16 Sep 2026 Y is CH2 and Z is W is a PEG group having an average molecular weight selected from 5kDa, lOkDa, 15kDa, 20kDa, 25kDa, 30kDa, 35kDa, 40kDa, 45kDa, 50kDa, 55 kDa, and 60kDa; X has the structure: X-l indicates the point of attachment to the preceding amino acid residue; and X+l indicates the point of attachment to the following amino acid residue. In some embodiments, the IL- 2 conjugate is a pharmaceutically acceptable salt, solvate, or hydrate thereof. Further provided herein are IL-2 conjugates wherein Z is CH2 and Y is O O Further provided herein are IL-2 conjugates wherein Y is CH2 and Z is . Further provided O W herein are IL-2 conjugates wherein Z is CH2 and Y is O                         . Further provided herein are IL-2 conjugates wherein Z is CH2 and Y is O                         , and W is a PEG group having an average molecular weight selected from 15kDa, 20kDa, 25kDa, 30kDa, 35kDa, 40kDa, 45kDa, 50kDa, 55 kDa, and 60kDa. Further provided herein are IL-2 conjugates wherein o \N       N        w Y is CH2 and Z is O                         . Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight selected from 5kDa, lOkDa, 20kDa, 30kDa, 40kDa, or 50kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 5kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 30kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 35kDa. Further provided herein are IL-2 conjugates wherein 2026234002   16 Sep 2026 the PEG group has an average molecular weight of 40kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 45kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 50kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 55kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 60kDa. Further provided herein are IL-2 conjugates wherein the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is selected from Al, P2, T3, S4, S5, S6, T7, K8, K9, QI 1, L12, E15, H16, L18, L19, D20, Q22, M23, N26, G27, N29, N30, Y31, K32, K35, T37, M46, P47, K48, A50, T51, E52, L53, H55, Q57, E60, E67, N71, Q74, S75, K76, N77, F78, H79, R81, P82, R83, D84, S87, N88,189, V91,192, L94, E95, K97, G98, S99, E100, T101, T102, F103, M104, C105, E106, Y107, A108, D109, D109 in the N88R variant, El 10, Till, Al 12, T113, El 16, N119, R120, T123, S125, Q126, S127, S130, T131, L132, and T133. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is selected from K9, H16, L19, D20, M23, N26, N88, V91,192, L94, E95, K97, G98, S99, E100, D109 in the N88R variant, N119, T123, S125, Q126, S127, S130, andT131. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is selected from K9, H16, L19, D20, M23, N26, N88, V91, E100, D109 in the N88R variant, N119, T123, S125, and T131. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is K9. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is H16. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is LI 9. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is D20. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is M23. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is N26. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is N88. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is V91. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is El 00. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is D109 in the N88R variant. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is N119. Further 2026234002   16 Sep 2026 described herein are IL-2 conjugates wherein the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is T123. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is S125. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is and T131.

[0006] Described herein are IL-2 conjugates comprising the amino acid sequence of any one of SEQ ID NOS: 34-48, and 199-213, wherein [AzKPEG] has the structure of Formula (II) or Formula (III), or a mixture of Formula (II) and Formula (III): Formula (II); Formula (III); wherein: W is a PEG group having an average molecular weight selected from 5kDa, lOkDa, 15kDa, 20kDa, 25kDa, 30kDa, 35kDa, 40kDa, 45kDa, 50kDa, 55kDa, and 60kDa; and X has the structure: X-1 I jvw X-1 indicates the point of attachment to the preceding amino acid residue; and X+l indicates the point of attachment to the following amino acid residue. In some embodiments, the IL-2 conjugate is a pharmaceutically acceptable salt, solvate, or hydrate thereof. Here and throughout, embodiments of Formula (II) and / or (III) also encompass a pharmaceutically acceptable salt, solvate, or hydrate thereof. Further described herein are IL-2 conjugates wherein the [AzK PEG] is a mixture of 2026234002   16 Sep 2026 Formula (II) and Formula (III). Further described herein are IL-2 conjugates wherein the [AzKPEG] has the structure of formula (II): Formula (II). Here and throughout, the structure of Formula (II) encompasses pharmaceutically acceptable salts, solvates, or hydrates thereof. Further described herein are IL-2 conjugates wherein the IL-2 conjugate has the amino acid sequence of any one of SEQ ID NOS: 34-48. Further described herein are IL-2 conjugates wherein W is a PEG group having an average molecular weight selected from 5kDa, lOkDa, 15kDa, 20kDa, 25kDa, 30kDa, 35kDa, 40kDa, 45kDa, 50kDa, 55kDa, or 60kDa. Further described herein are IL-2 conjugates wherein W is a PEG group having an average molecular weight selected from 25kDa, 30kDa, 35kDa, 40kDa, 45kDa, 50kDa, 55kDa, or 60kDa. Further described herein are IL-2 conjugates wherein W is a PEG group having an average molecular weight of 5kDa. Further described herein are IL-2 conjugates wherein W is a PEG group having an average molecular weight of 30kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 35kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 40kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 45kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 50kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 55kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 60kDa. Further described herein are IL-2 conjugates wherein the IL-2 conjugate has the amino acid sequence of any one of SEQ ID NOS: 199-213. Further described herein are IL-2 conjugates wherein W is a PEG group having an average molecular weight selected from 5kDa, lOkDa, 15kDa, 20kDa, 25kDa, 30kDa, 35kDa, 40kDa, 45kDa, 50kDa, 55kDa, or 60kDa. Further described herein are IL-2 conjugates wherein W is a PEG group having an average molecular weight selected from 50kDa and 30kDa. Further described herein are IL-2 conjugates wherein W is a PEG group having an average molecular weight of 5kDa. Further described herein are IL-2 conjugates wherein W is a PEG group having an average molecular weight of 30kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 35kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 40kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 45kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular 2026234002   16 Sep 2026 weight of 50kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 55kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 60kDa. Further described herein are IL-2 conjugates wherein the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 35 or 200. Further described herein are IL-2 conjugates wherein W is a PEG group having an average molecular weight selected from 5kDa, lOkDa, 15kDa, 20kDa, 25kDa, 30kDa, 35kDa, 40kDa, 45kDa, 50kDa, 55kDa, or 60kDa. Further described herein are IL-2 conjugates wherein W is a PEG group having an average molecular weight selected from 50kDa and 30kDa. Further described herein are IL-2 conjugates wherein W is a PEG group having an average molecular weight of 5kDa. Further described herein are IL-2 conjugates wherein W is a PEG group having an average molecular weight of 30kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 35kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 40kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 45kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 50kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 55kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 60kDa. Further described herein are IL-2 conjugates wherein the [AzKPEG] has the structure of formula (III) Formula (III). Here and throughout, the structure of Formula (III) encompasses pharmaceutically acceptable salts, solvates, or hydrates thereof. Further described herein are IL-2 conjugates wherein the IL-2 conjugate has the amino acid sequence of any one of SEQ ID NOS: 34-48. Further described herein are IL-2 conjugates wherein W is a PEG group having an average molecular weight selected from 5kDa, lOkDa, 15kDa, 20kDa, 25kDa, 30kDa, 35kDa, 40kDa, 45kDa, 50kDa, 55kDa, or 60kDa. Further described herein are IL-2 conjugates wherein W is a PEG group having an average molecular weight selected from 50kDa and 30kDa. Further described herein are IL-2 conjugates wherein W is a PEG group having an average molecular weight of 5kDa. Further described herein are IL-2 conjugates wherein W is a PEG group having an average molecular weight of 30kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 35kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 40kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 45kDa. Further 2026234002   16 Sep 2026 provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 50kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 55kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 60kDa. Further described herein are IL-2 conjugates wherein the IL-2 conjugate has the amino acid sequence of any one of SEQ ID NOS: 199-213. Further described herein are IL-2 conjugates wherein W is a PEG group having an average molecular weight selected from 5kDa, lOkDa, 15kDa, 20kDa, 25kDa, 30kDa, 35kDa, 40kDa, 45kDa, 50kDa, 55kDa, or 60kDa. Further described herein are IL-2 conjugates wherein W is a PEG group having an average molecular weight selected from 50kDa and 30kDa. Further described herein are IL-2 conjugates wherein W is a PEG group having an average molecular weight of 5kDa. Further described herein are IL-2 conjugates wherein W is a PEG group having an average molecular weight of 30kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 35kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 40kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 45kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 50kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 55kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 60kDa. Further provided herein are IL-2 conjugates wherein W is a linear or branched PEG group. Further provided herein are IL-2 conjugates wherein W is a linear PEG group. Further provided herein are IL-2 conjugates wherein W is a branched PEG group. Further provided herein are IL-2 conjugates wherein W is a methoxy PEG group. Further described herein are IL-2 conjugates wherein the methoxy PEG group is linear or branched. Further described herein are IL-2 conjugates wherein the methoxy PEG group is linear. Further described herein are IL-2 conjugates wherein the methoxy PEG group is branched.

[0007] Described herein are IL-2 conjugates comprising the amino acid sequence of any one of SEQ ID NOS: 49-63 and 214-228, wherein [AzK_PEG50kDa] has the structure of Formula (II) or Formula (III), or a mixture of Formula (II) and Formula (III): Formula (II); 2026234002   16 Sep 2026 Formula (III); wherein: W is a PEG group having an average molecular weight of 50kDa; and X has the structure: X-1 I JVW X-1 indicates the point of attachment to the preceding amino acid residue; and X+l indicates the point of attachment to the following amino acid residue. In some embodiments, the IL-2 conjugate is a pharmaceutically acceptable salt, solvate, or hydrate thereof. Further described herein are IL-2 conjugates wherein the IL-2 conjugate has the amino acid sequence of any one of SEQ ID NOS: 4963. Further described herein are IL-2 conjugates wherein the IL-2 conjugate has the amino acid sequence of any one of SEQ ID NOS: 214-228. Further described herein are IL-2 conjugates wherein the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 50 or 215. Further described herein are IL-2 conjugates wherein the [AzK_PEG50kDa] has the structure of formula (II) Formula (II). Further described herein are IL-2 conjugates wherein the IL-2 conjugate has the amino acid sequence of any one of SEQ ID NOS: 49-63. Further described herein are IL-2 conjugates wherein the IL-2 conjugate has the amino acid sequence of any one of SEQ ID NOS: 214-228. Further described herein are IL-2 conjugates wherein the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 50 or 215. Further described herein are IL-2 conjugates wherein the [AzK_PEG50kDa] has the structure of formula (III) 2026234002   16 Sep 2026 Formula (III). Further described herein are IL-2 conjugates wherein the IL-2 conjugate has the amino acid sequence of any one of SEQ ID NOS: 49-63. Further described herein are IL-2 conjugates wherein the IL-2 conjugate has the amino acid sequence of any one of SEQ ID NOS: 214-228. Further described herein are IL-2 conjugates wherein the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 50 or 215.

[0008] Described herein are IL-2 conjugates comprising the amino acid sequence of any one of SEQ ID NOS: 64-78 and 229-243, wherein [AzK_PEG30kDa] has the structure of Formula (II) or Formula (III), or is a mixture of the structures of Formula (II) and Formula (III): Formula (II); Formula (III); wherein: W is a PEG group having an average molecular weight of 30kDa; and X has the structure: X-1 X-l indicates the point of attachment to the preceding amino acid residue; and 2026234002   16 Sep 2026 X+l indicates the point of attachment to the following amino acid residue. In some embodiments, the IL-2 conjugate is a pharmaceutically acceptable salt, solvate, or hydrate thereof. Further described herein are IL-2 conjugates wherein the IL-2 conjugate has the amino acid sequence of any one of SEQ ID NOS: 6478. Further described herein are IL-2 conjugates wherein the IL-2 conjugate has the amino acid sequence of any one of SEQ ID NOS: 229-243. Further described herein are IL-2 conjugates wherein the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 65 or 230. Further described herein are IL-2 conjugates wherein the [AzK_PEG30kDa] has the structure of formula (II): Formula (II). Further described herein are IL-2 conjugates wherein the IL-2 conjugate has the amino acid sequence of any one of SEQ ID NOS: 64-78. Further described herein are IL-2 conjugates wherein the IL-2 conjugate has the amino acid sequence of any one of SEQ ID NOS: 229-243. Further described herein are IL-2 conjugates wherein the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 65 or 230. Further described herein are IL-2 conjugates wherein the [AzK_PEG30kDa] has the structure of formula (III) Formula (III). Further described herein are IL-2 conjugates wherein the IL-2 conjugate has the amino acid sequence of any one of SEQ ID NOS: 64-78. Further described herein are IL-2 conjugates wherein the IL-2 conjugate has the amino acid sequence of any one of SEQ ID NOS: 229-243. Further described herein are IL-2 conjugates wherein the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 65 or 230.

[0009] Described herein are IL-2 conjugates comprising the amino acid sequence of any one of SEQ ID NOS: 34-48 and 199-213, wherein [AzKPEG] is a mixture of the structures of Formula (II) and Formula (III): 2026234002   16 Sep 2026 Formula (II); Formula (III); wherein: W is a PEG group having an average molecular weight selected from 5kDa, lOkDa, 15kDa, 20kDa, 25kDa, 30kDa, 35kDa, 40kDa, 45kDa, 50kDa, 55 kDa, and 60kDa; and X has the structure: X-1 I JVVV X-1 indicates the point of attachment to the preceding amino acid residue; and X+l indicates the point of attachment to the following amino acid residue. In some embodiments, the IL-2 conjugate is a pharmaceutically acceptable salt, solvate, or hydrate thereof. Further described herein are IL-2 conjugates wherein the ratio of the amount of the structure of Formula (II) to the amount of the structure of Formula (III) comprising the total amount of [AzKPEG] in the IL-2 conjugate is about 1:1. Further described herein are IL-2 conjugates wherein the ratio of the amount of the structure of Formula (II) to the amount of the structure of Formula (III) comprising the total amount of [AzK PEG] in the IL-2 conjugate is greater than 1:1. Further described herein are IL-2 conjugates wherein the ratio of the amount of the structure of Formula (II) to the amount of the structure of Formula (III) comprising the total amount of [AzK PEG] in the IL-2 conjugate is less than 1:1. Further described herein are IL-2 conjugates wherein W is a linear or branched PEG group. Further described herein are IL-2 conjugates wherein W is a linear PEG group. Further described herein are IL-2 conjugates wherein W is a branched PEG group. Further described herein are IL-2 conjugates wherein W is a methoxy PEG group. Further described herein are IL-2 conjugates wherein the methoxy PEG group is linear or branched. Further 2026234002   16 Sep 2026 described herein are IL-2 conjugates wherein the methoxy PEG group is linear. Further described herein are IL-2 conjugates wherein the methoxy PEG group is branched.

[0010] Described herein are IL-2 conjugates comprising the amino acid sequence of any one of SEQ ID NOS: 49-63 and 214-228, wherein [AzK_PEG50kDa] is a mixture of the structures of Formula (II) and Formula (III): Formula (II); Formula (III); wherein: W is a PEG group having an average molecular weight of 50kDa; and X has the structure: X-1 i ^WV X-1 indicates the point of attachment to the preceding amino acid residue; and X+l indicates the point of attachment to the following amino acid residue. In some embodiments, the IL-2 conjugate is a pharmaceutically acceptable salt, solvate, or hydrate thereof. Further described herein are IL-2 conjugates wherein the ratio of the amount of the structure of Formula (II) to the amount of the structure of Formula (III) comprising the total amount of [AzK_PEG50kDa] in the IL-2 conjugate is about 1:1. Further described herein are IL-2 conjugates wherein the ratio of the amount of the structure of Formula (II) to the amount of the structure of Formula (III) comprising the total amount of [AzK_PEG50kDa] in the IL-2 conjugate is greater than 1:1. Further described herein are IL-2 conjugates wherein the ratio of the amount of the structure of Formula (II) to the amount of the structure of Formula (III) comprising the total amount of [AzK_PEG50kDa] in the IL-2 conjugate is less than 1:1. 2026234002   16 Sep 2026

[0011] Described herein are IL-2 conjugates comprising the amino acid sequence of any one of SEQ ID NOS: 64-78 and 229-243, wherein [AzK_PEG30kDa] is a mixture of the structures of Formula (II) and Formula (III): Formula (II); Formula (III); wherein: W is a PEG group having an average molecular weight of 30kDa; and X has the structure: X-1 I JVW X-1 indicates the point of attachment to the preceding amino acid residue; and X+l indicates the point of attachment to the following amino acid residue. In some embodiments, the IL-2 conjugate is a pharmaceutically acceptable salt, solvate, or hydrate thereof. Further described herein are IL-2 conjugates wherein the ratio of the amount of the structure of Formula (II) to the amount of the structure of Formula (III) comprising the total amount of [AzK_PEG30kDa] in the IL-2 conjugate is about 1:1. Further described herein are IL-2 conjugates wherein the ratio of the amount of the structure of Formula (II) to the amount of the structure of Formula (III) comprising the total amount of [AzK_PEG30kDa] in the IL-2 conjugate is greater than 1:1. Further described herein are IL-2 conjugates wherein the ratio of the amount of the structure of Formula (II) to the amount of the structure of Formula (III) comprising the total amount of [AzK_PEG30kDa] in the IL-2 conjugate is less than 1:1. 2026234002   16 Sep 2026

[0012] Described herein are IL-2 conjugates comprising the amino acid sequence of any one of SEQ ID NOS: 154-168 and 109-123, wherein [AzKLIPEG] has the structure of Formula (IV) or Formula (V), or a mixture of Formula (IV) and Formula (V): Formula (IV); Formula (V); wherein: W is a PEG group having an average molecular weight selected from 5kDa, lOkDa, 15kDa, 20kDa, 25kDa, 30kDa, 35kDa, 40kDa, 45kDa, 50kDa, 55 kDa, and 60kDa; and X has the structure: X-1 I JVW X-1 indicates the point of attachment to the preceding amino acid residue; and X+l indicates the point of attachment to the following amino acid residue. In some embodiments, the IL-2 conjugate is a pharmaceutically acceptable salt, solvate, or hydrate thereof. Here and throughout, embodiments of Formula (IV) and / or (V) also encompass a pharmaceutically acceptable salt, solvate, or hydrate thereof. Further described herein are IL-2 conjugates wherein the [AzK LI PEG] is a mixture of Formula (IV) and Formula (V). Further described herein are IL-2 conjugates wherein the [AzK LI PEG] has the structure of Formula (IV): 2026234002   16 Sep 2026 Formula (IV). Here and throughout, the structure of Formula (IV) encompasses pharmaceutically acceptable salts, solvates, or hydrates thereof. Further described herein are IL-2 conjugates wherein the IL-2 conjugate has the amino acid sequence of any one of SEQ ID NOS: 109-123. Further described herein are IL-2 conjugates wherein W is a PEG group having an average molecular weight selected from 5kDa, lOkDa, 15kDa, 20kDa, 25kDa, 30kDa, 35kDa, 40kDa, 45kDa, 50kDa, 55kDa, or 60kDa. Further described herein are IL-2 conjugates wherein W is a PEG group having an average molecular weight selected from 50kDa and 30kDa. Further described herein are IL-2 conjugates wherein W is a PEG group having an average molecular weight of 5kDa. Further described herein are IL-2 conjugates wherein W is a PEG group having an average molecular weight of 30kDa. Further described herein are IL-2 conjugates wherein the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 155 or 110. Further described herein are IL-2 conjugates wherein W is a PEG group having an average molecular weight selected from 5kDa, lOkDa, 15kDa, 20kDa, 25kDa, 30kDa, 35kDa, 40kDa, 45kDa, 50kDa, 55kDa, or 60kDa. Further described herein are IL-2 conjugates wherein W is a PEG group having an average molecular weight selected from 5kDa and 30kDa. Further described herein are IL-2 conjugates wherein W is a PEG group having an average molecular weight of 5kDa. Further described herein are IL-2 conjugates wherein W is a PEG group having an average molecular weight of 30kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 35kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 40kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 45kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 50kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 55kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 60kDa. Further described herein are IL-2 conjugates wherein the [AzK LI PEG] has the structure of Formula (V) Formula (V) 2026234002   16 Sep 2026 . Here and throughout, the structure of Formula (V) encompasses pharmaceutically acceptable salts, solvates, or hydrates thereof. Further described herein are IL-2 conjugates wherein the IL-2 conjugate has the amino acid sequence of any one of SEQ ID NOS: 109-123. Further described herein are IL-2 conjugates wherein W is a PEG group having an average molecular weight selected from 5kDa, lOkDa, 15kDa, 20kDa, 25kDa, 30kDa, 35kDa, 40kDa, 45kDa, 50kDa, 55kDa, or 60kDa. Further described herein are IL-2 conjugates wherein W is a PEG group having an average molecular weight selected from 50kDa and 30kDa. Further described herein are IL-2 conjugates wherein W is a PEG group having an average molecular weight of 5kDa. Further described herein are IL-2 conjugates wherein W is a PEG group having an average molecular weight of 30kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 35kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 40kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 45kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 50kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 55kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 60kDa. Further described herein are IL-2 conjugates wherein the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 155 or 110. Further described herein are IL-2 conjugates wherein W is a PEG group having an average molecular weight selected from 5kDa, lOkDa, 15kDa, 20kDa, 25kDa, 30kDa, 35kDa, 40kDa, 45kDa, 50kDa, 55kDa, or 60kDa. Further described herein are IL-2 conjugates wherein W is a PEG group having an average molecular weight selected from 50kDa and 30kDa. Further described herein are IL-2 conjugates wherein W is a PEG group having an average molecular weight of 5kDa. Further described herein are IL-2 conjugates wherein W is a PEG group having an average molecular weight of 30kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 35kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 40kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 45kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 50kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 55kDa. Further provided herein are IL-2 conjugates wherein the PEG group has an average molecular weight of 60kDa. Further described herein are IL-2 conjugates wherein W is a linear or branched PEG group. Further described herein are IL-2 conjugates wherein W is a linear PEG group. Further described herein are IL-2 conjugates wherein W is a branched PEG group. Further described herein are IL-2 conjugates wherein W is a methoxy PEG group. Further described herein are IL-2 conjugates wherein the methoxy PEG group 2026234002   16 Sep 2026 is linear or branched. Further described herein are IL-2 conjugates wherein the methoxy PEG group is linear. Further described herein are IL-2 conjugates wherein the methoxy PEG group is branched.

[0013] Described herein are IL-2 conjugates comprising the amino acid sequence of any one of SEQ ID NOS: 169-183 and 124-138, wherein [AzK_Ll_PEG50kDa] has the structure of Formula (IV) or Formula (V), or a mixture of Formula (IV) and Formula (V): Formula (IV); Formula (V); wherein: W is a PEG group having an average molecular weight of 50kDa; and X has the structure: X-1 i ^WV X-1 indicates the point of attachment to the preceding amino acid residue; and X+l indicates the point of attachment to the following amino acid residue. In some embodiments, the IL-2 conjugate is a pharmaceutically acceptable salt, solvate, or hydrate thereof. Further described herein are IL-2 conjugates wherein the IL-2 conjugate has the amino acid sequence of any one of SEQ ID NOS: 169-183. Further described herein are IL-2 conjugates wherein the IL-2 conjugate has the amino acid sequence of any one of SEQ ID NOS: 124-138. Further described herein are IL-2 conjugates wherein the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 170 or 125. Further described herein are IL-2 conjugates wherein the [AzK_Ll_PEG50kDa] has the structure of Formula (IV) 2026234002   16 Sep 2026 Formula (IV). Further described herein are IL-2 conjugates wherein the IL-2 conjugate has the amino acid sequence of any one of SEQ ID NOS: 169-183. Further described herein are IL-2 conjugates wherein the IL-2 conjugate has the amino acid sequence of any one of SEQ ID NOS: 124-138. Further described herein are IL-2 conjugates wherein the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 170 or 125. Further described herein are IL-2 conjugates wherein the [AzK_Ll_PEG50kDa] has the structure of Formula (V) Formula (V). Further described herein are IL-2 conjugates wherein the IL-2 conjugate has the amino acid sequence of any one of SEQ ID NOS: 169-183. Further described herein are IL-2 conjugates wherein the IL-2 conjugate has the amino acid sequence of any one of SEQ ID NOS: 124-138. Further described herein are IL-2 conjugates wherein the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 170 or 125.

[0014] Described herein are IL-2 conjugates comprising the amino acid sequence of any one of SEQ ID NOS: 184-198 and 139-153, wherein [AzK_Ll_PEG30kDa] has the structure of Formula (IV) or Formula (V), or is a mixture of the structures of Formula (IV) and Formula (V): Formula (IV); 2026234002   16 Sep 2026 Formula (V); wherein: W is a PEG group having an average molecular weight of 30kDa; and X has the structure: X-1 I jwv X-1 indicates the point of attachment to the preceding amino acid residue; and X+l indicates the point of attachment to the following amino acid residue. In some embodiments, the IL-2 conjugate is a pharmaceutically acceptable salt, solvate, or hydrate thereof. Further described herein are IL-2 conjugates wherein the IL-2 conjugate has the amino acid sequence of any one of SEQ ID NOS: 184-198. Further described herein are IL-2 conjugates wherein the IL-2 conjugate has the amino acid sequence of any one of SEQ ID NOS: 139-153. Further described herein are IL-2 conjugates wherein the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 185 or 140. Further described herein are IL-2 conjugates wherein the [AzK_Ll_PEG30kDa] has the structure of Formula (IV): Formula (IV). Further described herein are IL-2 conjugates wherein the IL-2 conjugate has the amino acid sequence of any one of SEQ ID NOS: 184-198. Further described herein are IL-2 conjugates wherein the IL-2 conjugate has the amino acid sequence of any one of SEQ ID NOS: 139-153. Further described herein are IL-2 conjugates wherein the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 185 or 140. Further described herein are IL-2 conjugates wherein the [AzK_Ll_PEG30kDa] has the structure of Formula (V) Formula (V). Further described herein are IL-2 conjugates wherein the IL-2 conjugate has the amino acid sequence of any one of SEQ ID NOS: 184-198. Further described herein are IL-2 conjugates wherein the 2026234002   16 Sep 2026 IL-2 conjugate has the amino acid sequence of any one of SEQ ID NOS: 139-153. Further described herein are IL-2 conjugates wherein the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 185 or 140.

[0015] Described herein are IL-2 conjugates comprising the amino acid sequence of any one of SEQ ID NOS: 154-168 and 109-123, wherein [AzkLIPEG] is a mixture of the structures of Formula (IV) and Formula (V): Formula (IV); Formula (V); wherein: W is a PEG group having an average molecular weight selected from 5kDa, lOkDa, 15kDa, 20kDa, 25kDa, 30kDa, 35kDa, 40kDa, 45kDa, 50kDa, 55 kDa, and 60kDa; and X has the structure: X-1 I JVW X-1 indicates the point of attachment to the preceding amino acid residue; and X+l indicates the point of attachment to the following amino acid residue. In some embodiments, the IL-2 conjugate is a pharmaceutically acceptable salt, solvate, or hydrate thereof. Further described herein are IL-2 conjugates wherein the ratio of the amount of the structure of Formula (IV) to the amount of the structure of Formula (V) comprising the total amount of [AzKLIPEG] in the IL-2 conjugate is about 1:1. Further described herein are IL-2 conjugates wherein the ratio of the amount of the structure of Formula (IV) to the amount of the structure of Formula (V) comprising the total amount of [AzK LI PEG] in the IL-2 conjugate is greater than 1:1. Further described herein are IL-2 conjugates 2026234002   16 Sep 2026 wherein the ratio of the amount of the structure of Formula (IV) to the amount of the structure of Formula (V) comprising the total amount of [AzKLIPEG] in the IL-2 conjugate is less than 1:1. Further described herein are IL-2 conjugates wherein W is a linear or branched PEG group. Further described herein are IL-2 conjugates wherein W is a linear PEG group. Further described herein are IL-2 conjugates wherein W is a branched PEG group. Further described herein are IL-2 conjugates wherein W is a methoxy PEG group. Further described herein are IL-2 conjugates wherein the methoxy PEG group is linear or branched. Further described herein are IL-2 conjugates wherein the methoxy PEG group is linear. Further described herein are IL-2 conjugates wherein the methoxy PEG group is branched.

[0016] Described herein are IL-2 conjugates comprising the amino acid sequence of any one of SEQ ID NOS: 169-183 and 124-138, wherein [AzK_Ll_PEG50kDa] is a mixture of the structures of Formula (IV) and Formula (V): Formula (IV); Formula (V); wherein: W is a PEG group having an average molecular weight of 50kDa; and X has the structure: X-1 i jwv X-1 indicates the point of attachment to the preceding amino acid residue; and X+l indicates the point of attachment to the following amino acid residue. In some embodiments, the IL-2 conjugate is a pharmaceutically acceptable salt, solvate, or hydrate thereof. Further described herein are IL-2 conjugates wherein the ratio of the amount of the structure of Formula (IV) to the amount of the 2026234002   16 Sep 2026 structure of Formula (V) comprising the total amount of [AzK_Ll_ PEG50kDa] in the IL-2 conjugate is about 1:1. Further described herein are IL-2 conjugates wherein the ratio of the amount of the structure of Formula (IV) to the amount of the structure of Formula (V) comprising the total amount of [AzK_Ll_PEG50kDa] in the IL-2 conjugate is greater than 1:1. Further described herein are IL-2 conjugates wherein the ratio of the amount of the structure of Formula (IV) to the amount of the structure of Formula (V) comprising the total amount of [AzK_Ll_PEG50kDa] in the IL-2 conjugate is less than 1:1.

[0017] Described herein are IL-2 conjugates comprising the amino acid sequence of any one of SEQ ID NOS: 184-198 and 139-153, wherein [AzKLl PEG30kDa] is a mixture of the structures of Formula (IV) and Formula (V): Formula (IV); Formula (V); wherein: W is a PEG group having an average molecular weight of 30kDa; and X has the structure: X-1 I < / VVV X-1 indicates the point of attachment to the preceding amino acid residue; and X+l indicates the point of attachment to the following amino acid residue. In some embodiments, the IL-2 conjugate is a pharmaceutically acceptable salt, solvate, or hydrate thereof. Further described herein are IL-2 conjugates wherein the ratio of the amount of the structure of Formula (IV) to the amount of the structure of Formula (V) comprising the total amount of [AzK_Ll_PEG30kDa] in the IL-2 conjugate is 2026234002   16 Sep 2026 about 1:1. Further described herein are IL-2 conjugates wherein the ratio of the amount of the structure of Formula (IV) to the amount of the structure of Formula (V) comprising the total amount of [AzK_Ll_PEG30kDa] in the IL-2 conjugate is greater than 1:1. Further described herein are IL-2 conjugates wherein the ratio of the amount of the structure of Formula (IV) to the amount of the structure of Formula (V) comprising the total amount of [AzK_Ll_PEG30kDa] in the IL-2 conjugate is less than 1:1.

[0018] Described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 3 in which at least one amino acid residue in the IL-2 conjugate is replaced by the structure of Formula (VI) or (VII), or a mixture of (VI) and (VII): (Vil); wherein: n is an integer in the range from about 2 to about 5000; and X-l indicates the point of attachment to the preceding amino acid residue; and X+l indicates the point of attachment to the following amino acid residue. In some embodiments, the IL-2 conjugate is a pharmaceutically acceptable salt, solvate, or hydrate thereof. Here and throughout, embodiments of Formula (VI) and / or (VII) also encompass a pharmaceutically acceptable salt, solvate, or hydrate thereof. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VI) or (VII), or a mixture of (VI) and (VII), in the amino acid sequence of the IL-2 conjugate is 2026234002   16 Sep 2026 selected from Pl, T2, S3, S4, S5, T6, K7, K8, Q10, Lil, E14, H15, L17, L18, D19, Q21, M22, N25, G26, N28, N29, Y30, K31, K34, T36, M45, P46, K47, A49, T50, E51, L52, K53, H54, Q56, E59, E66, N70, Q73, S74, K75, N76, F77, H78, R80, P81, R82, D83, S86, N87,188, V90,191, L93, E94, K96, G97, S98, E99, T100, T101, F102, M103, C104, E105, Y106, A107, D108, D108 in the N87R variant, E109, T110, Alli, T112, E115, N118, R119, T122, F123, S124, Q125, S126, S129, T130, L131, and T132. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VI) or (VII), or a mixture of (VI) and (VII), in the amino acid sequence of the IL-2 conjugate is selected from K8, H15, L18, D19, M22, N25, N87, V90,191, L93, E94, K96, G97, S98, E99, D108 in the N87R variant, N118, T122, S124, Q125, S126, S129, andT130. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VI) or (VII), or a mixture of (VI) and (VII), in the amino acid sequence of the IL-2 conjugate is selected from K8, H15, L18, D19, M22, N25, N87, V90, E99, D108 in the N87R variant, N118, T122, S124, and T130. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VI) or (VII), or a mixture of (VI) and (VII), in the amino acid sequence of the IL-2 conjugate is selected from in the amino acid sequence of the IL-2 conjugate is K8. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VI) or (VII), or a mixture of (VI) and (VII), in the amino acid sequence of the IL-2 conjugate is H15. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VI) or (VII), or a mixture of (VI) and (VII), in the amino acid sequence of the IL-2 conjugate is LI 8. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VI) or (VII), or a mixture of (VI) and (VII), in the amino acid sequence of the IL-2 conjugate is DI 9. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VI) or (VII), or a mixture of (VI) and (VII), in the amino acid sequence of the IL-2 conjugate is M22. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VI) or (VII), or a mixture of (VI) and (VII), in the amino acid sequence of the IL-2 conjugate is N25. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VI) or (VII), or a mixture of (VI) and (VII), in the amino acid sequence of the IL-2 conjugate is N87. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VI) or (VII), or a mixture of (VI) and (VII), in the amino acid sequence of the IL-2 conjugate is V90. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VI) or (VII), or a mixture of (VI) and (VII), in the amino acid sequence of the IL-2 conjugate is E99. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VI) or (VII), or a mixture of (VI) and (VII), in the amino acid sequence of the IL-2 conjugate is D108 in the N87R variant. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VI) or (VII), or a mixture of (VI) and (VII), in the amino acid sequence of the IL-2 conjugate is N118. Further described herein are IL-2 conjugates wherein the 2026234002   16 Sep 2026 position of the structure of Formula (VI) or (VII), or a mixture of (VI) and (VII), in the amino acid sequence of the IL-2 conjugate is T122. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VI) or (VII), or a mixture of (VI) and (VII), in the amino acid sequence of the IL-2 conjugate is S124. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VI) or (VII), or a mixture of (VI) and (VII), in the amino acid sequence of the IL-2 conjugate is T130. Further described herein are IL-2 conjugates wherein n is about 75 to about 1000. Further described herein are IL-2 conjugates wherein n is about 100 to about 1000. Further described herein are IL-2 conjugates wherein n is about 200 to about 5000. Further described herein are IL-2 conjugates wherein n is about 500 to about 1000. Further described herein are IL-2 conjugates wherein n is about 400 to about 800.

[0019] Described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 3 in which at least one amino acid residue in the IL-2 conjugate is replaced by the structure of Formula (VIII) or (IX), or a mixture of (VIII) and (IX): Formula (IX); wherein: n is an integer in the range from about 2 to about 5000; and X-1 i JWV .NH X has the structure:             , X-1 indicates the point of attachment to the preceding amino acid residue; and 2026234002   16 Sep 2026 X+l indicates the point of attachment to the following amino acid residue. In some embodiments, the IL-2 conjugate is a pharmaceutically acceptable salt, solvate, or hydrate thereof. Here and throughout, embodiments of Formula (VIII) and / or (IX) also encompass a pharmaceutically acceptable salt, solvate, or hydrate thereof. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VIII) or (IX), or a mixture of (VIII) and (IX), in the amino acid sequence of the IL-2 conjugate is selected from Pl, T2, S3, S4, S5, T6, K7, K8, Q10, Lil, E14, H15, L17, L18, D19, Q21, M22, N25, G26, N28, N29, Y30, K31, K34, T36, M45, P46, K47, A49, T50, E51, L52, K53, H54, Q56, E59, E66, N70, Q73, S74, K75, N76, F77, H78, R80, P81, R82, D83, S86, N87,188, V90,191, L93, E94, K96, G97, S98, E99, T100, T101, F102, M103, C104, E105, Y106, A107, D108, D108 in the N87R variant, E109, T110, Alli, T112, E115, N118, R119, T122, F123, S124, Q125, S126, S129, T130, L131, and T132. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VIII) or (IX), or a mixture of (VIII) and (IX), in the amino acid sequence of the IL-2 conjugate is selected from K8, H15, L18, D19, M22, N25, N87, V90,191, L93, E94, K96, G97, S98, E99, D108 in the N87R variant, N118, T122, S124, Q125, S126, S129, and T130. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VIII) or (IX), or a mixture of (VIII) and (IX), in the amino acid sequence of the IL-2 conjugate is selected from K8, H15, L18, D19, M22, N25, N87, V90, E99, D108 in the N87R variant, N118, T122, S124, and T130. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VIII) or (IX), or a mixture of (VIII) and (IX), in the amino acid sequence of the IL-2 conjugate is K8. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VIII) or (IX), or a mixture of (VIII) and (IX), in the amino acid sequence of the IL-2 conjugate is Hl 5. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VIII) or (IX), or a mixture of (VIII) and (IX), in the amino acid sequence of the IL-2 conjugate is LI 8. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VIII) or (IX), or a mixture of (VIII) and (IX), in the amino acid sequence of the IL-2 conjugate is DI 9. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VIII) or (IX), or a mixture of (VIII) and (IX), in the amino acid sequence of the IL-2 conjugate is M22. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VIII) or (IX), or a mixture of (VIII) and (IX), in the amino acid sequence of the IL-2 conjugate is N25. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VIII) or (IX), or a mixture of (VIII) and (IX), in the amino acid sequence of the IL-2 conjugate is N87. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VIII) or (IX), or a mixture of (VIII) and (IX), in the amino acid sequence of the IL-2 conjugate is V90. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VIII) or (IX), or a mixture of (VIII) and 2026234002   16 Sep 2026 (IX), in the amino acid sequence of the IL-2 conjugate is E99. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VIII) or (IX), or a mixture of (VIII) and (IX), in the amino acid sequence of the IL-2 conjugate is DI 08 in the N87R variant. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VIII) or (IX), or a mixture of (VIII) and (IX), in the amino acid sequence of the IL-2 conjugate is N118. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VIII) or (IX), or a mixture of (VIII) and (IX), in the amino acid sequence of the IL-2 conjugate is T122. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VIII) or (IX), or a mixture of (VIII) and (IX), in the amino acid sequence of the IL-2 conjugate is S124. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VIII) or (IX), or a mixture of (VIII) and (IX), in the amino acid sequence of the IL-2 conjugate is T130. Further described herein are IL-2 conjugates wherein n is about 75 to about 1000. Further described herein are IL-2 conjugates wherein n is about 100 to about 1000. Further described herein are IL-2 conjugates wherein n is about 200 to about 5000. Further described herein are IL-2 conjugates wherein n is about 500 to about 1000. Further described herein are IL-2 conjugates wherein n is about 400 to about 800.

[0020] Described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 3 in which at least one amino acid residue in the IL-2 conjugate is replaced by the structure of Formula (X) or (XI), or a mixture of (X) and (XI): Formula (X); Formula (XI); wherein: n is an integer in the range from about 2 to about 5000; and 2026234002   16 Sep 2026 the wavy lines indicate covalent bonds to amino acid residues within SEQ ID NO: 3 that are not replaced. Here and throughout, embodiments of Formula (X) and / or (XI) also encompass a pharmaceutically acceptable salt, solvate, or hydrate thereof. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (X) or (XI), or a mixture of (X) and (XI), in the amino acid sequence of the IL-2 conjugate is selected from Pl, T2, S3, S4, S5, T6, K7, K8, Q10, Lil, E14, H15, L17, L18, D19, Q21, M22, N25, G26, N28, N29, Y30, K31, K34, T36, M45, P46, K47, A49, T50, E51, L52, K53, H54, Q56, E59, E66, N70, Q73, S74, K75, N76, F77, H78, R80, P81, R82, D83, S86, N87,188, V90,191, L93, E94, K96, G97, S98, E99, T100, T101, F102, Ml03, C104, E105, Y106, A107, D108, D108 in the N87R variant, E109, T110, Alli, T112, El 15, N118, RI 19, T122, F123, S124, Q125, S126, S129, T130, L131, and T132. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (X) or (XI), or a mixture of (X) and (XI), in the amino acid sequence of the IL-2 conjugate is selected from K8, H15, L18, D19, M22, N25, N87, V90,191, L93, E94, K96, G97, S98, E99, D108 in the N87R variant, N118, T122, S124, Q125, S126, S129, and T130. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (X) or (XI), or a mixture of (X) and (XI), in the amino acid sequence of the IL-2 conjugate is selected from K8, Hl 5, L18, D19, M22, N25, N87, V90, E99, D108 in the N87R variant, N118, T122, S124, andT130. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (X) or (XI), or a mixture of (X) and (XI), in the amino acid sequence of the IL-2 conjugate is K8. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (X) or (XI), or a mixture of (X) and (XI), in the amino acid sequence of the IL-2 conjugate is Hl 5. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (X) or (XI), or a mixture of (X) and (XI), in the amino acid sequence of the IL-2 conjugate is LI 8. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (X) or (XI), or a mixture of (X) and (XI), in the amino acid sequence of the IL-2 conjugate is D19. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (X) or (XI), or a mixture of (X) and (XI), in the amino acid sequence of the IL-2 conjugate is M22. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (X) or (XI), or a mixture of (X) and (XI), in the amino acid sequence of the IL-2 conjugate is N25. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (X) or (XI), or a mixture of (X) and (XI), in the amino acid sequence of the IL-2 conjugate is N87. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (X) or (XI), or a mixture of (X) and (XI), in the amino acid sequence of the IL-2 conjugate is V90. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (X) or (XI), or a mixture of (X) and (XI), in the amino acid sequence of the IL-2 conjugate is E99. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (X) or (XI), or a mixture of 2026234002   16 Sep 2026 (X) and (XI), in the amino acid sequence of the IL-2 conjugate is D108 in the N87R variant. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (X) or (XI), or a mixture of (X) and (XI), in the amino acid sequence of the IL-2 conjugate is N118. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (X) or (XI), or a mixture of (X) and (XI), in the amino acid sequence of the IL-2 conjugate is T122. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (X) or (XI), or a mixture of (X) and (XI), in the amino acid sequence of the IL-2 conjugate ate is S124. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (X) or (XI), or a mixture of (X) and (XI), in the amino acid sequence of the IL-2 conjugate is T130. Further described herein are IL-2 conjugates wherein n is about 75 to about 1000. Further described herein are IL-2 conjugates wherein n is about 100 to about 1000. Further described herein are IL-2 conjugates wherein n is about 200 to about 5000. Further described herein are IL-2 conjugates wherein n is about 500 to about 1000. Further described herein are IL-2 conjugates wherein n is about 400 to about 800.

[0021] Described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 3 in which at least one amino acid residue in the IL-2 conjugate is replaced by the structure of Formula (XII) or (XIII), or a mixture of (XII) and (XIII): Formula (XII); Formula (XIII); wherein: n is an integer in the range from about 2 to about 5000; and the wavy lines indicate covalent bonds to amino acid residues within SEQ ID NO: 3 that are not replaced. Here and throughout, embodiments of Formula (XU) and / or (XIII) also encompass a 2026234002   16 Sep 2026 pharmaceutically acceptable salt, solvate, or hydrate thereof. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XII) or (XIII), or a mixture of (XII) and (XIII), in the amino acid sequence of the IL-2 conjugate is selected from Pl, T2, S3, S4, S5, T6, K7, K8, Q10, Lil, E14, H15, L17, L18, D19, Q21, M22, N25, G26, N28, N29, Y30, K31, K34, T36, M45, P46, K47, A49, T50, E51, L52, K53, H54, Q56, E59, E66, N70, Q73, S74, K75, N76, F77, H78, R80, P81, R82, D83, S86, N87,188, V90,191, L93, E94, K96, G97, S98, E99, T100, T101, F102, M103, C104, E105, Y106, A107, D108, D108 in the N87R variant, E109, T110, Alli, T112, El 15, N118, RI 19, T122, F123, S124, Q125, S126, S129, T130, L131, andT132. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XII) or (XIII), or a mixture of (XII) and (XIII), in the amino acid sequence of the IL-2 conjugate is selected from K8, Hl 5, LI 8, DI 9, M22, N25, N87, V90,191, L93, E94, K96, G97, S98, E99, D108 in the N87R variant, N118, T122, S124, Q125, S126, S129, and T130. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XII) or (XIII), or a mixture of (XII) and (XIII), in the amino acid sequence of the IL-2 conjugate is selected from K8, H15, L18, D19, M22, N25, N87, V90, E99, D108 in the N87R variant, N118, T122, S124, and T130. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XII) or (XIII), or a mixture of (XU) and (XIII), in the amino acid sequence of the IL-2 conjugate is K8. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XII) or (XIII), or a mixture of (XII) and (XIII), in the amino acid sequence of the IL-2 conjugate is Hl 5. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XU) or (XIII), or a mixture of (XII) and (XIII), in the amino acid sequence of the IL-2 conjugate is LI 8. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XU) or (XIII), or a mixture of (XII) and (XIII), in the amino acid sequence of the IL-2 conjugate is D19. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XU) or (XIII), or a mixture of (XII) and (XIII), in the amino acid sequence of the IL-2 conjugate is M22. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XU) or (XIII), or a mixture of (XII) and (XIII), in the amino acid sequence of the IL-2 conjugate is N25. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XU) or (XIII), or a mixture of (XII) and (XIII), in the amino acid sequence of the IL-2 conjugate is N87. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XU) or (XIII), or a mixture of (XII) and (XIII), in the amino acid sequence of the IL-2 conjugate is V90. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XU) or (XIII), or a mixture of (XII) and (XIII), in the amino acid sequence of the IL-2 conjugate is E99. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XU) or (XIII), or a mixture of (XII) and (XIII), in the amino acid sequence of the IL-2 2026234002   16 Sep 2026 conjugate is D108 in the N87R variant. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XII) or (XIII), or a mixture of (XII) and (XIII), in the amino acid sequence of the IL-2 conjugate is N118. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XII) or (XIII), or a mixture of (XII) and (XIII), in the amino acid sequence of the IL-2 conjugate is T122. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XII) or (XIII), or a mixture of (XII) and (XIII), in the amino acid sequence of the IL-2 conjugate is S124. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XII) or (XIII), or a mixture of (XII) and (XIII), in the amino acid sequence of the IL-2 conjugate is T130. Further described herein are IL-2 conjugates wherein n is about 75 to about 1000. Further described herein are IL-2 conjugates wherein n is about 100 to about 1000. Further described herein are IL-2 conjugates wherein n is about 200 to about 5000. Further described herein are IL-2 conjugates wherein n is about 500 to about 1370. Further described herein are IL-2 conjugates wherein n is about 400 to about 800. Further described herein are IL-2 conjugates wherein n is about 400 to about 1370. Further described herein are IL-2 conjugates wherein n is about 400 to about 1250. Further described herein are IL-2 conjugates wherein n is about 600 to about 1370. Further described herein are IL-2 conjugates wherein n is about 600 to about 1250. Further described herein are IL-2 conjugates wherein n is about 675 to about 1250. Further described herein are IL-2 conjugates wherein n is about 680 to about 1250. Further described herein are IL-2 conjugates wherein n is about 680 to about 1140. Further described herein are IL-2 conjugates wherein n is about 450. Further described herein are IL-2 conjugates wherein n is about 568. Further described herein are IL-2 conjugates wherein n is about 682. Further described herein are IL-2 conjugates wherein n is about 795. Further described herein are IL-2 conjugates wherein n is about 909. Further described herein are IL-2 conjugates wherein n is about 1022. Further described herein are IL-2 conjugates wherein n is about 1136. Further described herein are IL-2 conjugates wherein n is about 1250. Further described herein are IL-2 conjugates wherein n is about 1363.

[0022] Described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 4 in which at least one amino acid residue in the IL-2 conjugate is replaced by the structure of Formula (VI) or (VII), or a mixture of (VI) and (VII): 2026234002   16 Sep 2026 (Vil); wherein: n is an integer in the range from about 2 to about 5000; and X has the structure: X+1 X-l indicates the point of attachment to the preceding amino acid residue; and X+1 indicates the point of attachment to the following amino acid residue. In some embodiments, the IL-2 conjugate is a pharmaceutically acceptable salt, solvate, or hydrate thereof. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VI) or (VII), or a mixture of (VI) and (VII), in the amino acid sequence of the IL-2 conjugate is selected from Al, P2, T3, S4, S5, S6, T7, K8, K9, Qll, L12, E15, H16, L18, L19, D20, Q22, M23, N26, G27, N29, N30, Y31, K32, K35, T37, M46, P47, K48, A50, T51, E52, L53, H55, Q57, E60, E67, N71, Q74, S75, K76, N77, F78, H79, R81, P82, R83, D84, S87, N88,189, V91,192, L94, E95, K97, G98, S99, E100, T101, T102, F103, Ml04, C105, E106, Y107, A108, D109, D109 in the N88R variant, El 10, Till, A112, T113, E116, N119, R120, T123, S125, Q126, S127, S130, T131, L132, andT133. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VI) or (VII), or a mixture of (VI) and (VII), in the amino acid sequence of the IL-2 conjugate is selected from K9, Hl 6, L19, D20, M23, N26, N88, V91,192, L94, E95, K97, G98, S99, E100, D109 in the N88R variant, N119, T123, S125, Q126, S127, S130, and T131. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VI) or (VII), or a mixture of (VI) and (VII), in the amino acid sequence of the IL-2 conjugate is selected from K9, H16, L19, D20, M23, N26, N88, V91, E100, D109 in the N88R variant, N119, T123, SI25, and T131. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VI) or (VII), or a mixture of (VI) and (VII), in the amino acid sequence of the IL-2 conjugate is K9. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VI) or (VII), or a mixture of (VI) and (VII), in the amino acid sequence of the IL-2 conjugate is Hl 6. Further described herein are IL-2 conjugates wherein the position of the 2026234002   16 Sep 2026 structure of Formula (VI) or (VII), or a mixture of (VI) and (VII), in the amino acid sequence of the IL-2 conjugate is LI 9. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VI) or (VII), or a mixture of (VI) and (VII), in the amino acid sequence of the IL-2 conjugate is D20. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VI) or (VII), or a mixture of (VI) and (VII), in the amino acid sequence of the IL-2 conjugate is M23. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VI) or (VII), or a mixture of (VI) and (VII), in the amino acid sequence of the IL-2 conjugate is N26. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VI) or (VII), or a mixture of (VI) and (VII), in the amino acid sequence of the IL-2 conjugate is N88. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VI) or (VII), or a mixture of (VI) and (VII), in the amino acid sequence of the IL-2 conjugate is V91. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VI) or (VII), or a mixture of (VI) and (VII), in the amino acid sequence of the IL-2 conjugate is E100. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VI) or (VII), or a mixture of (VI) and (VII), in the amino acid sequence of the IL-2 conjugate is D109 in the N88R variant. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VI) or (VII), or a mixture of (VI) and (VII), in the amino acid sequence of the IL-2 conjugate is N119. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VI) or (VII), or a mixture of (VI) and (VII), in the amino acid sequence of the IL-2 conjugate is T123. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VI) or (VII), or a mixture of (VI) and (VII), in the amino acid sequence of the IL-2 conjugate is S125. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VI) or (VII), or a mixture of (VI) and (VII), in the amino acid sequence of the IL-2 conjugate is T131. Further described herein are IL-2 conjugates wherein n is about 75 to about 1000. Further described herein are IL-2 conjugates wherein n is about 100 to about 1000. Further described herein are IL-2 conjugates wherein n is about 200 to about 5000. Further described herein are IL-2 conjugates wherein n is about 500 to about 1370. Further described herein are IL-2 conjugates wherein n is about 400 to about 800. Further described herein are IL-2 conjugates wherein n is about 400 to about 1370. Further described herein are IL-2 conjugates wherein n is about 400 to about 1250. Further described herein are IL-2 conjugates wherein n is about 600 to about 1370. Further described herein are IL-2 conjugates wherein n is about 600 to about 1250. Further described herein are IL-2 conjugates wherein n is about 675 to about 1250. Further described herein are IL-2 conjugates wherein n is about 680 to about 1250. Further described herein are IL-2 conjugates wherein n is about 680 to about 1140. Further described herein are IL-2 conjugates wherein n is about 450. Further described herein are IL-2 conjugates wherein n is about 568. Further described herein are IL-2 2026234002   16 Sep 2026 conjugates wherein n is about 682. Further described herein are IL-2 conjugates wherein n is about 795. Further described herein are IL-2 conjugates wherein n is about 909. Further described herein are IL-2 conjugates wherein n is about 1022. Further described herein are IL-2 conjugates wherein n is about 1136. Further described herein are IL-2 conjugates wherein n is about 1250. Further described herein are IL-2 conjugates wherein n is about 1363.

[0023] Described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 4 in which at least one amino acid residue in the IL-2 conjugate is replaced by the structure of Formula (VIII) or (IX), or a mixture of (VIII) and (IX): Formula (IX); wherein: n is an integer in the range from about 2 to about 5000; and X has the structure: X-1 X-l indicates the point of attachment to the preceding amino acid residue; and X+l indicates the point of attachment to the following amino acid residue. In some embodiments, the IL-2 conjugate is a pharmaceutically acceptable salt, solvate, or hydrate thereof. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VIII) or (IX), or a mixture of (VIII) and (IX), in the amino acid sequence of the IL-2 conjugate is selected from Al, P2, T3, S4, S5, S6, T7, K8, K9, Qll, L12, E15, H16, L18, L19, D20, Q22, M23, N26, G27, N29, N30, Y31, K32, K35, T37, M46, 2026234002   16 Sep 2026 P47, K48, A50, T51, E52, L53, H55, Q57, E60, E67, N71, Q74, S75, K76, N77, F78, H79, R81, P82, R83, D84, S87, N88,189, V91,192, L94, E95, K97, G98, S99, E100, T101, T102, F103, M104, C105, E106, Y107, A108, D109, D109 in the N88R variant, El 10, Till, Al 12, T113, El 16, N119, R120, T123, S125, Q126, S127, S130, T131, L132, and T133. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VIII) or (IX), or a mixture of (VIII) and (IX), in the amino acid sequence of the IL-2 conjugate is selected from K9, H16, L19, D20, M23, N26, N88, V91, 192, L94, E95, K97, G98, S99, E100, D109 in the N88R variant, N119, T123, S125, Q126, S127, S130, and T131. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VIII) or (IX), or a mixture of (VIII) and (IX), in the amino acid sequence of the IL-2 conjugate is selected from K9, H16, L19, D20, M23, N26, N88, V91, E100, D109 in the N88R variant, N119, T123, S125, and T131. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VIII) or (IX), or a mixture of (VIII) and (IX), in the amino acid sequence of the IL-2 conjugate is K9. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VIII) or (IX), or a mixture of (VIII) and (IX), in the amino acid sequence of the IL-2 conjugate is Hl 6. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VIII) or (IX), or a mixture of (VIII) and (IX), in the amino acid sequence of the IL-2 conjugate is LI 9. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VIII) or (IX), or a mixture of (VIII) and (IX), in the amino acid sequence of the IL-2 conjugate is D20. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VIII) or (IX), or a mixture of (VIII) and (IX), in the amino acid sequence of the IL-2 conjugate is M23. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VIII) or (IX), or a mixture of (VIII) and (IX), in the amino acid sequence of the IL-2 conjugate is N26. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VIII) or (IX), or a mixture of (VIII) and (IX), in the amino acid sequence of the IL-2 conjugate is N88. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VIII) or (IX), or a mixture of (VIII) and (IX), in the amino acid sequence of the IL-2 conjugate is V91. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VIII) or (IX), or a mixture of (VIII) and (IX), in the amino acid sequence of the IL-2 conjugate is El 00. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VIII) or (IX), or a mixture of (VIII) and (IX), in the amino acid sequence of the IL-2 conjugate is DI 09 in the N88R variant. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VIII) or (IX), or a mixture of (VIII) and (IX), in the amino acid sequence of the IL-2 conjugate is N119. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VIII) or (IX), or a mixture of (VIII) and (IX), in the amino acid sequence of the IL-2 conjugate is T123. Further described herein are IL-2 2026234002   16 Sep 2026 conjugates wherein the position of the structure of Formula (VIII) or (IX), or a mixture of (VIII) and (IX), in the amino acid sequence of the IL-2 conjugate is S125. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (VIII) or (IX), or a mixture of (VIII) and (IX), in the amino acid sequence of the IL-2 conjugate is T131. Further described herein are IL-2 conjugates wherein n is about 75 to about 1000. Further described herein are IL-2 conjugates wherein n is about 100 to about 1000. Further described herein are IL-2 conjugates wherein n is about 200 to about 5000. Further described herein are IL-2 conjugates wherein n is about 500 to about 1370. Further described herein are IL-2 conjugates wherein n is about 400 to about 800. Further described herein are IL-2 conjugates wherein n is about 400 to about 1370. Further described herein are IL-2 conjugates wherein n is about 400 to about 1250. Further described herein are IL-2 conjugates wherein n is about 600 to about 1370. Further described herein are IL-2 conjugates wherein n is about 600 to about 1250. Further described herein are IL-2 conjugates wherein n is about 675 to about 1250. Further described herein are IL-2 conjugates wherein n is about 680 to about 1250. Further described herein are IL-2 conjugates wherein n is about 680 to about 1140. Further described herein are IL-2 conjugates wherein n is about 450. Further described herein are IL-2 conjugates wherein n is about 568. Further described herein are IL-2 conjugates wherein n is about 682. Further described herein are IL-2 conjugates wherein n is about 795. Further described herein are IL-2 conjugates wherein n is about 909. Further described herein are IL-2 conjugates wherein n is about 1022. Further described herein are IL-2 conjugates wherein n is about 1136. Further described herein are IL-2 conjugates wherein n is about 1250. Further described herein are IL-2 conjugates wherein n is about 1363.

[0024] Described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 4 in which at least one amino acid residue in the IL-2 conjugate is replaced by the structure of Formula (X) or (XI), or a mixture of (X) and (XI): Formula (X); 2026234002   16 Sep 2026 Formula (XI); wherein: n is an integer in the range from about 2 to about 5000; and the wavy lines indicate covalent bonds to amino acid residues within SEQ ID NO: 4 that are not replaced. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (X) or (XI), or a mixture of (X) and (XI), in the amino acid sequence of the IL-2 conjugate is selected from Al, P2, T3, S4, S5, S6, T7, K8, K9, Qll, L12, E15, H16, L18, L19, D20, Q22, M23, N26, G27, N29, N30, Y31, K32, K35, T37, M46, P47, K48, A50, T51, E52, L53, H55, Q57, E60, E67, N71, Q74, S75, K76, N77, F78, H79, R81, P82, R83, D84, S87, N88,189, V91,192, L94, E95, K97, G98, S99, E100, T101, T102, F103, M104, C105, E106, Y107, A108, D109, D109 in the N88R variant, El 10, Till, A112, T113, E116, N119, R120, T123, S125, Q126, S127, S130, T131, L132, andT133. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (X) or (XI), or a mixture of (X) and (XI), in the amino acid sequence of the IL-2 conjugate is selected from K9, H16, L19, D20, M23, N26, N88, V91,192, L94, E95, K97, G98, S99, E100, D109 in the N88R variant, N119, T123, S125, Q126, S127, S130, and T131. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (X) or (XI), or a mixture of (X) and (XI), in the amino acid sequence of the IL-2 conjugate is selected from K9, H16, L19, D20, M23, N26, N88, V91, E100, D109 in the N88R variant, Nil9, T123, S125, and T131. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (X) or (XI), or a mixture of (X) and (XI), in the amino acid sequence of the IL-2 conjugate is K9. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (X) or (XI), or a mixture of (X) and (XI), in the amino acid sequence of the IL-2 conjugate is H16. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (X) or (XI), or a mixture of (X) and (XI), in the amino acid sequence of the IL-2 conjugate is L19. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (X) or (XI), or a mixture of (X) and (XI), in the amino acid sequence of the IL-2 conjugate is D20. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (X) or (XI), or a mixture of (X) and (XI), in the amino acid sequence of the IL-2 conjugate is M23. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (X) or (XI), or a mixture of 2026234002   16 Sep 2026 (X) and (XI), in the amino acid sequence of the IL-2 conjugate is N26. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (X) or (XI), or a mixture of (X) and (XI), in the amino acid sequence of the IL-2 conjugate is N88. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (X) or (XI), or a mixture of (X) and (XI), in the amino acid sequence of the IL-2 conjugate is V91. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (X) or (XI), or a mixture of (X) and (XI), in the amino acid sequence of the IL-2 conjugate is E100. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (X) or (XI), or a mixture of (X) and (XI), in the amino acid sequence of the IL-2 conjugate is D109 in the N88R variant. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (X) or (XI), or a mixture of (X) and (XI), in the amino acid sequence of the IL-2 conjugate is N119. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (X) or (XI), or a mixture of (X) and (XI), in the amino acid sequence of the IL-2 conjugate is T123. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (X) or (XI), or a mixture of (X) and (XI), in the amino acid sequence of the IL-2 conjugate is SI 25. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (X) or (XI), or a mixture of (X) and (XI), in the amino acid sequence of the IL-2 conjugate is T131. Further described herein are IL-2 conjugates wherein n is about 75 to about 1000. Further described herein are IL-2 conjugates wherein n is about 100 to about 1000. Further described herein are IL-2 conjugates wherein n is about 200 to about 5000. Further described herein are IL-2 conjugates wherein n is about 500 to about 1370. Further described herein are IL-2 conjugates wherein n is about 400 to about 800. Further described herein are IL-2 conjugates wherein n is about 400 to about 1370. Further described herein are IL-2 conjugates wherein n is about 400 to about 1250. Further described herein are IL-2 conjugates wherein n is about 600 to about 1370. Further described herein are IL-2 conjugates wherein n is about 600 to about 1250. Further described herein are IL-2 conjugates wherein n is about 675 to about 1250. Further described herein are IL-2 conjugates wherein n is about 680 to about 1250. Further described herein are IL-2 conjugates wherein n is about 680 to about 1140. Further described herein are IL-2 conjugates wherein n is about 450. Further described herein are IL-2 conjugates wherein n is about 568. Further described herein are IL-2 conjugates wherein n is about 682. Further described herein are IL-2 conjugates wherein n is about 795. Further described herein are IL-2 conjugates wherein n is about 909. Further described herein are IL-2 conjugates wherein n is about 1022. Further described herein are IL-2 conjugates wherein n is about 1136. Further described herein are IL-2 conjugates wherein n is about 1250. Further described herein are IL-2 conjugates wherein n is about 1363. 2026234002   16 Sep 2026

[0025] Described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 4 in which at least one amino acid residue in the IL-2 conjugate is replaced by the structure of Formula (XII) or (XIII), or a mixture of (XII) and (XIII): Formula (XII); Formula (XIII); wherein: n is an integer in the range from about 2 to about 5000; and the wavy lines indicate covalent bonds to amino acid residues within SEQ ID NO: 4 that are not replaced. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XII) or (XIII), or a mixture of (XII) and (XIII), in the amino acid sequence of the IL-2 conjugate is selected from Al, P2, T3, S4, S5, S6, T7, K8, K9, Qll, L12, E15, Hl6, L18, L19, D20, Q22, M23, N26, G27, N29, N30, Y31, K32, K35, T37, M46, P47, K48, A50, T51, E52, L53, H55, Q57, E60, E67, N71, Q74, S75, K76, N77, F78, H79, R81, P82, R83, D84, S87, N88,189, V91,192, L94, E95, K97, G98, S99, E100, T101, T102, F103, M104, C105, E106, Y107, A108, D109, D109 in the N88R variant, El 10, Till, A112, T113, E116, N119, R120, T123, S125, Q126, S127, S130, T131, L132, andT133. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XII) or (XIII), or a mixture of (XII) and (XIII), in the amino acid sequence of the IL-2 conjugate is selected from K9, Hl 6, L19, D20, M23, N26, N88, V91,192, L94, E95, K97, G98, S99, E100, D109 in the N88R variant, N119, T123, S125, Q126, S127, S130, and T131. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XII) or (XIII), or a mixture of (XII) and (XIII), in the amino acid sequence of the IL-2 conjugate is selected from K9, H16, L19, D20, M23, N26, N88, V91, E100, D109 in the N88R variant, N119, T123, SI25, and T131. Further described herein are IL-2 conjugates wherein 2026234002   16 Sep 2026 the position of the structure of Formula (XII) or (XIII), or a mixture of (XII) and (XIII), in the amino acid sequence of the IL-2 conjugate is K9. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XII) or (XIII), or a mixture of (XII) and (XIII), in the amino acid sequence of the IL-2 conjugate is Hl 6. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XII) or (XIII), or a mixture of (XII) and (XIII), in the amino acid sequence of the IL-2 conjugate is LI 9. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XII) or (XIII), or a mixture of (XII) and (XIII), in the amino acid sequence of the IL-2 conjugate is D20. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XII) or (XIII), or a mixture of (XII) and (XIII), in the amino acid sequence of the IL-2 conjugate is M23. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XII) or (XIII), or a mixture of (XII) and (XIII), in the amino acid sequence of the IL-2 conjugate is N26. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XII) or (XIII), or a mixture of (XII) and (XIII), in the amino acid sequence of the IL-2 conjugate is N88. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XII) or (XIII), or a mixture of (XII) and (XIII), in the amino acid sequence of the IL-2 conjugate is V91. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XII) or (XIII), or a mixture of (XII) and (XIII), in the amino acid sequence of the IL-2 conjugate is E100. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XU) or (XIII), or a mixture of (XII) and (XIII), in the amino acid sequence of the IL-2 conjugate is D109 in the N88R variant. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XII) or (XIII), or a mixture of (XII) and (XIII), in the amino acid sequence of the IL-2 conjugate is N119. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XII) or (XIII), or a mixture of (XU) and (XIII), in the amino acid sequence of the IL-2 conjugate is T123. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XII) or (XIII), or a mixture of (XII) and (XIII), in the amino acid sequence of the IL-2 conjugate is S125. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XU) or (XIII), or a mixture of (XII) and (XIII), in the amino acid sequence of the IL-2 conjugate is T131. Further described herein are IL-2 conjugates wherein n is about 75 to about 1000. Further described herein are IL-2 conjugates wherein n is about 100 to about 1000. Further described herein are IL-2 conjugates wherein n is about 200 to about 5000. Further described herein are IL-2 conjugates wherein n is about 500 to about 1370. Further described herein are IL-2 conjugates wherein n is about 400 to about 800. Further described herein are IL-2 conjugates wherein n is about 400 to about 1370. Further described herein are IL-2 conjugates wherein n is about 400 to about 1250. Further described herein are IL-2 conjugates wherein n is about 600 to about 1370. Further described herein are 2026234002   16 Sep 2026 IL-2 conjugates wherein n is about 600 to about 1250. Further described herein are IL-2 conjugates wherein n is about 675 to about 1250. Further described herein are IL-2 conjugates wherein n is about 680 to about 1250. Further described herein are IL-2 conjugates wherein n is about 680 to about 1140. Further described herein are IL-2 conjugates wherein n is about 450. Further described herein are IL-2 conjugates wherein n is about 568. Further described herein are IL-2 conjugates wherein n is about 682. Further described herein are IL-2 conjugates wherein n is about 795. Further described herein are IL-2 conjugates wherein n is about 909. Further described herein are IL-2 conjugates wherein n is about 1022. Further described herein are IL-2 conjugates wherein n is about 1136. Further described herein are IL-2 conjugates wherein n is about 1250. Further described herein are IL-2 conjugates wherein n is about 1363.

[0026] Described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 3 or SEQ ID NO: 4 in which at least one amino acid residue in the IL-2 conjugate is replaced by the structure of Formula (XIV) or (XV), or a mixture of (XIV) and (XV): Formula (XIV) Formula (XV) wherein: m is an integer from 0 to 20; p is an integer from 0 to 20; n is an integer in the range from about 2 to about 5000; and the wavy lines indicate covalent bonds to amino acid residues within SEQ ID NO: 3 or SEQ ID NO: 4 that are not replaced. Here and throughout, embodiments of Formula (XIV) and / or (XV) also encompass a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments 2026234002   16 Sep 2026 described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 3 in which at least one amino acid residue in the IL-2 conjugate is replaced by the structure of Formula (XIV) or (XV), or a mixture of (XIV) and (XV), wherein m, p, n, and the meaning of the wavy line are as described above. In some embodiments described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 4 in which at least one amino acid residue in the IL-2 conjugate is replaced by the structure of Formula (XIV) or (XV), or a mixture of (XIV) and (XV), wherein m, p, n, and the meaning of the wavy line are as described above.

[0027] In some embodiments, the stereochemistry of the chiral center within Formula (XIV) and Formula (XV) is racemic, is enriched in (R), is enriched in (S), is substantially (R), is substantially (S), is (R) or is (S). In some embodiments, the stereochemistry of the chiral center within Formula (XIV) and Formula (XV) is racemic. In some embodiments, the stereochemistry of the chiral center within Formula (XIV) and Formula (XV) is enriched in (R). In some embodiments, the stereochemistry of the chiral center within Formula (XIV) and Formula (XV) is enriched in (S). In some embodiments, the stereochemistry of the chiral center within Formula (XIV) and Formula (XV) is substantially (R). In some embodiments, the stereochemistry of the chiral center within Formula (XIV) and Formula (XV) is substantially (S). In some embodiments, the stereochemistry of the chiral center within Formula (XIV) and Formula (XV) is (R). In some embodiments, the stereochemistry of the chiral center within Formula (XIV) and Formula (XV) is (S).

[0028] In some embodiments of an IL-2 conjugate described herein, m in the compounds of Formula (XIV) and (XV) is from 0 to 20, or from 1 to 18, or from 1 to 16, or from 1 to 14, or from 1 to 12, or from 1 to 10, or from 1 to 9, or from 1 to 8, or from 1 to 7, or from 1 to 6, or from 1 to 5, or from 1 to 4, or from 1 to 3, or from 1 to 2. In some embodiments of an IL-2 conjugate described herein, m in the compounds of Formula (XIV) and (XV) is 1. In some embodiments of an IL-2 conjugate described herein, m in the compounds of Formula (XIV) and (XV) is 2. In some embodiments of an IL-2 conjugate described herein, m in the compounds of Formula (XIV) and (XV) is 3. In some embodiments of an IL-2 conjugate described herein, m in the compounds of Formula (XIV) and (XV) is 4. In some embodiments of an IL-2 conjugate described herein, m in the compounds of Formula (XIV) and (XV) is 5. In some embodiments of an IL-2 conjugate described herein, m in the compounds of Formula (XIV) and (XV) is 6. In some embodiments of an IL-2 conjugate described herein, m in the compounds of Formula (XIV) and (XV) is 7. In some embodiments of an IL-2 conjugate described herein, m in the compounds of Formula (XIV) and (XV) is 8. In some embodiments of an IL-2 conjugate described herein, m in the compounds of Formula (XIV) and (XV) is 9. In some embodiments of an IL-2 conjugate described herein, m in the compounds of Formula (XIV) and (XV) is 10. In some embodiments of an IL-2 conjugate described herein, m in the compounds of Formula (XIV) and (XV) is 2026234002   16 Sep 2026 11. In some embodiments of an IL-2 conjugate described herein, m in the compounds of Formula (XIV) and (XV) is 12. In some embodiments of an IL-2 conjugate described herein, m in the compounds of Formula (XIV) and (XV) is 13. In some embodiments of an IL-2 conjugate described herein, m in the compounds of Formula (XIV) and (XV) is 14. In some embodiments of an IL-2 conjugate described herein, m in the compounds of Formula (XIV) and (XV) is 15. In some embodiments of an IL-2 conjugate described herein, m in the compounds of Formula (XIV) and (XV) is 16. In some embodiments of an IL-2 conjugate described herein, m in the compounds of Formula (XIV) and (XV) is 17. In some embodiments of an IL-2 conjugate described herein, m in the compounds of Formula (XIV) and (XV) is 18. In some embodiments of an IL-2 conjugate described herein, m in the compounds of Formula (XIV) and (XV) is 19. In some embodiments of an IL-2 conjugate described herein, m in the compounds of Formula (XIV) and (XV) is 20.

[0029] In some embodiments of an IL-2 conjugate described herein, p in the compounds of Formula (XIV) and (XV) is from 1 to 20, or from 1 to 18, or from 1 to 16, or from 1 to 14, or from 1 to 12, or from 1 to 10, or from 1 to 9, or from 1 to 8, or from 1 to 7, or from 1 to 6, or from 1 to 5, or from 1 to 4, or from 1 to 3, or from 1 to 2. In some embodiments of an IL-2 conjugate described herein, p in the compounds of Formula (XIV) and (XV) is 1. In some embodiments of an IL-2 conjugate described herein, p in the compounds of Formula (XIV) and (XV) is 2. In some embodiments of an IL-2 conjugate described herein, p in the compounds of Formula (XIV) and (XV) is 3. In some embodiments of an IL-2 conjugate described herein, p in the compounds of Formula (XIV) and (XV) is 4. In some embodiments of an IL-2 conjugate described herein, p in the compounds of Formula (XIV) and (XV) is 5. In some embodiments of an IL-2 conjugate described herein, p in the compounds of Formula (XIV) and (XV) is 6. In some embodiments of an IL-2 conjugate described herein, p in the compounds of Formula (XIV) and (XV) is 7. In some embodiments of an IL-2 conjugate described herein, p in the compounds of Formula (XIV) and (XV) is 8. In some embodiments of an IL-2 conjugate described herein, p in the compounds of Formula (XIV) and (XV) is 9. In some embodiments of an IL-2 conjugate described herein, p in the compounds of Formula (XIV) and (XV) is 10. In some embodiments of an IL-2 conjugate described herein, p in the compounds of Formula (XIV) and (XV) is 11. In some embodiments of an IL-2 conjugate described herein, p in the compounds of Formula (XIV) and (XV) is 12. In some embodiments of an IL-2 conjugate described herein, p in the compounds of Formula (XIV) and (XV) is 13. In some embodiments of an IL-2 conjugate described herein, p in the compounds of Formula (XIV) and (XV) is 14. In some embodiments of an IL-2 conjugate described herein, p in the compounds of Formula (XIV) and (XV) is 15. In some embodiments of an IL-2 conjugate described herein, m in the compounds of Formula (XIV) and (XV) is 16. In some embodiments of an IL-2 conjugate described herein, p in the compounds of Formula (XIV) and (XV) is 17. In some 2026234002   16 Sep 2026 embodiments of an IL-2 conjugate described herein, p in the compounds of Formula (XIV) and (XV) is 18. In some embodiments of an IL-2 conjugate described herein, p in the compounds of Formula (XIV) and (XV) is 19. In some embodiments of an IL-2 conjugate described herein, p in the compounds of Formula (XIV) and (XV) is 20.

[0030] In some embodiments of an IL-2 conjugate described herein, n in the compounds of Formula (XIV) and (XV) is in the range from about 5 to about 4600, or from about 10 to about 4000, or from about 20 to about 3000, or from about 100 to about 3000, or from about 100 to about 2900, or from about 150 to about 2900, or from about 125 to about 2900, or from about 100 to about 2500, or from about 100 to about 2000, or from about 100 to about 1900, or from about 100 to about 1850, or from about 100 to about 1750, or from about 100 to about 1650, or from about 100 to about 1500, or from about 100 to about 1400, or from about 100 to about 1300, or from about 100 to about 1250, or from about 100 to about 1150, or from about 100 to about 1100, or from about 100 to about 1000, or from about 100 to about 900, or from about 100 to about 750, or from about 100 to about 700, or from about 100 to about 600, or from about 100 to about 575, or from about 100 to about 500, or from about 100 to about 450, or from about 100 to about to about 350, or from about 100 to about 275, or from about 100 to about 230, or from about 150 to about 475, or from about 150 to about 340, or from about 113 to about 340, or from about 450 to about 800, or from about 454 to about 796, or from about 454 to about 682, or from about 340 to about 795, or from about 341 to about 682, or from about 568 to about 909, or from about 227 to about 1500, or from about 225 to about 2280, or from about 460 to about 2160, or from about 460 to about 2050, or from about 341 to about 1820, or from about 341 to about 1710, or from about 341 to about 1250, or from about 225 to about 1250, or from about 341 to about 1250, or from about 341 to about 1136, or from about 341 to about 1023, or from about 341 to about 910, or from about 341 to about 796, or from about 341 to about 682, or from about 341 to about 568, or from about 114 to about 1000, or from about 114 to about 950, or from about 114 to about 910, or from about 114 to about 800, or from about 114 to about 690, or from about 114 to about 575.

[0031] In some embodiments of an IL-2 conjugate described herein in the compounds of Formula (XIV) and (XV), m is an integer from 1 to 6, p is an integer from 1 to 6, and n is an integer selected from 113, 114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137. In some embodiments of an IL-2 conjugate described herein in the compounds of Formula (XIV) and (XV), m is an integer from 2 to 6, p is an integer from 2 to 6, and n is an integer selected from 113,114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137. In some embodiments of an IL-2 conjugate described herein in the compounds of Formula (XIV) and (XV), m is an integer from 2 to 4, p is an integer from 2 to 4, and n is an integer selected from 113,114, 227, 228, 340, 341, 454, 455, 568, 569, 2026234002   16 Sep 2026 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137. In some embodiments of an IL-2 conjugate described herein in the compounds of Formula (XIV) and (XV), m is 1, p is 2, and n is an integer selected from 113,114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137. In some embodiments of an IL-2 conjugate described herein in the compounds of Formula (XIV) and (XV), m is 2, p is 2, and n is an integer selected from 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 an IL-2 conjugate described herein in the compounds of Formula (XIV) and (XV), m is 3, p is 2, and n is an integer selected from 113, 114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137. In some embodiments of an IL-2 conjugate described herein in the compounds of Formula (XIV) and (XV), m is 4, p is 2, and n is an integer selected from 113, 114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137. In some embodiments of an IL-2 conjugate described herein in the compounds of Formula (XIV) and (XV), m is 5, p is 2, and n is an integer selected from 113,114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137. In some embodiments of an IL-2 conjugate described herein in the compounds of Formula (XIV) and (XV), m is 6, p is 2, and n is an integer selected from 113,114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137. In some embodiments of an IL-2 conjugate described herein in the compounds of Formula (XIV) and (XV), m is 7, p is 2, and n is an integer selected from 113, 114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137. In some embodiments of an IL-2 conjugate described herein in the compounds of Formula (XIV) and (XV), m is 8, p is 2, and n is an integer selected from 113,114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137. In some embodiments of an IL-2 conjugate described herein in the compounds of Formula (XIV) and (XV), m is 9, p is 2, and n is an integer selected from 113, 114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137. In some embodiments of an IL-2 conjugate described herein in the compounds of Formula (XIV) and (XV), m is 10, p is 2, and n is an integer selected from 113, 114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137. In some embodiments of an IL-2 conjugate described herein in the compounds of Formula (XIV) and (XV), m is 11, p is 2, and n is an integer selected from 113, 114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137. In some embodiments of an IL-2 conjugate described herein in the compounds of Formula (XIV) and (XV), m is 12, p is 2, and n is an integer selected from 113, 114, 227, 2026234002   16 Sep 2026 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 an IL-2 conjugate described herein in the compounds of Formula (XIV) and (XV), m is 2, p is 2, and n is an integer selected from 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137.

[0032] In some embodiments of an IL-2 conjugate described herein, n in the compounds of Formula (XIV) and (XV) is an integer selected from 2, 5, 10, 11, 22, 23, 113, 114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, 1137, 1249, 1250, 1251, 1362, 1363, 1364, 1476, 1477, 1478, 1589, 1590, 1591, 1703, 1704, 1705, 1817, 1818, 1819, 1930, 1931, 1932, 2044, 2045, 2046, 2158, 2159, 2160, 2271, 2272, 2273, 2839, 2840, 2841, 2953, 2954, 2955, 3408, 3409, 3410, 3976, 3977, 3978, 4544, 4545, and 4546.

[0033] In some embodiments of an IL-2 conjugate described herein, when the IL-2 conjugate comprises SEQ ID NO: 3, the position of the structure of Formula (XIV) and (XV) or a mixture of Formula (XIV) and (XV) in the amino acid sequence of the IL-2 conjugate is selected from Pl, T2, S3, S4, S5, T6, K7, K8, Q10, Lil, E14, H15, L17, L18, D19, Q21, M22, N25, G26, N28, N29, Y30, K31, K34, T36, M45, P46, K47, A49, T50, E51, L52, K53, H54, Q56, E59, E66, N70, Q73, S74, K75, N76, F77, H78, R80, P81, R82, D83, S86, N87,188, V90,191, L93, E94, K96, G97, S98, E99, T100, T101, F102, M103, C104, E105, Y106, A107, D108, D108 in the N87R variant, E109, T110, Alli, T112, El 15, N118, RI 19, T122, F123, S124, Q125, S126, S129, T130, L131, and T132. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XIV) or (XV), or a mixture of (XIV) and (XV), in the amino acid sequence of the IL-2 conjugate is selected from K8, Hl 5, LI 8, D19, M22, N25, N87, V90,191, L93, E94, K96, G97, S98, E99, D108 in the N87R variant, N118, T122, S124, Q125, S126, S129, and T130. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XIV) or (XV), or a mixture of (XIV) and (XV), in the amino acid sequence of the IL-2 conjugate is selected from K8, H15, L18, D19, M22, N25, N87, V90, E99, D108 in the N87R variant, N118, T122, S124, and T130. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XIV) or (XV), or a mixture of (XIV) and (XV), in the amino acid sequence of the IL-2 conjugate is K8. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XIV) or (XV), or a mixture of (XIV) and (XV), in the amino acid sequence of the IL-2 conjugate is Hl 5. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XIV) or (XV), or a mixture of (XIV) and (XV), in the amino acid sequence of the IL-2 conjugate is LI 8. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XIV) or (XV), or a mixture of (XIV) and (XV), in the amino acid sequence of the IL-2 conjugate is D19. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XIV) or (XV), or a mixture of (XIV) and (XV), in the amino acid sequence of the IL-2 2026234002   16 Sep 2026 conjugate is M22. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XIV) or (XV), or a mixture of (XIV) and (XV), in the amino acid sequence of the IL-2 conjugate is N25. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XIV) or (XV), or a mixture of (XIV) and (XV), in the amino acid sequence of the IL-2 conjugate is N87. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XIV) or (XV), or a mixture of (XIV) and (XV), in the amino acid sequence of the IL-2 conjugate is V90. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XIV) or (XV), or a mixture of (XIV) and (XV), in the amino acid sequence of the IL-2 conjugate is E99. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XIV) or (XV), or a mixture of (XIV) and (XV), in the amino acid sequence of the IL-2 conjugate is D108 in the N87R variant. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XIV) or (XV), or a mixture of (XIV) and (XV), in the amino acid sequence of the IL-2 conjugate is N118. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XIV) or (XV), or a mixture of (XIV) and (XV), in the amino acid sequence of the IL-2 conjugate is T122. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XIV) or (XV), or a mixture of (XIV) and (XV), in the amino acid sequence of the IL-2 conjugate is S124. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XIV) or (XV), or a mixture of (XIV) and (XV), in the amino acid sequence of the IL-2 conjugate is T130. In some embodiments of an IL-2 conjugate described herein, the ratio of the amount of the structure of Formula (XIV) to the amount of the structure of Formula (XV) comprising the total amount of the IL-2 conjugate is about 1:1. In some embodiments of an IL-2 conjugate described herein, the ratio of the amount of the structure of Formula (XIV) to the amount of the structure of Formula (XV) comprising the total amount of the IL-2 conjugate is greater than 1:1. In some embodiments of an IL-2 conjugate described herein, the ratio of the amount of the structure of Formula (XIV) to the amount of the structure of Formula (XV) comprising the total amount of the IL-2 conjugate is less than 1:1.

[0034] In some embodiments of an IL-2 conjugate described herein, when the IL-2 conjugate comprises SEQ ID NO: 4, the position of the structure of Formula (XIV) and (XV) or a mixture of Formula (XIV) and (XV) in the amino acid sequence of the IL-2 conjugate is selected from Al, P2, T3, S4, S5, S6, T7, K8, K9, Qll, L12, E15, Hl6, L18, L19, D20, Q22, M23, N26, G27, N29, N30, Y31, K32, K35, T37, M46, P47, K48, A50, T51, E52, L53, H55, Q57, E60, E67, N71, Q74, S75, K76, N77, F78, H79, R81, P82, R83, D84, S87, N88,189, V91,192, L94, E95, K97, G98, S99, E100, T101, T102, F103, M104, C105, E106, Y107, A108, D109, D109 in the N88R variant, El 10, Till, Al 12, T113, El 16, N119, R120, T123, S125, Q126, S127, S130, T131, L132, and T133. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XIV) or (XV), or a mixture of (XIV) 2026234002   16 Sep 2026 and (XV), in the amino acid sequence of the IL-2 conjugate is selected from K9, H16, L19, D20, M23, N26, N88, V91,192, L94, E95, K97, G98, S99, E100, D109 in the N88R variant, N119, T123, S125, Q126, S127, S130, and T131. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XIV) or (XV), or a mixture of (XIV) and (XV), in the amino acid sequence of the IL-2 conjugate is selected from K9, Hl6, L19, D20, M23, N26, N88, V91, E100, D109 in the N88R variant, N119, T123, S125, and T131. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XIV) or (XV), or a mixture of (XIV) and (XV), in the amino acid sequence of the IL-2 conjugate is K9. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XIV) or (XV), or a mixture of (XIV) and (XV), in the amino acid sequence of the IL-2 conjugate is H16. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XIV) or (XV), or a mixture of (XIV) and (XV), in the amino acid sequence of the IL-2 conjugate is LI 9. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XIV) or (XV), or a mixture of (XIV) and (XV), in the amino acid sequence of the IL-2 conjugate is D20. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XIV) or (XV), or a mixture of (XIV) and (XV), in the amino acid sequence of the IL-2 conjugate is M23. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XIV) or (XV), or a mixture of (XIV) and (XV), in the amino acid sequence of the IL-2 conjugate is N26. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XIV) or (XV), or a mixture of (XIV) and (XV), in the amino acid sequence of the IL-2 conjugate is N88. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XIV) or (XV), or a mixture of (XIV) and (XV), in the amino acid sequence of the IL-2 conjugate is V91. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XIV) or (XV), or a mixture of (XIV) and (XV), in the amino acid sequence of the IL-2 conjugate is E100. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XIV) or (XV), or a mixture of (XIV) and (XV), in the amino acid sequence of the IL-2 conjugate is D109 in the N88R variant. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XIV) or (XV), or a mixture of (XIV) and (XV), in the amino acid sequence of the IL-2 conjugate is N119. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XIV) or (XV), or a mixture of (XIV) and (XV), in the amino acid sequence of the IL-2 conjugate is T123. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XIV) or (XV), or a mixture of (XIV) and (XV), in the amino acid sequence of the IL-2 conjugate is S125. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XIV) or (XV), or a mixture of (XIV) and (XV), in the amino acid sequence of the IL-2 conjugate is T131. In some embodiments of an IL-2 conjugate described herein, the ratio of the amount 2026234002   16 Sep 2026 of the structure of Formula (XIV) to the amount of the structure of Formula (XV) comprising the total amount of the IL-2 conjugate is about 1:1. In some embodiments of an IL-2 conjugate described herein, the ratio of the amount of the structure of Formula (XIV) to the amount of the structure of Formula (XV) comprising the total amount of the IL-2 conjugate is greater than 1:1. In some embodiments of an IL-2 conjugate described herein, the ratio of the amount of the structure of Formula (XIV) to the amount of the structure of Formula (XV) comprising the total amount of the IL-2 conjugate is less than 1:1.

[0035] In some embodiments described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 3 in which at least one amino acid residue in the IL-2 conjugate is replaced by the structure of Formula (XIV) or (XV), or a mixture of (XIV) and (XV), wherein the amino acid residue in in SEQ ID NO: 3 that is replaced is selected from K8, H15, L18, D19, M22, N25, N87, V90, E99, D108 in the N87R variant, N118, T122, S124, and T130, and wherein n is an integer from 100 to about 1150, or from about 100 to about 1100, or from about 100 to about 1000, or from about 100 to about 900, or from about 100 to about 750, or from about 100 to about 700, or from about 100 to about 600, or from about 100 to about 575, or from about 100 to about 500, or from about 100 to about 450, or from about 100 to about to about 350, or from about 100 to about 275, or from about 100 to about 230, or from about 150 to about 475, or from about 150 to about 340, or from about 113 to about 340, or from about 450 to about 800, or from about 454 to about 796, or from about 454 to about 682, or from about 340 to about 795, or from about 341 to about 682, or from about 568 to about 909, or from about 227 to about 1500, or from about 225 to about 2280, or from about 460 to about 2160, or from about 460 to about 2050, or from about 341 to about 1820, or from about 341 to about 1710, or from about 341 to about 1250, or from about 225 to about 1250, or from about 341 to about 1250, or from about 341 to about 1136, or from about 341 to about 1023, or from about 341 to about 910, or from about 341 to about 796, or from about 341 to about 682, or from about 341 to about 568, or from about 114 to about 1000, or from about 114 to about 950, or from about 114 to about 910, or from about 114 to about 800, or from about 114 to about 690, or from about 114 to about 575. In some embodiments of an IL-2 conjugate described herein, n in the compounds of formula (XIV) and (XV) is an integer selected from 2, 5, 10, 11, 22, 23, 113, 114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, 1137, 1249, 1250, 1251, 1362, 1363, 1364, 1476, 1477, 1478, 1589, 1590, 1591, 1703, 1704, 1705, 1817, 1818, 1819, 1930, 1931, 1932, 2044, 2045, 2046, 2158, 2159, 2160, 2271, 2272, 2273, 2839, 2840, 2841, 2953, 2954, 2955, 3408, 3409, 3410, 3976, 3977, 3978, 4544, 4545, and 4546.

[0036] In some embodiments described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 4 in which at least one amino acid residue in the IL-2 conjugate is replaced by the structure of Formula (XIV) or (XV), or a mixture of (XIV) and (XV), wherein the amino acid residue in in SEQ ID NO: 3 that is replaced is selected from K9, Hl6, L19, D20, M23, N26, N88, V91,192, L94, 2026234002   16 Sep 2026 E95, K97, G98, S99, E100, D109 in the N88R variant, N119, T123, S125, Q126, S127, S130, and T131, and wherein n is an integer from 100 to about 1150, or from about 100 to about 1100, or from about 100 to about 1000, or from about 100 to about 900, or from about 100 to about 750, or from about 100 to about 700, or from about 100 to about 600, or from about 100 to about 575, or from about 100 to about 500, or from about 100 to about 450, or from about 100 to about to about 350, or from about 100 to about 275, or from about 100 to about 230, or from about 150 to about 475, or from about 150 to about 340, or from about 113 to about 340, or from about 450 to about 800, or from about 454 to about 796, or from about 454 to about 682, or from about 340 to about 795, or from about 341 to about 682, or from about 568 to about 909, or from about 227 to about 1500, or from about 225 to about 2280, or from about 460 to about 2160, or from about 460 to about 2050, or from about 341 to about 1820, or from about 341 to about 1710, or from about 341 to about 1250, or from about 225 to about 1250, or from about 341 to about 1250, or from about 341 to about 1136, or from about 341 to about 1023, or from about 341 to about 910, or from about 341 to about 796, or from about 341 to about 682, or from about 341 to about 568, or from about 114 to about 1000, or from about 114 to about 950, or from about 114 to about 910, or from about 114 to about 800, or from about 114 to about 690, or from about 114 to about 575. In some embodiments of an IL-2 conjugate described herein, n in the compounds of formula (XIV) and (XV) is an integer selected from 2, 5, 10, 11,22, 23, 113, 114, 227, 228,340,341,454, 455, 568,569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, 1137, 1249, 1250, 1251, 1362, 1363, 1364, 1476, 1477, 1478, 1589, 1590, 1591, 1703, 1704, 1705, 1817, 1818, 1819, 1930, 1931, 1932, 2044, 2045, 2046, 2158, 2159, 2160, 2271, 2272, 2273, 2839, 2840, 2841, 2953, 2954, 2955, 3408, 3409, 3410, 3976, 3977, 3978, 4544, 4545, and 4546.

[0037] Described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 3 or SEQ ID NO: 4 in which at least one amino acid residue in the IL-2 conjugate is replaced by the structure of Formula (XIV) or (XV), or a mixture of (XIV) and (XV), wherein n is an integer such that the molecular weight of the PEG moiety is in the range from about 1,000 Daltons about 200,000 Daltons, or from about 2,000 Daltons to about 150,000 Daltons, or from about 3,000 Daltons to about 125,000 Daltons, or from about 4,000 Daltons to about 100,000 Daltons, or from about 5,000 Daltons to about 100,000 Daltons, or from about 6,000 Daltons to about 90,000 Daltons, or from about 7,000 Daltons to about 80,000 Daltons, or from about 8,000 Daltons to about 70,000 Daltons, or from about 5,000 Daltons to about 70,000 Daltons, or from about 5,000 Daltons to about 65,000 Daltons, or from about 5,000 Daltons to about 60,000 Daltons, or from about 5,000 Daltons to about 50,000 Daltons, or from about 6,000 Daltons to about 50,000 Daltons, or from about 7,000 Daltons to about 50,000 Daltons, or from about 7,000 Daltons to about 45,000 Daltons, or from about 7,000 Daltons to about 40,000 Daltons, or from about 8,000 Daltons to about 40,000 Daltons, or from about 8,500 Daltons to about 40,000 Daltons, 2026234002   16 Sep 2026 or from about 8,500 Daltons to about 35,000 Daltons, or from about 9,000 Daltons to about 50,000 Daltons, or from about 9,000 Daltons to about 45,000 Daltons, or from about 9,000 Daltons to about 40,000 Daltons, or from about 9,000 Daltons to about 35,000 Daltons, or from about 9,000 Daltons to about 30,000 Daltons, or from about 9,500 Daltons to about 35,000 Daltons, or from about 9,500 Daltons to about 30,000 Daltons, or from about 10,000 Daltons to about 50,000 Daltons, or from about 10,000 Daltons to about 45,000 Daltons, or from about 10,000 Daltons to about 40,000 Daltons, or from about 10,000 Daltons to about 35,000 Daltons, or from about 10,000 Daltons to about 30,000 Daltons, or from about 15,000 Daltons to about 50,000 Daltons, or from about 15,000 Daltons to about 45,000 Daltons, or from about 15,000 Daltons to about 40,000 Daltons, or from about 15,000 Daltons to about 35,000 Daltons, or from about 15,000 Daltons to about 30,000 Daltons, or from about 20,000 Daltons to about 50,000 Daltons, or from about 20,000 Daltons to about 45,000 Daltons, or from about 20,000 Daltons to about 40,000 Daltons, or from about 20,000 Daltons to about 35,000 Daltons, or from about 20,000 Daltons to about 30,000 Daltons. Described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 3 or SEQ ID NO: 4 in which at least one amino acid residue in the IL-2 conjugate is replaced by the structure of Formula (XIV) or (XV), or a mixture of (XIV) and (XV), wherein n is an integer such that the molecular weight of the PEG moiety is about 5,000 Daltons, about 7,500 Daltons, about 10,000 Daltons, about 15,000 Daltons, about 20,000 Daltons, about 25,000 Daltons, about 30,000 Daltons, about 35,000 Daltons, about 40,000 Daltons, about 45,000 Daltons, about 50,000 Daltons, about 60,000 Daltons, about 70,000 Daltons, about 80,000 Daltons, about 90,000 Daltons, about 100,000 Daltons, about 125,000 Daltons, about 150,000 Daltons, about 175,000 Daltons or about 200,000 Daltons. Described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 3 or SEQ ID NO: 4 in which at least one amino acid residue in the IL-2 conjugate is replaced by the structure of Formula (XIV) or (XV), or a mixture of (XIV) and (XV), wherein n is an integer such that the molecular weight of the PEG moiety is about 5,000 Daltons, about 7,500 Daltons, about 10,000 Daltons, about 15,000 Daltons, about 20,000 Daltons, about 25,000 Daltons, about 30,000 Daltons, about 35,000 Daltons, about 40,000 Daltons, about 45,000 Daltons, or about 50,000 Daltons.

[0038] In some embodiments described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 3 in which at least one amino acid residue in the IL-2 conjugate is replaced by the structure of Formula (XIV) or (XV), or a mixture of (XIV) and (XV), wherein the amino acid residue in SEQ ID NO: 3 that is replaced is Hl 5, and wherein m is an integer from 1 to 6, p is an integer from 1 to 6, and n is an integer from about 450 to about 800, or from about 454 to about 796, or from about 454 to about 682, or from about 568 to about 909. In some embodiments of an IL-2 conjugate described herein in the compounds of formula (XIV) and (XV), m is 2, p is 2, and n is an integer selected from 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910. 2026234002   16 Sep 2026

[0039] In some embodiments described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 3 in which at least one amino acid residue in the IL-2 conjugate is replaced by the structure of Formula (XIV) or (XV), or a mixture of (XIV) and (XV), wherein the amino acid residue in SEQ ID NO: 3 that is replaced is Hl 5, and wherein m is an integer from 1 to 6, p is an integer from 1 to 6, and n is an integer from about 450 to about 800, or from about 454 to about 796, or from about 454 to about 682, or from about 568 to about 909. In some embodiments of an IL-2 conjugate described herein in the compounds of formula (XIV) and (XV), m is 2, p is 2, and n is an integer selected from 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910. In some embodiments, n is from about 500 to about 1000. In some embodiments, n is from about 550 to about 800. In some embodiments, n is about 681.

[0040] In some embodiments described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 4 in which at least one amino acid residue in the IL-2 conjugate is replaced by the structure of Formula (XIV) or (XV), or a mixture of (XIV) and (XV), wherein the amino acid residue in SEQ ID NO: 4 that is replaced is Hl6, and wherein m is an integer from 1 to 6, p is an integer from 1 to 6, and n is an integer from about 450 to about 800, or from about 454 to about 796, or from about 454 to about 682, or from about 568 to about 909. In some embodiments of an IL-2 conjugate described herein in the compounds of formula (XIV) and (XV), m is 2, p is 2, and n is an integer selected from 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910.

[0041] In some embodiments described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 4 in which at least one amino acid residue in the IL-2 conjugate is replaced by the structure of Formula (XIV) or (XV), or a mixture of (XIV) and (XV), wherein the amino acid residue in SEQ ID NO: 4 that is replaced is Hl6, and wherein m is an integer from 1 to 6, p is an integer from 1 to 6, and n is an integer from about 450 to about 800, or from about 454 to about 796, or from about 454 to about 682, or from about 568 to about 909. In some embodiments of an IL-2 conjugate described herein in the compounds of formula (XIV) and (XV), m is 2, p is 2, and n is an integer selected from 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910. In some embodiments, n is from about 500 to about 1000. In some embodiments, n is from about 550 to about 800. In some embodiments, n is about 681.

[0042] Described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 3 or SEQ ID NO: 4 in which at least one amino acid residue in the IL-2 conjugate is replaced by the structure of Formula (XVI) or (XVII), or a mixture of (XVI) and (XVII): 2026234002   16 Sep 2026 Formula (XVI) Formula (XVII) wherein: m is an integer from 0 to 20; n is an integer in the range from about 2 to about 5000; and the wavy lines indicate covalent bonds to amino acid residues within SEQ ID NO: 3 or SEQ ID NO: 4 that are not replaced. Here and throughout, embodiments of Formula (XVI) and / or (XVII) also encompass a pharmaceutically acceptable salt, solvate, or hydrate thereof. In some embodiments described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 3 in which at least one amino acid residue in the IL-2 conjugate is replaced by the structure of Formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), wherein m, p, n, and the meaning of the wavy line are as described above. In some embodiments described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 4 in which at least one amino acid residue in the IL-2 conjugate is replaced by the structure of Formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), wherein m, p, n, and the meaning of the wavy line are as described above.

[0043] In some embodiments, the stereochemistry of the chiral center within Formula (XVI) and Formula (XVII) is racemic, is enriched in (R), is enriched in (S), is substantially (R), is substantially (S), is (R) or is (S). In some embodiments, the stereochemistry of the chiral center within Formula (XVI) and Formula (XVII) is racemic. In some embodiments, the stereochemistry of the chiral center within Formula (XVI) and Formula (XVII) is enriched in (R). In some embodiments, the stereochemistry of the chiral center within Formula (XVI) and Formula (XVII) is enriched in (S). In some embodiments, the stereochemistry of the chiral center within Formula (XVI) and Formula (XVII) is substantially (R). In -56- 2026234002   16 Sep 2026 some embodiments, the stereochemistry of the chiral center within Formula (XVI) and Formula (XVII) is substantially (S). In some embodiments, the stereochemistry of the chiral center within Formula (XVI) and Formula (XVII) is (R). In some embodiments, the stereochemistry of the chiral center within Formula (XVI) and Formula (XVII) is (S).

[0044] In some embodiments of an IL-2 conjugate described herein, m in the compounds of Formula (XVI) and (XVII) is from 1 to 20, or from 1 to 18, or from 1 to 16, or from 1 to 14, or from 1 to 12, or from 1 to 10, or from 1 to 9, or from 1 to 8, or from 1 to 7, or from 1 to 6, or from 1 to 5, or from 1 to 4, or from 1 to 3, or from 1 to 2. In some embodiments of an IL-2 conjugate described herein, m in the compounds of Formula (XVI) and (XVII) is 1. In some embodiments of an IL-2 conjugate described herein, m in the compounds of Formula (XVI) and (XVII) is 2. In some embodiments of an IL-2 conjugate described herein, m in the compounds of Formula (XVI) and (XVII) is 3. In some embodiments of an IL-2 conjugate described herein, m in the compounds of Formula (XVI) and (XVII) is 4. In some embodiments of an IL-2 conjugate described herein, m in the compounds of Formula (XVI) and (XVII) is 5. In some embodiments of an IL-2 conjugate described herein, m in the compounds of Formula (XVI) and (XVII) is 6. In some embodiments of an IL-2 conjugate described herein, m in the compounds of Formula (XVI) and (XVII) is 7. In some embodiments of an IL-2 conjugate described herein, m in the compounds of Formula (XVI) and (XVII) is 8. In some embodiments of an IL-2 conjugate described herein, m in the compounds of Formula (XVI) and (XVII) is 9. In some embodiments of an IL-2 conjugate described herein, m in the compounds of Formula (XVI) and (XVII) is 10. In some embodiments of an IL-2 conjugate described herein, m in the compounds of Formula (XVI) and (XVII) is 11. In some embodiments of an IL-2 conjugate described herein, m in the compounds of Formula (XVI) and (XVII) is 12. In some embodiments of an IL-2 conjugate described herein, m in the compounds of Formula (XVI) and (XVII) is 13. In some embodiments of an IL-2 conjugate described herein, m in the compounds of Formula (XVI) and (XVII) is 14. In some embodiments of an IL-2 conjugate described herein, m in the compounds of Formula (XVI) and (XVII) is 15. In some embodiments of an IL-2 conjugate described herein, m in the compounds of Formula (XVI) and (XVII) is 16. In some embodiments of an IL-2 conjugate described herein, m in the compounds of Formula (XVI) and (XVII) is 17. In some embodiments of an IL-2 conjugate described herein, m in the compounds of Formula (XVI) and (XVII) is 18. In some embodiments of an IL-2 conjugate described herein, m in the compounds of Formula (XVI) and (XVII) is 19. In some embodiments of an IL-2 conjugate described herein, m in the compounds of Formula (XVI) and (XVII) is 20.

[0045] In some embodiments of an IL-2 conjugate described herein, n in the compounds of Formula (XVI) and (XVII) is in the range from about 5 to about 4600, or from about 10 to about 4000, or from 2026234002   16 Sep 2026 about 20 to about 3000, or from about 100 to about 3000, or from about 100 to about 2900, or from about 150 to about 2900, or from about 125 to about 2900, or from about 100 to about 2500, or from about 100 to about 2000, or from about 100 to about 1900, or from about 100 to about 1850, or from about 100 to about 1750, or from about 100 to about 1650, or from about 100 to about 1500, or from about 100 to about 1400, or from about 100 to about 1300, or from about 100 to about 1250, or from about 100 to about 1150, or from about 100 to about 1100, or from about 100 to about 1000, or from about 100 to about 900, or from about 100 to about 750, or from about 100 to about 700, or from about 100 to about 600, or from about 100 to about 575, or from about 100 to about 500, or from about 100 to about 450, or from about 100 to about to about 350, or from about 100 to about 275, or from about 100 to about 230, or from about 150 to about 475, or from about 150 to about 340, or from about 113 to about 340, or from about 450 to about 800, or from about 454 to about 796, or from about 454 to about 682, or from about 340 to about 795, or from about 341 to about 682, or from about 568 to about 909, or from about 227 to about 1500, or from about 225 to about 2280, or from about 460 to about 2160, or from about 460 to about 2050, or from about 341 to about 1820, or from about 341 to about 1710, or from about 341 to about 1250, or from about 225 to about 1250, or from about 341 to about 1250, or from about 341 to about 1136, or from about 341 to about 1023, or from about 341 to about 910, or from about 341 to about 796, or from about 341 to about 682, or from about 341 to about 568, or from about 114 to about 1000, or from about 114 to about 950, or from about 114 to about 910, or from about 114 to about 800, or from about 114 to about 690, or from about 114 to about 575.

[0046] In some embodiments of an IL-2 conjugate described herein in the compounds of Formula (XVI) and (XVII), m is an integer from 1 to 6, and n is an integer selected from 113,114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137. In some embodiments of an IL-2 conjugate described herein in the compounds of Formula (XVI) and (XVII), m is an integer from 2 to 6, and n is an integer selected from 113,114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137. In some embodiments of an IL-2 conjugate described herein in the compounds of Formula (XVI) and (XVII), m is an integer from 2 to 4, and n is an integer selected from 113,114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137. In some embodiments of an IL-2 conjugate described herein in the compounds of Formula (XVI) and (XVII), m is 1, and n is an integer selected from 113,114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137. In some embodiments of an IL-2 conjugate described herein in the compounds of Formula (XVI) and (XVII), m is 2, and n is an integer selected from 113,114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794,795,796,908,909,910, 1021, 1022, 1023, 1135, 1136, and 1137. In some embodiments of an IL-2 2026234002   16 Sep 2026 conjugate described herein in the compounds of Formula (XVI) and (XVII), m is 3, and n is an integer selected from 113, 114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137. In some embodiments of an IL-2 conjugate described herein in the compounds of Formula (XVI) and (XVII), m is 4, and n is an integer selected from 113, 114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137. In some embodiments of an IL-2 conjugate described herein in the compounds of Formula (XVI) and (XVII), m is 5, and n is an integer selected from 113,114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137. In some embodiments of an IL-2 conjugate described herein in the compounds of Formula (XVI) and (XVII), m is 6, and n is an integer selected from 113,114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137. In some embodiments of an IL-2 conjugate described herein in the compounds of Formula (XVI) and (XVII), m is 7, and n is an integer selected from 113,114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794,795,796,908,909,910, 1021, 1022, 1023, 1135, 1136, and 1137. In some embodiments of an IL-2 conjugate described herein in the compounds of Formula (XVI) and (XVII), m is 8, and n is an integer selected from 113, 114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137. In some embodiments of an IL-2 conjugate described herein in the compounds of Formula (XVI) and (XVII), m is 9, and n is an integer selected from 113, 114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137. In some embodiments of an IL-2 conjugate described herein in the compounds of Formula (XVI) and (XVII), m is 10, and n is an integer selected from 113, 114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137. In some embodiments of an IL-2 conjugate described herein in the compounds of Formula (XVI) and (XVII), mis 11, and n is an integer selected from 113, 114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137. In some embodiments of an IL-2 conjugate described herein in the compounds of Formula (XVI) and (XVII), m is 12, and n is an integer selected from 113,114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794,795,796,908,909,910, 1021, 1022, 1023, 1135, 1136, and 1137. In some embodiments of an IL-2 conjugate described herein in the compounds of Formula (XVI) and (XVII), m is 2, and n is an integer selected from 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, and 1137.

[0047] In some embodiments of an IL-2 conjugate described herein, n in the compounds of Formula (XVI) and (XVII) is an integer selected from 2, 5, 10, 11, 22, 23, 113, 114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, 1137, 1249, 1250, 1251, 1362, 1363, 1364, 1476, 1477, 1478, 1589, 1590, 1591, 1703, 1704, 1705, 1817, 1818, 1819, 1930, 2026234002   16 Sep 2026 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.

[0048] In some embodiments of an IL-2 conjugate described herein, the position of the structure of Formula (XVI) and (XVII) or a mixture of Formula (XVI) and (XVII) in the amino acid sequence of the IL-2 conjugate comprising SEQ ID NO: 3 is selected from Pl, T2, S3, S4, S5, T6, K7, K8, Q10, Lil, E14, H15, L17, L18, D19, Q21, M22, N25, G26, N28, N29, Y30, K31, K34, T36, M45, P46, K47, A49, T50, E51, L52, K53, H54, Q56, E59, E66, N70, Q73, S74, K75, N76, F77, H78, R80, P81, R82, D83, S86, N87,188, V90,191, L93, E94, K96, G97, S98, E99, T100, T101, F102, M103, C104, E105, Y106, A107, D108, D108 in the N87R variant, E109, T110, Alli, T112, El 15, N118, RI 19, T122, F123, S124, Q125, S126, S129, T130, L131, and T132. In some embodiments of an IL-2 conjugate described herein, the position of the structure of Formula (XVI) and (XVII) or a mixture of Formula (XVI) and (XVII) in the amino acid sequence of the IL-2 conjugate of SEQ ID NO: 3 is selected from K8, Hl 5, L18, D19, M22, N25, N87, V90,191, L93, E94, K96, G97, S98, E99, D108 in the N87R variant, N118, T122, S124, Q125, S126, S129, and T130. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), in the amino acid sequence of the IL-2 conjugate is selected from K8, H15, L18, D19, M22, N25, N87, V90, E99, D108 in the N87R variant, N118, T122, S124, and T130. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), in the amino acid sequence of the IL-2 conjugate is K8. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), in the amino acid sequence of the IL-2 conjugate is Hl 5. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), in the amino acid sequence of the IL-2 conjugate is LI 8. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), in the amino acid sequence of the IL-2 conjugate is D19. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), in the amino acid sequence of the IL-2 conjugate is M22. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), in the amino acid sequence of the IL-2 conjugate is N25. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), in the amino acid sequence of the IL-2 conjugate is N87. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), in the amino acid sequence of the IL-2 conjugate is V90. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), in 2026234002   16 Sep 2026 the amino acid sequence of the IL-2 conjugate is E99. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), in the amino acid sequence of the IL-2 conjugate is DI 08 in the N87R variant. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), in the amino acid sequence of the IL-2 conjugate is N118. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), in the amino acid sequence of the IL-2 conjugate is T122. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), in the amino acid sequence of the IL-2 conjugate is SI 24. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), in the amino acid sequence of the IL-2 conjugate is T130. In some embodiments of an IL-2 conjugate 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 about 1:1. In some embodiments of an IL-2 conjugate 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 greater than 1:1. In some embodiments of an IL-2 conjugate 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 less than 1:1.

[0049] In some embodiments described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 3 in which at least one amino acid residue in the IL-2 conjugate is replaced by the structure of Formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), wherein the amino acid residue in in SEQ ID NO: 3 that is replaced is selected from K8, Hl 5, LI 8, DI9, M22, N25, N87, V90, E99, D108 in the N87R variant, N118, T122, S124, and T130, and wherein n is an integer from 100 to about 1150, or from about 100 to about 1100, or from about 100 to about 1000, or from about 100 to about 900, or from about 100 to about 750, or from about 100 to about 700, or from about 100 to about 600, or from about 100 to about 575, or from about 100 to about 500, or from about 100 to about 450, or from about 100 to about to about 350, or from about 100 to about 275, or from about 100 to about 230, or from about 150 to about 475, or from about 150 to about 340, or from about 113 to about 340, or from about 450 to about 800, or from about 454 to about 796, or from about 454 to about 682, or from about 340 to about 795, or from about 341 to about 682, or from about 568 to about 909, or from about 227 to about 1500, or from about 225 to about 2280, or from about 460 to about 2160, or from about 460 to about 2050, or from about 341 to about 1820, or from about 341 to about 1710, or from about 341 to about 1250, or from about 225 to about 1250, or from about 341 to about 1250, or from about 341 to about 1136, or from about 341 to about 1023, or from about 341 to about 910, or from about 341 to about 2026234002   16 Sep 2026 796, or from about 341 to about 682, or from about 341 to about 568, or from about 114 to about 1000, or from about 114 to about 950, or from about 114 to about 910, or from about 114 to about 800, or from about 114 to about 690, or from about 114 to about 575. In some embodiments of an IL-2 conjugate described herein, n in the compounds of formula (XVI) and (XVII) is an integer selected from 2, 5, 10, 11, 22, 23, 113, 114, 227, 228, 340, 341, 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, 1137, 1249, 1250, 1251, 1362, 1363, 1364, 1476, 1477, 1478, 1589, 1590, 1591, 1703, 1704, 1705, 1817, 1818, 1819, 1930, 1931, 1932, 2044, 2045, 2046, 2158, 2159, 2160, 2271, 2272, 2273, 2839, 2840, 2841, 2953, 2954, 2955, 3408, 3409, 3410, 3976, 3977, 3978, 4544, 4545, and 4546.

[0050] In some embodiments described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 3 in which at least one amino acid residue in the IL-2 conjugate is replaced by the structure of Formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), wherein the amino acid residue in in SEQ ID NO: 3 that is replaced is selected from Hl 5, 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 an IL-2 conjugate described herein, n in the compounds of formula (XVI) and (XVII) is an integer selected from 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, 1137, and 1249.

[0051] In some embodiments described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 3 in which at least one amino acid residue in the IL-2 conjugate is replaced by the structure of Formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), wherein the amino acid residue in SEQ ID NO: 3 that is replaced is selected from Hl 5, 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 an IL-2 conjugate described herein, n in the compounds of formula (XVI) and (XVII) is an integer selected from 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910.

[0052] In some embodiments described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 3 in which at least one amino acid residue in the IL-2 conjugate is replaced by the structure of Formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), wherein the amino acid residue in SEQ ID NO: 3 that is replaced is Hl 5, 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 an IL-2 conjugate described herein, n in the compounds of formula (XVI) and (XVII) is an integer selected from 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910. In some embodiments, n is from about 500 to about 1000. In some embodiments, n is from about 550 to about 800. In some embodiments, n is about 681. 2026234002   16 Sep 2026

[0053] In some embodiments of an IL-2 conjugate described herein, the position of the structure of Formula (XVI) and (XVII) or a mixture of Formula (XVI) and (XVII) in the amino acid sequence of the IL-2 conjugate comprising SEQ ID NO: 4 is selected from Al, P2, T3, S4, S5, S6, T7, K8, K9, QI 1, L12, E15, H16, L18, L19, D20, Q22, M23, N26, G27, N29, N30, Y31, K32, K35, T37, M46, P47, K48, A50, T51, E52, L53, H55, Q57, E60, E67, N71, Q74, S75, K76, N77, F78, H79, R81, P82, R83, D84, S87, N88,189, V91,192, L94, E95, K97, G98, S99, E100, T101, T102, F103, M104, C105, E106, Y107, A108, D109, D109 in the N88R variant, El 10, Till, Al 12, T113, El 16, N119, R120, T123, S125, Q126, S127, S130, T131, L132, and T133. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), in the amino acid sequence of the IL-2 conjugate is selected from K9, Hl 6, L19, D20, M23, N26, N88, V91,192, L94, E95, K97, G98, S99, E100, D109 in the N88R variant, N119, T123, S125, Q126, S127, S130, and T131. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), in the amino acid sequence of the IL-2 conjugate is selected fromK9, Hl6, L19, D20, M23, N26, N88, V91, E100, D109 in the N88R variant, N119, T123, S125, and T131. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), in the amino acid sequence of the IL-2 conjugate is K9. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), in the amino acid sequence of the IL-2 conjugate is Hl 6. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), in the amino acid sequence of the IL-2 conjugate is LI 9. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), in the amino acid sequence of the IL-2 conjugate is D20. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), in the amino acid sequence of the IL-2 conjugate is M23. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), in the amino acid sequence of the IL-2 conjugate is N26. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), in the amino acid sequence of the IL-2 conjugate is N88. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), in the amino acid sequence of the IL-2 conjugate is V91. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), in the amino acid sequence of the IL-2 conjugate is El 00. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), in the amino acid sequence of the IL-2 conjugate is DI 09 in 2026234002   16 Sep 2026 the N88R variant. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), in the amino acid sequence of the IL-2 conjugate is N119. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), in the amino acid sequence of the IL-2 conjugate is T123. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), in the amino acid sequence of the IL-2 conjugate is S125. Further described herein are IL-2 conjugates wherein the position of the structure of Formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), in the amino acid sequence of the IL-2 conjugate is T131.

[0054] Described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 3 or SEQ ID NO: 4 in which at least one amino acid residue in the IL-2 conjugate is replaced by the structure of Formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), wherein n is an integer such that the molecular weight of the PEG moiety is in the range from about 1,000 Daltons about 200,000 Daltons, or from about 2,000 Daltons to about 150,000 Daltons, or from about 3,000 Daltons to about 125,000 Daltons, or from about 4,000 Daltons to about 100,000 Daltons, or from about 5,000 Daltons to about 100,000 Daltons, or from about 6,000 Daltons to about 90,000 Daltons, or from about 7,000 Daltons to about 80,000 Daltons, or from about 8,000 Daltons to about 70,000 Daltons, or from about 5,000 Daltons to about 70,000 Daltons, or from about 5,000 Daltons to about 65,000 Daltons, or from about 5,000 Daltons to about 60,000 Daltons, or from about 5,000 Daltons to about 50,000 Daltons, or from about 6,000 Daltons to about 50,000 Daltons, or from about 7,000 Daltons to about 50,000 Daltons, or from about 7,000 Daltons to about 45,000 Daltons, or from about 7,000 Daltons to about 40,000 Daltons, or from about 8,000 Daltons to about 40,000 Daltons, or from about 8,500 Daltons to about 40,000 Daltons, or from about 8,500 Daltons to about 35,000 Daltons, or from about 9,000 Daltons to about 50,000 Daltons, or from about 9,000 Daltons to about 45,000 Daltons, or from about 9,000 Daltons to about 40,000 Daltons, or from about 9,000 Daltons to about 35,000 Daltons, or from about 9,000 Daltons to about 30,000 Daltons, or from about 9,500 Daltons to about 35,000 Daltons, or from about 9,500 Daltons to about 30,000 Daltons, or from about 10,000 Daltons to about 50,000 Daltons, or from about 10,000 Daltons to about 45,000 Daltons, or from about 10,000 Daltons to about 40,000 Daltons, or from about 10,000 Daltons to about 35,000 Daltons, or from about 10,000 Daltons to about 30,000 Daltons, or from about 15,000 Daltons to about 50,000 Daltons, or from about 15,000 Daltons to about 45,000 Daltons, or from about 15,000 Daltons to about 40,000 Daltons, or from about 15,000 Daltons to about 35,000 Daltons, or from about 15,000 Daltons to about 30,000 Daltons, or from about 20,000 Daltons to about 50,000 Daltons, or from about 20,000 Daltons to about 45,000 Daltons, or from about 20,000 Daltons to about 40,000 Daltons, or from about 20,000 Daltons to about 35,000 Daltons, or from about 20,000 2026234002   16 Sep 2026 Daltons to about 30,000 Daltons. Described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 3 or SEQ ID NO: 4 in which at least one amino acid residue in the IL-2 conjugate is replaced by the structure of Formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), wherein n is an integer such that the molecular weight of the PEG moiety is about 5,000 Daltons, about 7,500 Daltons, about 10,000 Daltons, about 15,000 Daltons, about 20,000 Daltons, about 25,000 Daltons, about 30,000 Daltons, about 35,000 Daltons, about 40,000 Daltons, about 45,000 Daltons, about 50,000 Daltons, about 60,000 Daltons, about 70,000 Daltons, about 80,000 Daltons, about 90,000 Daltons, about 100,000 Daltons, about 125,000 Daltons, about 150,000 Daltons, about 175,000 Daltons or about 200,000 Daltons. Described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 3 or SEQ ID NO: 4 in which at least one amino acid residue in the IL-2 conjugate is replaced by the structure of Formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), wherein n is an integer such that the molecular weight of the PEG moiety is about 5,000 Daltons, about 7,500 Daltons, about 10,000 Daltons, about 15,000 Daltons, about 20,000 Daltons, about 25,000 Daltons, about 30,000 Daltons, about 35,000 Daltons, about 40,000 Daltons, about 45,000 Daltons, or about 50,000 Daltons.

[0055] In some embodiments described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 4 in which at least one amino acid residue in the IL-2 conjugate is replaced by the structure of Formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), wherein the amino acid residue in in SEQ ID NO: 4 that is H16, m is an integer from 1 to 6, and n is an integer from about 450 to about 800, or from about 454 to about 796, or from about 454 to about 682, or from about 568 to about 909. In some embodiments of an IL-2 conjugate described herein in the compounds of formula (XVI) and (XVII), m is 2, and n is an integer selected from 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, 910, 1021, 1022, 1023, 1135, 1136, 1137, and 1249.

[0056] In some embodiments described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 4 in which at least one amino acid residue in the IL-2 conjugate is replaced by the structure of Formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), wherein the amino acid residue in SEQ ID NO: 4 that is replaced is Hl6, and wherein m is an integer from 1 to 6, and n is an integer from about 450 to about 800, or from about 454 to about 796, or from about 454 to about 682, or from about 568 to about 909. In some embodiments of an IL-2 conjugate described herein in the compounds of formula (XVI) and (XVII), m is 2, and n is an integer selected from 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910.

[0057] In some embodiments described herein are IL-2 conjugates comprising the amino acid sequence of SEQ ID NO: 4 in which at least one amino acid residue in the IL-2 conjugate is replaced by the structure of Formula (XVI) or (XVII), or a mixture of (XVI) and (XVII), wherein the amino acid residue in SEQ ID NO: 4 that is replaced is E61, and wherein m is an integer from 1 to 6, and n is an 2026234002   16 Sep 2026 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 an IL-2 conjugate described herein in the compounds of formula (XVI) and (XVII), m is 2, and n is an integer selected from 454, 455, 568, 569, 680, 681, 682, 794, 795, 796, 908, 909, and 910. 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.

[0058] Described herein are methods of treating an autoimmune disease in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of an IL-2 conjugate described herein. Further described herein are methods wherein the autoimmune disease is selected from the group consisting of graft versus host disease (GVHD), atopic dermatitis, Crohn’s disease, alopecia areata, autoimmune hemolytic anemia, autoimmune hepatitis, dermatomyositis, type 1 diabetes, juvenile / pediatric type 1 diabetes juvenile idiopathic arthritis, glomerulonephritis, Graves’ disease, Guillain-Barre syndrome, idiopathic thrombocytopenic purpura, myasthenia gravis, multiple sclerosis, pemphigus / pemphigoid, pernicious anemia, polyarteritis nodosa, polymyositis, primary biliary cholangitis, primary biliary cirrhosis, nonalcoholic steatohepatitis (NASH), psoriasis, rheumatoid arthritis, scleroderma, CREST syndrome, Sjogren’s syndrome, systemic lupus erythematosus, thyroiditis, uveitis, vitiligo, Wegener’s granulomatosis, Addison’s disease (adrenal insufficiency), Hashimoto thyroiditis, autoimmune hepatitis, infertility, ANCA-associated vasculitis, psoriatic arthritis, Celiac disease, ulcerative colitis, lichen sclerosus, and Behcet’s disease. Further described herein are methods wherein the autoimmune disease is selected from the group consisting of graft versus host disease (GVHD), atopic dermatitis, Crohn’s disease, type 1 diabetes, multiple sclerosis, rheumatoid arthritis, myasthenia gravis, primary biliary cirrhosis, nonalcoholic steatohepatitis (NASH), glomerulonephritis, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, scleroderma, CREST syndrome, psoriasis, Celiac disease, ulcerative colitis, pemphigus, psoriatic arthritis, and infertility. Further described herein are methods wherein the autoimmune disease is graft versus host disease (GVHD). Further described herein are methods wherein the autoimmune disease is atopic dermatitis. Further described herein are methods wherein the autoimmune disease is Crohn’s disease. Further described herein are methods wherein the autoimmune disease is type 1 diabetes. Further described herein are methods wherein the autoimmune disease is multiple sclerosis. Further described herein are methods wherein the autoimmune disease is rheumatoid arthritis. Further described herein are methods wherein the autoimmune disease is myasthenia gravis. Further described herein are methods wherein the autoimmune disease is primary biliary cholangitis or primary biliary cirrhosis. Further described herein are methods wherein the autoimmune disease is nonalcoholic steatohepatitis (NASH). Further described herein are methods wherein the autoimmune disease is glomerulonephritis. Further described herein are methods wherein the autoimmune disease is idiopathic thrombocytopenic purpura. Further described 2026234002   16 Sep 2026 herein are methods wherein the autoimmune disease is systemic lupus erythematosus. Further described herein are methods wherein the autoimmune disease is scleroderma. Further described herein are methods wherein the autoimmune disease is CREST syndrome. Further described herein are methods wherein the autoimmune disease is infertility. Further described herein are methods wherein the IL-2 conjugate is administered to the subject in need thereof once per week, once every two weeks, once every three weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks, or once every 8 weeks. Further described herein are methods wherein the IL-2 conjugate is administered to the subject in need thereof once per week, once every two weeks, once every three weeks, or once every 4 weeks. Further described herein are methods wherein the IL-2 conjugate is administered to the subject in need thereof once per week. Further described herein are methods wherein the IL-2 conjugate is administered to the subject in need thereof once every two weeks. Further described herein are methods wherein the IL-2 conjugate is administered to the subject in need thereof once every three weeks. Further described herein are methods wherein the IL-2 conjugate is administered to the subject in need thereof once every four weeks. Further described herein are methods wherein the subject in need thereof is determined to exhibit an increased concentration of rheumatoid factor in the blood of the subject prior to administration to the subject of the therapeutically effective amount of the IL-2 conjugate. Further described herein are methods wherein the increased concentration of rheumatoid factor in the blood of the subject is about 14 lU / mL or higher, or about 15 lU / mL or higher. Further described herein are methods wherein the increased concentration of rheumatoid factor in the blood of the subject is about 14 lU / mL or higher. Further described herein are methods wherein the increased concentration of rheumatoid factor in the blood of the subject is about 15 lU / mL or higher.

[0059] Described herein are methods of treating rheumatoid arthritis in a subject in need thereof, comprising: (a) determining the concentration of rheumatoid factor in the blood of the subject; and (b) administering to the subject in need thereof a therapeutically effective amount of an IL-2 conjugate described herein if the concentration of rheumatoid factor in the blood of the subject is greater than about 14 lU / mL. Further described herein are methods wherein a therapeutically effective amount of the IL-2 conjugate is administered to the subject in need thereof if the concentration of rheumatoid factor in the blood of the subject is greater than about 15 lU / mL.

[0060] Described herein are methods of treating rheumatoid arthritis in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of an IL-2 conjugate described herein if the concentration of rheumatoid factor in the blood of the subject is determined to be greater than about 14 lU / mL.

[0061] Described herein are methods of treating rheumatoid arthritis in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of an IL-2 2026234002   16 Sep 2026 conjugate described herein if the concentration of rheumatoid factor in the blood of the subject is determined to be greater than about 15 lU / mL. Further provided herein are methods wherein the subject in need thereof is determined to exhibit an abnormal erythrocyte sedimentation rate (ESR) test prior to administration to the subject of the therapeutically effective amount of the IL-2 conjugate. Further described herein are methods wherein the subject is determined to exhibit an abnormal erythrocyte sedimentation rate (ESR) test using the Westergren rate method prior to administration to the subject of the therapeutically effective amount of the IL-2 conjugate. Further described herein are methods wherein the subject is determined to exhibit an abnormal erythrocyte sedimentation rate (ESR) test using the Wintrobe rate method prior to administration to the subject of the therapeutically effective amount of the IL-2 conjugate. Further provided herein are methods wherein the subject is a woman under age 50 and exhibits a Westergren rate greater than about 20 mm / hr. Further provided herein are methods wherein the subject is a woman greater than age 50 and exhibits a Westergren rate greater than about 30 mm / hr. Further provided herein are methods wherein the subject is a man under age 50 and exhibits a Westergren rate greater than about 15 mm / hr. Further provided herein are methods wherein the subject is a man greater than age 50 and exhibits a Westergren rate greater than 20 mm / hr. Further provided herein are methods wherein the subject is a child and exhibits a Westergren rate greater than about 10 mm / hr.

[0062] Described herein are methods of treating an autoimmune disease in a subject in need thereof, comprising: (a) determining the erythrocyte sedimentation rate (ESR) in the subject; and (b) administering to the subject in need thereof a therapeutically effective amount of an IL-2 conjugate described herein if the ESR is determined to be abnormal. Further described herein are methods wherein the subject is determined to exhibit an abnormal erythrocyte sedimentation rate (ESR) test using the Wintrobe rate method. Further described herein are methods wherein the subject is determined to exhibit an abnormal erythrocyte sedimentation rate (ESR) test using the Westergren rate method. Further described herein are methods wherein the subject is a woman under age 50 and exhibits a Westergren rate greater than about 20 mm / hr. Further described herein are methods wherein the subject is a woman greater than age 50 and exhibits a Westergren rate greater than about 30 mm / hr. Further described herein are methods wherein the subject is a man under age 50 and exhibits a Westergren rate greater than about 15 mm / hr. Further described herein are methods wherein the subject is a man greater than age 50 and exhibits a Westergren rate greater than 20 mm / hr. Further described herein are methods wherein the subject is a child and exhibits a Westergren rate greater than about 10 mm / hr. Further provided herein are methods wherein the subject in need thereof is determined to exhibit an increased concentration of C-reactive protein (CRP) in the blood of the subject prior to administration to the subject the therapeutically effective amount of the IL-2 conjugate. Further described herein are methods wherein the subject in need 2026234002   16 Sep 2026 thereof is determined to exhibit a concentration of C-reactive protein (CRP) in the blood greater than 10 mg / L prior to administration to the subject the therapeutically effective amount of the IL-2 conjugate.

[0063] Described herein are methods of treating an autoimmune disease in a subject in need thereof, comprising: (a) determining the concentration of C-reactive protein (CRP) in the blood of the subject; and (b) administering to the subject in need thereof a therapeutically effective amount of an IL-2 conjugate described herein if the concentration of C-reactive protein (CRP) in the blood of the subject is determined to be abnormal. Further described herein are methods wherein the subject in need thereof is determined to exhibit a concentration of C-reactive protein (CRP) in the blood greater than 10 mg / L prior to administration to the subject of the therapeutically effective amount of the IL-2 conjugate.

[0064] Described herein are methods of treating rheumatoid arthritis in a subject in need thereof, comprising: (a) determining the concentration of anti-cyclic citrullinated peptide (anti-CCP) in the blood of the subject; and (b) administering to the subject in need thereof a therapeutically effective amount of an IL-2 conjugate described herein if the concentration of rheumatoid factor in the blood of the subject is determined to be abnormal. Further described herein are methods wherein a therapeutically effective amount of the IL-2 conjugate is administered to the subject in need thereof if the concentration of anti-cyclic citrullinated peptide (anti-CCP) in the blood of the subject is determined to be greater than about 20 lu / mL.

[0065] Described herein are methods of treating rheumatoid arthritis in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of an IL-2 conjugate described herein if the concentration of anti-cyclic citrullinated peptide (anti-CCP) in the blood of the subject is determined to be abnormal.

[0066] Described herein are methods of treating rheumatoid arthritis in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of an IL-2 conjugate described herein if the concentration of anti-cyclic citrullinated peptide (anti-CCP) in the blood of the subject is determined to be greater than about 20 lu / mL. Further described herein are methods wherein the autoimmune disease is psoriasis. Further described herein are methods wherein the autoimmune disease is Celiac disease. Further described herein are methods wherein the autoimmune disease is ulcerative colitis. Further described herein are methods wherein the autoimmune disease is pemphigus.

[0067] Described herein are methods of alleviating or eliminating an autoimmune condition modeled by, represented by, and / or characterized by delayed-type hypersensitivity (DTH) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an IL-2 conjugate described herein. 2026234002   16 Sep 2026 BRIEF DESCRIPTION OF THE DRAWINGS

[0068] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

[0069] Fig. 1 shows exemplary unnatural amino acids. This figure is adapted from Fig. 2 of Young et al., “Beyond the canonical 20 amino acids: expanding the genetic lexicon,” J. of Biological Chemistry 285(15): 11039-11044 (2010).

[0070] Figs. 2A-Fig. 2B illustrate exemplary unnatural amino acids. Fig 2A illustrates exemplary lysine derivatives. Fig. 2B illustrates exemplary phenylalanine derivatives.

[0071] Figs. 3A-Fig. 3D illustrate exemplary unnatural amino acids. These unnatural amino acids (UAAs) have been genetically encoded in proteins (Fig. 3A - UAA #1-42; Fig. 3B - UAA # 43-89; Fig. 3C - UAA # 90-128; Fig. 3D - UAA # 129-167). Figs. 3A-3D are adopted from Table 1 of Dumas et al., Chemical Science 2015, 6, 50-69.

[0072] Figs. 4A-Fig. 4B show the dose response curves of an exemplary IL-2 variant for pSTAT5 signaling in human LRS primary cell (Fig. 4A) and proliferation response in mouse CTLL-2 populations (Fig. 4B)

[0073] Figs. 5A-Fig. 5C show plots from a screen for functional activity of IL-2 conjugates at Discoverx (Fremont CA) using the PathHunter IL-2 Cytokine Receptor assay from Example 3. Fig. 5A shows plots generated from assays with IL-2 and IL-2 conjugate D20_30kD. Fig. 5B shows plots generated from assays with IL-2 conjugates H16_30kD and L19_30kD. Fig. 5C shows plots generated from assays with IL-2 conjugates N88_30kD and L12_30kD. X-axis: in pg / ml; Y-axis: % of maximal response.

[0074] Fig. 6 shows the plasma concentration profiles of IL-2 conjugates K9_30kD, L19_30kD, N88R / D109_30kD, H16_30kD, Q126_30kD, and N88_30kD (all dosed at 0.9 mg / kg) following dosing in C57 / BL6 mice from Example 4.

[0075] Fig. 7 shows the mean fold change of Treg (% in singlets) following the dosing of IL-2 conjugates in C57 / BL6 mice from Example 4.

[0076] Fig. 8 shows the proportion of the Treg (CD3+ CD4+ CD25+ FoxP3+) cell population within the total cell population (singlets) of IL-2 conjugates in C57 / BL6 mice from Example 4.

[0077] Fig. 9A shows the proportion of the CD8+ T cell population (CD3+ CD4- CD8+) within the total cell population (singlets) following a single dose of IL-2 conjugates K9_30kD, L19_30kD, Q126_30kD, and H16_30kD in C57 / BL6 mice from Example 4. 2026234002   16 Sep 2026

[0078] Fig. 9B shows the proportion of the CD8+ T cell (CD3+ CD4- CD8+) population within the total cell population (singlets) following a single dose of IL-2 conjugates E100_30kD, N88R / D109_30kD, T123_30kD, N88_30kD, and V91_30kD in C57 / BL6 mice from Example 4.

[0079] Fig. 10 shows the plasma concentration profiles of IL-2 conjugates following dosing in Cynomolgus monkey from Example 5.

[0080] Fig. 11 shows the proportion of the Treg cell population within the total blood cell population (singlets) in Cynomolgus monkeys following dosing with IL-2 conjugates from Example 5.

[0081] Fig. 12 shows the proportion of the CD8+ T cell population within the total blood cell population (singlets) in Cynomolgus monkeys following dosing with IL-2 conjugates from Example 5.

[0082] Fig. 13 shows the plots of plasma concentration versus time for the H16_30kD variant in non-human primates at doses of 0.12 mg / kg and 0.67 mg / kg from Example 6, wherein the 0.12 mg / kg dose is shown as the lower trace, while the 0.67 mg / kg dose is shown as the upper trace.

[0083] Fig. 14 shows the plots of plasma concentration versus time for the H16_30kDa variant and the H16_50kDa variant in non-human primates at a dose of 0.12 mg / kg, and the H16_50kDa variant at a dose of 0.2 mg / kg from Example 6, wherein the trace for the 30 kDa variant is shown as the lower trace (squares) and the trace for the 50 kDa variant is shown as the upper trace (triangles).

[0084] Fig. 15 shows plots of Treg percent in singles versus time post-dose in non-human primates from Example 6 for the H16_30kDa variant at a dose of 0.12 mg / kg, and the H16_50kDa variant at a dose of 0.2 mg / kg, wherein the trace for the vehicle is the lower trace (squares), the trace for the 30 kDa variant is shown in the middle trace, and the trace for the 50 kDa variant is shown in the upper trace.

[0085] Fig. 16 shows the study design of Example 7 to assess the effects of H16_50kD on delayed-type hypersensitivity (DTH) in C57BL / 6 mice. DTH in mice was induced with keyhole limpet hemocyanin (KLH) (challenge at Day 7 following sensitization at Day 1 via subcutaneous injection) with dosing of H16_50kD (Day 0 and 3), at a dose of 0.03 mg / kg, 0.1 mg / kg, and 0.3 mg / kg from Example 7.

[0086] Fig. 17A- Fig. 17C show changes in ear thickness measurements and blood immunotypes of C57BL / 6 mice from Example 7. Fig. 17A shows Area Under Curve (AUC) of increased ear thickness as compared to the mice with KLH challenge on Day 7 only. Fig. 17B shows changes in ear thickness measurements in the C57BL / 6 mice prior to KLH challenge (on Day 7) and then subsequently on Days 8, 9 and 10. Fig. 17C shows changes over time in the relative percentage of 2026234002   16 Sep 2026 CD4+ T cells within CD25+FoxP3+ cell population in whole blood samples from the mice. “KLH only” indicates KLH challenge on Day 7 only (without senitization on Day 1) with dosing of vehicle only. “Vehicle” indicates KLH sensitization (Day 1) and challenge (Day 7) with dosing of vehicle only. “0.03” indicates KLH sensitization and challenge with dosing of H16_50kD at a dose of 0.03 mg / kg. “0.1” indicates KLH sensitization and challenge with dosing of H16_50kD at a dose of 0.1 mg / kg. “0.3” indicates KLH sensitization and challenge with dosing of H16_50kD at a dose of 0. 3 mg / kg. “CsA” indicates KLH sensitization and challenge with dosing of Cyclosporine A. See also Table 10 in Example 7.

[0087] Figs. 18A-Fig. 18C show changes over time in the relative percentage of CD4+CD25+FoxP3+ cells within CD45+ cell population (Fig. 18A), within TCRP+ cell population (Fig. 18B), and within CD4+ cell population (Fig. 18C) in whole blood samples from the mice from Example 7.

[0088] Fig. 19 shows the absolute counts of CD4+CD25+FoxP3+ cells on Day 10 in whole blood samples from the mice from Example 7. DETAILED DESCRIPTION OF THE DISCLOSURE

[0089] Cytokines comprise a family of cell signaling proteins such as chemokines, interferons, interleukins, lymphokines, tumor necrosis factors, and other growth factors playing roles in innate and adaptive immune cell homeostasis. Cytokines are produced by immune cells such as macrophages, B lymphocytes, T lymphocytes and mast cells, endothelial cells, fibroblasts, and different stromal cells. In some instances, cytokines modulate the balance between humoral and cell-based immune responses.

[0090] Interleukins are signaling proteins which modulate the development and differentiation of T and B lymphocytes, cell of the monocytic lineage, neutrophils, basophils, eosinophils, megakaryocytes, and hematopoietic cells. Interleukins are produced by helper CD4 T and B lymphocytes, monocytes, macrophages, endothelial cells, and other tissue residents.

[0091] Interleukin 2 (IL-2) is a pleiotropic type-1 cytokine whose structure comprises a 15.5 kDa four a-helix bundle. The precursor form of IL-2 is 153 amino acid residues in length, with the first 20 amino acids forming a signal peptide and residues 21-153 forming the mature form. IL-2 is produced primarily by CD4+ T cells post antigen stimulation and to a lesser extent, by CD8+ cells, Natural Killer (NK) cells, and Natural killer T (NKT) cells, activated dendritic cells (DCs), and mast cells. IL-2 signaling occurs through interaction with specific combinations of IL-2 receptor (IL-2R) subunits, IL-2Ra (also known as CD25), IL-2RP (also known as CD122), and IL-2Ry (also known as CD132). Interaction of IL-2 with the IL-2Ra forms the “low-affinity” IL-2 receptor complex with a Ka of about 1 O'8 M. Interaction of IL-2 2026234002   16 Sep 2026 with IL-2RP and IL-2Ry forms the “intermediate-affinity” IL-2 receptor complex with a Ka of about 10'9 M. Interaction of IL-2 with all three subunits, IL-2Ra, IL-2RP, and IL-2Ry, forms the “high-affinity” IL-2 receptor complex with a Ka of about >1041 M.

[0092] In some instances, IL-2 signaling via the “high-affinity” IL-2RaPy complex modulates the activation and proliferation of regulatory T cells. Regulatory T cells, or CD4+CD25+Foxp3+regulatory T (Treg) cells, mediate maintenance of immune homeostasis by suppression of effector cells such as CD4+ T cells, CD8+ T cells, B cells, NK cells, and NKT cells. In some instances, Treg cells are generated from the thymus (tTreg cells) or are induced from naive T cells in the periphery (pTreg cells). In some cases, Treg cells are considered as the mediator of peripheral tolerance. Indeed, in one study, transfer of CD25-depleted peripheral CD4+ T cells produced a variety of autoimmune diseases in nude mice, whereas cotransfer of CD4+CD25+ T cells suppressed the development of autoimmunity (Sakaguchi, et al., “Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25),” J. Immunol. 155(3): 1151-1164 (1995)). Augmentation of the Treg cell population down-regulates effector T cell proliferation and suppresses autoimmunity and T cell anti-tumor responses.

[0093] Disclosed herein, in certain embodiments, is a method of selectively upregulating distinct population(s) of lymphocytes (e.g., CD4+ helper cells, CD8+ effector naive and memory cells, NK cells, or NKT cells) through cytokine / cytokine receptor signaling. In some instances, the cytokine comprises an interleukin, an interferon, or a tumor necrosis factor. In some cases, the cytokine is a cytokine conjugate, e.g., an interleukin conjugate, an interferon conjugate, or a tumor necrosis factor conjugate. In additional cases, described herein comprise pharmaceutical compositions and kits comprising one or more cytokine conjugates described herein.

[0094] In some embodiments, also described herein is a method of selectively upregulating CD4+ helper cell, CD8+ effector naive and memory cell, NK cell, and / or NKT cell populations through IL-2 / IL-2R signaling. In some instances, IL-2 is an IL-2 conjugate, which interacts with the “intermediateaffinity” IL-2RPy complex, optionally with a similar potency as the IL-2RaPy complex, and with a weakened IL-2Ra interaction relative to wild-type IL-2. In some embodiments, further described herein are methods of treating a cancer with use of an IL-2 conjugate described herein. In additional embodiments, described herein are pharmaceutical compositions and kits which comprise one or more IL-2 conjugates described herein. In some embodiments, the IL-2 conjugates comprise conjugating moieties (e.g., a PEG) that contribute to an increase or a decrease in “clearance rate,” or plasma half-life in a subject, without affecting the pharmacokinetics, including the desired cytokine-receptor interactions and immune cell expansion. Cytokine Conjugates 2026234002   16 Sep 2026

[0095] In some embodiments, described herein are cytokine conjugates. In some instances, the cytokine comprises an interleukins, a tumor necrosis factor, an interferon, a chemokine, a lymphokine, or a growth factor. In some instances, the cytokine is an interleukin. In some cases, the cytokine is an interferon. In additional cases, the cytokine is a tumor necrosis factor. In further cases, the cytokine is a growth factor.

[0096] In some embodiments, described herein is an interleukin conjugate. Exemplary interleukins include, but are not limited to interleukin 2 (IL-2). IL-2 Conjugates

[0097] Described herein are polypeptides shown in Table 1. In some embodiments, IL-2 conjugates described herein are exemplified in Table 1.

[0098] Table 1 Name Sequence SEQ ID NO: IL-2 (homo sapiens) (mature form) APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSII STLT 1 IL-2 (homo sapiens) (precursor) NCBI Accession No.: AAB46883.1 MYRMQLLSCIALSLALVTNSAPTSSSTKKTQLQLEHLLLDLQ MILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELK PLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEY ADETATIVEFLNRWITFCQSIISTLT 2 aldesleukin PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIIST LT 3 IL-2C125S APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSII STLT 4 IL-2K9X APTSSSTKXTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSII STLT 5 IL-2H16X APTSSSTKKTQLQLEXLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSII STLT 6 IL-2L19X APTSSSTKKTQLQLEHLLXDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSII STLT 7 IL-2D20X APTSSSTKKTQLQLEHLLLXLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD 8 2026234002   16 Sep 2026 LISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSII STLT IL-2M23X APTSSSTKKTQLQLEHLLLDLQXILNGINNYKNPKLTRMLTFK FYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDL ISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIIS TLT 9 IL-2_N26X APTSSSTKKTQLQLEHLLLDLQMILXGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSII STLT 10 IL-2_N88X APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISXINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSII STLT 11 IL-2_E100X APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNINVIVLELKGSXTTFMCEYADETATIVEFLNRWITFSQSII STLT 12 IL-2_N119X APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNINVIVLELKGSETTFMCEYADETATIVEFLXRWITFSQSII STLT 13 IL-2T123X APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNINVIVLELKGSETTFMCEYADETATIVEFLNRWIXFSQSII STLT 14 IL-2Q126X APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSXSII STLT 15 IL-2_S127X APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQXII STLT 16 IL-2T131X APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSII SXLT 17 IL-2_N88R_D109X APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISRINVIVLELKGSETTFMCEYAXETATIVEFLNRWITFSQSII STLT 18 IL-2_V91X APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNINXIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSII STLT 19 IL-2_K9[AzK] APTSSSTK[AzK]TQLQLEHLLLDLQMILNGINNYKNPKLTRM LTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLR PRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFS QSIISTLT 20 IL-2_H16[AzK] APTSSSTKKTQLQLE[AzK]LLLDLQMILNGINNYKNPKLTRM LTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLR 21 2026234002   16 Sep 2026 PRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFS QSIISTLT IL-2_L19[AzK] APTS SSTKKTQLQLEHLL [AzK] DLQMILNGINNYKNPKLTRM LTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLR PRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFS QSIISTLT 22 IL-2_D20[AzK] APTSSSTKKTQLQLEHLLL[AzK]LQMILNGINNYKNPKLTRM LTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLR PRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFS QSIISTLT 23 IL-2_M23 [AzK] APTSSSTKKTQLQLEHLLLDLQ[AzK]ILNGINNYKNPKLTRML TFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRP RDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQ SIISTLT 24 IL-2_N26[AzK] APTSSSTKKTQLQLEHLLLDLQMIL[AzK]GINNYKNPKLTRM LTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLR PRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFS QSIISTLT 25 IL-2_N88[AzK] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISjAzKlINVIVLELKGSETTFMCEYADETATIVEFLNRWITFS QSIISTLT 26 IL-2_E100[AzK] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNINVIVLELKGSJAzKlTTFMCEYADETATIVEFLNRWITFS QSIISTLT 27 IL-2N119 [AzK] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNINVIVLELKGSETTFMCEYADETATIVEFLJAzK[RWITFS QSIISTLT 28 IL-2_T123[AzK] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNINVIVLELKGSETTFMCEYADETATIVEFLNRWIlAzKIFS QSIISTLT 29 IL-2_Q126[AzK] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSjAzK 1SIISTLT 30 IL-2_S127[AzK] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQJAz KJIISTLT 31 IL-2_T131[AzK] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSII SJAzKLLT 32 IL-2_N88R_D109[AzK] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISRINVIVLELKGSETTFMCEYA [AzK] ETATIVEFLNRWITFS QSIISTLT 33 IL-2_K9[AzK_PEG] APTSSSTK[AzK PEG1TQLQLEHLLLDLQMILNGINNYKNPKL TRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNF 34 2026234002   16 Sep 2026 HLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWI TFSQSIISTLT IL-2_H16[AzK_PEG] APTSSSTKKTQLQLE[AzK PEG1LLLDLQMILNGINNYKNPKL TRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNF HLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWI TFSQSIISTLT 35 IL-2_L19[AzK_PEG] APTSSSTKKTQLQLEHLL[AzK PEG1DLQMILNGINNYKNPKL TRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNF HLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWI TFSQSIISTLT 36 IL-2_D20[AzK_PEG] APTSSSTKKTQLQLEHLLL[AzK PEG1LQMILNGINNYKNPKL TRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNF HLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWI TFSQSIISTLT 37 IL-2M23 [AzKPEG] APTSSSTKKTQLQLEHLLLDLQ[AzK PEG1ILNGINNYKNPKL TRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNF HLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWI TFSQSIISTLT 38 IL-2_N26[AzK_PEG] APTSSSTKKTOLOLEHLLLDLOMILrAzK PEG1GINNYKNPKL TRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNF HLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWI TFSQSIISTLT 39 IL-2_N88[AzK_PEG] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LIS [AzK PEG] INVIVLELKGSETTFMCEYADETATIVEFLNR WITFSQSIISTLT 40 IL-2_E100[AzK_PEG] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNINVIVLELKGS [AzK PEG] TTFMCEYADETATIVEFLNR WITFSQSIISTLT 41 IL-2N119[AzK_PEG] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNINVIVLELKGSETTFMCEYADETATIVEFL [AzK PEG] R WITFSQSIISTLT 42 IL-2_T123[AzK_PEG] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNINVIVLELKGSETTFMCEYADETATIVEFLNRWI [AzK PE G1FSQSIISTLT 43 IL-2_Q126[AzK_PEG] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFS[AzK PEGISIISTLT 44 IL-2_S127[AzK_PEG] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQJAz K PEGUISTLT 45 IL-2_T131[AzK_PEG] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSII S[AzK PEG] LT 46 IL- 2 N88R DI 09 [AzK PEG] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD 47 2026234002   16 Sep 2026 LISRINVIVLELKGSETTFMCEYA [AzK PEG] ETATIVEFLNR WITFSQSIISTLT IL-2_V91[AzK_PEG] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNIN [AzK PEG] IVLELKGSETTFMCEYADETATIVEFLNR WITFSQSIISTLT 48 IL-2K9 [AzK_PEG5 OkDa] APTSSSTK[AzK PEG50kPa]TQLQLEHLLLDLQMILNGINNY KNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLA QSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEF LNRWITFSQSIISTLT 49 IL- 2_H 16 [AzK_PEG5 OkDa] APTSSSTKKTQLQLE[AzK PEG50kPa]LLLDLQMILNGINNY KNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLA QSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEF LNRWITFSQSIISTLT 50 IL-2_L 19 [ AzK_PEG5 OkDa] APTSSSTKKTQLQLEHLL[AzK PEG50kDa]DLQMILNGINNY KNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLA QSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEF LNRWITFSQSIISTLT 51 IL-2D20 [AzK_PEG5 OkDa] APTSSSTKKTOLOLEHLLL[AzK PEG50kDa]LQMILNGINNY KNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLA QSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEF LNRWITFSQSIISTLT 52 IL- 2_M23 [AzK_PEG5 OkDa] APTSSSTKKTOLOLEHLLLDLQ[AzK PEG50kDa]ILNGINNYK NPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQ SKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFL NRWITFSQSIISTLT 53 IL- 2N26 [AzK_PEG5 OkDa] APTSSSTKKTOLOLEHLLLDLOMIL[AzK PEG50kDa]GINNY KNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLA QSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEF LNRWITFSQSIISTLT 54 IL- 2_N8 8 [AzK_PEG5 OkDa] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LIS [AzK PEG50kDa] INVIVLELKGSETTFMCEYADETATIVEF LNRWITFSQSIISTLT 55 IL- 2_E 100 [AzK_PEG5 OkDa] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNINVIVLELKGS [AzK PEG50kPa]TTFMCEYADETATIVEF LNRWITFSQSIISTLT 56 IL- 2_N 119 [ AzK_PEG5 OkDa] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNINVIVLELKGSETTFMCEYADETATIVEFLfAzK PEG50k PalRWITFSQSIISTLT 57 IL- 2_T 123 [AzK_PEG5 OkDa] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNINVIVLELKGSETTFMCEYADETATIVEFLNRWI [AzK PE G50kPalFSQSIISTLT 58 IL- 2_Q 126 [ AzK_PEG5 OkDa] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSjAzK PEG50kPa]SIISTLT 59 IL- 2 SI 27 [AzK PEG50kDa] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD 60 2026234002   16 Sep 2026 LISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQJAz K PEG50kDa]IISTLT IL- 2_T 131 [AzK_PEG5 OkDa] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSII SJAzK PEG50kDa]LT 61 IL-2_N8 8 RD 109 [AzK_PEG5 OkDa] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISRINVIVLELKGSETTFMCEYA[AzK PEG50kDa]ETATIVEF LNRWITFSQSIISTLT 62 IL- 2_V91 [AzK_PEG5 OkDa] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNIN [AzK_PEG50kDa] IVLELKGSETTFMCEYADETATIVEF LNRWITFSQSIISTLT 63 IL-2K9 [AzK_PEG3 OkDa] APTSSSTKIAzK PEG30kDa]TQLQLEHLLLDLQMILNGINNY KNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLA QSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEF LNRWITFSQSIISTLT 64 IL- 2_H 16 [AzK_PEG3 OkDa] APTSSSTKRTOLOLEIAzK PEG30kDa]LLLDLOMILNGINNY KNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLA QSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEF LNRWITFSQSIISTLT 65 IL-2_L 19 [ AzK_PEG3 OkDa] APTSSSTKKTOLOLEHLLrAzK PEG30kDa]DLQMILNGINNY KNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLA QSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEF LNRWITFSQSIISTLT 66 IL-2_D20 [AzK_PEG3 OkDa] APTSSSTKKTOLOLEHLLLrAzK PEG30kDa]LQMILNGINNY KNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLA QSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEF LNRWITFSQSIISTLT 67 IL- 2_M23 [AzK_PEG3 OkDa] APTSSSTKKTOLOLEHLLLDLQIAzK PEG30kDa]ILNGINNYK NPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQ SKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFL NRWITFSQSIISTLT 68 IL- 2_N26 [AzK_PEG3 OkDa] APTSSSTKKTOLOLEHLLLDLOMILrAzK PEG30kDa]GINNY KNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLA QSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEF LNRWITFSQSIISTLT 69 IL- 2_N8 8 [AzK_PEG3 OkDa] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LIS [AzK PEG30kPa1 INVIVLELKGSETTFMCEYADETATIVEF LNRWITFSQSIISTLT 70 IL- 2_E 100 [AzK_PEG3 OkDa] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNINVIVLELKGS [AzK PEG30kPa]TTFMCEYADETATIVEF LNRWITFSQSIISTLT 71 IL- 2_N 119 [ AzK_PEG3 OkDa] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNINVIVLELKGSETTFMCEYADETATIVEFLIAzK PEG30k PalRWITFSQSIISTLT 72 IL- 2 T123 [AzK PEG30kDa] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD 73 2026234002   16 Sep 2026 LISNINVIVLELKGSETTFMCEYADETATIVEFLNRWI [AzK PE G30kDa]FSQSIISTLT IL- 2_Q 126 [ AzK_PEG3 OkDa] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSrAzK PEG30kDa]SIISTLT 74 IL- 2_S 127 [AzK_PEG3 OkDa] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQJAz K PEG30kDa]IISTLT 75 IL- 2_T 131 [AzK_PEG3 OkDa] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSII SfAzK PEG30kDa]LT 76 IL-2_N8 8 RD 109 [AzK_PEG3 OkDa] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISRINVIVLELKGSETTFMCEYA[AzK PEG30kDa]ETATIVEF LNRWITFSQSIISTLT 77 IL- 2_V91 [AzK_PEG3 OkDa] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNIN [AzK_PEG30kDa] IVLELKGSETTFMCEYADETATIVEF LNRWITFSQSIISTLT 78 IL-2K8X PTSSSTKXTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIIST LT 79 IL-2H15X PTSSSTKKTQLQLEXLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIIST LT 80 IL-2L18X PTSSSTKKTQLQLEHLLXDLQMILNGINNYKNPKLTRMLTFK FYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDL ISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIIS TLT 81 IL-2D19X PTSSSTKKTQLQLEHLLLXLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIIST LT 82 IL-2M22X PTSSSTKKTQLQLEHLLLDLQXILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIIST LT 83 IL-2_N25X PTSSSTKKTQLQLEHLLLDLQMILXGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIIST LT 84 IL-2_N87X PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SXINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIIST LT 85 IL-2E99X PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI 86 2026234002   16 Sep 2026 SNINVIVLELKGSXTTFMCEYADETATIVEFLNRWITFSQSIIST LT IL-2_N118X PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNINVIVLELKGSETTFMCEYADETATIVEFLXRWITFSQSIIST LT 87 IL-2T122X PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNINVIVLELKGSETTFMCEYADETATIVEFLNRWIXFSQSIIST LT 88 IL-2Q125X PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSXSIIST LT 89 IL-2_S126X PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQXIIST LT 90 IL-2T130X PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISX LT 91 IL-2_N87R_D108X PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SRINVIVLELKGSETTFMCEYAXETATIVEFLNRWITFSQSIIST LT 92 IL-2_V90X PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNINXIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIIST LT 93 IL-2_K8[AzK] PTSSSTK[AzK]TOLOLEHLLLDLOMILNGINNYKNPKLTRMLT FKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPR DLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSI ISTLT 94 IL-2_H15[AzK] PTS S STKKTOLOLE [AzK] LLLDLOMILNGINNYKNPKLTRMLT FKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPR DLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSI ISTLT 95 IL-2_L18[AzK] PTS S STKKTQLQLEHLL [AzK] DLQMILNGINNYKNPKLTRML TFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRP RDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQ SIISTLT 96 IL-2_D19[AzK] PTS S STKKTQLQLEHLLL [AzK] LQMILNGINNYKNPKLTRMLT FKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPR DLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSI ISTLT 97 IL-2_M22[AzK] PTSSSTKKTQLQLEHLLLDLQ[AzK]ILNGINNYKNPKLTRMLT FKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPR DLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSI ISTLT 98 IL-2_N25 [AzK] PTSSSTKKTQLQLEHLLLDLQMIL[AzK]GINNYKNPKLTRMLT FKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPR 99 2026234002   16 Sep 2026 DLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSI ISTLT IL-2_N87[AzK] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI S [AzK] INVIVLELKGSETTFMCEYADETATIVEFLNRWITFSOS IISTLT 100 IL-2E99 [AzK] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNINVIVLELKGS [AzK] TTFMCEYADETATIVEFLNRWITFSQS IISTLT 101 IL-2_N118[AzK]-l PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNINVIVLELKGSETTFMCEYADETATIVEFL[AzK]RWITFSOS IISTLT 102 IL-2_T122[AzK]-l PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNINVIVLELKGSETTFMCEYADETATIVEFLNRWI[AzK]FSOS IISTLT 103 IL-2_Q125[AzK] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSIAzKlS IISTLT 104 IL-2_S126[AzK] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQJAzK 1IISTLT 105 IL-2_T130[AzK] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISJ. AzKILT 106 IL-2_N87R_D108[AzK] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SRINVIVLELKGSETTFMCEYA[AzK]ETATIVEFLNRWITFSQS IISTLT 107 IL-2_V90[AzK] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNIN[AzK]IVLELKGSETTFMCEYADETATIVEFLNRWITFSQS IISTLT 108 IL-2K8 [AzK_Ll_PEG] PTSSSTK[AzK LI PEG1TOLOLEHLLLDLOMILNGINNYKNP KLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSK NFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNR WITFSQSIISTLT 109 IL-2H15 [AzK_L 1_PEG] PTSSSTKKTQLQLE[AzK LI PEGILLLDLQMILNGINNYKNP KLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSK NFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNR WITFSQSIISTLT 110 IL-2L18 [AzK_L 1PEG] PTSSSTKKTQLQLEHLL[AzK LI PEG1DLQMILNGINNYKNP KLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSK NFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNR WITFSQSIISTLT 111 IL-2D19[AzK_L 1PEG] PTSSSTKKTQLQLEHLLL[AzK LI PEG1LQMILNGINNYKNP KLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSK 112 2026234002   16 Sep 2026 NFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNR WITFSQSIISTLT IL-2M22 [ AzKL 1 PEG] PTSSSTKKTQLQLEHLLLDLQ[AzK LI PEG1ILNGINNYKNP KLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSK NFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNR WITFSQSIISTLT 113 IL-2N25 [AzKL 1PEG] PTSSSTKKTQLQLEHLLLDLQMIL[AzK LI PEG1GINNYKNP KLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSK NFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNR WITFSQSIISTLT 114 IL-2_N87[AzK_L 1PEG] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI S[AzK LI PEG]INVIVLELKGSETTFMCEYADETATIVEFLNR WITFSQSIISTLT 115 IL-2E99 [AzKLIPEG] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNINVIVLELKGSIAzK LI PEG1TTFMCEYADETATIVEFLNR WITFSQSIISTLT 116 IL-2N118 [AzKLIPEG] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNINVIVLELKGSETTFMCEYADETATIVEFL[AzK LI PEG]R WITFSQSIISTLT 117 IL-2_T122[AzK_Ll_PEG] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNINVIVLELKGSETTFMCEYADETATIVEFLNRWI [AzK L1 PEG]FSQSIISTLT 118 IL-2Q125 [AzKLIPEG] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFS[AzK LI PEG1SIISTLT 119 IL-2S126 [AzKL 1PEG] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQJAzK LI PEG1IISTLT 120 IL-2T13 0 [AzKL 1 PEG] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISJ. AzK LI PEGLLT 121 IL-2N87RD108 [AzKL IP EG] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SRINVIVLELKGSETTFMCEYA[AzK LI PEG1ETATIVEFLNR WITFSQSIISTLT 122 IL-2_V90[AzK_L 1PEG] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNINIAzK LI PEGHVLELKGSETTFMCEYADETATIVEFLNR WITFSQSIISTLT 123 IL- 2 K8[AzK LI PEG50kDa ] PTSSSTK[AzK LI PEG50kDa]TQLQLEHLLLDLQMILNGINN YKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNL AQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIV EFLNRWITFSQSIISTLT 124 IL- 2_H 15 [AzKL 1 PEG5 OkD a] PTSSSTKKTQLQLE[AzK LI PEG50kDa]LLLDLQMILNGINN YKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNL 125 2026234002   16 Sep 2026 AQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIV EFLNRWITFSQSIISTLT IL- 2_L 18 [AzKL 1 PEG5 OkD a] PTSSSTKKTQLQLEHLL[AzK LI PEG50kDa]DLQMILNGINN YKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNL AQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIV EFLNRWITFSQSIISTLT 126 IL- 2_D 19 [AzKL 1 PEG5 OkD a]-l PTSSSTKKTQLQLEHLLL[AzK LI PEG50kDa]LQMILNGINN YKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNL AQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIV EFLNRWITFSQSIISTLT 127 IL-2M22 [AzKL 1 PEG5 OkD a] PTSSSTKKTQLQLEHLLLDLQ[AzK LI PEG50kPa]ILNGINN YKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNL AQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIV EFLNRWITFSQSIISTLT 128 IL-2_N25[AzK_Ll_PEG50kD a] PTSSSTKKTQLQLEHLLLDLQMIL[AzK LI PEG50kPa]GINN YKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNL AQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIV EFLNRWITFSQSIISTLT 129 IL-2_N87[AzK_Ll_PEG50kD a] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI S[AzK LI PEG50kPa]INVIVLELKGSETTFMCEYADETATIV EFLNRWITFSQSIISTLT 130 IL-2E99 [AzKL 1 PEG5 OkD a] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNINVIVLELKGS[AzK LI PEG50kPa]TTFMCEYADETATIV EFLNRWITFSQSIISTLT 131 IL-2_N118[AzK_Ll_PEG50k Da] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNINVIVLELKGSETTFMCEYADETATIVEFL[AzK LI PEG50 kPalRWITFSQSIISTLT 132 IL- 2_T 122 [ AzKL 1 PEG5 Ok Da] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNINVIVLELKGSETTFMCEYADETATIVEFLNRWI [AzK L1 PEG50kPalFSQSIISTLT 133 IL- 2_Q 125 [AzKL 1PEG5 Ok Da] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFS[AzK LI PEG50kPalSIISTLT 134 IL- 2_S 126[AzK_Ll_PEG50k Da] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQ[AzK LI PEG50kPalIISTLT 135 IL-2_T130[AzK_Ll_PEG50k Da] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISJ, AzK LI PEG50kPalLT 136 IL-2N87RD108 [AzKL IP EG50kDa] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SRINVIVLELKGSETTFMCEYA[AzK LI PEG50kPa]ETATIV EFLNRWITFSQSIISTLT 137 IL- 2_V91 [AzKL 1 PEG5 OkD a]-l PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI 138 2026234002   16 Sep 2026 SNINIAzK LI PEG50kDa]IVLELKGSETTFMCEYADETATIV EFLNRWITFSQSIISTLT IL- 2 K8[AzK LI PEG30kDa ] PTSSSTK[AzK LI PEG30kDa]TQLQLEHLLLDLQMILNGINN YKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNL AQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIV EFLNRWITFSQSIISTLT 139 IL- 2_H 15 [AzKL 1 PEG3 OkD a] PTSSSTKKTQLQLE[AzK LI PEG30kDa]LLLDLQMILNGINN YKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNL AQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIV EFLNRWITFSQSIISTLT 140 IL- 2_L 18 [AzKL 1 PEG3 OkD a] PTSSSTKKTQLQLEHLL[AzK LI PEG30kDa]DLQMILNGINN YKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNL AQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIV EFLNRWITFSQSIISTLT 141 IL- 2_D 19 [AzKL 1 PEG3 OkD a] PTSSSTKKTQLQLEHLLL[AzK LI PEG30kDa]LQMILNGINN YKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNL AQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIV EFLNRWITFSQSIISTLT 142 IL-2M22 [AzKL 1 PEG3 OkD a] PTSSSTKKTOLOLEHLLLDLQ[AzK LI PEG30kDa]ILNGINN YKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNL AQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIV EFLNRWITFSQSIISTLT 143 IL-2_N25[AzK_Ll_PEG30kD a] PTSSSTKKTOLOLEHLLLDLOMIL[AzK LI PEG30kDa]GINN YKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNL AQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIV EFLNRWITFSQSIISTLT 144 IL-2_N87[AzK_Ll_PEG30kD a] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI S[AzK LI PEG30kPa]INVIVLELKGSETTFMCEYADETATIV EFLNRWITFSQSIISTLT 145 IL-2E99 [AzKL 1 PEG3 OkD a] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNINVIVLELKGS[AzK LI PEG30kPa]TTFMCEYADETATIV EFLNRWITFSQSIISTLT 146 IL-2_N118[AzK_Ll_PEG30k Da] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNINVIVLELKGSETTFMCEYADETATIVEFL[AzK LI PEG30 kPalRWITFSQSIISTLT 147 IL- 2_T 122 [ AzKL 1 PEG3 Ok Da] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNINVIVLELKGSETTFMCEYADETATIVEFLNRWI [AzK L1 PEG30kPalFSQSIISTLT 148 IL- 2_Q 125 [AzKL 1PEG3 Ok Da] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFS[AzK LI PEG30kPalSIISTLT 149 IL- 2_S 126[AzK_Ll_PEG30k Da] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQJAzK LI PEG30kPa]IISTLT 150 IL-2_T130[AzK_Ll_PEG30k Da] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI 151 2026234002   16 Sep 2026 SNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISJ, AzK LI PEG30kDalLT IL-2N87RD108 [AzK_L IP EG30kDa] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SRINVIVLELKGSETTFMCEYA[AzK LI PEG30kDa]ETATIV EFLNRWITFSQSIISTLT 152 IL-2V90 [AzKL 1 PEG3 OkD a] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNIN[AzK LI PEG30kDa]IVLELKGSETTFMCEYADETATIV EFLNRWITFSQSIISTLT 153 IL-2K9 [AzKL 1 PEG] APTSSSTK[AzK LI PEG1TQLQLEHLLLDLQMILNGINNYKN PKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQS KNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLN RWITFSQSIISTLT 154 IL-2H16 [AzKL 1 PEG] APTSSSTKKTQLQLE[AzK LI PEG1LLLDLQMILNGINNYKN PKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQS KNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLN RWITFSQSIISTLT 155 IL-2L19 [AzKL 1PEG] APTSSSTKKTOLOLEHLL[AzK LI PEG1DLOMILNGINNYKN PKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQS KNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLN RWITFSQSIISTLT 156 IL-2_D20[AzK_Ll_PEG] APTSSSTKKTOLOLEHLLL[AzK LI PEG1LOMILNGINNYKN PKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQS KNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLN RWITFSQSIISTLT 157 IL-2M23 [AzKL 1PEG] APTSSSTKKTOLOLEHLLLDLQ[AzK LI PEG1ILNGINNYKN PKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQS KNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLN RWITFSQSIISTLT 158 IL-2_N26[AzK_Ll_PEG] APTSSSTKKTOLOLEHLLLDLOMIL[AzK LI PEG1GINNYKN PKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQS KNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLN RWITFSQSIISTLT 159 IL-2N88 [AzKL 1PEG] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LIS[AzK LI PEGIINVIVLELKGSETTFMCEYADETATIVEFL NRWITFSQSIISTLT 160 IL-2E100 [AzKL 1PEG] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNINVIVLELKGSIAzK LI PEG1TTFMCEYADETATIVEFL NRWITFSQSIISTLT 161 IL-2N119[AzK_Ll_PEG] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNINVIVLELKGSETTFMCEYADETATIVEFL[AzK LI PEG 1RWITFSQSIISTLT 162 IL-2T123 [ AzKL 1 PEG] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNINVIVLELKGSETTFMCEYADETATIVEFLNRWI[AzK LI PEG]FSQSIISTLT 163 IL-2Q126 [AzKL 1 PEG] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD 164 2026234002   16 Sep 2026 LISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFS[AzK LI PEG1SIISTLT IL-2S127 [AzKL 1 PEG] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQJAz K LI PEGUISTLT 165 IL-2T131 [AzKLIPEG] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSII S[AzK LI PEG]LT 166 IL- 2_N8 8 RD 109 [AzKL IP EG] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISRINVIVLELKGSETTFMCEYA[AzK LI PEG1ETATIVEFL NRWITFSQSIISTLT 167 IL-2V91 [AzKLIPEG] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNIN[AzK LI PEG]IVLELKGSETTFMCEYADETATIVEFL NRWITFSQSIISTLT 168 IL- 2 K9[AzK LI PEG50kDa ] APTSSSTKIAzK LI PEG50kDa]TOLOLEHLLLDLQMILNGIN NYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVL NLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETAT IVEFLNRWITFSQSIISTLT 169 IL- 2_H 16 [AzKL 1 PEG5 OkD a] APTSSSTKKTOLOLE[AzK LI PEG50kDa]LLLDLQMILNGIN NYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVL NLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETAT IVEFLNRWITFSQSIISTLT 170 IL- 2_L 19 [AzKL 1 PEG5 OkD a] APTSSSTKKTOLOLEHLL[AzK LI PEG50kDa]DLQMILNGIN NYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVL NLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETAT IVEFLNRWITFSQSIISTLT 171 IL- 2_D20 [AzKL 1 PEG5 OkD a]-2 APTSSSTKKTOLOLEHLLL[AzK LI PEG50kDa]LQMILNGIN NYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVL NLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETAT IVEFLNRWITFSQSIISTLT 172 IL-2_M23[AzK_Ll_PEG50kD a] APTSSSTKKTOLOLEHLLLDLQ[AzK LI PEG50kDa]ILNGIN NYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVL NLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETAT IVEFLNRWITFSQSIISTLT 173 IL-2N26 [AzKL 1PEG5 OkD a] APTSSSTKKTQLQLEHLLLDLQMIL[AzK LI PEG50kDa]GIN NYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVL NLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETAT IVEFLNRWITFSQSIISTLT 174 IL-2_N8 8 [AzKL 1PEG5 OkD a] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISIAzK LI PEG50kPa]INVIVLELKGSETTFMCEYADETATI VEFLNRWITFSQSIISTLT 175 IL- 2_E 100 [ AzKL 1 PEG5 Ok Da] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNINVIVLELKGS[AzK LI PEG50kPa]TTFMCEYADETATI VEFLNRWITFSQSIISTLT 176 IL-2_N119[AzK_Ll_PEG50k Da] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD 177 2026234002   16 Sep 2026 LISNINVIVLELKGSETTFMCEYADETATIVEFL[AzK LI PEG 50kDalRWITFSQSIISTLT IL- 2_T 123 [ AzKL 1 PEG5 Ok Da] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNINVIVLELKGSETTFMCEYADETATIVEFLNRWI[AzK LI PEG50kDalFSQSIISTLT 178 IL- 2_Q 126 [AzKL 1PEG5 Ok Da] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSJAzK LI PEG50kDa] SIISTLT 179 IL- 2_S 127[AzK_Ll_PEG50k Da] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQJAz K LI PEG50kDa]IISTLT 180 IL-2T131 [AzK_Ll_PEG50k Da] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSII S[AzK LI PEG50kDa]LT 181 IL- 2_N8 8 RD 109 [AzKL IP EG50kDa] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISRINVIVLELKGSETTFMCEYA[AzK LI PEG50kDa]ETATI VEFLNRWITFSQSIISTLT 182 IL-2_V91 [AzKL 1 PEG5 OkD a] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNIN [AzKL l_PEG50kDa] IVLELKGSETTFMCEYADETATI VEFLNRWITFSQSIISTLT 183 IL- 2 K9[AzK LI PEG30kDa ] APTSSSTKIAzK LI PEG30kDa]TOLOLEHLLLDLQMILNGIN NYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVL NLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETAT IVEFLNRWITFSQSIISTLT 184 IL- 2_H 16 [AzKL 1 PEG3 OkD a] APTSSSTKKTOLOLE[AzK LI PEG30kDa]LLLDLOMILNGIN NYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVL NLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETAT IVEFLNRWITFSQSIISTLT 185 IL- 2_L 19 [AzKL 1 PEG3 OkD a] APTSSSTKKTOLOLEHLL[AzK LI PEG30kDa]DLQMILNGIN NYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVL NLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETAT IVEFLNRWITFSQSIISTLT 186 IL-2_D20 [AzKL 1 PEG3 OkD a] APTSSSTKKTQLQLEHLLL[AzK LI PEG30kDa]LQMILNGIN NYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVL NLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETAT IVEFLNRWITFSQSIISTLT 187 IL-2_M23[AzK_Ll_PEG30kD a] APTSSSTKKTQLQLEHLLLDLQ[AzK LI PEG30kDa]ILNGIN NYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVL NLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETAT IVEFLNRWITFSQSIISTLT 188 IL-2_N26 [AzKL 1_PEG3 OkD a] APTSSSTKKTQLQLEHLLLDLQMIL[AzK LI PEG30kPa]GIN NYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVL NLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETAT IVEFLNRWITFSQSIISTLT 189 IL-2_N8 8 [AzKL 1PEG3 OkD a] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD 190 2026234002   16 Sep 2026 LIS[AzK LI PEG30kDa]INVIVLELKGSETTFMCEYADETATI VEFLNRWITFSQSIISTLT IL- 2_E 100 [ AzKL 1 PEG3 Ok Da] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNINVIVLELKGS[AzK LI PEG30kDa]TTFMCEYADETATI VEFLNRWITFSQSIISTLT 191 IL-2_N119[AzK_Ll_PEG30k Da] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNINVIVLELKGSETTFMCEYADETATIVEFL[AzK LI PEG 30kPa]RWITFSQSIISTLT 192 IL- 2_T 123 [ AzKL 1 PEG3 Ok Da] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNINVIVLELKGSETTFMCEYADETATIVEFLNRWI[AzK LI PEG30kPa] FSQ SIISTLT 193 IL- 2_Q 126 [AzKL 1PEG3 Ok Da] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSJAzK LI PEG30kPa] SIISTLT 194 IL- 2_S 127[AzK_Ll_PEG30k Da] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQjAz K LI PEG30kDa]IISTLT 195 IL-2T131 [AzK_Ll_PEG30k Da] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSII S[AzK LI PEG30kDa[LT 196 IL- 2_N8 8 RD 109 [AzKL IP EG30kDa] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISRIVKIVLELKGSETTFMCEYA[AzK LI PEG30kDa]ETATI VEFLNRWITFSQSIISTLT 197 IL-2_V91 [AzKL 1 PEG3 OkD a] APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNIN[AzK LI PEG30kDa]IVLELKGSETTFMCEYADETATI VEFLNRWITFSQSIISTLT 198 IL-2_K8[AzK_PEG] PTSSSTKIAzK PEG1TOLOLEHLLLDLOMILNGINNYKNPKLT RMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNF HLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWI TFSQSIISTLT 199 IL-2_H15[AzK_PEG] PTSSSTKKTQLQLE[AzK PEG1LLLDLQMILNGINNYKNPKLT RMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNF HLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWI TFSQSIISTLT 200 IL-2_L18[AzK_PEG] PTSSSTKKTQLQLEHLL[AzK PEG1DLQMILNGINNYKNPKLT RMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNF HLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWI TFSQSIISTLT 201 IL-2_D19[AzK_PEG] PTSSSTKKTQLQLEHLLL[AzK PEG1LQMILNGINNYKNPKLT RMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNF HLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWI TFSQSIISTLT 202 IL-2_M22[AzK_PEG] PTSSSTKKTQLQLEHLLLDLQ[AzK PEG1ILNGINNYKNPKLT RMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNF 203 2026234002   16 Sep 2026 HLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWI TFSQSIISTLT IL-2_N25[AzK_PEG] PTSSSTKKTQLQLEHLLLDLQMIL[AzK PEG1GINNYKNPKLT RMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNF HLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWI TFSQSIISTLT 204 IL-2_N87[AzK_PEG] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI S [AzK PEG] INVI VLELKGSETTFMCEYADETATIVEFLNRWI TFSQSIISTLT 205 IL-2_E99[AzK_PEG] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNINVIVLELKGS [AzK PEG] TTFMCEYADETATIVEFLNRWI TFSQSIISTLT 206 IL-2N118[AzK_PEG] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNINVIVLELKGSETTFMCEYADETATIVEFL [AzK PEG] RWI TFSQSIISTLT 207 IL-2_T122[AzK_PEG] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNINVIVLELKGSETTFMCEYADETATIVEFLNRWI [AzK PEG 1FSQSIISTLT 208 IL-2_Q125[AzK_PEG] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFS[AzK PEG]SIISTLT 209 IL-2_S126[AzK_PEG] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQJAzK PEGUISTLT 210 IL-2_T130[AzK_PEG] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISJ. AzK PEG1LT 211 IL-2N87RD 109 [AzKPEG] -1 PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SRINVIVLELKGSETTFMCEYA [AzK PEG] ETATIVEFLNRWI TFSQSIISTLT 212 IL-2_V90[AzK_PEG] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNIN [AzK PEG] IVLELKGSETTFMCEYADETATIVEFLNRWI TFSQSIISTLT 213 IL-2K8 [AzK_PEG5 OkDa] PTSSSTK[AzK PEG50kDa]TQLQLEHLLLDLQMILNGINNYK NPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQ SKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFL NRWITFSQSIISTLT 214 IL- 2_H 15 [AzK_PEG5 OkDa] PTSSSTKKTQLQLE[AzK PEG50kDa]LLLDLQMILNGINNYK NPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQ SKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFL NRWITFSQSIISTLT 215 IL- 2 L18[AzK PEG50kDa] PTSSSTKKTQLQLEHLL[AzK PEG50kDa]DLQMILNGINNYK NPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQ 216 2026234002   16 Sep 2026 SKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFL NRWITFSQSIISTLT IL- 2_D 19 [AzK_PEG5 OkDa] PTSSSTKKTQLQLEHLLL[AzK PEG50kPa]LQMILNGINNYK NPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQ SKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFL NRWITFSQSIISTLT 217 IL- 2_M22 [AzK_PEG5 OkDa] PTSSSTKKTQLQLEHLLLDLQ[AzK PEG50kPa]ILNGINNYKN PKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQS KNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLN RWITFSQSIISTLT 218 IL- 2_N25 [AzK_PEG5 OkDa] PTSSSTKKTQLQLEHLLLDLQMIL[AzK PEG50kPa]GINNYK NPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQ SKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFL NRWITFSQSIISTLT 219 IL-2_N8 7 [AzK_PEG5 OkDa] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SIAzK PEG50kPa] INVIVLELKGSETTFMCEYADETATIVEFL NRWITFSQSIISTLT 220 IL-2_E99[AzK_PEG5 OkDa] -1 PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNINVIVLELKGS [AzK PEG50kPa]TTFMCEYADETATIVEFL NRWITFSQSIISTLT 221 IL- 2_N 118 [ AzK_PEG5 OkDa] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNINVIVLELKGSETTFMCEYADETATIVEFL [AzK PEG50kPa 1RWITFSQSIISTLT 222 IL- 2_T 122 [AzK_PEG5 OkDa] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNINVIVLELKGSETTFMCEYADETATIVEFLNRWI [AzK PEG 50kPalFSQSIISTLT 223 IL- 2_Q 125 [ AzK_PEG5 OkDa] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFS[AzK PEG50kPalSIISTLT 224 IL- 2_S 126 [AzK_PEG5 OkDa] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQJAzK PEG50kPalIISTLT 225 IL- 2_T 13 0 [AzK_PEG5 OkDa] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISJ, AzK PEG50kPalLT 226 IL-2N87RD108 [AzK_PEG5 OkDa] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SRINVIVLELKGSETTFMCEYA [AzK PEG50kPa] ETATIVEFL NRWITFSQSIISTLT 227 IL- 2_V90 [AzK_PEG5 OkDa] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNIN[AzK PEG50kPa]IVLELKGSETTFMCEYADETATIVEFL NRWITFSQSIISTLT 228 IL-2K8 [AzK_PEG3 OkDa] PTSSSTK[AzK PEG30kPa]TQLQLEHLLLDLQMILNGINNYK NPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQ 229 2026234002   16 Sep 2026 SKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFL NRWITFSQSIISTLT IL- 2_H 15 [AzK_PEG3 OkDa] PTSSSTKKTQLQLE[AzK PEG30kPa]LLLDLQMILNGINNYK NPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQ SKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFL NRWITFSQSIISTLT 230 IL- 2_L 18 [ AzK_PEG3 OkDa] PTSSSTKKTQLQLEHLL[AzK PEG30kPa]DLQMILNGINNYK NPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQ SKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFL NRWITFSQSIISTLT 231 IL- 2_D 19 [AzK_PEG3 OkDa] PTSSSTKKTQLQLEHLLL[AzK PEG30kPa]LQMILNGINNYK NPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQ SKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFL NRWITFSQSIISTLT 232 IL- 2_M22 [AzK_PEG3 OkDa] PTSSSTKKTQLQLEHLLLDLQ[AzK PEG30kPa]ILNGINNYKN PKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQS KNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLN RWITFSQSIISTLT 233 IL- 2_N25 [AzK_PEG3 OkDa] PTSSSTKKTOLOLEHLLLDLOMILrAzK PEG30kDa]GINNYK NPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQ SKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFL NRWITFSQSIISTLT 234 IL- 2_N8 7 [AzK_PEG3 OkDa] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI S [AzK PEG30kDa] INVIVLELKGSETTFMCEYADETATIVEFL NRWITFSQSIISTLT 235 IL-2E99 [ AzK_PEG3 OkDa] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNINVIVLELKGS [AzK PEG30kPa]TTFMCEYADETATIVEFL NRWITFSQSIISTLT 236 IL- 2_N 118 [ AzK_PEG3 OkDa] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNINVIVLELKGSETTFMCEYADETATIVEFL [AzK PEG30kPa 1RWITFSQSIISTLT 237 IL- 2_T 122 [AzK_PEG3 OkDa] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNINVIVLELKGSETTFMCEYADETATIVEFLNRWI [AzK PEG 30kPalFSQSIISTLT 238 IL- 2_Q 125 [ AzK_PEG3 OkDa] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFS[AzK PEG30kPalSIISTLT 239 IL- 2_S 126 [AzK_PEG3 OkDa] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQ[AzK PEG30kPalIISTLT 240 IL- 2_T 13 0 [AzK_PEG3 OkDa] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISJ. AzK PEG30kPa]LT 241 IL-2N87RD108 [AzK_PEG3 OkDa] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI 242 2026234002   16 Sep 2026 SRINVIVLELKGSETTFMCEYA fAzK PEG30kDa] ETATIVEFL NRWITFSQSIISTLT IL- 2_V90 [AzK_PEG3 OkDa] PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKF YMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLI SNINfAzK PEG30kPa]IVLELKGSETTFMCEYADETATIVEFL NRWITFSQSIISTLT 243 IL-2_L 12 [ AzK_PEG3 OkDa] APTSSSTKKTQfAzK PEG30kPa] QLEHLLLDLQMILNGINNY KNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLA QSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEF LNRWITFSQSIISTLT 244 IL- 2_E 15 [ AzK_PEG3 OkDa] APTSSSTKKTOLQLfAzK PEG30kPa]HLLLDLQMILNGINNY KNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLA QSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEF LNRWITFSQSIISTLT 245 IL-2_V91K_C125S APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISNINKIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSII STLT 246 IL-2N88RC125S APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTF KFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRD LISRINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSII STLT 247 CTP Peptide (30 amino acids) FQSSSSKAPPPSLPSPSRLPGPSDTPILPQ 248 CTP Peptide (31 amino acids) FQDSSSSKAPPPSLPSPSRLPGPSDTPILPQ 249 X = site comprising an unnatural amino acid. [AzK] = N6-((2-azidoethoxy)-carbonyl)-L-lysine (the structure of which is disclosed as compound 90 in FIG. 3C), having Chemical Abstracts Registry No. 1167421-25-1. [AzKPEG]= N6-((2-azidoethoxy)-carbonyl)-L-lysine stably-conjugated to PEG via DBCO-mediated click chemistry, to form a compound comprising a structure of Formula (II) or Formula (III). For example, if specified, PEG50kD indicates a linear polyethylene glycol chain with an average molecular weight of 50 kDa, capped with a methoxy group. The ratio of regioisomers generated from the click reaction is about 1:1 or greater than 1:1. The term “DBCO” means a chemical moiety comprising a dibenzocyclooctyne group, such as comprising the mPEG-DBCO compound illustrated in Scheme 1 of Example 1. An exemplary structure of a methoxy PEG group is illustrated in the mPEG-DBCO structure in Scheme 1 of Example 1. [AzK_Ll_PEG] = N6-((2-azidoethoxy)-carbonyl)-L-lysine stably-conjugated to PEG via DBCO-mediated click chemistry to form a compound comprising a structure of Formula (IV) or Formula (V). For example, if specified, PEG50kD indicates a linear polyethylene glycol chain with an average molecular weight of 50 kDa, capped with a methoxy group. The ratio of regioisomers generated from the click reaction is about 1:1 or greater than 1:1. The term “DBCO” means a chemical moiety comprising a 2026234002   16 Sep 2026 dibenzocyclooctyne group, such as comprising the mPEG-DBCO compound illustrated in Scheme 1 of Example 1.

[0099] In some embodiments, described herein are IL-2 conjugates modified at an amino acid position. In some instances, the modification is to a natural amino acid. In some instances, the modification is to an unnatural amino acid. In some instances, described herein is an isolated and modified IL-2 polypeptide that comprises at least one unnatural amino acid. In some instances, the IL-2 polypeptide is an isolated and purified mammalian IL-2, for example, a rodent IL-2 protein, or a human IL-2 protein. In some cases, the IL-2 polypeptide is a human IL-2 protein. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 1. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 1. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 1. In additional cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 2. In additional cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 2. In additional cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 2. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 3. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 3. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 3. In additional cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 4. In additional cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 4. In additional cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 4. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 3448. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 34-48. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 34-48. In additional cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 199-213. In additional cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 199213. In additional cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 199-213. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 49-63. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 49-63. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 49-63. In additional cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 213-228. In additional cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 213-228. In additional cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 213-228. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 64-78. In some cases, the IL-2 polypeptide 2026234002   16 Sep 2026 comprises the sequence of SEQ ID NO: 64-78. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 64-78. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 229-243. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 229-243. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 229-243. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 154-168. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 154-168. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 154-168. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 109123. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 109-123. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 109-123. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 169-183. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 169-183. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 169-183. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 123-138. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 123-138. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 123-138. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 184-198. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 184-198. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 184-198. In some cases, the IL-2 polypeptide comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 139-153. In some cases, the IL-2 polypeptide comprises the sequence of SEQ ID NO: 139-153. In some cases, the IL-2 polypeptide consists of the sequence of SEQ ID NO: 139-153.

[0100] In some instances, the IL-2 polypeptide is a truncated variant. In some instances, the truncation is an N-terminal deletion. In other instances, the truncation is a C-terminal deletion. In additional instances, the truncation comprises both N-terminal and C-terminal deletions. For example, the truncation can be a deletion of at least or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, or more residues from either the N-terminus or the C-terminus, or both termini. In some cases, the IL-2 polypeptide comprises an N-terminal deletion of at least or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, or more residues. In some cases, the IL-2 polypeptide comprises an N-terminal deletion of at least or about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 residues. In some cases, the IL-2 polypeptide comprises an N-terminal deletion of at least or about 2 residues. In some cases, the IL-2 polypeptide comprises an N-terminal deletion of at least or about 3 residues. In some cases, the IL-2 polypeptide comprises an N- 2026234002   16 Sep 2026 terminal deletion of at least or about 4 residues. In some cases, the IL-2 polypeptide comprises an N- terminal deletion of at least or about 5 residues. In some cases, the IL-2 polypeptide comprises an N- terminal deletion of at least or about 6 residues. In some cases, the IL-2 polypeptide comprises an N- terminal deletion of at least or about 7 residues. In some cases, the IL-2 polypeptide comprises an N- terminal deletion of at least or about 8 residues. In some cases, the IL-2 polypeptide comprises an N- terminal deletion of at least or about 9 residues. In some cases, the IL-2 polypeptide comprises an N- terminal deletion of at least or about 10 residues.

[0101] In some embodiments, the IL-2 polypeptide is a functionally active fragment. In some cases, the functionally active fragment comprises IL-2 region 10-133, 20-133, 30-133, 10-130, 20-130, 30-130, 10-125, 20-125, 30-125, 1-130, or 1-125, wherein the residue positions are in reference to the positions in SEQ ID NO: 1. In some cases, the functionally active fragment comprises IL-2 region 10-133, wherein the residue positions are in reference to the positions in SEQ ID NO: 1. In some cases, the functionally active fragment comprises IL-2 region 20-133, wherein the residue positions are in reference to the positions in SEQ ID NO: 1. In some cases, the functionally active fragment comprises IL-2 region SOBS, wherein the residue positions are in reference to the positions in SEQ ID NO: 1. In some cases, the functionally active fragment comprises IL-2 region 10-125, wherein the residue positions are in reference to the positions in SEQ ID NO: 1. In some cases, the functionally active fragment comprises IL-2 region 20-125, wherein the residue positions are in reference to the positions in SEQ ID NO: 1. In some cases, the functionally active fragment comprises IL-2 region 1-130, wherein the residue positions are in reference to the positions in SEQ ID NO: 1. In some cases, the functionally active fragment comprises IL-2 region 1-125, wherein the residue positions are in reference to the positions in SEQ ID NO: 1.

[0102] In some embodiments, described herein is an IL-2 conjugate that comprises an isolated, purified, and modified IL-2 polypeptide and a conjugating moiety. In some instances, the IL-2 conjugate has a decreased affinity to an IL-2 receptor a (IL-2Ra) subunit relative to a wild-type IL-2 polypeptide. In some cases, the conjugating moiety is bound to an amino acid residue that interacts with IL-2Ra (e.g., at the IL-2 / IL-2Ra interface). In some cases, the conjugating moiety is bound to an amino acid residue that is proximal to the IL-2 / IL-2Ra interface (e.g., about 5A, about 10A, about 15A, or about 20A away from the IL-2 / IL-2Ra interface). As used herein, the residues involved in the IL-2 / IL-2Ra interface comprise IL-2 residues that form hydrophobic interactions, hydrogen bonds, or ionic interactions with residues from the IL-2Ra subunit.

[0103] In some instances, the conjugating moiety is bound to an amino acid residue selected from an ammo acid position Al, P2, T3, S4, S5, S6, T7, K8, K9, QI 1, L12, E15, H16, L18, L19, D20, Q22, M23, N26, G27, N29, N30, Y31, K32, K35, T37, M46, P47, K48, A50, T51, E52, L53, H55, Q57, E60, E67, N71, Q74, S75, K76, N77, F78, H79, R81, P82, R83, D84, S87, N88,189, V91,192, L94, E95, K97, G98, S99, 2026234002   16 Sep 2026 E100, T101, T102, F103, M104, C105, E106, Y107, A108, D109, D109 in the N88R variant, El 10, T111, Al 12, T113, El 16, N119, R120, T123, S125, Q126, S127, S130, T131, L132, or T133, in which the numbering of the amino acid residues corresponds to SEQ ID NO: 1. In some instances, the amino acid position is selected from Al, P2, T3, S4, S5, S6, T7, K8, K9, Qll, L12, E15, H16, L18, L19, D20, Q22, M23, N26, G27, N29, N30, Y31, K32, K35, T37, M46, P47, K48, A50, T51, E52, L53, H55, Q57, E60, E67, N71, Q74, S75, K76, N77, F78, H79, R81, P82, R83, D84, S87, N88,189, V91,192, L94, E95, K97, G98, S99, E100, T101, T102, F103, M104, C105, E106, Y107, A108, D109, D109 in the N88R variant, El 10, Till, A112,T113, E116,N119, R120, T123, S125, Q126, S127, S130, T131, L132, andT133. In some instances, the amino acid position is selected from Al, P2, T3, S4, S5, S6, T7, K8, K9, Qll, L12, E15, H16, LI8, L19, D20, Q22, M23, N26, G27, N29, N30, and Y31. In some instances, the amino acid position is selected from K32, K35, T37, M46, P47, K48, A50, T51, E52, L53, H55, Q57, E60, E67, N71, Q74, S75, K76, N77, F78, H79, R81, P82, R83, D84, S87, N88,189, V91,192, L94, E95, K97, G98, S99, E100, T101, T102, F103, M104, C105, E106, Y107, A108, D109, D109 in the N88R variant, El 10, T111, Al 12, T113, E116, N119, R120, T123, S125, Q126, S127, S130, T131, L132, and T133. In some instances, the amino acid position is selected from K9, Qll, L12, E15, H16, L18, L19, K35, T37, M46, P47, K48, A50, K76, N77, F78, H79, R81, P82, R83, D84, S87, N88, F103, M104, C105, E106, Y107, A108, D109, D109 in the N88R variant. In some instances, the amino acid position is selected from S99, E100, T101, T102, F103, M104, C105, E106, Y107, A108, D109, D109 in the N88R variant, El 10, Till, Al 12, T113, E116, N119, R120, T123, S125, Q126, S127, S130, T131, L132, and T133. In some instances, the amino acid position is selected from K8, H15, L18, D19, M22, N25, N87, V90,191, L93, E94, K96, G97, S98, E99, D108 in the N87R variant, N118, T122, S124, Q125, S126, S129, andT130.

[0104] In some instances, the IL-2 conjugate further comprises an additional mutation. In some cases, the additional mutation is at an amino acid position selected from K8, H15, L18, D19, M22, N25, N87, V90,191, L93, E94, K96, G97, S98, E99, D108 in the N87R variant, N118, T122, S124, Q125, S126, S129, and T130. In such cases, the amino acid is conjugated to an additional conjugating moiety for increase in serum half-life, stability, or a combination thereof. Alternatively, the amino acid is first mutated to a natural amino acid such as lysine, cysteine, histidine, arginine, aspartic acid, glutamic acid, serine, threonine, or tyrosine; or to an unnatural amino acid prior to binding to the additional conjugating moiety.

[0105] In some instances, the receptor signaling potency is measured by an ED50 value. In some instances, the modified IL-2 polypeptide provides a first ED50 value for activating IL-2Py signaling complex and a second ED50 value for activating IL-2aPy signaling complex, and wherein a difference between the first ED50 and the second ED50 value is less than 10-fold. In some instances, the modified IL-2 polypeptide provides a first ED50 value for activating IL-2Py signaling complex and a second ED50 value for activating IL-2aPy signaling complex, and wherein a difference between the first ED50 and the -97- 2026234002   16 Sep 2026 second ED50 value is less than 5-fold. In some cases, the difference is less than 9-fold, less than 8-fold, less than 7-fold, less than 6-fold, less than 5-fold, less than 4-fold, less than 3-fold, less than 2-fold, or less than 1-fold.

[0106] In some embodiments, the conjugating moiety is linked to the N-terminus or the C-terminus of an IL-2 polypeptide, either directly or indirectly through a linker peptide. In some cases, the conjugating moiety (e.g., a polymer, a protein, or a peptide) is genetically fused to the IL-2, at the N-terminus or the C-terminus of IL-2, and either directly or indirectly through a linker peptide. In some instances, the conjugating moiety is linked to the N-terminus or the C-terminus amino acid residue. In some instances, the conjugating moiety is linked to a reactive group that is bound to the N-terminus or C-terminus amino acid residue.

[0107] In some embodiments, the IL-2 conjugate with reduced binding affinity to IL-2Ra is capable of expanding CD4+ helper cell, CD8+ effector naive and memory T cell, Natural Killer (NK) cell, or Natural killer T (NKT) cell populations. In some cases, the conjugating moiety impairs or blocks binding of IL-2 with IL-2Ra.

[0108] In some cases, activation of CD4+ helper cell, CD8+ effector naive and memory cell, Natural Killer (NK) cell, or Natural killer T (NKT) cell population via the IL-2RPy complex by the modified IL-2 polypeptide retains significant potency of activation of said cell population relative to a wild-type IL-2 polypeptide. In some instances, the activation by the modified IL-2 polypeptide is equivalent to that of the wild-type IL-2 polypeptide. In other instances, the activation by the modified IL-2 polypeptide is higher than that of the wild-type IL-2 polypeptide. In some cases, the receptor signaling potency of the modified IL-2 polypeptide to the IL-2RPy complex is higher than a receptor signaling potency of the wild-type IL-2 polypeptide to the IL-2RPy complex. In some cases, the receptor signaling potency of the modified IL-2 polypeptide is at least 1-fold higher than the respective potency of the wild-type IL-2 polypeptide. In some cases, the receptor signaling potency of the modified IL-2 polypeptide is about or at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-folod, 20-fold, 25-fold, 30fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 150-fold, 200-fold, 300-fold, 400-fold, 500-fold, 1,000-fold, or higher than the respective potency of the wild-type IL-2 polypeptide. In such cases, the dose or concentration of the modified IL-2 polypeptide used for achieving a similar level of activation of the CD4+ helper cell, CD8+ effector naive and memory cell, Natural Killer (NK) cell, or Natural killer T (NKT) cell population as a wild-type 11-2 polypeptide is lower than a dose or concentration used for the wild-type IL-2 polypeptide.

[0109] In some embodiments, activation of CD4+ helper cell, CD8+ effector naive and memory cell, Natural Killer (NK) cell, or Natural killer T (NKT) cell population via the IL-2RPy complex by the modified IL-2 polypeptide retains significant potency of activation of said cell population by a wild-type 2026234002   16 Sep 2026 IL-2 polypeptide. In some cases, the receptor signaling potency of the modified IL-2 polypeptide the IL-2RPy complex is lower than a receptor signaling potency of the wild-type IL-2 polypeptide the IL-2RPy complex. In some cases, the receptor signaling potency of the modified IL-2 polypeptide is about or at least 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 20-fold, or 50-fold lower than the respective potency of the wild-type IL-2 polypeptide.

[0110] In some embodiments, the modified IL-2 polypeptide exhibits a first receptor signaling potency to IL-2RPy and a second receptor signaling potency to IL-2RaPy. In some instances, the first receptor signaling potency to IL-2RPy is an improved potency relative to a wild-type IL-2 polypeptide. In some instances, the second receptor signaling potency to IL-2RaPy is an impaired potency relative to the wildtype IL-2 polypeptide. In some embodiments, the modified IL-2 polypeptide exhibits a first receptor signaling potency to IL-2RPy and a second receptor signaling potency to IL-2RaPy, and wherein the first receptor signaling potency is at least 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 30-fold, 50-fold, 100-fold, 500-fold, 1000-fold, or higher than the second receptor signaling potency. In some instances, the first receptor signaling potency is at least 1-fold or higher than the second receptor signaling potency. In some instances, the first receptor signaling potency is at least 2fold or higher than the second receptor signaling potency. In some instances, the first receptor signaling potency is at least 5-fold or higher than the second receptor signaling potency. In some instances, the first receptor signaling potency is at least 10-fold or higher than the second receptor signaling potency. In some instances, the first receptor signaling potency is at least 20-fold or higher than the second receptor signaling potency. In some instances, the first receptor signaling potency is at least 50-fold or higher than the second receptor signaling potency. In some instances, the first receptor signaling potency is at least 100-fold or higher than the second receptor signaling potency. In some instances, the first receptor signaling potency is at least 500-fold or higher than the second receptor signaling potency. In some instances, the first receptor signaling potency is at least 1000-fold or higher than the second receptor signaling potency. In some instances, the first receptor signaling potency of the modified IL-2 polypeptide is higher than a receptor signaling potency of the wild-type IL-2 polypeptide to the IL-2RPy, and the second receptor signaling potency of the modified IL-2 polypeptide is lower than a receptor signaling potency of the wild-type IL-2 polypeptide to the IL-2RuPy. In some cases, both receptor signaling potencies are lower than their respective potencies in a wild-type IL-2 polypeptide. In other cases, both receptor signaling potencies are higher than their respective potencies in a wild-type IL-2 polypeptide.

[0111] In some embodiments, the IL-2 conjugate decreases a toxic adverse event in a subject administered with the IL-2 conjugate. Exemplary toxic adverse events include eosinophilia, capillary leak, and vascular leak syndrome (VLS). In some instances, the IL-2 conjugate decreases the occurrence 2026234002   16 Sep 2026 of a toxic adverse event in the subject by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or about 100%, relative to a second subject administered with a wild-type IL-2 or aldesleukin. In some instances, the IL-2 conjugate decreases the severity of a toxic adverse event in the subject by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or about 100%, relative to a second subject administered with a wild-type IL-2 or aldesleukin.

[0112] In some instances, the toxic adverse event is eosinophilia. In some cases, the IL-2 conjugate decreases the occurrence of eosinophilia in the subject by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or about 100%, relative to a second subject administered with a wild-type IL-2 or aldesleukin. In some cases, the IL-2 conjugate decreases the severity of eosinophilia in the subject by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or about 100%, relative to a second subject administered with a wild-type IL-2 or aldesleukin.

[0113] In some instances, the toxic adverse event is capillary leak. In some cases, the IL-2 conjugate decreases the occurrence of capillary leak in the subject by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or about 100%, relative to a second subject administered with a wild-type IL-2 or aldesleukin. In some cases, the IL-2 conjugate decreases the severity of capillary leak in the subject by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or about 100%, relative to a second subject administered with a wild-type IL-2 or aldesleukin.

[0114] In some instances, the toxic adverse event is VLS. In some cases, the IL-2 conjugate decreases the occurrence of VLS in the subject by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or about 100%, relative to a second subject administered with a wild-type IL-2 or aldesleukin. In some cases, the IL-2 conjugate decreases the severity of VLS in the subject by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or about 100%, relative to a second subject administered with a wild-type IL-2 or aldesleukin.

[0115] In some embodiments, the IL-2 conjugate comprises a plasma half-life of greater than 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 18 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or more. In some embodiments, the IL-2 conjugate comprises a plasma half-life of greater than 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, or more. In some embodiments, the IL-2 conjugate comprises a plasma half-life of greater than 1 hour. In some embodiments, the IL-2 conjugate comprises a plasma half-life of greater than 2 hours. In some embodiments, the IL-2 conjugate comprises a plasma half-life of greater than 3 hours. In some embodiments, the IL-2 conjugate comprises a plasma half-life of greater than 4 hours. In some embodiments, the IL-2 conjugate comprises a plasma half-life of greater than 5 hours. In some embodiments, the IL-2 conjugate comprises a plasma half-life of greater than 6 hours. In some embodiments, the IL-2 conjugate comprises a plasma half-life of greater than 7 hours. In some 2026234002   16 Sep 2026 embodiments, the IL-2 conjugate comprises a plasma half-life of greater than 8 hours. In some embodiments, the IL-2 conjugate comprises a plasma half-life of greater than 9 hours. In some embodiments, the IL-2 conjugate comprises a plasma half-life of greater than 10 hours. In some embodiments, the IL-2 conjugate comprises a plasma half-life of greater than 12 hours. In some embodiments, the IL-2 conjugate comprises a plasma half-life of greater than 18 hours. In some embodiments, the IL-2 conjugate comprises a plasma half-life of greater than 24 hours.

[0116] In some embodiments, the IL-2 conjugate comprises a plasma half-life of at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 15 hours, 18 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or more. In some embodiments, the IL-2 conjugate comprises a plasma half-life of at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 15 hours, 18 hours, 24 hours, or more. In some embodiments, the IL-2 conjugate comprises a plasma half-life of at least 1 hour. In some embodiments, the IL-2 conjugate comprises a plasma half-life of at least 2 hours. In some embodiments, the IL-2 conjugate comprises a plasma half-life of at least 3 hours. In some embodiments, the IL-2 conjugate comprises a plasma half-life of at least 4 hours. In some embodiments, the IL-2 conjugate comprises a plasma halflife of at least 5 hours. In some embodiments, the IL-2 conjugate comprises a plasma half-life of at least 6 hours. In some embodiments, the IL-2 conjugate comprises a plasma half-life of at least 7 hours. In some embodiments, the IL-2 conjugate comprises a plasma half-life of at least 8 hours. In some embodiments, the IL-2 conjugate comprises a plasma half-life of at least 9 hours. In some embodiments, the IL-2 conjugate comprises a plasma half-life of at least 10 hours. In some embodiments, the IL-2 conjugate comprises a plasma half-life of at least 12 hours. In some embodiments, the IL-2 conjugate comprises a plasma half-life of at least 18 hours. In some embodiments, the IL-2 conjugate comprises a plasma half-life of at least 24 hours.

[0117] In some embodiments, the IL-2 conjugate comprises a plasma half-life of from about 1 hour to about 7 days, from about 12 hours to about 7 days, from about 18 hours to about 7 days, from about 24 hours to about 7 days, from about 1 hours to about 5 days, from about 12 hours to about 5 days, from about 24 hours to about 5 days, from about 2 days to about 5 days, or from about 2 days to about 3 days.

[0118] In some embodiments, the IL-2 conjugate comprises a plasma half-life of from about 1 hour to about 18 hours, from about 1 hour to about 12 hours, from about 2 hours to about 10 hours, from about 2 hours to about 8 hours, from about 4 hours to about 18 hours, from about 4 hours to about 12 hours, from about 4 hours to about 10 hours, from about 4 hours to about 8 hours, from about 6 hours to about 18 hours, from about 6 hours to about 12 hours, from about 6 hours to about 10 hours, from about 6 hours to about 8 hours, from about 8 hours to about 18 hours, from about 8 hours to about 12 hours, or from about 8 hours to about 10 hours. 2026234002   16 Sep 2026

[0119] In some embodiments, the IL-2 conjugate comprises a plasma half-life that is capable of proliferating and / or expanding a CD4+ helper cell, CD8+ effector naive and memory T cell, NK cell, NKT cell, or a combination thereof, but does not exert a deleterious effect such as apoptosis.

[0120] In some embodiments, the IL-2 conjugate comprises an extended plasma half-life, e.g., by at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 15 hours, 18 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or more relative to a wild-type IL-2. In some embodiments, the IL-2 conjugate comprises an extended plasma half-life, e.g., by at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 15 hours, 18 hours, 24 hours, or more relative to a wild-type IL-2.

[0121] In some embodiments, the IL-2 conjugate comprises an extended plasma half-life, e.g., from about 1 hour to about 18 hours, from about 1 hour to about 12 hours, from about 2 hours to about 10 hours, from about 2 hours to about 8 hours, from about 4 hours to about 18 hours, from about 4 hours to about 12 hours, from about 4 hours to about 10 hours, from about 4 hours to about 8 hours, from about 6 hours to about 18 hours, from about 6 hours to about 12 hours, from about 6 hours to about 10 hours, from about 6 hours to about 8 hours, from about 8 hours to about 18 hours, from about 8 hours to about 12 hours, or from about 8 hours to about 10 hours relative to a wild-type IL-2.

[0122] In some embodiments, the IL-2 conjugate comprises an extended plasma half-life, e.g., by at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 15 hours, 18 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or more relative to aldesleukin. In some embodiments, the IL-2 conjugate comprises an extended plasma half-life, e.g., by at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 15 hours, 18 hours, 24 hours, or more relative to aldesleukin.

[0123] In some embodiments, the IL-2 conjugate comprises an extended plasma half-life, e.g., from about 1 hour to about 18 hours, from about 1 hour to about 12 hours, from about 2 hours to about 10 hours, from about 2 hours to about 8 hours, from about 4 hours to about 18 hours, from about 4 hours to about 12 hours, from about 4 hours to about 10 hours, from about 4 hours to about 8 hours, from about 6 hours to about 18 hours, from about 6 hours to about 12 hours, from about 6 hours to about 10 hours, from about 6 hours to about 8 hours, from about 8 hours to about 18 hours, from about 8 hours to about 12 hours, or from about 8 hours to about 10 hours relative to aldesleukin.

[0124] In some embodiments, the IL-2 conjugate comprises an extended plasma half-life with a reduced toxicity. In some instances, the IL-2 conjugate comprises an extended plasma half-life of at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 15 hours, 18 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or more with a reduced toxicity. In some instances, the IL-2 conjugate comprises an extended plasma half-life of at least 1 hour, 2 hours, 2026234002   16 Sep 2026 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 15 hours, 18 hours, 24 hours, or more with a reduced toxicity. In some instances, the IL-2 conjugate comprises an extended plasma half-life of from about 1 hour to about 18 hours, from about 1 hour to about 12 hours, from about 2 hours to about 10 hours, from about 2 hours to about 8 hours, from about 4 hours to about 18 hours, from about 4 hours to about 12 hours, from about 4 hours to about 10 hours, from about 4 hours to about 8 hours, from about 6 hours to about 18 hours, from about 6 hours to about 12 hours, from about 6 hours to about 10 hours, from about 6 hours to about 8 hours, from about 8 hours to about 18 hours, from about 8 hours to about 12 hours, or from about 8 hours to about 10 hours with a reduced toxicity. In some cases, the reduced toxicity is at least 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 30-fold, 50-fold, 100-fold, or more reduced relative to a wild-type IL2. In some cases, the reduced toxicity is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500%, or more reduced relative to a wild-type IL-2.

[0125] In some embodiments, the IL-2 conjugate comprises an extended plasma half-life with a reduced toxicity. In some instances, the IL-2 conjugate comprises an extended plasma half-life of at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 15 hours, 18 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or more with a reduced toxicity. In some instances, the IL-2 conjugate comprises an extended plasma half-life of at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 15 hours, 18 hours, 24 hours, or more with a reduced toxicity. In some instances, the IL-2 conjugate comprises an extended plasma half-life of from about 1 hour to about 18 hours, from about 1 hour to about 12 hours, from about 2 hours to about 10 hours, from about 2 hours to about 8 hours, from about 4 hours to about 18 hours, from about 4 hours to about 12 hours, from about 4 hours to about 10 hours, from about 4 hours to about 8 hours, from about 6 hours to about 18 hours, from about 6 hours to about 12 hours, from about 6 hours to about 10 hours, from about 6 hours to about 8 hours, from about 8 hours to about 18 hours, from about 8 hours to about 12 hours, or from about 8 hours to about 10 hours with a reduced toxicity. In some cases, the reduced toxicity is at least 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 30-fold, 50-fold, 100-fold, or more reduced relative to aldesleukin. In some cases, the reduced toxicity is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500%, or more reduced relative to aldesleukin.

[0126] In some embodiments, the IL-2 conjugate comprises a conjugating moiety in which the size (e.g., the volume or length) of the conjugating moiety enhances plasma stability but does not reduce potency. In some instances, the size of the conjugating moiety extends plasma half-life by at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 15 hours, 18 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or more. In some instances, the size of the 2026234002   16 Sep 2026 conjugating moiety extends plasma half-life by at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 15 hours, 18 hours, 24 hours, or more. In some instances, the size of the conjugating moiety extends plasma half-life from about 1 hour to about 18 hours, from about 1 hour to about 12 hours, from about 2 hours to about 10 hours, from about 2 hours to about 8 hours, from about 4 hours to about 18 hours, from about 4 hours to about 12 hours, from about 4 hours to about 10 hours, from about 4 hours to about 8 hours, from about 6 hours to about 18 hours, from about 6 hours to about 12 hours, from about 6 hours to about 10 hours, from about 6 hours to about 8 hours, from about 8 hours to about 18 hours, from about 8 hours to about 12 hours, or from about 8 hours to about 10 hours. In some instances, the size of the conjugating moiety reduces the potency by less than 5%, 4%, 3%, 2%, 1%, or less relative to aldesleukin.

[0127] In some embodiments, the IL-2 conjugate comprises a conjugating moiety in which the size (e.g., the volume or length) of the conjugating moiety enhances plasma stability and potency. In some instances, the size of the conjugating moiety extends plasma half-life by at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 15 hours, 18 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or more. In some instances, the size of the conjugating moiety extends plasma half-life by at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 15 hours, 18 hours, 24 hours, or more. In some instances, the size of the conjugating moiety extends plasma half-life from about 1 hour to about 18 hours, from about 1 hour to about 12 hours, from about 2 hours to about 10 hours, from about 2 hours to about 8 hours, from about 4 hours to about 18 hours, from about 4 hours to about 12 hours, from about 4 hours to about 10 hours, from about 4 hours to about 8 hours, from about 6 hours to about 18 hours, from about 6 hours to about 12 hours, from about 6 hours to about 10 hours, from about 6 hours to about 8 hours, from about 8 hours to about 18 hours, from about 8 hours to about 12 hours, or from about 8 hours to about 10 hours. In some instances, the size of the conjugating moiety further enhances the potency by more than 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, or more relative to aldesleukin.

[0128] In some embodiments, described herein is an IL-2 conjugate comprising an unnatural amino acid covalently attached to a conjugating moiety, wherein the unnatural amino acid is located in region 35-107, and wherein the region 35-107 corresponds to residues K35-Yl07 of SEQ ID NO: 1.

[0129] In some embodiments, described herein is an interleukin 2 Py receptor (IL-2RPy) binding protein, wherein the binding affinity for an interleukin 2 a receptor (IL-2Ra) of said binding protein is less than that of wild-type human IL-2 (hIL-2), wherein the binding affinity for an interleukin 2 a receptor (IL-2Ra) of said binding protein is less than that of wild-type human IL-2 (hIL-2). In some embodiments, described herein is an interleukin 2 Py receptor (IL-2RPy) binding protein, wherein the binding affinity for an interleukin 2 a receptor (IL-2Ra) of said binding protein is less than that of wild- 2026234002   16 Sep 2026 type human IL-2 (hIL-2), and wherein said binding protein comprises at least one unnatural amino acid. In some instances, said binding protein is a modified IL-2 polypeptide or a functionally active fragment thereof, wherein the modified IL-2 polypeptide comprises at least one unnatural amino acid. In some instances, the at least one unnatural amino acid is located in region 35-107, and wherein the region 35107 corresponds to residues K35-Yl07 of SEQ ID NO: 1.

[0130] In some embodiments, described herein is an IL-2 / IL-2RPy complex comprising a modified IL-2 polypeptide comprising a mutation and an IL-2RPy, wherein the modified IL-2 polypeptide has a reduced binding affinity toward IL-2Ra, and wherein the reduced binding affinity is compared to a binding affinity between a wild-type IL-2 polypeptide and IL-2Ra. In some instances, the modified IL-2 polypeptide further comprises a conjugating moiety covalently attached to site of mutation. In some instances, the site of mutation comprises an amino acid mutated to a natural amino acid. In some cases, the site of mutation comprises an amino acid mutated to a cysteine residue. In other cases, the site of mutation comprises an amino acid mutated to a lysine residue.

[0131] In some embodiments, described herein is an IL-2 / IL-2RPy complex comprising a modified IL-2 polypeptide comprising an unnatural amino acid and an IL-2RPy, wherein the modified IL-2 polypeptide has a reduced binding affinity toward IL-2Ra, and wherein the reduced binding affinity is compared to a binding affinity between a wild-type IL-2 polypeptide and IL-2Ra. In some instances, the modified IL-2 polypeptide further comprises a conjugating moiety covalently attached to the unnatural amino acid.

[0132] In some embodiments, described herein is an IL-2 / IL-2RPy complex comprising a modified IL-2 polypeptide comprising an unnatural amino acid and an IL-2RPy, wherein the modified IL-2 polypeptide has a reduced receptor signaling potency toward IL-2Ra, and wherein the reduced receptor signaling potency is compared to a receptor signaling potency between a wild-type IL-2 polypeptide and IL-2Ra. In some instances, the modified IL-2 polypeptide further comprises a conjugating moiety covalently attached to the unnatural amino acid.

[0133] In some embodiments, described herein is an activator of a CD4+ helper cell, CD8+ effector naive and memory T cell, Natural Killer (NK) cell, or a Natural killer T (NKT) cell that selectively expands CD4+ helper cells, CD8+ effector naive and memory T cells, NK cells, NKT cells, or a combination thereof in a cell population, wherein said activator comprises a modified interleukin 2 (IL-2) polypeptide comprising at least one mutation. In some instances, the mutation is to a natural amino acid. In other instances, the mutation is to an unnatural amino acid. In some embodiments, described herein is an activator of a CD4+ helper cell, CD8+ effector naive and memory T cell, Natural Killer (NK) cell, or a Natural killer T (NKT) cell that selectively expands CD4+ helper cells, CD8+ effector naive and memory T cells, NK cells, NKT cells, or a combination thereof in a cell population, wherein said 2026234002   16 Sep 2026 activator comprises a modified interleukin 2 (IL-2) polypeptide comprising at least one unnatural amino acid. In some instances, said activator expands CD4+ T regulatory (Treg) cells by less than 20%, 15%, 10%, 5%, 1%, or less than 0.1% when said activator is in contact with said CD3+ cell population compared to an expansion of CD4+ Treg cells in the CD3+ cell population contacted with a wild-type IL-2 polypeptide. In some instances, said activator does not expand Treg cells in said cell population. In some instances, said cell population is an in vivo cell population. In some instances, said cell population is an in vitro cell population. In some instances, said cell population is an ex vivo cell population.

[0134] In some instances, also described herein is a method of expanding a CD4+ helper cell, CD8+ effector naive and memory T cell, Natural Killer (NK) cell, or a Natural killer T (NKT) cell population, comprising contacting said cell population with a therapeutically effective amount of a CD4+ helper cell, CD8+ effector naive and memory T cell, Natural Killer (NK) cell, or a Natural killer T (NKT) cell activator, in which said activator comprises a modified interleukin 2 (IL-2) polypeptide comprising at least one mutation, thereby expanding the CD4+ helper cell, CD8+ effector naive and memory T cell, Natural Killer (NK) cell, or Natural killer T (NKT) cell population. In some instances, the mutation is to a natural amino acid. In other instances, the mutation is to an unnatural amino acid. In some instances, also described herein is a method of expanding a CD4+ helper cell, CD8+ effector naive and memory T cell, Natural Killer (NK) cell, or a Natural killer T (NKT) cell population, comprising contacting said cell population with a therapeutically effective amount of a CD4+ helper cell, CD8+ effector naive and memory T cell, Natural Killer (NK) cell, or a Natural killer T (NKT) cell activator, in which said activator comprises a modified interleukin 2 (IL-2) polypeptide comprising at least one unnatural amino acid, thereby expanding the CD4+ helper cell, CD8+ effector naive and memory T cell, Natural Killer (NK) cell, or Natural killer T (NKT) cell population.

[0135] In some embodiments, the modified IL-2 polypeptide comprising a mutation at K35 corresponding to residue position 35, of SEQ ID NO: 1, comprises a conjugating moiety comprising a PEG having a molecular weight of about 2,000-50,000 Da. In some embodiments, the molecular weight comprises 5,000 Da. In some embodiments, the molecular weight comprises 10,000 Da. In some embodiments, the molecular weight comprises 15,000 Da. In some embodiments, the molecular weight comprises 20,000 Da. In some embodiments, the molecular weight comprises 25,000 Da. In some embodiments, the molecular weight comprises 30,000 Da. In some embodiments, the molecular weight comprises 35,000 Da. In some embodiments, the molecular weight comprises 40,000 Da. In some embodiments, the molecular weight comprises 45,000 Da. In some embodiments, the molecular weight comprises 50,000 Da. In some embodiments, the molecular weight comprises 55,000 Da. In some embodiments, the molecular weight comprises 60,000 Da. In some embodiments, the molecular weight of the PEG determines, at least in part, the in vivo plasma half-life of the modified IL-2 polypeptide. In 2026234002   16 Sep 2026 some instances, the PEG corresponds with a longer in vivo plasma half-life of the modified IL-2 polypeptide, as compared to the in vivo plasma half-life of a smaller PEG. In some instances, the PEG corresponds with a shorter in vivo plasma half-life of the modified IL-2 polypeptide, as compared to the in vivo plasma half-life of a larger PEG. In some embodiments, the molecular weight of the PEG does not affect, nor has minimal effect, on the receptor signaling potency of the modified IL-2 polypeptide to the IL-2Py or IL-2aPy signaling complexes. In some embodiments, the molecular weight of the PEG does not affect, or has minimal effect, on the desired reduced binding of the modified IL-2 polypeptide to IL-2Ra or the maintained binding with IL-2RPy signaling complex, wherein the reduced binding to IL-2Ra is compared to binding between a wild-type IL-2 polypeptide and IL-2Ra. In some embodiments, the molecular weight of the PEG does not affect the formation of the modified IL-2polypeptide / IL-2RPy complex, wherein the reduced binding to IL-2Ra is compared to binding between a wild-type IL-2 polypeptide and IL-2Ra

[0136] In some embodiments, the modified IL-2 polypeptide comprising a mutation at residue T37 corresponding to a position 37 of SEQ ID NO: 1, comprises a conjugating moiety comprising a PEG having a molecular weight of about 2,000-50,000 Da. In some embodiments, the molecular weight comprises 5,000 Da. In some embodiments, the molecular weight comprises 10,000 Da. In some embodiments, the molecular weight comprises 15,000 Da. In some embodiments, the molecular weight comprises 20,000 Da. In some embodiments, the molecular weight comprises 25,000 Da. In some embodiments, the molecular weight comprises 30,000 Da. In some embodiments, the molecular weight comprises 35,000 Da. In some embodiments, the molecular weight comprises 40,000 Da. In some embodiments, the molecular weight comprises 45,000 Da. In some embodiments, the molecular weight comprises 50,000 Da. In some embodiments, the molecular weight comprises 55,000 Da. In some embodiments, the molecular weight comprises 60,000 Da. In some embodiments, the molecular weight of the PEG determines, at least in part, the in vivo plasma half-life of the modified IL-2 polypeptide. In some instances, the PEG corresponds with a longer in vivo plasma half-life of the modified IL-2 polypeptide, as compared to the in vivo plasma half-life of a smaller PEG. In some instances, the PEG corresponds with a shorter in vivo plasma half-life of the modified IL-2 polypeptide, as compared to the in vivo plasma half-life of a larger PEG. In some embodiments, the molecular weight of the PEG does not affect, nor has minimal effect, on the receptor signaling potency of the modified IL-2 polypeptide to the IL-2Py or IL-2aPy signaling complexes. In some embodiments, the molecular weight of the PEG does not affect, or has minimal effect, on the desired reduced binding of the modified IL-2 polypeptide to IL-2Ra or the maintained binding with IL-2RPy signaling complex, wherein the reduced binding to IL-2Ra is compared to binding between a wild-type IL-2 polypeptide and IL-2Ra. In some embodiments, the molecular weight of the PEG does not affect the formation of the modified IL-2polypeptide / IL-2RPy 2026234002   16 Sep 2026 complex, wherein the reduced binding to IL-2Ra is compared to binding between a wild-type IL-2 polypeptide and IL-2Ra.

[0137] In some instances, the conjugating moiety is bound to an amino acid residue selected from an ammo acid position Al, P2, T3, S4, S5, S6, T7, K8, K9, Qll, L12, E15, H16, L18, L19, D20, Q22, M23, N26, G27, N29, N30, Y31, K32, K35, T37, M46, K47, K48, A50, T51, E52, K53, H55, Q57, E60, E67, N71, Q74, S75, K76, N77, F78, H79, R81, P82, R83, D84, S87, N88, N89, V91,192, L94, E95, K97, G98, S99, E100, T101, T102, F103, Ml04, C105, E106, Y107, A108, D109, E110, Till, A112, T113, El 16, N119, R120, T123, A125, Q126, S127, S130, T131, L132, and T133, in which the numbering of the amino acid residues corresponds to SEQ ID NO: 1. In some instances, the amino acid position is selected from K8, K9, Qll, L12, E15, H16, L18, L19, D20, Q22, M23, N26, R81, D84, S87, N88, V91, 192, L94, E95, El 16, N119, R120, T123, A125, Q126, S127, S130, T131, L132, andT133. In some instances, the amino acid position is selected from Al, P2, T3, S4, S5, S6, T7, G27, N29, N30, Y31, K32, K35, T37, M46, K47, K48, A50, T51, E52, K53, H55, Q57, E60, E67, N71, Q74, S75, K76, N77, F78, H79, P82, R83, N89, K97, G98, S99, E100, T101, T102, F103, M104, C105, E106, Y107, A108, D109, El 10, T111, Al 12, and T113. In some instances, the amino acid position is selected from K8, K9, L12, E15, Hl6, L19, D20, Q22, M23, N26, D84, N88, E95, and Q126. In some instances, the amino acid position is selected from K8, K9, and Hl 6. In some instances, the amino acid position is selected from Q22, N26, N88, and Q126. In some instances, the amino acid position is selected from El 5, D20, D84, and E95. In some instances, the amino acid position is selected from L12, L19, and M23. In some instances, the amino acid position is selected from Q22 and N26. In some cases, the amino acid position is at K8. In some cases, the amino acid position is at K9. In some cases, the amino acid position is at QI 1. In some cases, the amino acid position is at L12. In some cases, the amino acid position is at El5. In some cases, the amino acid position is at Hl6. In some cases, the amino acid position is at LI 8. In some cases, the amino acid position is at LI9. In some cases, the amino acid position is at D20. In some cases, the amino acid position is at Q22. In some cases, the amino acid position is at M23. In some cases, the amino acid position is at N26. In some cases, the amino acid position is at R81. In some cases, the amino acid position is at D84. In some cases, the amino acid position is at S87. In some cases, the amino acid position is at N88. In some cases, the amino acid position is at V91. In some cases, the amino acid position is at 192. In some cases, the amino acid position is at L94. In some cases, the amino acid position is at E95. In some cases, the amino acid position is at El 16. In some cases, the amino acid position is at N119. In some cases, the amino acid position is at RI20. In some cases, the amino acid position is at T123. In some cases, the amino acid position is at A125. In some cases, the amino acid position is at QI26. In some cases, the amino acid position is at SI27. In some cases, the amino acid 2026234002   16 Sep 2026 position is at S130. In some cases, the amino acid position is at T131. In some cases, the amino acid position is at L132. In some cases, the amino acid position is at T133.

[0138] In some instances, the IL-2 conjugate further comprises an additional mutation. In such cases, the amino acid is conjugated to an additional conjugating moiety for increase in serum half-life, stability, or a combination thereof. Alternatively, the amino acid is first mutated to a natural amino acid such as lysine, cysteine, histidine, arginine, aspartic acid, glutamic acid, serine, threonine, or tyrosine; or to an unnatural amino acid prior to binding to the additional conjugating moiety.

[0139] In some embodiments, the IL-2 conjugate has a decreased binding affinity to IL-2 receptor P (IL-2RP) subunit, IL-2 receptor y (IL-2Ry) subunit, or a combination thereof, of the IL-2RaPy complex, relative to a wild-type IL-2 polypeptide. In some instances, the decreased affinity of the IL-2 conjugate to IL-2 receptor P (IL-2RP) subunit, IL-2 receptor y (IL-2Ry) subunit, or a combination thereof, relative to a wild-type IL-2 polypeptide, is about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or greater than 99%. In some cases, the decreased affinity is about 10%. In some cases, the decreased affinity is about 20%. In some cases, the decreased affinity is about 40%. In some cases, the decreased affinity is about 50%. In some cases, the decreased affinity is about 60%. In some cases, the decreased affinity is about 80%. In some cases, the decreased affinity is about 90%. In some cases, the decreased affinity is about 99%. In some cases, the decreased affinity is greater than 99%. In some cases, the decreased affinity is about 80%. In some cases, the decreased affinity is about 100%.

[0140] In some embodiments, the decreased binding affinity of the IL-2 conjugate to IL-2 receptor P (IL-2RP) subunit, IL-2 receptor y (IL-2Ry) subunit, or a combination thereof, relative to a wild-type IL-2 polypeptide, is about 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 30-fold, 50-fold, 100-fold, 200-fold, 300-fold, 400-fold, 500-fold, 1,000-fold, or more. In some cases, the decreased affinity is about 1-fold. In some cases, the decreased affinity is about 2-fold. In some cases, the decreased affinity is about 4-fold. In some cases, the decreased affinity is about 5-fold. In some cases, the decreased affinity is about 6-fold. In some cases, the decreased affinity is about 8-fold. In some cases, the decreased affinity is about 10-fold. In some cases, the decreased affinity is about 30-fold. In some cases, the decreased affinity is about 50-fold. In some cases, the decreased affinity is about 100-fold. In some cases, the decreased affinity is about 300-fold. In some cases, the decreased affinity is about 500-fold. In some cases, the decreased affinity is about 1000-fold. In some cases, the decreased affinity is more than 1,000-fold.

[0141] In some embodiments, the IL-2 conjugate has a reduced IL-2Ry subunit recruitment to the IL-2 / IL-2RP complex. In some cases, the reduced recruitment is compared to an IL-2Ry subunit recruitment by an equivalent IL-2 polypeptide without the unnatural amino acid (e.g., a wild-type IL-2 polypeptide). In some cases, the decrease in IL-2Ry subunit recruitment is about 10%, 20%, 30%, 40%, 50%, 60%, 2026234002   16 Sep 2026 70%, 80%, 90%, 95%, 99%, or greater than 99% decrease relative to an equivalent IL-2 polypeptide without the unnatural amino acid modification. In some cases, the decrease in IL-2Ry subunit recruitment is about 10%. In some cases, the decrease in IL-2Ry subunit recruitment is about 20%. In some cases, the decrease in IL-2Ry subunit recruitment is about 40%. In some cases, the decrease in IL-2Ry subunit recruitment is about 50%. In some cases, the decrease in IL-2Ry subunit recruitment is about 60%. In some cases, the decrease in IL-2Ry subunit recruitment is about 70%. In some cases, the decrease in IL-2Ry subunit recruitment is about 80%. In some cases, the decrease in IL-2Ry subunit recruitment is about 90%. In some cases, the decrease in IL-2Ry subunit recruitment is about 99%. In some cases, the decrease in IL-2Ry subunit recruitment is greater than 99%. In some cases, the decrease in IL-2Ry subunit recruitment is about 100%. In some instances, the IL-2 conjugate further has an increase in IL-2Ra subunit recruitment.

[0142] In some embodiments, the decrease in IL-2Ry subunit recruitment is about 1-fold, 2-fold, 3fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 30-fold, 50-fold, 100-fold, 200-fold, 300-fold, 400-fold, 500-fold, 1,000-fold, or more relative to an equivalent IL-2 polypeptide without the unnatural amino acid modification (e.g., a wild-type IL-2 polypeptide). In some cases, the decrease in IL-2Ry subunit recruitment is about 1-fold. In some cases, the decrease in IL-2Ry subunit recruitment is about 2fold. In some cases, the decrease in IL-2Ry subunit recruitment is about 4-fold. In some cases, the decrease in IL-2Ry subunit recruitment is about 5-fold. In some cases, the decrease in IL-2Ry subunit recruitment is about 6-fold. In some cases, the decrease in IL-2Ry subunit recruitment is about 8-fold. In some cases, the decrease in IL-2Ry subunit recruitment is about 10-fold. In some cases, the decrease in IL-2Ry subunit recruitment is about 30-fold. In some cases, the decrease in IL-2Ry subunit recruitment is about 50-fold. In some cases, the decrease in IL-2Ry subunit recruitment is about 100-fold. In some cases, the decrease in IL-2Ry subunit recruitment is about 300-fold. In some cases, the decrease in IL-2Ry subunit recruitment is about 500-fold. In some cases, the decrease in IL-2Ry subunit recruitment is about 1000-fold. In some cases, the decrease in IL-2Ry subunit recruitment is more than 1,000-fold. In some instances, the IL-2 conjugate further has an increase in IL-2Ra subunit recruitment.

[0143] In some embodiments, the IL-2 conjugate has an increase in IL-2Ra subunit recruitment to the IL-2 polypeptide. In some cases, the reduced recruitment is compared to an IL-2Ra subunit recruitment by an equivalent IL-2 polypeptide without the unnatural amino acid (e.g., a wild-type IL-2 polypeptide). In some cases, the increase in IL-2Ra subunit recruitment is about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or greater than 99% increase relative to an equivalent IL-2 polypeptide without the unnatural amino acid modification. In some cases, the increase in IL-2Ra subunit recruitment is about 10%. In some cases, the increase in IL-2Ra subunit recruitment is about 20%. In some cases, the 2026234002   16 Sep 2026 increase in IL-2Ra subunit recruitment is about 40%. In some cases, the increase in IL-2Ra subunit recruitment is about 50%. In some cases, the increase in IL-2Ra subunit recruitment is about 60%. In some cases, the increase in IL-2Ra subunit recruitment is about 70%. In some cases, the increase in IL-2Ra subunit recruitment is about 80%. In some cases, the increase in IL-2Ra subunit recruitment is about 90%. In some cases, the increase in IL-2Ra subunit recruitment is about 99%. In some cases, the increase in IL-2Ra subunit recruitment is greater than 99%. In some cases, the increase in IL-2Ra subunit recruitment is about 100%. In some instances, the IL-2 conjugate further has a decrease in recruitment of an IL-2RP subunit and / or IL-2Ry subunit.

[0144] In some embodiments, the increase in IL-2Ra subunit recruitment is about 1-fold, 2-fold, 3fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 30-fold, 50-fold, 100-fold, 200-fold, 300-fold, 400-fold, 500-fold, 1,000-fold, or more relative to an equivalent IL-2 polypeptide without the unnatural amino acid modification (e.g., a wild-type IL-2 polypeptide). In some cases, the increase in IL-2Ra subunit recruitment is about 1-fold. In some cases, the increase in IL-2Ra subunit recruitment is about 2fold. In some cases, the increase in IL-2Ra subunit recruitment is about 4-fold. In some cases, the increase in IL-2Ra subunit recruitment is about 5-fold. In some cases, the increase in IL-2Ra subunit recruitment is about 6-fold. In some cases, the increase in IL-2Ra subunit recruitment is about 8-fold. In some cases, the increase in IL-2Ra subunit recruitment is about 10-fold. In some cases, the increase in IL-2Ra subunit recruitment is about 30-fold. In some cases, the increase in IL-2Ra subunit recruitment is about 50-fold. In some cases, the increase in IL-2Ra subunit recruitment is about 100-fold. In some cases, the increase in IL-2Ra subunit recruitment is about 300-fold. In some cases, the increase in IL-2Ra subunit recruitment is about 500-fold. In some cases, the increase in IL-2Ra subunit recruitment is about 1000-fold. In some cases, the increase in IL-2Ra subunit recruitment is more than 1,000-fold. In some instances, the IL-2 conjugate further has a decrease in recruitment of an IL-2RP subunit and / or IL-2Ry subunit.

[0145] In some embodiments, an IL-2 polypeptide described herein has a decrease in receptor signaling potency to IL-2RPy. In some instances, the decrease in receptor signaling potency is about 1fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 30-fold, 50-fold, 100-fold, 200fold, 300-fold, 400-fold, 500-fold, 1000-fold, or more to IL-2RPy relative to a wild-type IL-2 polypeptide. In some cases, the decrease in receptor signaling potency is about 2-fold. In some cases, the decrease in receptor signaling potency is about 5-fold. In some cases, the decrease in receptor signaling potency is about 10-fold. In some cases, the decrease in receptor signaling potency is about 20-fold. In some cases, the decrease in receptor signaling potency is about 30-fold. In some cases, the decrease in receptor signaling potency is about 40-fold. In some cases, the decrease in receptor signaling potency is about 50-fold. In some cases, the decrease in receptor signaling potency is about 100-fold. In some cases, 2026234002   16 Sep 2026 the decrease in receptor signaling potency is about 200-fold. In some cases, the decrease in receptor signaling potency is about 300-fold. In some cases, the decrease in receptor signaling potency is about 400-fold. In some cases, the decrease in receptor signaling potency is about 500-fold. In some cases, the decrease in receptor signaling potency is about 1000-fold.

[0146] In some instances, the receptor signaling potency is measured by an EC50 value. In some cases, the decrease in receptor signaling potency is an increase in EC50. In some instances, the increase in EC50 is about 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 30-fold, 50fold, 100-fold, 200-fold, 300-fold, 400-fold, 500-fold, 1000-fold, or more relative to a wild-type IL-2 polypeptide.

[0147] In some instances, the receptor signaling potency is measured by an ED50 value. In some cases, the decrease in receptor signaling potency is an increase in ED50. In some instances, the increase in ED50 is about 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 30-fold, 50fold, 100-fold, 200-fold, 300-fold, 400-fold, 500-fold, 1000-fold, or more relative to a wild-type IL-2 polypeptide.

[0148] In some embodiments, an IL-2 polypeptide described herein has an expanded therapeutic window compared to a therapeutic window of a wild-type IL-2 polypeptide. In some instances, the expanded therapeutic window is due to a decrease in binding between the IL-2 polypeptide and interleukin 2 receptor Py (IL-2RPy), a decrease in receptor signaling potency to fL-2RPy, a decrease in recruitment of an IL-2Ry subunit to the IL-2 / IL-2RP complex, or an increase in recruitment of an IL-2Ra subunit to the IL-2 polypeptide. In some instances, the IL-2 polypeptide does not have an impaired activation of interleukin 2 aPy receptor (IL-2RaPy).

[0149] In some embodiments, the modified IL-2 polypeptide exhibits a first receptor signaling potency to an IL-2Py signaling complex and a second receptor signaling potency to an IL-2aPy signaling complex, and wherein a difference between the first receptor signaling potency and the second receptor signaling potency is at least 1-fold. In some instances, the difference is at least 2-fold, 3-fold, 4-fold, 5fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold, 100-fold, 200-fold, 300-fold, 400-fold, 500-fold, 1000-fold, or more. In some instances, the first receptor signaling potency is less than the second receptor signaling potency. In some instances, the first receptor signaling potency is at least 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 30-fold, 50-fold, 100-fold, 500-fold, 1000-fold, or lower than the second receptor signaling potency. In some cases, the modified IL-2 polypeptide has a lower receptor signaling potency to an IL-2Py signaling complex than a second receptor signaling potency to an IL-2aPy signaling complex. In some cases, the first receptor signaling potency of the modified IL-2 polypeptide is at least 1-fold lower than a receptor signaling potency of the wild-type IL-2 polypeptide. In some cases, the first 2026234002   16 Sep 2026 receptor signaling potency of the modified IL-2 polypeptide is at least 2-fold, 3-fold, 4-fold, 5-fold, 10fold, 20-fold, 50-fold, 100-fold, 200-fold, or 500-fold lower than a receptor signaling potency of the wild-type IL-2 polypeptide. In some cases, the first receptor signaling potency and the second receptor signaling potency are both lower that the respective potencies of the wild-type IL-2 polypeptide, but the first receptor signaling potency is lower than the second receptor signaling potency. In some cases, the difference between the first receptor signaling potency and the second receptor signaling potency increases the therapeutic window for the modified IL-2 polypeptide.

[0150] In some instances, the conjugating moiety impairs or blocks the receptor signaling potency of IL-2 with IL-2RPy, or reduces recruitment of the IL-2Ry subunit to the IL-2 / IL-2RP complex.

[0151] In some instances, the modified IL-2 polypeptide with the decrease in receptor signaling potency to IL-2RPy is capable of expanding CD4+ T regulatory (Treg) cells.

[0152] In some embodiments, CD4+ Treg cell proliferation by the modified IL-2 / EL-2RaPy complex is equivalent or greater to that of a wild-type IL-2 polypeptide.

[0153] In some embodiments, the IL-2 / EL-2RaPy complex induces proliferation of the CD4+ Treg cells to a population that is sufficient to modulate a disease course in an animal model.

[0154] In some embodiments, described herein is an interleukin 2 aPy receptor (IL-2RaPy) binding protein, wherein the receptor signaling potency for an interleukin 2 Py receptor (IL-2RPy) of said binding protein is less than that of wild-type human IL-2 (hIL-2), and wherein said binding protein comprises at least one unnatural amino acid. In some cases, said binding protein is a modified IL-2 polypeptide or a functionally active fragment thereof, wherein the modified IL-2 polypeptide comprises at least one unnatural amino acid.

[0155] In some embodiments, described herein is an interleukin 2 aPy receptor (IL-2RaPy) binding protein, wherein a recruitment of an IL-2Ry subunit to an IL-2 / IL-2RP complex by said binding protein is less than that of wild-type human IL-2 (hIL-2), and wherein said binding protein comprises at least one unnatural amino acid. In some cases, said binding protein is a modified IL-2 ...

Claims

1. An IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3 in which at least one amino acid residue in the IL-2 conjugate is replaced by the structure of Formula (I):Formula (I);wherein:Y is CH2 and Z isY isW is a PEG group having an average molecular weight selected from 5kDa, lOkDa, 15kDa, 20kDa, 25kDa, 30kDa, 35kDa, 40kDa, 45kDa, 50kDa, 55 kDa, and 60kDa; andX has the structure:2026234002   16 Sep 2026X-1X-l indicates the point of attachment to the preceding amino acid residue;X+l indicates the point of attachment to the following amino acid residue; andthe position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is selected from Pl, T2, S3, S4, S5, T6, K7, K8, Q10, Lil, E14, H15, L17, L18, D19, Q21, M22, N25, G26, N28, N29, Y30, K31, K34, T36, M45, P46, K47, A49, T50, E51, L52, K53, H54, Q56, E59, E66, N70, Q73, S74, K75, N76, F77, H78, R80, P81, R82, D83, S86, N87,188, V90, 191, L93, E94, K96, G97, S98, E99, TWO, T101, F102, M103, C104, E105, Y106, A107, D108, D108 in the N87R variant, E109, T110, Alli, T112, El 15, N118, RI 19, T122, F123, S124, Q125, S126, S129, T130, L131, and T132.

2. An IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 4 in which at least one amino acid residue in the IL-2 conjugate is replaced by the structure of Formula (I):Formula (I);wherein:Z is CEL and Y isY is CEE and Z is2026234002   16 Sep 2026Y is CH2 and Z isW is a PEG group having an average molecular weight selected from 5kDa, lOkDa, 15kDa, 20kDa, 25kDa, 30kDa, 35kDa, 40kDa, 45kDa, 50kDa, 55 kDa, and 60kDa;X has the structure:X-l indicates the point of attachment to the preceding amino acid residue;X+l indicates the point of attachment to the following amino acid residue; andthe position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is selected from Al, P2, T3, S4, S5, S6, T7, K8, K9, QI 1, L12, E15, H16, L18, L19, D20, Q22, M23, N26, G27, N29, N30, Y31, K32, K35, T37, M46, P47, K48, A50, T51, E52, L53, H55, Q57, E60, E67, N71, Q74, S75, K76, N77, F78, H79, R81, P82, R83, D84, S87, N88,189, V91, 192, L94, E95, K97, G98, S99, E100, T101, T102, F103, M104, C105, E106, Y107, A108, D109, D109 in the N88R variant, El 10, T111, Al 12, T113, El 16, N119, R120, T123, S125, Q126, S127, S130, T131,L132, andT133.H N3. The IL-2 conjugate of claim 1 or 2 wherein Z is CEL and Y is O2026234002   16 Sep 2026h4. The IL-2 conjugate of claim 1 or 2 wherein Y is CH2 and Z is O O4^ o\N       N        W5. The IL-2 conjugate of claim 1 or 2 wherein Z is CH2 and Y is     O6. The IL-2 conjugate of claim 1 or 2 wherein Z is CH2 and Y is     Oand W is a PEG group having an average molecular weight selected from 15kDa, 20kDa, 25kDa, 30kDa, 35kDa, 40kDa, 45kDa, 50kDa, 55 kDa, and 60kDa.4- o7. The IL-2 conjugate of claim 1 or 2 wherein Y is CH2 and Z is O8. The IL-2 conjugate of any one of the preceding claims, wherein the PEG group has an average molecular weight selected from 5kDa, lOkDa, 20kDa, 30kDa, 40kDa, or 50kDa.

9. The IL-2 conjugate of claim 8 wherein the PEG group has an average molecular weight of 50kDa.

10. The IL-2 conjugate of claim 8 wherein the PEG group has an average molecular weight of 30kDa.

11. The IL-2 conjugate of any one of claims 1-10, wherein the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is K9.

12. The IL-2 conjugate of any one of claims 1-10, wherein the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is H16.

13. The IL-2 conjugate of any one of claims 1-10, wherein the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is L19.

14. The IL-2 conjugate of any one of claims 1-10, wherein the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is D20.2026234002   16 Sep 202615. The IL-2 conjugate of any one of claims 1-10, wherein the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is M23.

16. The IL-2 conjugate of any one of claims 1-10, wherein the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is N26.

17. The IL-2 conjugate of any one of claims 1-10, wherein the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is N88.

18. The IL-2 conjugate of any one of claims 1-10, wherein the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is V91.

19. The IL-2 conjugate of any one of claims 1-10, wherein the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is El 00.

20. The IL-2 conjugate of any one of claims 1-10, wherein the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is DI 09 in the N88R variant.

21. The IL-2 conjugate of any one of claims 1-10, wherein the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is N119.

22. The IL-2 conjugate of any one of claims 1-10, wherein the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is T123.

23. The IL-2 conjugate of any one of claims 1-10, wherein the position of the structure of Formula (I) in the amino acid sequence of the IL-2 conjugate is and T131.

24. An IL-2 conjugate comprising the amino acid sequence of any one of SEQ ID NOS: 34-48, and 199213, wherein [AzKPEG] has the structure of Formula (II) or Formula (III), or a mixture of Formula (II) and Formula (III):2026234002   16 Sep 2026Formula (II);Formula (III);wherein:W is a PEG group having an average molecular weight selected from 5kDa, lOkDa, 15kDa, 20kDa, 25kDa, 30kDa, 35kDa, 40kDa, 45kDa, 50kDa, 55 kDa, and 60kDa; andX has the structure:X-l indicates the point of attachment to the preceding amino acid residue; and X+l indicates the point of attachment to the following amino acid residue.

25. An IL-2 conjugate comprising the amino acid sequence of any one of SEQ ID NOS: 49-63 and 214228, wherein [AzK_PEG50kDa] has the structure of Formula (II) or Formula (III), or a mixture of Formula (II) and Formula (III):2026234002   16 Sep 2026Formula (II);Formula (III);wherein:W is a PEG group having an average molecular weight of 50kDa; andX has the structure:X-l indicates the point of attachment to the preceding amino acid residue; andX+l indicates the point of attachment to the following amino acid residue.

26. An IL-2 conjugate comprising the amino acid sequence of any one of SEQ ID NOS: 64-78 and 229245, wherein [AzK_PEG30kDa] has the structure of Formula (II) or Formula (III), or is a mixture of the structures of Formula (II) and Formula (III):Formula (II);2026234002   16 Sep 2026Formula (III);wherein:W is a PEG group having an average molecular weight of 30kDa; andX has the structure:X-1X-l indicates the point of attachment to the preceding amino acid residue; andX+l indicates the point of attachment to the following amino acid residue. .

27. The IL-2 conjugate of claim 26, wherein the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 64.

28. The IL-2 conjugate of claim 26, wherein the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 65.

29. The IL-2 conjugate of claim 26, wherein the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 66.

30. The IL-2 conjugate of claim 26, wherein the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 67.2026234002   16 Sep 202631. The IL-2 conjugate of claim 26, wherein the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 68.

32. The IL-2 conjugate of claim 26, wherein the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 69.

33. The IL-2 conjugate of claim 26, wherein the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 71.

34. The IL-2 conjugate of claim 26, wherein the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 72.

35. The IL-2 conjugate of claim 26, wherein the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 73.

36. The IL-2 conjugate of claim 26, wherein the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 74.

37. The IL-2 conjugate of claim 26, wherein the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 75.

38. The IL-2 conjugate of claim 26, wherein the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 76.

39. The IL-2 conjugate of claim 26, wherein the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 244.

40. The IL-2 conjugate of claim 26, wherein the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 245.

41. An IL-2 conjugate comprising the amino acid sequence of any one of SEQ ID NOS: 34-48 and 199213, wherein [AzKPEG] is a mixture of the structures of Formula (II) and Formula (III):2026234002   16 Sep 2026Formula (II);Formula (III);wherein:W is a PEG group having an average molecular weight selected from 5kDa, lOkDa, 15kDa, 20kDa, 25kDa, 30kDa, 35kDa, 40kDa, 45kDa, 50kDa, 55 kDa, and 60kDa; andX has the structure:X-1X-l indicates the point of attachment to the preceding amino acid residue; and X+l indicates the point of attachment to the following amino acid residue.

42. An IL-2 conjugate comprising the amino acid sequence of any one of SEQ ID NOS: 49-63 and 214228, wherein [AzK_PEG50kDa] is a mixture of the structures of Formula (II) and Formula (III):2026234002   16 Sep 2026Formula (II);Formula (III);wherein:W is a PEG group having an average molecular weight of 50kDa; andX has the structure:X-1X-l indicates the point of attachment to the preceding amino acid residue; and X+l indicates the point of attachment to the following amino acid residue.

43. An IL-2 conjugate comprising the amino acid sequence of any one of SEQ ID NOS: 64-78 and 229245, wherein [AzK_PEG30kDa] is a mixture of the structures of Formula (II) and Formula (III):2026234002   16 Sep 2026Formula (II);Formula (III);wherein:W is a PEG group having an average molecular weight of 30kDa; andX has the structure:X-1X-l indicates the point of attachment to the preceding amino acid residue; and X+l indicates the point of attachment to the following amino acid residue.

44. An IL-2 conjugate comprising the amino acid sequence of any one of SEQ ID NOS: 154-168 and 109-123, wherein [AzK LI PEG] has the structure of Formula (IV) or Formula (V), or a mixture of Formula (IV) and Formula (V):2026234002   16 Sep 2026Formula (IV);Formula (V);wherein:W is a PEG group having an average molecular weight selected from 5kDa, lOkDa, 15kDa, 20kDa, 25kDa, 30kDa, 35kDa, 40kDa, 45kDa, 50kDa, 55 kDa, and 60kDa; andX has the structure:X-1X-l indicates the point of attachment to the preceding amino acid residue; andX+l indicates the point of attachment to the following amino acid residue.

45. An IL-2 conjugate comprising the amino acid sequence of any one of SEQ ID NOS: 169-183 and 124-138, wherein [AzK_Ll_PEG50kDa] has the structure of Formula (IV) or Formula (V), or a mixture of Formula (IV) and Formula (V):2026234002   16 Sep 2026Formula (IV);Formula (V);wherein:W is a PEG group having an average molecular weight of 50kDa; andX has the structure:X-l indicates the point of attachment to the preceding amino acid residue; andX+l indicates the point of attachment to the following amino acid residue.

46. The IL-2 conjugate of claim 45, wherein the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 170.2026234002   16 Sep 202647. An IL-2 conjugate comprising the amino acid sequence of any one of SEQ ID NOS: 184-198 and 139-153, wherein [AzK_Ll_PEG30kDa] has the structure of Formula (IV) or Formula (V), or is a mixture of the structures of Formula (IV) and Formula (V):Formula (V);wherein:W is a PEG group having an average molecular weight of 30kDa; andX has the structure:X-1X-l indicates the point of attachment to the preceding amino acid residue; and X+l indicates the point of attachment to the following amino acid residue.2026234002   16 Sep 202648. The IL-2 conjugate of claim 47, wherein the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 185.

49. The IL-2 conjugate of claim 47, wherein the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 190.

50. The IL-2 conjugate of claim 47, wherein the IL-2 conjugate has the amino acid sequence of SEQ ID NO: 197.

51. An IL-2 conjugate comprising the amino acid sequence of any one of SEQ ID NOS: 154-168 and 109-123, wherein [AzkLIPEG] is a mixture of the structures of Formula (IV) and Formula (V):Formula (V);wherein:W is a PEG group having an average molecular weight selected from 5kDa, lOkDa, 15kDa, 20kDa, 25kDa, 30kDa, 35kDa, 40kDa, 45kDa, 50kDa, 55 kDa, and 60kDa; andX has the structure:2026234002   16 Sep 2026X-1X-l indicates the point of attachment to the preceding amino acid residue; and X+l indicates the point of attachment to the following amino acid residue.

52. An IL-2 conjugate comprising the amino acid sequence of any one of SEQ ID NOS: 169-183 and 124-138, wherein [AzK_Ll_PEG50kDa] is a mixture of the structures of Formula (IV) and Formula (V):Formula (V);wherein:W is a PEG group having an average molecular weight of 50kDa; andX has the structure:2026234002   16 Sep 2026X-1X-l indicates the point of attachment to the preceding amino acid residue; and X+l indicates the point of attachment to the following amino acid residue.

53. An IL-2 conjugate comprising the amino acid sequence of any one of SEQ ID NOS: 184-198 and 139-153, wherein [AzK_Ll_PEG30kDa] is a mixture of the structures of Formula (IV) and Formula (V):Formula (V);wherein:W is a PEG group having an average molecular weight of 30kDa; andX has the structure:2026234002   16 Sep 2026X-1X-l indicates the point of attachment to the preceding amino acid residue; and X+l indicates the point of attachment to the following amino acid residue..

54. An IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3 in which at least one amino acid residue in the IL-2 conjugate is replaced by the structure of Formula (VI) or (VII), or a mixture of (VI) and (VII):Formula (VII);wherein:n is an integer in the range from about 2 to about 5000; and2026234002   16 Sep 2026X-1X has the structure:X+1X-1 indicates the point of attachment to the preceding amino acid residue; and X+1 indicates the point of attachment to the following amino acid residue.

55. An IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3 in which at least one amino acid residue in the IL-2 conjugate is replaced by the structure of Formula (VIII) or (IX), or a mixture of (VIII) and (IX):OFormula (VIII);OFormula (IX);wherein:2026234002   16 Sep 2026n is an integer in the range from about 2 to about 5000; andX has the structure:X-1X+1X-1 indicates the point of attachment to the preceding amino acid residue; and X+1 indicates the point of attachment to the following amino acid residue.

56. An IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3 in which at least one amino acid residue in the IL-2 conjugate is replaced by the structure of Formula (X) or (XI), or a mixture of (X) and (XI):Formula (XI);2026234002   16 Sep 2026wherein:n is an integer in the range from about 2 to about 5000; andthe wavy lines indicate covalent bonds to amino acid residues within SEQ ID NO: 3 that are not replaced.

57. An IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 3 in which at least one amino acid residue in the IL-2 conjugate is replaced by the structure of Formula (XII) or (XIII), or a mixture of (XII) and (XIII):Formula (XII);Formula (XIII);wherein:n is an integer in the range from about 2 to about 5000; and2026234002   16 Sep 2026the wavy lines indicate covalent bonds to amino acid residues within SEQ ID NO: 3 that are not replaced.

58. An IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 4 in which at least one amino acid residue in the IL-2 conjugate is replaced by the structure of Formula (VI) or (VII), or a mixture of (VI) and (VII):Formula (VII);wherein:n is an integer in the range from about 2 to about 5000; andX has the structure:X-1X+1X-1 indicates the point of attachment to the preceding amino acid residue; and X+1 indicates the point of attachment to the following amino acid residue.2026234002   16 Sep 202659. An IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 4 in which at least one amino acid residue in the IL-2 conjugate is replaced by the structure of Formula (VIII) or (IX), or a mixture of (VIII) and (IX):Formula (IX);wherein:n is an integer in the range from about 2 to about 5000; andX-l indicates the point of attachment to the preceding amino acid residue; and X+l indicates the point of attachment to the following amino acid residue.2026234002   16 Sep 202660. An IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 4 in which at least one amino acid residue in the IL-2 conjugate is replaced by the structure of Formula (X) or (XI), or a mixture of (X) and (XI):Formula (X);Formula (XI);wherein:n is an integer in the range from about 2 to about 5000; andthe wavy lines indicate covalent bonds to amino acid residues within SEQ ID NO: 4 that are not replaced.

61. An IL-2 conjugate comprising the amino acid sequence of SEQ ID NO: 4 in which at least one amino acid residue in the IL-2 conjugate is replaced by the structure of Formula (XII) or (XIII), or a mixture of (XII) and (XIII):2026234002   16 Sep 2026Formula (XII);Formula (XIII);wherein:n is an integer in the range from about 2 to about 5000; andthe wavy lines indicate covalent bonds to amino acid residues within SEQ ID NO: 4 that are not replaced.

62. A method of treating an autoimmune disease in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of an IL-2 conjugate according to any one of claims 1 to 61.

63. The method of claim 62, wherein the autoimmune disease is selected from the group consisting of graft versus host disease (GVHD), atopic dermatitis, Crohn’s disease, alopecia areata, autoimmune hemolytic anemia, autoimmune hepatitis, dermatomyositis, type 1 diabetes, juvenile / pediatric type 1 diabetes juvenile idiopathic arthritis, glomerulonephritis, Graves’ disease, Guillain-Barre syndrome, idiopathic thrombocytopenic purpura, myasthenia gravis, multiple sclerosis, pemphigus / pemphigoid, pernicious anemia, polyarteritis nodosa, polymyositis, primary biliary cholangitis, primary biliary2026234002   16 Sep 2026cirrhosis, nonalcoholic steatohepatitis (NASH), psoriasis, rheumatoid arthritis, scleroderma, CREST syndrome, Sjogren’s syndrome, systemic lupus erythematosus, thyroiditis, uveitis, vitiligo, Wegener’s granulomatosis, Addison’s disease (adrenal insufficiency), Hashimoto thyroiditis, autoimmune hepatitis, infertility, ANCA-associated vasculitis, psoriatic arthritis, Celiac disease, ulcerative colitis, lichen sclerosus, and Behcet’s disease.

64. The method of any one of claims 62-63, wherein the subject in need thereof is determined to exhibit an increased concentration of rheumatoid factor in the blood of the subject prior to administration to the subject of the therapeutically effective amount of the IL-2 conjugate.

65. A method of treating rheumatoid arthritis in a subject in need thereof, comprising:(a) determining the concentration of rheumatoid factor in the blood of the subject; and(b) administering to the subject in need thereof a therapeutically effective amount of an IL-2 conjugate according to any one of claims 1 to 61 if the concentration of rheumatoid factor in the blood of the subject is greater than about 14 lU / mL.

66. The method of any one of claims 62-63, wherein the subject in need thereof is determined to exhibit an abnormal erythrocyte sedimentation rate (ESR) test, optionally using the Westergren rate method or the Wintrobe rate method, prior to administration to the subject of the therapeutically effective amount of the IL-2 conjugate.

67. A method of treating an autoimmune disease in a subject in need thereof, comprising:(a) determining the erythrocyte sedimentation rate (ESR) in the subject; and(b) administering to the subject in need thereof a therapeutically effective amount of an IL-2 conjugate according to any one of claims 1 to 61 if the ESR is determined to be abnormal.

68. A method of treating an autoimmune disease in a subject in need thereof, comprising:(a) determining the concentration of C-reactive protein (CRP) in the blood of the subject; and(b) administering to the subject in need thereof a therapeutically effective amount of an IL-2 conjugate according to any one of claims 1 to 61 if the concentration of C-reactive protein (CRP) in the blood of the subject is determined to be abnormal.2026234002   16 Sep 202669. The method of claim 6868, wherein the subject in need thereof is determined to exhibit a concentration of C-reactive protein (CRP) in the blood greater than 10 mg / L prior to administration to the subject of the therapeutically effective amount of the IL-2 conjugate.

70. A method of treating rheumatoid arthritis in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of an IL-2 conjugate according to any one of claims 1 to 61 if the concentration of anti-cyclic citrullinated peptide (anti-CCP) in the blood of the subject is determined to be abnormal.

71. A method of treating rheumatoid arthritis in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of an IL-2 conjugate according to any one of claims 1 to 61 if the concentration of anti-cyclic citrullinated peptide (anti-CCP) in the blood of the subject is determined to be greater than about 20 lu / mL.

72. A method of making an IL-2 conjugate, comprising:reacting an IL-2 polypeptide comprising an unnatural amino acid of formulaPosition X-1Position ”X'wherein the IL-2 polypeptide comprises the amino acid sequence of SEQ ID NO: 3 or 4 in which at least one amino acid residue in the IL-2 polypeptide is replaced by the unnatural amino acid, Position X-l indicates the point of attachment to the preceding amino acid residue, Position X+l indicates the point of attachment to the following amino acid residue, and Position X indicates the position of the amino acid for which the unnatural amino acid substitutes,with an mPEG-DBCO of formulawherein n is such that the mPEG-DBCO comprises a PEG having a molecular weight of about 5 kDa,2026234002   16 Sep 202610 kDa, 15 kDa, 20 kDa, 25 kDa, 30 kDa, 35 kDa, 40 kDa, 45 kDa, or 50 kDa, thereby producing the IL-2 conjugate,wherein position X in the amino acid sequence of the IL-2 conjugate is selected from Pl, T2, S3, S4, S5, T6, K7, K8, Q10, Lil, E14, H15, L17, L18, D19, Q21, M22, N25, G26, N28, N29, Y30, K31, K34, T36, M45, P46, K47, A49, T50, E51, L52, K53, H54, Q56, E59, E66, N70, Q73, S74, K75, N76, F77, H78, R80, P81, R82, D83, S86, N87,188, V90,191, L93, E94, K96, G97, S98, E99, TWO, TI0I, F102, M103, C104, E105, Y106, A107, D108, D108 in the N87R variant, E109, T110, Al 11, T112, El 15, N118, RI 19, T122, F123, S124, Q125, S126, S129, T130, L131, and T132 of SEQ ID NO: 3, or position X in the amino acid sequence of the IL-2 conjugate is selected from Al, P2, T3, S4, S5, S6, T7, K8, K9, QI 1, L12, E15, H16, L18, L19, D20, Q22, M23, N26, G27, N29, N30, Y31, K32, K35, T37, M46, P47, K48, A50, T51, E52, L53, H55, Q57, E60, E67, N71, Q74, S75, K76, N77, F78, H79, R81, P82, R83, D84, S87, N88,189, V91,192, L94, E95, K97, G98, S99, E100, TI0I, T102, F103, M104, C105, E106, Y107, A108, D109, D109 in the N88R variant, E110, Till, Al 12, T113, El 16, N119, R120, T123, S125, Q126, S127, S130, T131, L132, or T133, in reference to the amino acid positions within SEQ ID NO: 4.

73. The method of claim 72, wherein Position X is Pl, T2, S3, S4, S5, T6, K7, K8, Q10, Lil, E14, H15, L17, L18, D19, Q21, M22, N25, G26, N28, N29, Y30, K31, K34, T36, M45, P46, K47, A49, T50, E51, L52, K53, H54, Q56, E59, E66, N70, Q73, S74, K75, N76, F77, H78, R80, P81, R82, D83, S86, N87,188, V90,191, L93, E94, K96, G97, S98, E99, TWO, T101, FW2, MW3, CW4, EW5, YW6, AW7, DW8, DW8 in the N87R variant, E109, T110, Al 11, T112, El 15, N118, RI 19, T122, F123, S124, Q125, S126, S129, T130, L131, or T132, in reference to the amino acid positions within SEQ ID NO: 3.

74. The method of claim 72, wherein Position X is Al, P2, T3, S4, S5, S6, T7, K8, K9, QI 1, L12, E15, H16, L18, L19, D20, Q22, M23, N26, G27, N29, N30, Y31, K32, K35, T37, M46, P47, K48, A50, T51, E52, L53, H55, Q57, E60, E67, N71, Q74, S75, K76, N77, F78, H79, R81, P82, R83, D84, S87, N88,189, V91,192, L94, E95, K97, G98, S99, EW0, T101, TW2, FW3, MW4, CW5, EW6, YW7, AW8, DW9, DW9 in the N88R variant, El 10, Till, Al 12, T113, El 16, N119, R120, T123, S125, Q126, S127, 8130, T131, L132, or T133, in reference to the amino acid positions within SEQ ID NO: 4.

75. The method of any one of claims 72-74, wherein the PEG has a molecular weight of about 30 kDa.

76. The method of any one of claims 72-74, wherein the PEG has a molecular weight of about 50 kDa.

77. The method of claim 74, wherein the IL-2 conjugate is the IL-2 conjugate of any one of claims 1-61.

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