Interleukin-2-Fc fusion proteins and methods of use

Abstract

[1083] Provided are serum half-life extended-IL-2 variant (IL-2v) heterodimers having reduced binding to the IL2Ra (CD25) subunit. In particular, Fc-IL-2v heterodimers 5 are provided and methods for making and using, e.g. for enhancing an immune response, e.g. in the prevention and treatment of viral infections and cancer. 20 24 20 29 88 06 M ay 2 02 4 1 0 0 5 2 4 2 1 3 9 2 0 2 4 2 0 2 9 8 8 0 6 M a y 2 0 2 4 5

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a divisional application of Australian application no. 2021365129, the entire disclosure of which is incorporated herein by reference. This application 5 claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No. 63 / 104,376, filed on October 22, 2020 and U.S. Provisional Application No. 63 / 181,075, filed on April 28, 2021, which are hereby incorporated herein by reference in their entireties for all purposes. SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted 10 electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on September 20, 2021, is named 1348-WO-PCT_SL.txt and is 569,532 bytes in size. BACKGROUND

[0003] Interleukin-2 (IL-2, NCBI Gene ID: 3558) is an immunomodulatory cytokine that 15   plays an important role in the generation, differentiation, survival and homeostasis of immune cells. IL-2 has therapeutic potential for treatment of cancer and chronic viral diseases through its immunostimulatory effects on CD4+ and CD8+ T cells as well as NK cells, however, this is compromised by its ability to preferentially stimulate and expand regulatory T (Treg) cells which suppress the immune system. In addition to this preferential activity on 20 immunosuppressive Treg cells, IL-2 has a very short half-life in humans necessitating frequent dosing and can also induce life-threatening toxicities. The short half-life complicates the ability to administer a dose of IL-2 sufficient to elicit a desired immunostimulatory with reduced or minimal immunosuppressive effects but also avoiding toxicity, and presents significant challenges for the treatment of patients. See, e.g., Schwartz, et al., “Managing toxicities of high- 25 dose interleukin-2,” in Oncology (Williston Park) (2002) Nov;16(l 1 Suppl 13):11-20. SUMMARY

[0004] In one aspect, provided are interleukin-2 variants (IL-2v). In various embodiments, the IL-2v is truncated at the N-terminus by at least 5 amino acids relative to wildtype IL-2; and binds to the interleukin-2 receptor alpha subunit (IL-2RA; CD25) with reduced 30 binding affinity in comparison to wild-type IL-2 (wt IL-2). In some embodiments, the IL-2v binds to IL-2RA with an equilibrium dissociation constant (KD) of at least 60 pM (e.g., 60 pM 2024202988   06 May 2024 or higher). In some embodiments, the IL-2v binds to a complex of interleukin 2 receptor subunit beta (IL-2RB; CD122) and interleukin 2 receptor subunit gamma (IL-2RG; CD132) with a KD of less than 150 nM, e.g., less than 1.5 nM, e.g., less than 120 pM, e.g., less than 100 pM, e.g., less than 80 pM, e.g., less than 75 pM, e.g., less than 70 pM. In some embodiments, the IL-2v 5 promotes equivalent or greater proliferation of CD8+ T cells relative to wild-type (wt) IL-2, or an IL 2v of any one of SEQ ID NOs: 43 and 44. In some embodiments, the concentration at which the IL-2v elicits 50% of maximal (EC50) signal transducer and activator of transcription 5 (STAT5) activation or signaling of regulatory T (Treg) cells is at least 1000-fold, e.g., at least 1500-fold, e.g., at least 1700-fold, e.g., at least 2000-fold, e.g., at least 2500-fold higher, relative 10 to the EC50 for STAT5 activation or signaling of wt IL-2, or an IL-2v of any one of SEQ ID NOs: 43 and 44. In some embodiments, the concentration at which the IL-2v elicits EC50 of IL-2RaPy-mediated STAT5 activation or signaling (e.g., measured as STAT5 activation of CTLL2 cells) is at least 2500-fold, e.g., at least 5000-fold, e.g., at least 7500-fold, e.g., at least 10,000fold, e.g., at least 15,000-fold, e.g., at least 20,000-fold higher, relative to the EC50 for STAT5 15 activation or signaling of wt IL-2, or an IL-2v of any one of SEQ ID NOs: 43 and 44. In some embodiments, the concentration at which the IL-2v elicits 50% of maximal (EC50) proliferation of natural killer (NK) cells is at least 10-fold, e.g., at least 12-fold, e.g., at least 15-fold, e.g., at least 16-fold, e.g., at least 18-fold, e.g., at least 20-fold higher, e.g., as measured using KHYG-1 cells, relative to the EC50 for proliferation of wt IL-2, or an IL-2v of any one of SEQ ID NOs: 20   43 and 44. In some embodiments, the IL-2v comprises a serine at position 125 (C125) and at least two, or at least three, substitutions at amino acid positions selected from the group consisting of R38, F42, Y45, E61 and E62, wherein the position numbers are with respect to an IL-2v of SEQ ID NO:44. In some embodiments, the IL-2v comprises a serine at position 125 (Cl25) and at least two, or at least three, substitutions at amino acid positions selected from the 25 group consisting of R38, F42, Y45 and E62, wherein the position numbers are with respect to an IL-2v of SEQ ID NO:44. In some embodiments, the IL-2v comprises a serine at position 125 (Cl25) and at least two, or at least three, substitutions at amino acid positions selected from the group consisting of R38, F42 and E62, wherein the position numbers are with respect to an IL-2v of SEQ ID NO :44. In some embodiments, the IL-2v does not comprise amino acid 30 substitutions at one or more positions selected from the group consisting of Y45, E61, E68 and L72. In some embodiments, the IL-2v does not comprise an amino acid substitution at one or more, or all, of positions selected from the group consisting of D20, Y45, E61, E68, V69, L72, A73, L80, R81, L85, L86,187,192 and Q126. In some embodiments, the IL-2v does not comprise an amino acid substitution at one or more, or all, of positions selected from the group 35 consisting of H16, D20, E61, N88 and V91. In some embodiments, the IL-2v is PEGylated. 2024202988   06 May 2024

[0005] In one aspect, provided are fusion protein. In some embodiments, the fusion proteins comprise a serum half-life extending polypeptide operably linked to an interleukin-2 variant (IL-2v), wherein the IL-2v is truncated at the N-terminus by at least 5 amino acids relative to wild-type IL-2; and binds to the interleukin-2 receptor alpha subunit (IL-2RA; CD25) 5 with reduced binding affinity in comparison to wild-type IL-2 (wt IL-2). In some embodiments, the serum half-life extending polypeptide is selected from the group consisting of: an immunoglobulin fragment crystallizable region (Fc region), a serum albumin, an albumin binding protein or peptide, an IgG, an XTEN polypeptide, a proline / alanine / serine-rich (PAS) polypeptide, an elastin-like polypeptide. In some embodiments, the serum half-life extending 10 polypeptide is an immunoglobulin fragment crystallizable region (Fc region). In some embodiments, the fusion protein binds to IL-2RA with an equilibrium dissociation constant (KD) of at least 60 pM (e.g., 60 pM or higher). In some embodiments, the IL-2v binds to a complex of interleukin 2 receptor subunit beta (IL-2RB; CD 122) and interleukin 2 receptor subunit gamma (IL-2RG; CD132) with a KD of less than 150 nM, e.g., less than 1.5 nM, e.g., 15 less than 120 pM, e.g., less than 100 pM, e.g., less than 80 pM, e.g., less than 75 pM, e.g., less than 70 pM. In some embodiments, the fusion protein promotes equivalent or greater proliferation of CD8+ T cells relative to an IL-2v of any one of SEQ ID NOs: 43 and 44, a fusion protein comprising Fc operably linked to wt IL-2, or a fusion protein of any one of SEQ ID NOs. 117, 118, 161 and 162. In some embodiments, the concentration at which the IL-2v 20 fusion protein elicits 50% of maximal (EC50) signal transducer and activator of transcription 5 (STAT5) activation or signaling of regulatory T (Treg) cells is at least 1000-fold, e.g., at least 1500-fold, e.g., at least 1700-fold, e.g., at least 2000-fold, e.g., at least 2500-fold higher, relative to the EC50 for STAT5 for activation or signaling of wt IL-2, or an IL-2v of any one of SEQ ID NOs: 43 and 44, a fusion protein comprising Fc operably linked to wt IL-2, or a fusion protein 25 of any one of SEQ ID NOs. 117, 118, 161 or 162. In some embodiments, the concentration at which the IL-2v fusion protein elicits EC50 of IL-2RaPy-mediated STAT5 activation or signaling (e.g., measured as STAT5 activation of CTLL2 cells) is at least 2500-fold, e.g., at least 5000-fold, e.g., at least 7500-fold, e.g., at least 10,000-fold, e.g., at least 15,000-fold, e.g., at least 20,000-fold higher, relative to the EC50 for STAT5 activation or signaling of wt IL-2, or 30 an IL-2v of any one of SEQ ID NOs: 43 and 44, a fusion protein comprising Fc operably linked to wt IL 2, or a fusion protein of any one of SEQ ID NOs. 117, 118, 161 or 162. In some embodiments, the concentration at which the IL-2v fusion protein elicits 50% of maximal (EC50) proliferation of natural killer (NK) cells is at least 10-fold, e.g., at least 12-fold, e.g., at least 15-fold, e.g., at least 16-fold, e.g., at least 18-fold, e.g., at least 20-fold higher, e.g., as 35 measured using KHYG-1 cells, relative to the EC50 for proliferation of wt IL-2, or an IL-2v of 2024202988   06 May 2024 any one of SEQ ID NOs: 43 and 44, a fusion protein comprising Fc operably linked to wt IL 2, or a fusion protein of any one of SEQ ID NOs. 117, 118, 161 or 162. In some embodiments, the IL-2v comprises a serine at position 125 (C125) and at least two, or at least three, substitutions at amino acid positions selected from the group consisting of R38, F42, Y45, E61 and E62, 5 wherein the position numbers are with respect to an IL-2v of SEQ ID NO:44. In some embodiments, the IL-2v comprises a serine at position 125 (C125) and at least two, or at least three, substitutions at amino acid positions selected from the group consisting of R38, F42, Y45 and E62, wherein the position numbers are with respect to an IL-2v of SEQ ID NO:44. In some embodiments, the IL-2v comprises a serine at position 125 (C125) and at least two, or at least 10 three, substitutions at amino acid positions selected from the group consisting of R38, F42 and E62, wherein the position numbers are with respect to an IL-2v of SEQ ID NO:44. In some embodiments, the IL-2v does not comprise amino acid substitutions at one or more positions selected from the group consisting of Y45, E61, E68 and L72. In some embodiments, the IL-2v does not comprise the amino acid sequence APTSS (SEQ ID NO: 163). In some embodiments, 15 the IL-2v is from a human wild-type IL-2. In some embodiments, the IL-2v comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-42 or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-42. In some 20 embodiments, the Fc region is from a human IgGl, IgG2, IgG3 or IgG4. In some embodiments, the Fc region is from a human IgGl or IgG4. In some embodiments, the Fc region comprises a human IgGl isotype and comprises one or more amino acid substitutions in the Fc region at a residue position selected from the group consisting of: N297A, N297G, N297Q, N297G, D265A, L234A, L235A, C226S, C229S, P238S, E233P, L234V, P238A, A327Q, A327G, 25   P329A, P329G, K322A, L234F, L235E, P331S, T394D, A330L, M252Y, S254T, T256E, M428L, N434S, T366W, T366S, L368A, F405L, Y407V, K409R, H435R, Y436F, and any combination thereof, wherein the numbering of the residues is according to EU numbering. In some embodiments, the Fc region comprises a human IgGl isotype and comprises one or more amino acid substitutions in the Fc region at a residue position selected from the group consisting 30 of: L234A, L234V, L234F, L235A, L235E, D265A, P329G, P331S, and any combination thereof, wherein the numbering of the residues is according to EU numbering. In some embodiments, the Fc region comprises a human IgG4 isotype and comprises one or more amino acid substitutions in the Fc region at a residue position selected from the group consisting of: E233P, F234V, F234A, L235A, G237A, E318A, S228P, L235E, T394D, M252Y, S254T, 35   T256E, N297A, N297G, N297Q, T366W, T366S, L368A, F405L, Y407V, K409R, M428L, 2024202988   06 May 2024 N434S, H435R, Y436F, and any combination thereof, wherein the numbering of the residues is according to EU numbering. In some embodiments, the Fc region comprises a human IgG4 isotype and comprises one or more amino acid substitutions in the Fc region at a residue position selected from the group consisting of: F234V, F234A, L235A, L235E, S228P, and any 5 combination thereof, wherein the numbering of the residues is according to EU numbering. In some embodiments, the Fc region comprises the following amino acids at the indicated positions (EU index numbering): Tyrosine at position 252, threonine at position 254 and glutamic acid at position 256 (YTE); or Leucine at position 428 and serine at position 434 (LS). In some embodiments, the Fc region comprises the following amino acids at the indicated positions (EU 10 index numbering): an arginine at position 435 and a phenylalanine at position 436. In some embodiments, the terminal Fc amino acid residue (e.g., K447) is removed or eliminated. In some embodiments, the Fc region comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 45-72, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at 15 least 97%, at least 98%, or at least 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 45-72. In some embodiments, the Fc region comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 45, 47, 49, 52, 54, 56, 57, 59, 61, 63, 65, 67, 69 and 71, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at 20 least 97%, at least 98%, or at least 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 45, 47, 49, 52, 54, 56, 57, 59, 61, 63, 65, 67, 69 and 71. In some embodiments, the fusion protein comprises in sequential order from N-terminus to C-terminus, the Fc region and the IL-2v. In some embodiments, the fusion protein comprises a flexible linker between the Fc region and the IL-2v. In some embodiments, the linker has a 25 length of from 4 to 50 amino acids, e.g., from 5 amino acids to 25 amino acids, e.g., from 15 amino acids to 25 amino acids. In some embodiments, the linker comprises from 1 to 10 units, e.g., 1 to 5 units, e.g., 3 to 5 units, of a poly-glycine serine linker selected from GGGS (SEQ ID NO: 265), GGGGS (SEQ ID NO: 264) and combinations thereof. In some embodiments, the fusion protein comprises an amino acid sequence selected from the group consisting of SEQ ID 30 NOs: 75-116 and 119-160, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 75-116 and 119-160. In some embodiments, the fusion protein comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 166-171, 35 or comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 2024202988   06 May 2024 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 166-171. In some embodiments, the fusion protein does not specifically bind any antigen other than an Fc receptor or a complex of interleukin 2 receptor subunit beta (IL-2RB; 5 CD 122) and interleukin 2 receptor subunit gamma (IL-2RG; CD 132). In some embodiments, the fusion protein comprises an N terminal signal peptide or leader sequence. In some embodiments, the IL-2v in the fusion protein is not PEGylated.

[0006] Further provided is a homodimer comprising two Fc-IL-2v fusion proteins, as described above and herein. 10

[0007] In another aspect, provided is a heterodimer comprising: (i) a first Fc-IL-2v fusion protein, as described above and herein, comprising a first Fc domain, and (ii) a second Fc-IL-2v fusion protein, as described above and herein, comprising a second Fc domain. In another aspect, provided is a heterodimer comprising: (i) an (i.e., one) Fc-IL-2v fusion protein, as described above and herein, comprising a first Fc domain, and (ii) a second Fc domain, e.g., 15 that is empty or without a targeting moiety or an antigen binding domain. In some embodiments, the first Fc domain and the second Fc domain comprise the following amino acid substitutions (EU numbering), respectively: T366W and T366S / L368A / Y407V; T366S / L368A / Y407V and T366W; T366W / S354C and T366S / L368A / Y407V / Y349C; T366S / L368A / Y407V / Y349C and T366W / S354C; S364H / F405A and Y349T / T394F; 20  Y349T / T394F and S364H / F405A; T350V / L351Y / F405A / Y407V and T350V / T366L / K392L / T394W; T350V / T366L / K392L / T394W and T350V / L351Y / F405A / Y407V; K360D / D399M / Y407A and E345R / Q347R / T366V / K409V; E345R / Q347R / T366V / K409V and K360D / D399M / Y407A; K409D / K392D and D399K / E356K; D399K / E356K and K409D / K392D; K360E / K409W and Q347R / D399V / F405T; 25  Q347R / D399V / F405T and K360E / K409W; K360E / K409W / Y349C and Q347R / D399V / F405T / S354C; Q347R / D399V / F405T / S354C and K360E / K409W / Y349C; K370E / K409W and E357N / D399V / F405T; or E357N / D399V / F405T and K370E / K409W. In some embodiments, one or both of the first Fc domain and the second Fc domain comprise the following amino acids at the indicated positions (EU index numbering): Tyrosine at position 30   252, threonine at position 254 and glutamic acid at position 256 (YTE); or Leucine at position 428 and serine at position 434 (LS). In some embodiments, one or both of the first Fc domain and the second Fc domain comprise the following amino acids at the indicated positions (EU index numbering): an arginine at position 435 and a phenylalanine at position 436. In some embodiments, one or both of the first Fc domain and the second Fc domain comprise a human 2024202988   06 May 2024 IgG4 isotype and comprises one or more amino acid substitutions in the Fc region at a residue position selected from the group consisting of: F234V, F234A, L235A, L235E, S228P, and any combination thereof, wherein the numbering of the residues is according to EU numbering. In some embodiments, one or both of the first Fc domain and the second Fc domain comprise a 5 human IgGl isotype and comprises one or more amino acid substitutions in the Fc region at a residue position selected from the group consisting of: L234A, L234V, L234F, L235A, L235E, P33 IS, and any combination thereof, wherein the numbering of the residues is according to EU numbering. In some embodiments, the terminal Fc amino acid residue (e.g., K447) is removed or eliminated from one or both of the first Fc domain and the second Fc domain. In some 10 embodiments, the first Fc domain and the second Fc domain comprise amino acid sequences set forth, respectively, below, or comprise amino acid sequences that are at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequences set forth, respectively, below: SEQ ID NOs.: 45 and 46; SEQ ID NOs.: 47 and 48; SEQ ID NOs.: 49 and 15   46; SEQ ID NOs.: 45 and 51; SEQ ID NOs.: 49 and 51; SEQ ID NOs.: 52 and 48; SEQ ID NOs.: 47 and 53; SEQ ID NOs.: 52 and 53; SEQ ID NOs.: 54 and 46; SEQ ID NOs.: 45 and 55; SEQ ID NOs.: 54 and 55; SEQ ID NOs.: 56 and 48; SEQ ID NOs.: 47 and 50; SEQ ID NOs.: 56 and 50; SEQ ID NOs.: 57 and 58; SEQ ID NOs.: 59 and 60; SEQ ID NOs.: 61 and 58; SEQ ID NOs.: 57 and 62; SEQ ID NOs.: 63 and 64; SEQ ID NOs.: 65 and 60; SEQ ID NOs.: 59 and 66; 20 SEQ ID NOs.: 67 and 68; SEQ ID NOs.: 69 and 58; SEQ ID NOs.: 57 and 70; SEQ ID NOs.: 69 and 70; SEQ ID NOs.: 71 and 60; SEQ ID NOs.: 59 and 72; or SEQ ID NOs.: 71 and 72. In some embodiments, the heterodimer comprises a human IgG4 Fc-IL-2v fusion protein comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 75-116, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 25   92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 75-116; and a second Fc region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 46, 51 and 55, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at 30 least 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 46, 51 and 55. In some embodiments, the heterodimer comprises a human IgG4 Fc-IL-2v fusion protein comprising (i) a first amino acid sequence as set forth below, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 35   97%, at least 98%, or at least 99% identical to a first amino acid sequence set forth below; and 2024202988   06 May 2024 (ii) a second Fc region comprising a second amino acid sequence set forth below, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to a second amino acid sequence set forth below, respectively: SEQ ID NO: 75 and 5 SEQ ID NO: 46; SEQ ID NO: 76 and SEQ ID NO: 46; SEQ ID NO: 77 and SEQ ID NO: 46; SEQ ID NO: 78 and SEQ ID NO: 46; SEQ ID NO: 79 and SEQ ID NO: 46; SEQ ID NO: 80 and SEQ ID NO: 46; SEQ ID NO: 81 and SEQ ID NO: 46; SEQ ID NO: 82 and SEQ ID NO: 46; SEQ ID NO: 83 and SEQ ID NO: 46; SEQ ID NO: 84 and SEQ ID NO: 46; SEQ ID NO: 85 and SEQ ID NO: 46; SEQ ID NO: 86 and SEQ ID NO: 46; SEQ ID NO: 87 and SEQ ID NO: 46; 10 SEQ ID NO: 88 and SEQ ID NO: 46; SEQ ID NO: 89 and SEQ ID NO: 46; SEQ ID NO: 90 and SEQ ID NO: 46; SEQ ID NO: 91 and SEQ ID NO: 46; SEQ ID NO: 92 and SEQ ID NO: 46; SEQ ID NO: 93 and SEQ ID NO: 46; SEQ ID NO: 94 and SEQ ID NO: 46; SEQ ID NO: 95 and SEQ ID NO: 46; SEQ ID NO: 96 and SEQ ID NO: 46; SEQ ID NO: 97 and SEQ ID NO: 46; SEQ ID NO: 98 and SEQ ID NO: 46; SEQ ID NO: 99 and SEQ ID NO: 46; SEQ ID NO: 100 15 and SEQ ID NO: 46; SEQ ID NO: 101 and SEQ ID NO: 46; SEQ ID NO: 102 and SEQ ID NO: 46; SEQ ID NO: 103 and SEQ ID NO: 46; SEQ ID NO: 104 and SEQ ID NO: 46; SEQ ID NO: 105 and SEQ ID NO: 46; SEQ ID NO: 106 and SEQ ID NO: 46; SEQ ID NO: 107 and SEQ ID NO: 46; SEQ ID NO: 108 and SEQ ID NO: 46; SEQ ID NO: 109 and SEQ ID NO: 46; SEQ ID NO: 110 and SEQ ID NO: 46; SEQ ID NO: 111 and SEQ ID NO: 46; SEQ ID NO: 112 and 20 SEQ ID NO: 46; SEQ ID NO: 113 and SEQ ID NO: 46; SEQ ID NO: 114 and SEQ ID NO: 46; SEQ ID NO: 115 and SEQ ID NO: 46; or SEQ ID NO: 116 and SEQ ID NO: 46. In some embodiments, the heterodimer comprises a human IgG4 Fc-IL-2v fusion protein comprising (i) a first amino acid sequence as set forth below, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at 25 least 96%, at least 97%, at least 98%, or at least 99% identical to a first amino acid sequence set forth below; and (ii) a second Fc region comprising a second amino acid sequence set forth below, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to a second amino acid sequence set forth below, respectively: SEQ ID NO: 30   80 and SEQ ID NO: 46; SEQ ID NO: 107 and SEQ ID NO: 46; or SEQ ID NO: 114 and SEQ ID NO: 46. In some embodiments, the heterodimer comprises a human IgG4 Fc-IL-2v fusion protein comprising (i) a first amino acid sequence of SEQ ID NO: 114 or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to 35 SEQ ID NO: 114; and (ii) a second Fc region comprising an amino acid sequence of SEQ ID 2024202988   06 May 2024 NO: 46, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 46. In some embodiments, the heterodimer comprises a human IgGl Fc-IL-2v fusion protein comprising an amino acid sequence selected from the 5 group consisting of SEQ ID NOs: 119-160, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 119-160; and a second Fc region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 58, 62 and 70, or an 10 amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 58, 62 and 70. In some embodiments, the heterodimer comprises a human IgGl Fc-IL-2v fusion protein comprising (i) a first amino acid sequence as set forth below, or an amino acid sequence 15 that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to a first amino acid sequence set forth below; and (ii) a second Fc region comprising a second amino acid sequence set forth below, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at 20 least 97%, at least 98%, or at least 99% identical to a second amino acid sequence set forth below, respectively: SEQ ID NO: 119 and SEQ ID NO: 58; SEQ ID NO: 120 and SEQ ID NO: 58; SEQ ID NO: 121 and SEQ ID NO: 58; SEQ ID NO: 122 and SEQ ID NO: 58; SEQ ID NO: 123 and SEQ ID NO: 58; SEQ ID NO: 124 and SEQ ID NO: 58; SEQ ID NO: 125 and SEQ ID NO: 58; SEQ ID NO: 126 and SEQ ID NO: 58; SEQ ID NO: 127 and SEQ ID NO: 58; SEQ ID 25 NO: 128 and SEQ ID NO: 58; SEQ ID NO: 129 and SEQ ID NO: 58; SEQ ID NO: 130 and SEQ ID NO: 58; SEQ ID NO: 131 and SEQ ID NO: 58; SEQ ID NO: 132 and SEQ ID NO: 58; SEQ ID NO: 133 and SEQ ID NO: 58; SEQ ID NO: 134 and SEQ ID NO: 58; SEQ ID NO: 135 and SEQ ID NO: 58; SEQ ID NO: 136 and SEQ ID NO: 58; SEQ ID NO: 137 and SEQ ID NO: 58; SEQ ID NO: 138 and SEQ ID NO: 58; SEQ ID NO: 139 and SEQ ID NO: 58; SEQ ID NO: 30   140 and SEQ ID NO: 58; SEQ ID NO: 141 and SEQ ID NO: 58; SEQ ID NO: 142 and SEQ ID NO: 58; SEQ ID NO: 143 and SEQ ID NO: 58; SEQ ID NO: 144 and SEQ ID NO: 58; SEQ ID NO: 145 and SEQ ID NO: 58; SEQ ID NO: 146 and SEQ ID NO: 58; SEQ ID NO: 147 and SEQ ID NO: 58; SEQ ID NO: 148 and SEQ ID NO: 58; SEQ ID NO: 149 and SEQ ID NO: 58; SEQ ID NO: 150 and SEQ ID NO: 58; SEQ ID NO: 151 and SEQ ID NO: 58; SEQ ID NO: 152 35 and SEQ ID NO: 58; SEQ ID NO: 153 and SEQ ID NO: 58; SEQ ID NO: 154 and SEQ ID NO: 2024202988   06 May 2024 58; SEQ ID NO: 155 and SEQ ID NO: 58; SEQ ID NO: 156 and SEQ ID NO: 58; SEQ ID NO: 157 and SEQ ID NO: 58; SEQ ID NO: 158 and SEQ ID NO: 58; SEQ ID NO: 159 and SEQ ID NO: 58; or SEQ ID NO: 160 and SEQ ID NO: 58. In some embodiments, the heterodimer comprises a human IgGl Fc-IL-2v fusion protein comprising (i) a first amino acid sequence as 5 set forth below, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to a first amino acid sequence set forth below; and (ii) a second Fc region comprising a second amino acid sequence set forth below, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, 10 at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to a second amino acid sequence set forth below, respectively: SEQ ID NO: 124 and SEQ ID NO: 58; SEQ ID NO: 151 and SEQ ID NO: 58; or SEQ ID NO: 158 and SEQ ID NO: 58. In some embodiments of the heterodimer, the polypeptide comprising the first Fc domain comprises a first N terminal signal peptide or leader sequence and the polypeptide comprising the second Fc 15   domain comprises a second N terminal signal peptide or leader sequence. In some embodiments, the first N terminal signal peptide or leader sequence and the second first N terminal signal peptide or leader sequence are the same. In some embodiments, the first N terminal signal peptide or leader sequence and the second first N terminal signal peptide or leader sequence are different. In some embodiments, the heterodimer does not specifically bind 20 any antigen other than an Fc receptor or a complex of interleukin 2 receptor subunit beta (IL- 2RB; CD122) and interleukin 2 receptor subunit gamma (IL-2RG; CD132). In some embodiments, the second Fc domain is not fused to an antigen binding domain. In some embodiments, neither the first Fc domain nor the second Fc domain is fused to an antigen binding domain. In some embodiments, the heterodimer comprises a serum half-life in a human 25 of at least 6, 9, 12, 15, 18, 21, 24 hours, e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 days, or longer. In some embodiments, the second Fc domain is fused to an antigen binding domain. In some embodiments, the antigen binding domain binds to CD8. In some embodiments, the antigen binding domain binds to an immune checkpoint protein. In some embodiments, the immune checkpoint protein is selected from the group consisting of: CD27, 30   CD70; CD40, CD40LG; CD47, CD48 (SLAMF2), transmembrane and immunoglobulin domain containing 2 (TMIGD2, CD28H), CD84 (LY9B, SLAMF5), CD96, CD160 (NK1, NK28, BY55), MS4A1 (CD20), CD244 (SLAMF4); CD276 (B7H3); V-set domain containing T cell activation inhibitor 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); natural killer cell 35 cytotoxicity receptor 3 ligand 1 (NCR3LG1, B7H6); HERV-H LTR-associating 2 (HHLA2, 2024202988   06 May 2024 B7H7); inducible T cell co-stimulator (ICOS, CD278); inducible T cell costimulator ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF8 (CD30), TNFSF8 (CD30L); TNFRSF10A (CD261, DR4, TRAILRI), TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF10B (CD262, DR5, 5 TRAILR2), TNFRSF10 (TRAIL); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte associated (BTLA)); TNFRSF17 (BCMA, CD269), TNFSF13B (BAFF); TNFRSF18 (GITR), TNFSF18 (GITRL); MHC class I polypeptide-related sequence A (MICA); MHC class I polypeptide-related sequence B (MICB); CD274 (CD274, PDL1, PD-L1); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T-lymphocyte associated protein 4 10 (CTLA4, CD152); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); Poliovirus receptor (PVR) cell adhesion molecule (PVR, CD 155); PVR related immunoglobulin domain containing (PVRIG, CD112R); T cell immunoreceptor with Ig and ITIM domains (TIGIT); T cell immunoglobulin and mucin domain containing 4 (TIMD4; TIM4); hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3); galectin 9 (LGALS9); 15 lymphocyte activating 3 (LAG3, CD223); signaling lymphocytic activation molecule family member 1 (SLAMF1, SLAM, CD150); lymphocyte antigen 9 (LY9, CD229, SLAMF3); SLAM family member 6 (SLAMF6, CD352); SLAM family member 7 (SLAMF7, CD319); sialic acid binding Ig like lectin 7 (SIGLEC7); sialic acid binding Ig like lectin 9 (SIGLEC9); ULI6 binding protein 1 (ULBP1); UL16 binding protein 2 (ULBP2); UL16 binding protein 3 20 (ULBP3); retinoic acid early transcript IE (RAET1E; ULBP4); retinoic acid early transcript IG (RAET1G; ULBP5); retinoic acid early transcript IL (RAET1L; ULBP6); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); CD 160; killer cell lectin like receptor Bl (KLRB1, CD 161); killer cell lectin like receptor Cl (KLRC1, NKG2A, CD159A); killer cell lectin like receptor KI (KLRK1, NKG2D, CD314); 25 killer cell lectin like receptor C2 (KLRC2, CD159c, NKG2C); killer cell lectin like receptor C3 (KLRC3, NKG2E); killer cell lectin like receptor C4 (KLRC4, NKG2F); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3 30 (KIR2DL3); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin like receptor DI (KLRD1); killer cell lectin like receptor G1 (KLRG1; CLEC15A, MAFA, 2F1); sialic acid binding Ig like lectin 7 (SIGLEC7); and sialic acid binding Ig like lectin 9 (SIGLEC9). In some embodiments, the immune checkpoint protein is selected from the group consisting of: CD274 (CD274, PDL1, PD-L1) and programmed cell 35 death 1 (PDCD1, PD1, PD-1). In some embodiments, the antigen binding domain binds to a 2024202988   06 May 2024 target selected from the group consisting of: asialoglycoprotein receptor 1 (ASGR1), asialoglycoprotein receptor 2 (ASGR2), ATP binding cassette (ABC) family transporter (e.g., ATP binding cassette subfamily B member 1 (ABCB1; P-GP), ATP binding cassette subfamily B member 4 (ABCB4; MDR3), ATP binding cassette subfamily C member 1 (ABCC1; MRP1), 5 ATP binding cassette subfamily C member 2 (ABCC2; MRP2), ATP binding cassette subfamily C member 3 (ABCC3; MRP3), ATP binding cassette subfamily C member 4 (ABCC4; MRP4), ATP binding cassette subfamily G member 2 (Junior blood group; ABCG2; BCRP), and ATP binding cassette subfamily B member 11 (ABCB11; a.k.a., Bile Salt Export Pump (BSEP)); a solute carrier (SLC) family transporter (e.g., solute carrier family 10 member 1 (SLC10A1; 10   a.k.a., Sodium-taurocholate Co-transporting Polypeptide (NTCP)); solute carrier family 16 member 1 (SLC16A1; MCT1), solute carrier family 22 member 1 (SLC22A1; OCTI), solute carrier family 22 member 3 (SLC22A3; OCT3), solute carrier family 22 member 7 (SLC22A7; OAT2), solute carrier family 27 member 5 (SLC27A5; FATP5), solute carrier organic anion transporter family member 1B1 (SLCO1B1; OATP1B1), solute carrier organic anion transporter 15 family member 1B3 (SLCO1B3; OATP1B3), and solute carrier organic anion transporter family member 2B1 (SLCO2B1; OATP2B1)), transferrin receptor 2 (TFR2, TFRC2) and an HBV epitope (e.g., HBV core 18-27; envl81-193; env 335-343; pol 575-583) presented in major histocompatibility complex (MHC) molecule (pMHC). In some embodiments, the antigen binding domain binds to a target selected from the group consisting of human immunodeficiency 20 virus (HIV) gpl20, HIV gp41, human CD4, and human interleukin 7 receptor (IL7R; CD127). In some embodiments, the antigen binding domain binds to a target selected from the group consisting of herpes simple virus (HSV) glycoprotein B (gB), glycoprotein C (gC), glycoprotein D (gD) and glycoprotein E (gE). In some embodiments, the antigen binding domain binds to a target or tumor associated antigen (TAA) selected from the group consisting of: CD 19; 25 membrane spanning 4-domains Al (MS4A1; CD20); CD22 (SIGLEC2); CD27 (TNFRSF7); TNFRSF8 (CD30); CD33 (SIGLEC3); CD37; CD38; CD40 (TNFRSF5), CD44; CD47; CD48 (SLAMF2); CD52; CD70 (TNFSF7; CD27L); 5'-nucleotidase ecto (NT5E; CD73), ectonucleoside triphosphate diphosphohydrolase 1 (CD39), CD74; CD79B; CD80; CD86; interleukin 3 receptor subunit alpha (IL3RA), prominin 1 (PROM1; CD133); TNFRSF9 30   (CD137); syndecan 1 (SDC1; CD138); CD200 molecule (CD200); alpha fetoprotein (AFP), BAG cochaperone 6 (BAG6); MET proto-oncogene, receptor tyrosine kinase (MET); KIT proto-oncogene, receptor tyrosine kinase (KIT); C-type lectin domain family 12 member A (CLEC12A; CD371); C-type lectin domain containing 9A (CLEC9A; CD370); cadherin 3 (CDH3); carbonic anhydrase 6 (CA6); carbonic anhydrase 9 (CA9); carcinoembryonic antigen 35 related cell adhesion molecule 3 (CEACAM3); carcinoembryonic antigen related cell adhesion 2024202988   06 May 2024 molecule 5 (CEACAM5); carcinoembryonic antigen related cell adhesion molecule 6 (CEACAM6); chorionic somatomammotropin hormone 1 (CSH1); coagulation factor III, tissue factor (F3); collectin subfamily member 10 (COLEC10; CLL1); delta like canonical Notch ligand 3 (DLL3); ectonucleotide pyrophosphatase / phosphodiesterase 3 (ENPP3); ephrin Al 5 (EFNA1); epidermal growth factor receptor (EGFR; ERBB; HER1); EGFR variant III (EGFRvIII); EPH receptor A2 (EPHA2); epithelial cell adhesion molecule (EPCAM); erb-b2 receptor tyrosine kinase 2 (ERBB2; HER-2 / neu); fibroblast activation protein alpha (FAP); fibroblast growth factor receptor 2 (FGFR2); fibroblast growth factor receptor 3 (FGFR3); folate hydrolase 1 (FOLH1); folate receptor 1 (FOLRI); GD2 ganglioside; glycoprotein NMB 10 (GPNMB; osteoactivin); guanylate cyclase 2C (GUCY2C); human papillomavirus (HPV) E6; HPV E7; major histocompatibility complex (MHC) class I-presented neoantigens, major histocompatibility complex (MHC) class Il-presented neoantigens, major histocompatibility complex, class I, E (HLA-E); major histocompatibility complex, class I, F (HLA-F); major histocompatibility complex, class I, G (HLA-G); MHC class I polypeptide-related sequence A 15 (MICA); MHC class I polypeptide-related sequence B (MICB); integrin subunit beta 7 (ITGB7); leukocyte immunoglobulin like receptor B1 (LILRB1; ILT2); leukocyte immunoglobulin like receptor B2 (LILRB2; ILT4); LY6 / PLAUR domain containing 3 (LYPD3); glypican 3 (GPC3); KRAS proto-oncogene, GTPase (KRAS); MAGE family member Al (MAGEA1); MAGE family member A3 (MAGEA3); MAGE family member A4 (MAGEA4); MAGE family 20 member Al 1 (MAGEA11); MAGE family member Cl (MAGECI); MAGE family member C2 (MAGEC2); MAGE family member C3 (MAGEC3); MAGE family member DI (MAGED1); MAGE family member D2 (MAGED2); mesothelin (MSLN); mucin 1 (MUC1) and splice variants thereof (e.g., including MUC1 / A, C, D, X, Y, Z and REP); mucin 16 (MUC16; CAI25); natural killer cell cytotoxicity receptor 3 ligand 1 (NCR3LG1; B7-H6); necdin, MAGE family 25 member (NDN); nectin cell adhesion molecule 2 (NECTIN2); nectin cell adhesion molecule 4 (NECTIN4); SLIT and NTRK like family member 6 (SLITRK6); promyelocytic leukemia (PML); protein tyrosine kinase 7 (inactive) (PTK7); Poliovirus receptor (PVR) cell adhesion molecule (PVR); SLAM family member 6 (SLAMF6); SLAM family member 7 (SLAMF7); sialic acid binding Ig like lectin 7 (SIGLEC7); sialic acid binding Ig like lectin 9 (SIGLEC9); 30 sialic acid binding Ig like lectin 10 (SIGLEC10); signal regulatory protein alpha (SIRPA) solute carrier family 34 (sodium phosphate), member 2 (SLC34A2); solute carrier family 39 member 6 (SLC39A6); STEAP family member 1 (STEAP1); suppression of tumorigenicity 2 (ST2); TNF receptor superfamily member 4 (TNFRSF4; OX40); TNF superfamily member 9 (TNFSF9; 4-1BB-L, CD137L); TNFRSF10A (DR4, TRAILRI); TNFRSF10B (DR5, TRAILR2); 35 TNFRSF13B (BAFF); TNFRSF17 (BCMA); TNFRSF18 (GITR); transferrin (TF); transforming 2024202988   06 May 2024 growth factor beta 1 (TGFB1) and isoforms thereof; triggering receptor expressed on myeloid cells 1 (TREM1); triggering receptor expressed on myeloid cells 2 (TREM2); trophoblast glycoprotein (TPBG); trophinin (TRO); tumor associated calcium signal transducer 2 (TACSTD2); Fucosyl GM1; sialyl Lewis adhesion molecule (sLe); and Lewis Y antigen. In 5 some embodiments, the antigen binding domain binds to an epitope of a target or tumor associated antigen (TAA) presented in a major histocompatibility complex (MHC) molecule. In some embodiments, the TAA is a cancer testis antigen. In some embodiments, the cancer testis antigen is selected from the group consisting of acrosin binding protein (ACRBP), alpha fetoprotein (AFP), A-kinase anchoring protein 4 (AKAP4), ATPase family AAA domain 10 containing 2 (ATAD2), kinetochore scaffold 1 (KNL1; a.ka., CASC5), centrosomal protein 55 (CEP55), cancer / testis antigen 1A (CTAG1A; a.k.a., ESO1; CT6.1; LAGE-2; LAGE2A; NY-ESO-1), cancer / testis antigen IB (CTAG1B; a.k.a., CT6.1, CTAG, CTAG1, ESO1, LAGE-2, LAGE2B, NY-ESO-1), cancer / testis antigen 2 (CTAG2; a.k.a., CAMEL, CT2, CT6.2, CT6.2a, CT6.2b, ESO2, LAGE-1, LAGE2B), CCCTC-binding factor like (CTCFL), catenin alpha 2 15 (CTNNA2), cancer / testis antigen 83 (CT83), cyclin Al (CCNA1), DEAD-box helicase 43 (DDX43), developmental pluripotency associated 2 (DPPA2), fetal and adult testis expressed 1 (FATE1), FMRI neighbor (FMR1NB), HORMA domain containing 1 (HORMAD1), insulin like growth factor 2 mRNA binding protein 3 (IGF2BP3), leucine zipper protein 4 (LUZP4), lymphocyte antigen 6 family member K (LY6K), maelstrom spermatogenic transposon silencer 20 (MAEL), MAGE family member Al (MAGEA1); MAGE family member A3 (MAGEA3); MAGE family member A4 (MAGEA4); MAGE family member Al 1 (MAGEA11); MAGE family member Cl (MAGECI); MAGE family member C2 (MAGEC2); MAGE family member DI (MAGED1); MAGE family member D2 (MAGED2), kinesin family member 20B (KIF20B; a.k.a., MPHOSPH1), NUF2 component of NDC80 kinetochore complex (NUF2), nuclear RNA 25 export factor 2 (NXF2), PAS domain containing repressor 1 (PASD1), PDZ binding kinase (PBK), piwi like RNA-mediated gene silencing 2 (PIWIL-2), preferentially expressed antigen in melanoma (PRAME), sperm associated antigen 9 (SPAG9), sperm protein associated with the nucleus, X-linked, family member Al (SPANXA1), SPANX family member A2 (SPANXA2), SPANX family member C (SPANXC), SPANX family member D (SPANXD), SSX family 30 member 1 (SSX1), SSX family member 2 (SSX2), synaptonemal complex protein 3 (SYCP3), testis expressed 14, intercellular bridge forming factor (TEX14), transcription factor Dp family member 3 (TFDP3), serine protease 50 (PRSS50, a.k.a., TSP50), TTK protein kinase (TTK) and zinc finger protein 165 (ZNF165). 2024202988   06 May 2024

[0008] In a further aspect, provided is a conjugate comprising: an IL-2v described above and herein, an Fc-IL-2v fusion protein as described above and herein, a homodimer as described above and herein, or a heterodimer as described above and herein; attached to a therapeutic agent. In some embodiments, the therapeutic agent is covalently linked, e.g., to the IL-2v, the 5 Fc-IL-2v fusion protein, the homodimer or the heterodimer. In some embodiments, the therapeutic agent is a small organic compound. In some embodiments, the therapeutic agent is selected from GS-4224 and GS-4416. In some embodiments, the therapeutic agent is an agonist or activator of a pattern recognition receptor (PRR), e.g., a Toll-like receptor (TLR), a RIG-L like receptor (RLRs), a NOD-like receptors (NLR), an AIM2-like receptors (ALR), a C-type 10 lectin receptors (CLR), a DNA receptor or an RNA receptor. In some embodiments, the therapeutic agent is an agonist or activator of a toll-like receptor (TLR), DExD / H-box helicase 58 (DDX58; a.k.a., RIG-I) or a stimulator of interferon genes (STING) receptor. In some embodiments, the TLR agonist or activator is selected from the group consisting of a TLR2 agonist, a TLR3 agonist, a TLR4 agonist, a TLR5 agonist, a TLR7 agonist, a TLR8 agonist and 15 a TLR9 agonist. In some embodiments, the TLR7 agonist is selected from the group consisting of vesatolimod (GS-9620), DS-0509, LHC-165, TMX-101 (imiquimod), RO7020531 and JNJ-4964, and / or wherein the TLR8 agonist is selected from the group consisting of selgantolimod (GS-9688) and NKTR-262 (dual TLR7 / TLR8 agonist).

[0009] In a further aspect, provided is a polynucleotide encoding an IL-2v described 20 above and herein, an Fc-IL-2v fusion protein as described above and herein, or a homodimer as described above and herein. In some embodiments, the polynucleotide comprises a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 175-212, or a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to a 25 nucleic acid sequence selected from the group consisting of SEQ ID NOs: 175-212. Further provided is a polynucleotide or multiple polynucleotides encoding the Fc-IL-2v fusion protein and the second Fc region of a heterodimer described above and herein. In some embodiments, the polynucleotide or polynucleotides encoding the Fc-IL-2v fusion protein comprises a nucleic acid selected from the group consisting of SEQ ID NOs: 175-212, or a nucleic acid sequence 30 that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 175-212. In some embodiments, the polynucleotide or polynucleotides encoding the second Fc region comprises a nucleic acid selected from the group consisting of SEQ ID NOs: 214-215, or a nucleic acid 2024202988   06 May 2024 sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 214-215. In some embodiments, the polynucleotide or polynucleotides are selected from the group consisting of 5 DNA, cDNA, RNA or mRNA. Further provided is an expression cassette or multiple expression cassettes comprising one or more regulatory sequences operably linked to the polynucleotide or polynucleotides described above and herein.

[0010] In a further aspect, provided is a vector comprising the polynucleotide or polynucleotides, or an expression cassett, as described above and herein. In some embodiments, 10 the vector is a plasmid vector or a viral vector. In some embodiments, the viral vector comprises an oncolytic viral vector. In some embodiments, the viral vector comprises a DNA virus or an RNA virus. In some embodiments, the viral vector is from a viral family selected from the group consisting of: Adenoviridae (e.g., Adenovirus), Arenaviridae (e.g., lymphocytic choriomeningitis mammarenavirus, Cali mammarenavirus (a.k.a., Pichinde mammarenavirus), 15 Poxviridae (e.g., Vaccinia virus), Herpesviridae (e.g., Herpesvirus, e.g., HSV-1), Parvoviridae (e.g., Parvovirus Hl), Reoviridae (e.g., Reovirus), Retroviridae (e.g., Lentivirus), Picomaviridae (e.g., Coxsackievirus, Seneca Valley Virus, Poliovirus), Paramyxoviridae (e.g., Measles virus, Newcastle disease virus (NDV)), Rhabdoviridae (e.g., Vesicular stomatitis virus (VSV)), Togaviridae (e.g., Alphavirus, Sindbis virus) and Enteroviridae (e.g., Echovirus). Further 20 provided is a lipoplex, e.g., lipid nanoparticle (LNP), comprising the polynucleotide or polynucleotides, an expression cassette, or a vector, described above and herein.

[0011] In a further aspect, provided is a cell or population of cells comprising the polynucleotide or polynucleotides, an expression cassette or a vector, as described above and herein, wherein the cell or population of cells expresses an IL-2v, an Fc-IL-2v fusion protein, a 25 homodimer, or a heterodimer, as described above and herein. In some embodiments, the cell or population of cells is a eukaryotic cell. In some embodiments, the cell or population of cells comprises a mammalian cell, an insect cell, a plant cell or a yeast cell. In some embodiments, the mammalian cell is a Chinese Hamster Ovary (CHO) cell. In some embodiments, the mammalian cell is a human cell. In some embodiments, the cell is a human embryonic kidney 30 cell.

[0012] In a further aspect, provided are methods of producing an Fc-IL-2 fusion protein heterodimer. In some embodiments, the methods comprise: (a) culturing a cell or population of cells, as described above and herein, transformed with at least a polynucleotide or polynucleotides encoding an Fc-IL-2v fusion protein, as described herein, or the expression 2024202988   06 May 2024 cassette or multiple expression cassette, as described herein, in a cell culture under conditions sufficient to express the Fc-IL-2 fusion protein heterodimer molecules; and (b) isolating or purifying the Fc-IL-2 fusion protein heterodimer molecules from the cell culture. In some embodiments, the Fc-IL-2 fusion polypeptide and the Fc polypeptide are expressed and 5 assembled in the same cell. In some embodiments, the isolating or purifying step comprises Protein A chromatography. In some embodiments, the isolating or purifying step further comprises in-stream pH neutralization or immediate pH neutralization of Protein A chromatography eluate. In some embodiments, the isolating or purifying step further comprises anion exchange chromatography. In some embodiments, at least 90%, 91%, 92%, 93%, 94%, 10   95%, 96%, 97%, 98%, 99%, or more, of the Fc-IL-2 fusion protein heterodimer molecules are isolated or purified (e.g., in monodispersed form). In some embodiments, at least 95%, 96%, 97%, 98%, 99%, or more, of the Fc-IL-2 fusion protein heterodimer molecules are isolated or purified (e.g., in monodispersed form). In some embodiments, at least 98%, 99%, or more, of the Fc-IL-2 fusion protein heterodimer molecules are isolated or purified (e.g., in monodispersed 15 form). In some embodiments, the cell or population of cells are cultured in a culture volume of at least 2L, e.g., at least 5L, 10L, 50L, 100L, 150L, 200L, 250L, or more. In some embodiments, the methods further comprise formulating the Fc-IL-2 fusion protein heterodimer molecules into a sterile pharmaceutical composition suitable for administration to a human subject. 20

[0013] In a further aspect, provided is a pharmaceutical composition comprising an IL- 2v, an Fc-IL-2v fusion protein, a homodimer, a heterodimer, a conjugate, the polynucleotide or polynucleotides, an expression cassette, a vector, or the lipoplex (e.g., LNP), as described herein, and a pharmaceutically acceptable carrier. In some embodiments, the composition comprises an aqueous formulation. In some embodiments, the pharmaceutical composition 25 comprises the IL-2v, the Fc-IL-2v fusion protein, the homodimer, the heterodimer and / or the conjugate at a concentration in the range of 0.05 mg / ml to 50 mg / ml, e.g., from 0.05 mg / ml to 20 mg / ml, e.g., from 0.1 mg / ml to 40 mg / ml, e.g., from 1.0 mg / ml to 30 mg / ml, e.g., from 0.05 mg / ml to 0.06 mg / ml, 0.07 mg / ml, 0.08 mg / ml, 0.09 mg / ml, 0.1 mg / ml, 0.2 mg / ml, 0.3 mg / ml, 0.4 mg / ml, 0.5 mg / ml, 0.6 mg / ml, 0.7 mg / ml, 0.8 mg / ml, 0.9 mg / ml, 1.0 mg / ml, 1.5 mg / ml, 2.0 30 mg / ml, 2.5 mg / ml, 3.0 mg / ml, 3.5 mg / ml, 4.0 mg / ml, 4.5 mg / ml, 5.0 mg / ml, 6 mg / ml, 7 mg / ml, 8 mg / ml, 9 mg / ml, lOmg / ml, 11 mg / ml, 12 mg / ml, 13 mg / ml, 14 mg / ml, 15 mg / ml, 16 mg / ml, 17 mg / ml, 18 mg / ml, 19 mg / ml, 20 mg / ml, 25 mg / ml, 30 mg / ml, 35 mg / ml, 40 mg / ml, 45 mg / ml or 50 mg / ml. In some embodiments, the composition is lyophilized. In some embodiments, the pharmaceutical composition further comprises one or more additional therapeutic agents. In 2024202988   06 May 2024 some embodiments, the composition is lyophilized. In some embodiments, the pharmaceutical composition further comprises a second therapeutic agent. In some embodiments, the composition is lyophilized. In some embodiments, the pharmaceutical composition further comprises second and third therapeutic agents. 5

[0014] In a further aspect, provided are methods for eliciting an immune response to human hepatitis B virus (HBV) in a subject in need thereof. Further provided are methods of treating or preventing human hepatitis B virus (HBV) in a subject in need thereof. In some embodiments, the anti-HBV methods comprise administering to the subject a therapeutically effective amount of an IL-2v, an Fc-IL-2v fusion protein, a homodimer, a heterodimer, a 10 conjugate, the polynucleotide or polynucleotides, an expression cassette, a vector, the lipoplex (e.g., LNP), or a pharmaceutical composition, as described herein. In some embodiments, the subject is infected with HBV, is suspected of being infected with HBV, or is at risk of being infected with HBV. In some embodiments, the subject is asymptomatic. In some embodiments, the subject is chronically infected with HBV. In some embodiments, the subject is exhibiting or 15   experiencing one or more symptoms selected from hepatic failure, hepatic cancer, hepatic fibrosis and hepatic cirrhosis. In some embodiments, the subject is acutely infected with HBV. In some embodiments, the subject is exhibiting or experiencing one or more symptoms selected from jaundice, visible webs of swollen blood vessels in the skin, dark-colored (e.g., orange or brown) urine, light-colored feces, fever, persistent fatigue, malaise, abdominal pain, abdominal 20 fluid, loss of appetite, nausea, and vomiting. In some embodiments, the subject is co-infected with hepatitis D virus (HDV). In some embodiments, the subject is not receiving antiviral therapy or antiviral therapy is discontinued prior to administration of the IL-2v, the Fc-IL-2v fusion protein, the homodimer, the heterodimer, the conjugate, the polynucleotide or polynucleotides, the expression cassette, the vector, or the lipoplex (e.g., LNP) or the 25 pharmaceutical composition. In some embodiments, antiviral therapy is discontinued after one or more administrations of the IL-2v, the Fc-IL-2v fusion protein, the homodimer, the heterodimer, the conjugate, the polynucleotide, the vector, the lipoplex (e.g., LNP) and / or the pharmaceutical composition. In some embodiments, the methods further comprise coadministering to the subject one or more antiviral agents. In some embodiments, the one or 30 more antiviral agents are selected from the group consisting of lamivudine (LAM), adefovir dipivoxil (ADV), entecavir (ETV), telbivudine (LdT), tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF or VEMLIDY®), ledipasvir + sofosbuvir (HARVONI®) and a PEGylated interferon (e.g., PEG-IFN-a2a and / or PEG-IFN-a2b). In some embodiments, the methods further comprise co-administering to the subject one or more therapeutic agents 2024202988   06 May 2024 selected from the group consisting of HBV antigen inhibitors (e.g., HBV core antigen (HBcAg) inhibitors, HBV surface antigen (HBsAg) inhibitors, HBx inhibitors, HBV E antigen inhibitors), anti-HBV antigen antibodies, inhibitory nucleic acids targeting HBV (e.g., antisense oligonucleotide, short interfering RNA (siRNA), DNA-directed RNA interference (ddRNAi)), 5 gene editors targeting HBV (e.g., CRISPR-Cas (e.g., Cas9, Cas 12, Cascade, Cas 13), zinc finger nucleases, homing endonucleases, homing meganucleases (e.g., ARCUS), synthetic nucleases, TALENs), covalently closed circular DNA (cccDNA) inhibitors, HBsAg secretion or assembly inhibitors, HBV viral entry inhibitors, and CAR-T and T cell bispecific (redirected T cells) for specific killing of HBV-infected cells. 10

[0015] In a further aspect, provided are methods of activating a latent viral reservoir in a subject infected with human immunodeficiency virus (HIV). Further provided are methods of treating or preventing human immunodeficiency virus (HIV) in a subject in need thereof. In some embodiments, the anti-HIV methods comprise administering to the subject a therapeutically effective amount of an IL-2v, an Fc-IL-2v fusion protein, a homodimer, a 15 heterodimer, a conjugate, the polynucleotide or polynucleotides, an expression cassette, a vector, the lipoplex (e.g., LNP), or a pharmaceutical composition, as described herein. In some embodiments, the methods further comprise administering to the subject an additional therapeutic agent. In some embodiments, the methods further comprise administering to the subject one or more anti-HIV broadly neutralizing antibodies. In some embodiments, the one or 20 more anti-HIV broadly neutralizing antibodies bind to an epitope or region of gpl20 selected from the group consisting of: (i) third variable loop (V3) and / or high mannose patch comprising a N332 oligomannose glycan; (ii) second variable loop (V2) and / or Env trimer apex; (iii) CD4 binding site (CD4bs); (iv) gpl20 / gp41 interface; or (v) silent face of gpl20. In some embodiments, the one or more anti-HIV broadly neutralizing antibodies bind to an epitope or 25   region of gpl20 in the third variable loop (V3) and / or high mannose patch comprising a N332 oligomannose glycan and competes with or comprises VH and VL regions from an antibody selected from the group consisting of GS-9722, PGT-121, PGT-121.414, PGT-122, PGT-123, PGT-124, PGT-125, PGT-126, PGT-128, PGT-130, PGT-133, PGT-134, PGT-135, PGT-136, PGT-137, PGT-138, PGT-139, 10-1074, 10-1074-J, VRC24, 2G12, BG18, 354BG8, 354BG18, 30   354BG42, 354BG33, 354BG129, 354BG188, 354BG411, 354BG426, DH270.1, DH270.6, PGDM12, VRC41.01, PGDM21, PCDN-33A, BF520.1 and VRC29.03. In some embodiments, the one or more anti-HIV broadly neutralizing antibodies bind to an epitope or region of gpl20 in the second variable loop (V2) and / or Env trimer apex and competes with or comprises VH and VL regions from an antibody selected from the group consisting of PG9, PG16, PGC14, 2024202988   06 May 2024 PGG14, PGT-142, PGT-143, PGT-144, PGT-145, CHOI, CH59, PGDM1400, CAP256, CAP256-VRC26.08, CAP256-VRC26.09, CAP256-VRC26.25, PCT64-24E and VRC38.01. In some embodiments, the one or more anti-HIV broadly neutralizing antibodies bind to an epitope or region of gpl20 in the CD4 binding site (CD4bs) and competes with or comprises VH and 5 VL regions from an antibody selected from the group consisting of 3BNC117, GS-9723, 3BNC60, bl2, F105, VRC01, VRC07, VRC07-523, VRC03, VRC06, VRC06b01 VRC08, VRC0801, NIH45-46, VRC-PG04, PGV04; CH103, 44-VRC13.01, 1NC9, 12A12, N6, N49-P7, NC-Cowl, I0MA, CH235 and CH235.12, N49P6, N49P7, N49P11, N49P9 andN60P25. In some embodiments, the one or more anti-HIV broadly neutralizing antibodies bind to an epitope 10   or region of gpl20 in the gpl20 / gp41 interface and competes with or comprises VH and VL regions from an antibody selected from the group consisting of PGT-151, CAP248-2B, 35022, 8ANC195, ACS202, VRC34 and VRC34.01. In some embodiments, the one or more anti-HIV broadly neutralizing antibodies bind to an epitope or region of the gpl20 silent face and competes with or comprises VH and VL regions from an antibody selected from VRC-PG05 and 15   SF12. In some embodiments, the one or more anti-HIV broadly neutralizing antibodies bind to an epitope or region of gp41 in the membrane proximal region (MPER). In some embodiments, the one or more anti-HIV broadly neutralizing antibodies bind to an epitope or region of gp41 in the membrane proximal region (MPER) and competes with or comprises VH and VL regions from an antibody selected from the group consisting of 10E8, 10E8v4, 10E8-5R-100cF, 4E10, 20 DH511.11P, 2F5, 7b2, and LNOL In some embodiments, the one or more anti-HIV broadly neutralizing antibodies bind to an epitope or region of the gp41 fusion peptide and competes with or comprises VH and VL regions from an antibody selected from the group consisting of VRC34 and ACS202. In some embodiments, the subject is not receiving antiretroviral therapy (ART) or ART is discontinued prior to administration of the IL-2v, the Fc-IL-2v fusion protein, 25 the homodimer, the heterodimer, the conjugate, the polynucleotide or polynucleotides, the expression cassette, the vector, the lipoplex (e.g., LNP) or the pharmaceutical composition. In some embodiments, ART is discontinued after one or more administrations of the IL-2v, the Fc-IL-2v fusion protein, the homodimer, the heterodimer, the conjugate, the polynucleotide or polynucleotides, the expression cassette, the vector, the lipoplex (e.g., LNP) or the 30 pharmaceutical composition. In some embodiments, the methods further comprise administering one or more antiretroviral therapy (ART) agents to the subject. In some embodiments, the subject is chronically infected with HIV.

[0016] In a further aspect, provided are methods of enhancing, improving, and / or increasing the response to a vaccine therapy in a subject in need thereof. In some embodiments, 2024202988   06 May 2024 the vaccine enhancing methods comprise co-administering to the subject (1) an effective amount of an IL-2v, an Fc-IL-2v fusion protein, a homodimer, a heterodimer, a conjugate, the polynucleotide or polynucleotides, an expression cassette, a vector, the lipoplex (e.g., LNP), or a pharmaceutical composition, as described herein; and (2) an effective amount of a vaccine. In 5 some embodiments, the vaccine is selected from the group consisting of an antiviral vaccine, an antibacterial vaccine and an anticancer vaccine. In some embodiments, the vaccine comprises an antiviral vaccine against a virus selected from the group consisting of hepatitis A virus (HAV), hepatitis B virus (HBV), human immunodeficiency virus (HIV), cytomegalovirus (CMV), a herpes simplex virus (HSV), Epstein-Barr virus (EBV), human orthopneumovirus or 10 human respiratory syncytial virus (RSV), human papillomavirus (HPV), varicella-zoster virus, measles virus, mumps virus, poliovirus vaccine, influenza virus, paramyxovirus, rotavirus, Zika virus, Dengue virus, Ebola virus and coronavirus (e.g., betacoronavirus, e.g., severe acute respiratory syndrome-related coronavirus, e.g., SARS-CoV2). In some embodiments, the vaccine comprises an antibacterial vaccine against a bacterium selected from the group 15 consisting of mycobacterium tuberculosis, pertussis, tetanus, diphtheria, meningococcus, pneumococcus, Haemophilus influenza, cholera, typhoid, and anthrax. In some embodiments, the methods comprise a prime-boost regimen comprising administering a priming composition at a first time point and administering one or more boosting compositions at one or more subsequent time points. In some embodiments, the priming composition comprises an IL-2v, an 20 Fc-IL-2v fusion protein, a homodimer, a heterodimer, a conjugate, the polynucleotide or polynucleotides, an expression cassette, a vector, the lipoplex (e.g., LNP), or a pharmaceutical composition, as described herein. In some embodiments, the one or more boosting compositions comprise an IL-2v, an Fc-IL-2v fusion protein, a homodimer, a heterodimer, a conjugate, the polynucleotide or polynucleotides, an expression cassette, a vector, the lipoplex (e.g., LNP), or a 25 pharmaceutical composition, as described herein. In some embodiments, the priming composition and the boosting composition are the same. In some embodiments, the priming composition and the boosting composition are different.

[0017] In a further aspect, provided are methods of preventing, reducing and / or inhibiting the recurrence, growth, proliferation, migration and / or metastasis of a cancer cell or 30 population of cancer cells in a subject in need thereof. In some embodiments, the anti-cancer methods comprise administering to the subject a therapeutically effective amount of an IL-2v, an Fc-IL-2v fusion protein, a homodimer, a heterodimer, a conjugate, the polynucleotide or polynucleotides, an expression cassette, a vector, the lipoplex (e.g., LNP), or a pharmaceutical composition, as described herein. In some embodiments, the IL-2v, the Fc-IL-2v fusion protein, 2024202988   06 May 2024 the homodimer, the heterodimer, the conjugate, the polynucleotide, the vector, the lipoplex (e.g., LNP) and / or the pharmaceutical composition is co-administered with one or more antineoplastic or chemotherapeutic agents. In some embodiments, the one or more anti-neoplastic or chemotherapeutic agents are selected from the group consisting of a nucleoside analog (e.g., 5    5-fluorouracil, gemcitabine, cytarabine, cladribine, pentostatin, fludarabine), a taxane (e.g., paclitaxel, nab-paclitaxel, docetaxel, cabazitaxel), a platinum coordination complex (cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, satraplatin, dicycloplatin, eptaplatin, lobaplatin, miriplatin), a dihydrofolate reductase (DHFR) inhibitor (e.g., methotrexate, trimetrexate, pemetrexed), a topoisomerase inhibitor (e.g., doxorubicin, 10 daunorubicin, dactinomycin, eniposide, epirubicin, etoposide, idarubicin, irinotecan, mitoxantrone, pixantrone, sobuzoxane, topotecan, irinotecan, MM-398 (liposomal irinotecan), vosaroxin and GPX-150, aldoxorubicin, AR-67, mavelertinib, AST-2818, avitinib (ACEA-0010), irofulven (MGI-114)), an alkylating agent (e.g., a nitrogen mustard (e.g., cyclophosphamide, chlormethine, uramustine or uracil mustard, melphalan, chlorambucil, 15 ifosfamide, bendamustine, temozolomide, carmustine), a nitrosourea (e.g., carmustine, lomustine, streptozocin), an alkyl sulfonate (e.g., busulfan)), and mixtures thereof. In some embodiments, the IL-2v, the Fc-IL-2v fusion protein, the homodimer, the heterodimer, the conjugate, the polynucleotide, the vector, the lipoplex (e.g., LNP) and / or the pharmaceutical composition is co-administered with a FOLFOX regimen, a FOLFIRI regimen, a FOLFOXIRI 20 regimen or a FOLFIRINOX regimen. In some embodiments, the IL-2v, the Fc-IL-2v fusion protein, the homodimer, the heterodimer, the conjugate, the polynucleotide, the vector, the lipoplex (e.g., LNP) and / or the pharmaceutical composition is co-administered with an immunotherapy comprising one or more antibodies or antigen-binding antibody fragments thereof, or antibody-drug conjugates thereof, CD3-targeting multi-specific molecules, NK cell-25 activating receptor-targeting multi-specific molecules, or non-immunoglobulin antigen-binding domains or antibody mimetic proteins directed against one or more targets or tumor associated antigens (TAAs) selected from the group consisting of: CD 19; membrane spanning 4-domains Al (MS4A1; CD20); CD22 (SIGLEC2); CD27 (TNFRSF7); TNFRSF8 (CD30); CD33 (SIGLEC3); CD37; CD38; CD40 (TNFRSF5), CD44; CD47; CD48 (SLAMF2); CD52; CD70 30 (TNFSF7; CD27L); 5'-nucleotidase ecto (NT5E; CD73), ectonucleoside triphosphate diphosphohydrolase 1 (CD39), CD74; CD79B; CD80; CD86; interleukin 3 receptor subunit alpha (IL3RA), prominin 1 (PROM1; CD133); TNFRSF9 (CD137); syndecan 1 (SDC1; CD 138); CD200 molecule (CD200); alpha fetoprotein (AFP), BAG cochaperone 6 (BAG6); MET proto-oncogene, receptor tyrosine kinase (MET); KIT proto-oncogene, receptor tyrosine 35 kinase (KIT); C-type lectin domain family 12 member A (CLEC12A; CD371); C-type lectin 2024202988   06 May 2024 domain containing 9A (CLEC9A; CD370); cadherin 3 (CDH3); carbonic anhydrase 6 (CA6); carbonic anhydrase 9 (CA9); carcinoembryonic antigen related cell adhesion molecule 3 (CEACAM3); carcinoembryonic antigen related cell adhesion molecule 5 (CEACAM5); carcinoembryonic antigen related cell adhesion molecule 6 (CEACAM6); chorionic 5 somatomammotropin hormone 1 (CSH1); coagulation factor III, tissue factor (F3); collectin subfamily member 10 (COLEC10; CLL1); delta like canonical Notch ligand 3 (DLL3); ectonucleotide pyrophosphatase / phosphodiesterase 3 (ENPP3); ephrin Al (EFNA1); epidermal growth factor receptor (EGFR; ERBB; HER1); EGFR variant III (EGFRvIII); EPH receptor A2 (EPHA2); epithelial cell adhesion molecule (EPCAM); erb-b2 receptor tyrosine kinase 2 10 (ERBB2; HER-2 / neu); fibroblast activation protein alpha (FAP); fibroblast growth factor receptor 2 (FGFR2); fibroblast growth factor receptor 3 (FGFR3); folate hydrolase 1 (FOLH1); folate receptor 1 (FOLRI); GD2 ganglioside; glycoprotein NMB (GPNMB; osteoactivin); guanylate cyclase 2C (GUCY2C); human papillomavirus (HPV) E6; HPV E7; major histocompatibility complex (MHC) class I-presented neoantigens, major histocompatibility 15 complex (MHC) class Il-presented neoantigens, major histocompatibility complex, class I, E (HLA-E); major histocompatibility complex, class I, F (HLA-F); major histocompatibility complex, class I, G (HLA-G); MHC class I polypeptide-related sequence A (MICA); MHC class I polypeptide-related sequence B (MICB); integrin subunit beta 7 (ITGB7); leukocyte immunoglobulin like receptor Bl (LILRB1; ILT2); leukocyte immunoglobulin like receptor B2 20 (LILRB2; ILT4); LY6 / PLAUR domain containing 3 (LYPD3); glypican 3 (GPC3); KRAS proto-oncogene, GTPase (KRAS); MAGE family member Al (MAGEA1); MAGE family member A3 (MAGEA3); MAGE family member A4 (MAGEA4); MAGE family member All (MAGEA11); MAGE family member Cl (MAGECI); MAGE family member C2 (MAGEC2); MAGE family member C3 (MAGEC3); MAGE family member DI (MAGED1); MAGE family 25 member D2 (MAGED2); mesothelin (MSLN); mucin 1 (MUC1) and splice variants thereof (e.g., including MUC1 / A, C, D, X, Y, Z and REP); mucin 16 (MUC16; CA125); natural killer cell cytotoxicity receptor 3 ligand 1 (NCR3LG1; B7-H6); necdin, MAGE family member (NDN); nectin cell adhesion molecule 2 (NECTIN2); nectin cell adhesion molecule 4 (NECTIN4); SLIT and NTRK like family member 6 (SLITRK6); promyelocytic leukemia 30 (PML); protein tyrosine kinase 7 (inactive) (PTK7); Poliovirus receptor (PVR) cell adhesion molecule (PVR); SLAM family member 6 (SLAMF6); SLAM family member 7 (SLAMF7); sialic acid binding Ig like lectin 7 (SIGLEC7); sialic acid binding Ig like lectin 9 (SIGLEC9); sialic acid binding Ig like lectin 10 (SIGLEC10); signal regulatory protein alpha (SIRPA) solute carrier family 34 (sodium phosphate), member 2 (SLC34A2); solute carrier family 39 member 6 35   (SLC39A6); STEAP family member 1 (STEAP1); suppression of tumorigenicity 2 (ST2); TNF 2024202988   06 May 2024 receptor superfamily member 4 (TNFRSF4; 0X40); TNF superfamily member 9 (TNFSF9; 4-1BB-L, CD137L); TNFRSF10A (DR4, TRAILRI); TNFRSF10B (DR5, TRAILR2); TNFRSF13B (BAFF); TNFRSF17 (BCMA); TNFRSF18 (GITR); transferrin (TF); transforming growth factor beta 1 (TGFB1) and isoforms thereof; triggering receptor expressed on myeloid 5 cells 1 (TREM1); triggering receptor expressed on myeloid cells 2 (TREM2); trophoblast glycoprotein (TPBG); trophinin (TRO); tumor associated calcium signal transducer 2 (TACSTD2); Fucosyl GM1; sialyl Lewis adhesion molecule (sLe); and Lewis Y antigen. In some embodiments, the one or more antibodies or antigen-binding antibody fragments thereof, or antibody-drug conjugates thereof, CD3-targeting multi-specific molecules, NK cell-activating 10 receptor-targeting multi-specific molecules, or non-immunoglobulin antigen-binding domains or antibody mimetic proteins binds to an epitope of a target or tumor associated antigen (TAA) presented in a major histocompatibility complex (MHC) molecule. In some embodiments, the NK cell-activating receptor is selected from the group consisting of CD 16, NKp30, NKp44, NKp46, NKp80 and NKG2D. In some embodiments, the IL-2v, the Fc-IL-2v fusion protein, the 15 homodimer, the heterodimer, the conjugate, the polynucleotide, the vector, the lipoplex (e.g., LNP) and / or the pharmaceutical composition is co-administered with one or more cellular therapies selected from the group consisting of: natural killer (NK) cells, NK-T cells, T cells, cytokine-induced killer (CIK) cells, macrophage (MAC) cells, tumor infdtrating lymphocytes (TILs) and dendritic cells (DCs). In some embodiments, the one or more cellular therapies 20 comprise a T cell therapy selected from the group consisting of: alpha / beta TCR T cells, gamma / delta TCR T cells, regulatory T (Treg) cells and TRuC™ T cells. In some embodiments, the one or more cellular therapies comprise a NK cell therapy, e.g., comprising NK-92 cells. In some embodiments, the one or more cellular therapies comprise cells that are autologous, syngeneic or allogeneic to the subject. In some embodiments, the one or more cellular therapies 25 comprise cells comprising chimeric antigen receptors (CARs). In some embodiments, the cells in the cellular therapy bind to a target or tumor associated antigen (TAA) selected from the group consisting of selected from the group consisting of: CD 19; membrane spanning 4-domains Al (MS4A1; CD20); CD22 (SIGLEC2); CD27 (TNFRSF7); TNFRSF8 (CD30); CD33 (SIGLEC3); CD37; CD38; CD40 (TNFRSF5), CD44; CD47; CD48 (SLAMF2); CD52; CD70 30   (TNFSF7; CD27L); 5'-nucleotidase ecto (NT5E; CD73), ectonucleoside triphosphate diphosphohydrolase 1 (CD39), CD74; CD79B; CD80; CD86; interleukin 3 receptor subunit alpha (IL3RA), prominin 1 (PROM1; CD 133); TNFRSF9 (CD 137); syndecan 1 (SDC1; CD 138); CD200 molecule (CD200); alpha fetoprotein (AFP), BAG cochaperone 6 (BAG6); MET proto-oncogene, receptor tyrosine kinase (MET); KIT proto-oncogene, receptor tyrosine 35 kinase (KIT); C-type lectin domain family 12 member A (CLEC12A; CD371); C-type lectin 2024202988   06 May 2024 domain containing 9A (CLEC9A; CD370); cadherin 3 (CDH3); carbonic anhydrase 6 (CA6); carbonic anhydrase 9 (CA9); carcinoembryonic antigen related cell adhesion molecule 3 (CEACAM3); carcinoembryonic antigen related cell adhesion molecule 5 (CEACAM5); carcinoembryonic antigen related cell adhesion molecule 6 (CEACAM6); chorionic 5 somatomammotropin hormone 1 (CSH1); coagulation factor III, tissue factor (F3); collectin subfamily member 10 (COLEC10; CLL1); delta like canonical Notch ligand 3 (DLL3); ectonucleotide pyrophosphatase / phosphodiesterase 3 (ENPP3); ephrin Al (EFNA1); epidermal growth factor receptor (EGFR; ERBB; HER1); EGFR variant III (EGFRvIII); EPH receptor A2 (EPHA2); epithelial cell adhesion molecule (EPCAM); erb-b2 receptor tyrosine kinase 2 10 (ERBB2; HER-2 / neu); fibroblast activation protein alpha (FAP); fibroblast growth factor receptor 2 (FGFR2); fibroblast growth factor receptor 3 (FGFR3); folate hydrolase 1 (FOLH1); folate receptor 1 (FOLRI); GD2 ganglioside; glycoprotein NMB (GPNMB; osteoactivin); guanylate cyclase 2C (GUCY2C); human papillomavirus (HPV) E6; HPV E7; major histocompatibility complex (MHC) class I-presented neoantigens, major histocompatibility 15 complex (MHC) class Il-presented neoantigens, major histocompatibility complex, class I, E (HLA-E); major histocompatibility complex, class I, F (HLA-F); major histocompatibility complex, class I, G (HLA-G); MHC class I polypeptide-related sequence A (MICA); MHC class I polypeptide-related sequence B (MICB); integrin subunit beta 7 (ITGB7); leukocyte immunoglobulin like receptor Bl (LILRB1; ILT2); leukocyte immunoglobulin like receptor B2 20 (LILRB2; ILT4); LY6 / PLAUR domain containing 3 (LYPD3); glypican 3 (GPC3); KRAS proto-oncogene, GTPase (KRAS); MAGE family member Al (MAGEA1); MAGE family member A3 (MAGEA3); MAGE family member A4 (MAGEA4); MAGE family member All (MAGEA11); MAGE family member Cl (MAGECI); MAGE family member C2 (MAGEC2); MAGE family member C3 (MAGEC3); MAGE family member DI (MAGED1); MAGE family 25 member D2 (MAGED2); mesothelin (MSLN); mucin 1 (MUC1) and splice variants thereof (e.g., including MUC1 / A, C, D, X, Y, Z and REP); mucin 16 (MUC16; CA125); natural killer cell cytotoxicity receptor 3 ligand 1 (NCR3LG1; B7-H6); necdin, MAGE family member (NDN); nectin cell adhesion molecule 2 (NECTIN2); nectin cell adhesion molecule 4 (NECTIN4); SLIT and NTRK like family member 6 (SLITRK6); promyelocytic leukemia 30 (PML); protein tyrosine kinase 7 (inactive) (PTK7); Poliovirus receptor (PVR) cell adhesion molecule (PVR); SLAM family member 6 (SLAMF6); SLAM family member 7 (SLAMF7); sialic acid binding Ig like lectin 7 (SIGLEC7); sialic acid binding Ig like lectin 9 (SIGLEC9); sialic acid binding Ig like lectin 10 (SIGLEC10); signal regulatory protein alpha (SIRPA) solute carrier family 34 (sodium phosphate), member 2 (SLC34A2); solute carrier family 39 member 6 35   (SLC39A6); STEAP family member 1 (STEAP1); suppression of tumorigenicity 2 (ST2); TNF 2024202988   06 May 2024 receptor superfamily member 4 (TNFRSF4; 0X40); TNF superfamily member 9 (TNFSF9; 4-1BB-L, CD137L); TNFRSF10A (DR4, TRAILRI); TNFRSF10B (DR5, TRAILR2); TNFRSF13B (BAFF); TNFRSF17 (BCMA); TNFRSF18 (GITR); transferrin (TF); transforming growth factor beta 1 (TGFB1) and isoforms thereof; triggering receptor expressed on myeloid 5 cells 1 (TREM1); triggering receptor expressed on myeloid cells 2 (TREM2); trophoblast glycoprotein (TPBG); trophinin (TRO); tumor associated calcium signal transducer 2 (TACSTD2); Fucosyl GM1; sialyl Lewis adhesion molecule (sLe); and Lewis Y antigen. In some embodiments, the cells in the cellular therapy bind to an epitope of a target or tumor associated antigen (TAA) presented in a major histocompatibility complex (MHC) molecule. In 10 some embodiments, the TAA is a cancer testis antigen. In some embodiments, the cancer testis antigen is selected from the group consisting of acrosin binding protein (ACRBP), alpha fetoprotein (AFP), A-kinase anchoring protein 4 (AKAP4), ATPase family AAA domain containing 2 (ATAD2), kinetochore scaffold 1 (KNL1; a.ka., CASC5), centrosomal protein 55 (CEP55), cancer / testis antigen 1A (CTAG1A; a.k.a., ESO1; CT6.1; LAGE-2; LAGE2A; NY- 15   ESO-1), cancer / testis antigen IB (CTAG1B; a.k.a., CT6.1, CTAG, CTAG1, ESO1, LAGE-2, LAGE2B, NY-ESO-1), cancer / testis antigen 2 (CTAG2; a.k.a., CAMEL, CT2, CT6.2, CT6.2a, CT6.2b, ESO2, LAGE-1, LAGE2B), CCCTC-binding factor like (CTCFL), catenin alpha 2 (CTNNA2), cancer / testis antigen 83 (CT83), cyclin Al (CCNA1), DEAD-box helicase 43 (DDX43), developmental pluripotency associated 2 (DPPA2), fetal and adult testis expressed 1 20 (FATE1), FMRI neighbor (FMR1NB), HORMA domain containing 1 (HORMAD1), insulin like growth factor 2 mRNA binding protein 3 (IGF2BP3), leucine zipper protein 4 (LUZP4), lymphocyte antigen 6 family member K (LY6K), maelstrom spermatogenic transposon silencer (MAEL), MAGE family member Al (MAGEA1); MAGE family member A3 (MAGEA3); MAGE family member A4 (MAGEA4); MAGE family member Al 1 (MAGEA11); MAGE 25 family member Cl (MAGECI); MAGE family member C2 (MAGEC2); MAGE family member DI (MAGED1); MAGE family member D2 (MAGED2), kinesin family member 20B (KIF20B; a.k.a., MPHOSPH1), NUF2 component of NDC80 kinetochore complex (NUF2), nuclear RNA export factor 2 (NXF2), PAS domain containing repressor 1 (PASD1), PDZ binding kinase (PBK), piwi like RNA-mediated gene silencing 2 (PIWIL-2), preferentially expressed antigen in 30 melanoma (PRAME), sperm associated antigen 9 (SPAG9), sperm protein associated with the nucleus, X-linked, family member Al (SPANXA1), SPANX family member A2 (SPANXA2), SPANX family member C (SPANXC), SPANX family member D (SPANXD), SSX family member 1 (SSX1), SSX family member 2 (SSX2), synaptonemal complex protein 3 (SYCP3), testis expressed 14, intercellular bridge forming factor (TEX14), transcription factor Dp family 35 member 3 (TFDP3), serine protease 50 (PRSS50, a.k.a., TSP50), TTK protein kinase (TTK) and 2024202988   06 May 2024 zinc finger protein 165 (ZNF165). In some embodiments, the IL-2v, the Fc-IL-2v fusion protein, the homodimer, the heterodimer, the conjugate, the polynucleotide, the vector, the lipoplex (e.g., LNP) and / or the pharmaceutical composition is co-administered with a targeted E3 ligase ligand conjugate. In some embodiments, the IL-2v, the Fc-IL-2v fusion protein, the 5 homodimer, the heterodimer, the conjugate, the polynucleotide, the vector, the lipoplex (e.g., LNP) and / or the pharmaceutical composition is co-administered with one or more additional therapeutic agents comprising an inhibitor or antagonist of: protein tyrosine phosphatase, nonreceptor type 11 (PTPN11 or SHP2), myeloid cell leukemia sequence 1 (MCL1) apoptosis regulator, 5'-nucleotidase ecto (NT5E or CD73), ectonucleoside triphosphate 10 diphosphohydrolase 1 (ENTPD1 or CD39), transforming growth factor beta 1 (TGFB1 or TGFP), heme oxygenase 1 (HM0X1, HO-1 or HOI), heme oxygenase 2 (HM0X2, HO-2 or HO2), vascular endothelial growth factor A (VEGFA or VEGF), erb-b2 receptor tyrosine kinase 2 (ERBB2, HER2, HER2 / neu or CD340), epidermal growth factor receptor (EGFR, ERBB, ERBB1 or HER1), ALK receptor tyrosine kinase (ALK, CD246), poly(ADP-ribose) polymerase 15   1 (PARP1), poly(ADP-ribose) polymerase 2 (PARP2), TCDD inducible poly(ADP-ribose) polymerase (TIPARP, PARP7), cyclin dependent kinase 4 (CDK4), cyclin dependent kinase 6 (CDK6), TNF receptor superfamily member 14 (TNFRSF14, HVEM, CD270), C-C motif chemokine receptor 2 (CCR2, CD 192), C-C motif chemokine receptor 5 (CCR5, CD 195), C-C motif chemokine receptor 8 (CCR8, CDwl98), C-X-C motif chemokine receptor 2 (CXCR2, 20 CD 182), C-X-C motif chemokine receptor 3 (CXCR3, CD 182, CD 183), C-X-C motif chemokine receptor 4 (CXCR4, CD 184), arginase (ARG1, ARG2), carbonic anhydrase (CAI, CA2, CA3, CA4, CA5A, CA5B, CA6, CA7, CA8, CA9, CAIO, CA11, CA12, CAB, CAM), prostaglandin-endoperoxide synthase 1 (PTGS1, COX-1), prostaglandin-endoperoxide synthase 2 (PTGS2, COX-2), secreted phospholipase A2, prostaglandin E synthase (PTGES, PGES), 25 arachidonate 5-lipoxygenase (ALOX5, 5-LOX), soluble epoxide hydrolase 2 (EPHX2), indoleamine 2,3-dioxygenase 1 (IDO1), indoleamine 2,3-dioxygenase 2 (IDO2), hypoxia inducible factor 1 subunit alpha (HIF1A), angiopoietin 1 (ANGPT1), endothelial TEK tyrosine kinase (TIE-2, TEK), Janus kinase 1 (JAKI), catenin beta 1 (CTNNB1), histone deacetylase 9 (HDAC9), 5'-3' exoribonuclease 1 (XRN1), and / or WRN RecQ like helicase (WRN). In some 30 embodiments, the inhibitor comprises an antibody or an antigen-binding fragment thereof, or antibody-drug conjugate thereof, CD3-targeting multi-specific molecule, NK cell-activating receptor-targeting multi-specific molecule, non-immunoglobulin antigen binding molecule or antibody mimetic protein. In some embodiments, the inhibitor comprises an inhibitory nucleic acid. In some embodiments, the inhibitor comprises a small organic molecule. In some 35   embodiments, the inhibitor of 5'-nucleotidase ecto (NT5E or CD73) is selected from the group 2024202988   06 May 2024 consisting of MEDI9447 (oleclumab), CPI-006, BMS-986179, IPH5301, TJ4309 (TJD5), NZV-930, AB-680, PSB-12379, PSB-12441, PSB-12425, CB-708 and PBF-1662. In some embodiments, the inhibitor of CCR2 and / or CCR5 is selected from the group consisting of BMS-813160, PF-04136309 and CCX-872. In some embodiments, the inhibitor of MCL1 is 5 selected from the group consisting of GS-9716, tapotoclax (AMG-176), AMG-397, S-64315, AZD-5991, 483-LM, A 1210477, UMI-77, JKY-5-037, PRT-1419 and APG-3526. In some embodiments, the inhibitor of PTPN11 or SHP2 is selected from the group consisting of TNO155 (SHP-099), RMC-4550, JAB-3068 and RMC-4630. In some embodiments, the inhibitor of Janus kinase 1 (JAKI) is selected from the group consisting of fdgotinib, tofacitinib, 10 baricitinib and ABT-494. In some embodiments, the IL-2v, the Fc-IL-2v fusion protein, the homodimer, the heterodimer, the conjugate, the polynucleotide, the vector, the lipoplex (e.g., LNP) and / or the pharmaceutical composition is co-administered with an oncolytic viral vector. In some embodiments, the oncolytic viral vector comprises a DNA virus or a RNA virus. In some embodiments, the viral vector is from a viral family selected from the group consisting of: 15 Adenoviridae (e.g., Adenovirus), Arenaviridae (e.g., lymphocytic choriomeningitis mammarenavirus, Cali mammarenavirus (a.k.a., Pichinde mammarenavirus), Poxviridae (e.g., Vaccinia virus), Herpesviridae (e.g., Herpesvirus, e.g., HSV-1), Parvoviridae (e.g., Parvovirus Hl), Reoviridae (e.g., Reovirus), Picornaviridae (e.g., Coxsackievirus, Seneca Valley Virus, Poliovirus), Paramyxoviridae (e.g., Measles virus, Newcastle disease virus (NDV)), 20 Rhabdoviridae (e.g., Vesicular stomatitis virus (VSV)), Togaviridae (e.g., Alphavirus, Sindbis virus), Enteroviridae (e.g., Echovirus). In some embodiments, the subject has cancer. In some embodiments, the subject is in cancer remission. In some embodiments, the subject has a hematological cancer, e.g., a leukemia (e.g., Acute Myelogenous Leukemia (AML), Acute Lymphoblastic Leukemia (ALL), B-cell ALL, Myelodysplastic Syndrome (MDS), 25 myeloproliferative disease (MPD), Chronic Myelogenous Leukemia (CML), Chronic Lymphocytic Leukemia (CLL), undifferentiated leukemia), a lymphoma (e.g., small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), follicular lymphoma (FL), T-cell lymphoma, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), marginal zone lymphoma (MZL), Waldenstrom’s macroglobulinemia (WM)) and / or a myeloma (e.g., multiple 30 myeloma (MM)). In some embodiments, the subject has a solid tumor. In some embodiments, the tumor is a malignant tumor. In some embodiments, the tumor is a metastatic tumor. In some embodiments, the subject has a cancer selected from the group consisting of an epithelial tumor (e.g., a carcinoma, a squamous cell carcinoma, a basal cell carcinoma, a squamous intraepithelial neoplasia), a glandular tumor (e.g., an adenocarcinoma, an adenoma, an adenomyoma), a 35 mesenchymal or soft tissue tumor (e.g., a sarcoma, a rhabdomyosarcoma, a leiomyosarcoma, a 2024202988   06 May 2024 liposarcoma, a fibrosarcoma, a dermatofibrosarcoma, a neurofibrosarcoma, a fibrous histiocytoma, an angiosarcoma, an angiomyxoma, a leiomyoma, a chondroma, a chondrosarcoma, an alveolar soft-part sarcoma, an epithelioid hemangioendothelioma, a Spitz tumor, a synovial sarcoma), and a lymphoma. In some embodiments, the subject has a solid 5 tumor in or arising from a tissue or organ selected from the group consisting of: bone (e.g., adamantinoma, aneurysmal bone cysts, angiosarcoma, chondroblastoma, chondroma, chondromyxoid fibroma, chondrosarcoma, chordoma, dedifferentiated chondrosarcoma, enchondroma, epithelioid hemangioendothelioma, fibrous dysplasia of the bone, giant cell tumour of bone, haemangiomas and related lesions, osteoblastoma, osteochondroma, 10   osteosarcoma, osteoid osteoma, osteoma, periosteal chondroma, Desmoid tumor, Ewing sarcoma); lips and oral cavity (e.g., odontogenic ameloblastoma, oral leukoplakia, oral squamous cell carcinoma, primary oral mucosal melanoma); salivary glands (e.g., pleomorphic salivary gland adenoma, salivary gland adenoid cystic carcinoma, salivary gland mucoepidermoid carcinoma, salivary gland Warthin's tumors); esophagus (e.g., Barrett's 15 esophagus, dysplasia and adenocarcinoma); gastrointestinal tract, including stomach (e.g., gastric adenocarcinoma, primary gastric lymphoma, gastrointestinal stromal tumors (GISTs), metastatic deposits, gastric carcinoids, gastric sarcomas, neuroendocrine carcinoma, gastric primary squamous cell carcinoma, gastric adenoacanthomas), intestines and smooth muscle (e.g., intravenous leiomyomatosis), colon (e.g., colorectal adenocarcinoma), rectum, anus; 20 pancreas (e.g., serous neoplasms, including microcystic or macrocystic serous cystadenoma, solid serous cystadenoma, Von Hippel-Landau (VHL)-associated serous cystic neoplasm, serous cystadenocarcinoma; mucinous cystic neoplasms (MCN), intraductal papillary mucinous neoplasms (IPMN), intraductal oncocytic papillary neoplasms (IOPN), intraductal tubular neoplasms, cystic acinar neoplasms, including acinar cell cystadenoma, acinar cell 25 cystadenocarcinoma, pancreatic adenocarcinoma, invasive pancreatic ductal adenocarcinomas, including tubular adenocarcinoma, adenosquamous carcinoma, colloid carcinoma, medullary carcinoma, hepatoid carcinoma, signet ring cell carcinoma, undifferentiated carcinoma, undifferentiated carcinoma with osteoclast-like giant cells, acinar cell carcinoma, neuroendocrine neoplasms, neuroendocrine microadenoma, neuroendocrine tumors (NET), 30 neuroendocrine carcinoma (NEC), including small cell or large cell NEC, insulinoma, gastrinoma, glucagonoma, serotonin-producing NET, somatostatinoma, VIPoma, solid-pseudopapillary neoplasms (SPN), pancreatoblastoma); gall bladder (e.g. carcinoma of the gallbladder and extrahepatic bile ducts, intrahepatic cholangiocarcinoma); neuro-endocrine (e.g., adrenal cortical carcinoma, carcinoid tumors, phaeochromocytoma, pituitary adenomas); 35 thyroid (e.g., anaplastic (undifferentiated) carcinoma, medullary carcinoma, oncocytic tumors, 2024202988   06 May 2024 papillary carcinoma, adenocarcinoma); liver (e.g., adenoma, combined hepatocellular and cholangiocarcinoma, fibrolamellar carcinoma, hepatoblastoma, hepatocellular carcinoma, mesenchymal, nested stromal epithelial tumor, undifferentiated carcinoma; hepatocellular carcinoma, intrahepatic cholangiocarcinoma, bile duct cystadenocarcinoma, epithelioid 5 hemangioendothelioma, angiosarcoma, embryonal sarcoma, rhabdomyosarcoma, solitary fibrous tumor, teratoma, York sac tumor, carcinosarcoma, rhabdoid tumor); kidney (e.g., ALK-rearranged renal cell carcinoma, chromophobe renal cell carcinoma, clear cell renal cell carcinoma, clear cell sarcoma, metanephric adenoma, metanephric adenofibroma, mucinous tubular and spindle cell carcinoma, nephroma, nephroblastoma (Wilms tumor), papillary 10 adenoma, papillary renal cell carcinoma, renal oncocytoma, renal cell carcinoma, succinate dehydrogenase-deficient renal cell carcinoma, collecting duct carcinoma); breast (e.g., invasive ductal carcinoma, including without limitation, acinic cell carcinoma, adenoid cystic carcinoma, apocrine carcinoma, cribriform carcinoma, glycogen-rich / clear cell, inflammatory carcinoma, lipid-rich carcinoma, medullary carcinoma, metaplastic carcinoma, micropapillary carcinoma, 15   mucinous carcinoma, neuroendocrine carcinoma, oncocytic carcinoma, papillary carcinoma, sebaceous carcinoma, secretory breast carcinoma, tubular carcinoma; lobular carcinoma, including without limitation, pleomorphic carcinoma, signet ring cell carcinoma, peritoneum (e.g., mesothelioma; primary peritoneal cancer); female sex organ tissues, including ovary (e.g., choriocarcinoma, epithelial tumors, germ cell tumors, sex cord-stromal tumors), Fallopian tubes 20   (e.g., serous adenocarcinoma, mucinous adenocarcinoma, endometrioid adenocarcinoma, clear cell adenocarcinoma, transitional cell carcinoma, squamous cell carcinoma, undifferentiated carcinoma, Mullerian tumors, adenosarcoma, leiomyosarcoma, teratoma, germ cell tumors, choriocarcinoma, trophoblastic tumors), uterus (e.g., carcinoma of the cervix, endometrial polyps, endometrial hyperplasia, intraepithelial carcinoma (EIC), endometrial carcinoma (e.g., 25 endometrioid carcinoma, serous carcinoma, clear cell carcinoma, mucinous carcinoma, squamous cell carcinoma, transitional carcinoma, small cell carcinoma, undifferentiated carcinoma, mesenchymal neoplasia), leiomyoma (e.g., endometrial stromal nodule, leiomyosarcoma, endometrial stromal sarcoma (ESS), mesenchymal tumors), mixed epithelial and mesenchymal tumors (e.g., adenofibroma, carcinofibroma, adenosarcoma, carcinosarcoma 30 (malignant mixed mesodermal sarcoma - MMMT)), endometrial stromal tumors, endometrial malignant mullerian mixed tumours, gestational trophoblastic tumors (partial hydatiform mole, complete hydatiform mole, invasive hydatiform mole, placental site tumour)), vulva, vagina; male sex organ tissues, including prostate, testis (e.g., germ cell tumors, spermatocytic seminoma), penis; bladder (e.g., squamous cell carcinoma, urothelial carcinoma, bladder 35 urothelial carcinoma); brain, (e.g., gliomas (e.g., astrocytomas, including non-infdtrating, low- 2024202988   06 May 2024 grade, anaplastic, glioblastomas; oligodendrogliomas, ependymomas), meningiomas, gangliogliomas, schwannomas (neurilemmomas), craniopharyngiomas, chordomas, NonHodgkin lymphomas (NHLs), indolent non-Hodgkin’s lymphoma (iNHL), refractory iNHL, pituitary tumors; eye (e.g., retinoma, retinoblastoma, ocular melanoma, posterior uveal 5 melanoma, iris hamartoma); head and neck (e.g., nasopharyngeal carcinoma, Endolymphatic Sac Tumor (ELST), epidermoid carcinoma, laryngeal cancers including squamous cell carcinoma (SCC) (e.g., glottic carcinoma, supraglottic carcinoma, subglottic carcinoma, transglottic carcinoma), carcinoma in situ, verrucous, spindle cell and basaloid SCC, undifferentiated carcinoma, laryngeal adenocarcinoma, adenoid cystic carcinoma, 10 neuroendocrine carcinomas, laryngeal sarcoma), head and neck paragangliomas (e.g., carotid body, jugulotympanic, vagal); thymus (e.g., thymoma); heart (e.g., cardiac myxoma); lung (e.g, small cell carcinoma (SCLC), non-small cell lung carcinoma (NSCLC), including squamous cell carcinoma (SCC), adenocarcinoma and large cell carcinoma, carcinoids (typical or atypical), carcinosarcomas, pulmonary blastomas, giant cell carcinomas, spindle cell 15 carcinomas, pleuropulmonary blastoma); lymph (e.g, lymphomas, including Hodgkin’s lymphoma, non-Hodgkin’s lymphoma (NHL), indolent non-Hodgkin’s lymphoma (iNHL), refractory iNHL, Epstein-Barr virus (EBV)-associated lymphoproliferative diseases, including B cell lymphomas and T cell lymphomas (e.g, Burkitt lymphoma; large B cell lymphoma, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, indolent B-cell lymphoma, low grade 20 B cell lymphoma, fibrin-associated diffuse large cell lymphoma; primary effusion lymphoma; plasmablastic lymphoma; extranodal NK / T cell lymphoma, nasal type; peripheral T cell lymphoma, cutaneous T cell lymphoma, angioimmunoblastic T cell lymphoma; follicular T cell lymphoma; systemic T cell lymphoma), lymphangioleiomyomatosis); central nervous system (CNS) (e.g., gliomas including astrocytic tumors (e.g., pilocytic astrocytoma, pilomyxoid 25 astrocytoma, subependymal giant cell astrocytoma, pleomorphic xanthoastrocytoma, diffuse astrocytoma, fibrillary astrocytoma, gemistocytic astrocytoma, protoplasmic astrocytoma, anaplastic astrocytoma, glioblastoma (e.g., giant cell glioblastoma, gliosarcoma, glioblastoma multiforme) and gliomatosis cerebri), oligodendroglial tumors (e.g., oligodendroglioma, anaplastic oligodendroglioma), oligoastrocytic tumors (e.g., oligoastrocytoma, anaplastic 30 oligoastrocytoma), ependymal tumors (e.g., subependymom, myxopapillary ependymoma, ependymomas (e.g., cellular, papillary, clear cell, tanycytic), anaplastic ependymoma), optic nerve glioma, and non-gliomas (e.g., choroid plexus tumors, neuronal and mixed neuronal-glial tumors, pineal region tumors, embryonal tumors, medulloblastoma, meningeal tumors, primary CNS lymphomas, germ cell tumors, Pituitary adenomas, cranial and paraspinal nerve tumors, 35 stellar region tumors); neurofibroma, meningioma, peripheral nerve sheath tumors, peripheral 2024202988   06 May 2024 neuroblastic tumours (including without limitation neuroblastoma, ganglioneuroblastoma, ganglioneuroma), trisomy 19 ependymoma); neuroendocrine tissues (e.g., paraganglionic system including adrenal medulla (pheochromocytomas) and extra-adrenal paraganglia ((extraadrenal) paragangliomas); skin (e.g., clear cell hidradenoma, cutaneous benign fibrous 5 histiocytomas, cylindroma, hidradenoma, melanoma (including cutaneous melanoma, mucosal melanoma), pilomatricoma, Spitz tumors); and soft tissues (e.g., aggressive angiomyxoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, angiofibroma, angiomatoid fibrous histiocytoma, synovial sarcoma, biphasic synovial sarcoma, clear cell sarcoma, dermatofibrosarcoma protuberans, desmoid-type fibromatosis, small round cell tumor, 10 desmoplastic small round cell tumor, elastofibroma, embryonal rhabdomyosarcoma, Ewing's tumors / primitive neurectodermal tumors (PNET), extraskeletal myxoid chondrosarcoma, extraskeletal osteosarcoma, paraspinal sarcoma, inflammatory myofibroblastic tumor, lipoblastoma, lipoma, chondroid lipoma, liposarcoma / malignant lipomatous tumors, liposarcoma, myxoid liposarcoma, fibromyxoid sarcoma, lymphangioleiomyoma, malignant 15 myoepithelioma, malignant melanoma of soft parts, myoepithelial carcinoma, myoepithelioma, myxoinflammatory fibroblastic sarcoma, undifferentiated sarcoma, pericytoma, rhabdomyosarcoma, non-rhabdomyosarcoma soft tissue sarcoma (NRSTS), soft tissue leiomyosarcoma, undifferentiated sarcoma, well-differentiated liposarcoma. In some embodiments, the subject has a hematological cancer selected from the group consisting of 20 melanoma, leukemia, acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL); lymphoma; B-cell Non-Hodgkin Lymphoma; and multiple myeloma (MM); or a solid tumor cancer selected from the group consisting of melanoma; head and neck; ovarian; mesothelioma; endometrial; prostate; sarcoma; neuroblastoma; liver; lung; breast; esophageal, gastric and pancreatic. In some embodiments, the subject has a cancer selected from the group consisting of 25 a lung cancer, a colorectal cancer, a breast cancer, a prostate cancer, a cervical cancer and a head and neck cancer. In some embodiments, the subject is naive to or has not received chemotherapy. In some embodiments, the subject has received a lymphodepleting chemotherapy regimen. In some embodiments, the subject has bone marrow cells, or is not depleted of bone marrow cells. 30

[0018] With respect to the antiviral, anticancer and vaccine enhancement combination therapy methods, in some embodiments, the IL-2v, the Fc-IL-2v fusion protein, the homodimer, the heterodimer, the conjugate, the polynucleotide, the vector, the lipoplex (e.g., LNP) and / or the pharmaceutical composition is co-administered with one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents comprise one or more 2024202988   06 May 2024 agonists or activators of one or more toll-like receptors (TLRs). In some embodiments, the TLR agonist or activator is selected from the group consisting of a TLR2 agonist, a TLR3 agonist, a TLR4 agonist, a TLR5 agonist, a TLR7 agonist, a TLR8 agonist and a TLR9 agonist. In some embodiments, the TLR7 agonist is selected from the group consisting of GS 9620 (vesatolimod), 5   R848 (Resiquimod), DS-0509, LHC-165, TMX-101 (imiquimod), RO7020531 and JNJ-4964, and / or wherein the TLR8 agonist is selected from the group consisting of selgantolimod (GS-9688), R848 (Resiquimod) andNKTR-262 (dual TLR7 / TLR8 agonist). In some embodiments, the cytokine or chemokine therapy comprises co-administering one or more immunostimulatory cytokines or chemokines that promote or increase the proliferation or activation of a / p T cells, 10   y / 5 T cells, NK-T cells, NK cells, and / or dendritic cells. In some embodiments, the one or more immunostimulatory cytokines or chemokines are selected from the group consisting of: IL-10, IL-12, IL-18, gamma chain-dependent cytokines (e.g., IL-4, IL-7, IL-9, IL-15 and IL-21), fms related tyrosine kinase 3 (FLT3) ligand (FLT3L; FLT3LG; NCBI Gene ID: 2323), interferon (IFN)-a, IFN-P, a PEGylated interferon (e.g., PEG-IFN-a2a and / or PEG-IFN-a2b), IFN-y, 15 CXCL9 / Mig (monokine induced by interferon-y), CXCL10 / IP10 (interferon-y-inducible 10 kDa protein) and CXCL11 / I-TAC (interferon-inducible T cell a-chemoattractant), CXCL4 / PF4 (platelet factor 4), monocyte chemoattractant protein 2 (MCP-2), macrophage inflammatory protein 1 alpha (MIP-la), macrophage inflammatory protein 1 beta (MIP-ip) and regulated on activation normal T expressed and secreted protein (RANTES). In some embodiments, the one 20 or more additional therapeutic agents comprise one or more interleukin receptor agonists of an interleukin receptor selected from IL-10, IL-12, IL-18 and gamma chain-dependent cytokines (e.g., IL-4, IL-7, IL-9, IL-15 and IL-21). In some embodiments, the one or more additional therapeutic agents comprise one or more cytokines selected from the group consisting of IL-10, IL-12, IL-18, gamma chain-dependent cytokines (e.g., IL-4, IL-7, IL-9, IL-15 and IL-21), IFN- 25 a, IFN-P, a PEGylated interferon (e.g., PEG-IFN-a2a and / or PEG-IFN-a2b), IFN-y, and variants thereof. In some embodiments, the one or more additional therapeutic agents comprise one or more innate immune activators. In some embodiments, the one or more innate immune activators comprises an agonist of a receptor selected from the group consisting of fms related tyrosine kinase 3 (FLT3, a.k.a., CD135, FLK-2, FLK2, STK1), stimulator of interferon genes 30 (STING) receptor, DExD / H-box helicase 58 (DDX58; a.k.a., RIG-I), NLR family pyrin domain containing 3 (NLRP3) and nucleotide binding oligomerization domain containing 2 (NOD2). In some embodiments, the one or more innate immune activators comprise one or both of GS-3583 and GS-9992. In some embodiments, the one or more additional therapeutic agents comprise an immunotherapy, an immunostimulatory therapy, a cytokine therapy, a chemokine therapy, a 35 cellular therapy, a gene therapy, and combinations thereof. In some embodiments, the 2024202988   06 May 2024 immunotherapy comprises co-administering one or more antagonists or inhibitors of an inhibitory immune checkpoint protein or receptor and / or one or more activators or agonists of a stimulatory immune checkpoint protein or receptor. In some embodiments, the one or more immune checkpoint proteins or receptors are selected from the group consisting of: CD27, 5   CD70; CD40, CD40LG; CD47, CD48 (SLAMF2), transmembrane and immunoglobulin domain containing 2 (TMIGD2, CD28H), CD84 (LY9B, SLAMF5), CD96, CD160 (NK1, NK28, BY55), MS4A1 (CD20), CD244 (SLAMF4); CD276 (B7H3); V-set domain containing T cell activation inhibitor 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); natural killer cell 10 cytotoxicity receptor 3 ligand 1 (NCR3LG1, B7H6); HERV-H LTR-associating 2 (HHLA2, B7H7); inducible T cell co-stimulator (ICOS, CD278); inducible T cell costimulator ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF8 (CD30), TNFSF8 (CD30L); TNFRSF10A (CD261, DR4, TRAILRI), TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF10B (CD262, DR5, 15 TRAILR2), TNFRSF10 (TRAIL); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte associated (BTLA)); TNFRSF17 (BCMA, CD269), TNFSF13B (BAFF); TNFRSF18 (GITR), TNFSF18 (GITRL); MHC class I polypeptide-related sequence A (MICA); MHC class I polypeptide-related sequence B (MICB); CD274 (CD274, PDL1, PD-L1); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T-lymphocyte associated protein 4 20 (CTLA4, CD152); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); Poliovirus receptor (PVR) cell adhesion molecule (PVR, CD 155); PVR related immunoglobulin domain containing (PVRIG, CD112R); T cell immunoreceptor with Ig and ITIM domains (TIGIT); T cell immunoglobulin and mucin domain containing 4 (TIMD4; TIM4); hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3); galectin 9 (LGALS9); 25 lymphocyte activating 3 (LAG3, CD223); signaling lymphocytic activation molecule family member 1 (SLAMF1, SLAM, CD150); lymphocyte antigen 9 (LY9, CD229, SLAMF3); SLAM family member 6 (SLAMF6, CD352); SLAM family member 7 (SLAMF7, CD319); sialic acid binding Ig like lectin 7 (SIGLEC7); sialic acid binding Ig like lectin 9 (SIGLEC9); ULI6 binding protein 1 (ULBP1); UL16 binding protein 2 (ULBP2); UL16 binding protein 3 30 (ULBP3); retinoic acid early transcript IE (RAET1E; ULBP4); retinoic acid early transcript IG (RAET1G; ULBP5); retinoic acid early transcript IL (RAET1L; ULBP6); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); CD 160; killer cell lectin like receptor Bl (KLRB1, CD 161); killer cell lectin like receptor Cl (KLRC1, NKG2A, CD159A); killer cell lectin like receptor KI (KLRK1, NKG2D, CD314); 35 killer cell lectin like receptor C2 (KLRC2, CD159c, NKG2C); killer cell lectin like receptor C3 2024202988   06 May 2024 (KLRC3, NKG2E); killer cell lectin like receptor C4 (KLRC4, NKG2F); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3 5 (KIR2DL3); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin like receptor DI (KLRD1); killer cell lectin like receptor G1 (KLRG1; CLEC15A, MAFA, 2F1); sialic acid binding Ig like lectin 7 (SIGLEC7); and sialic acid binding Ig like lectin 9 (SIGLEC9). In some embodiments, the immunotherapy comprises co-administering one or more blockers or inhibitors of one or more T-cell inhibitory immune 10 checkpoint proteins or receptors. In some embodiments, the T-cell inhibitory immune checkpoint proteins or receptors are selected from the group consisting of CD274 (CD274, PDL1, PD-L1); programmed cell death 1 ligand 2 (PDCD1LG2, PD-L2, CD273); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T-lymphocyte associated protein 4 (CTLA4, CD 152); CD276 (B7H3); V-set domain containing T cell activation inhibitor 1 (VTCN1, 15   B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte associated (BTLA)); PVR related immunoglobulin domain containing (PVRIG, CD112R); T cell immunoreceptor with Ig and ITIM domains (TIGIT); lymphocyte activating 3 (LAG3, CD223); hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3); 20 galectin 9 (LGALS9); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); and killer cell immunoglobulin like 25 receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1). In some embodiments, the immunotherapy comprises co-administering one or more agonists or activators of one or more T-cell stimulatory immune checkpoint proteins or receptors. In some embodiments, the T-cell stimulatory immune checkpoint proteins or receptors are selected from the group consisting of CD27, CD70; CD40, CD40LG; inducible T cell costimulator (ICOS, CD278); inducible T cell 30 costimulator ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF9 (CD 137), TNFSF9 (CD137L); TNFRSF18 (GITR), TNFSF18 (GITRL); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); Poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155). In some embodiments, the immunotherapy comprises co-administering one or 35   more blockers or inhibitors of one or more NK-cell inhibitory immune checkpoint proteins or 2024202988   06 May 2024 receptors. In some embodiments, the NK-cell inhibitory immune checkpoint proteins or receptors are selected from the group consisting of killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin 5 like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); CD 160; killer cell lectin like receptor Bl (KLRB1, CD 161); killer cell lectin like receptor Cl (KLRC1, NKG2A, CD159A); killer cell lectin like receptor DI (KLRD1, CD94), killer cell 10 lectin like receptor G1 (KLRG1; CLEC15A, MAFA, 2F1); sialic acid binding Ig like lectin 7 (SIGLEC7); and sialic acid binding Ig like lectin 9 (SIGLEC9). In some embodiments, the immunotherapy comprises co-administering one or more agonists or activators of one or more NK-cell stimulatory immune checkpoint proteins or receptors. In some embodiments, the NK-cell stimulatory immune checkpoint proteins or receptors are selected from CD 16, CD226 15   (DNAM-1); killer cell lectin like receptor KI (KLRK1, NKG2D, CD314); and SLAM family member 7 (SLAMF7). In some embodiments, the one or more immune checkpoint inhibitors comprises a proteinaceous (e.g., antibody) inhibitor of PD-L1 (CD274), PD-1 (PDCD1) or CTLA4. In some embodiments, the one or more immune checkpoint proteins or receptors are selected from the group consisting of: CD274 (CD274, PDL1, PD-L1) and programmed cell 20 death 1 (PDCD1, PD1, PD-1). In some embodiments, the proteinaceous (e.g., antibody) inhibitor of CTLA4 is selected from the group consisting of ipilimumab, tremelimumab, BMS-986218, AGEN1181, AGEN1884 (zalifrelimab), BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002, BCD-145, APL-509, JS-007, BA-3071, ONC-392, AGEN-2041, JHL-1155, KN-044, CG-0161, ATOR-1144, PBI-5D3H5, FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 25   (PD-1 / CTLA4), MGD-019 (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4), MEDI-5752 (CTLA4 / PD- 1), XmAb-20717 (PD-1 / CTLA4) and AK-104 (CTLA4 / PD-1). In some embodiments, the proteinaceous (e.g., antibody) inhibitor of programmed cell death 1 (PDCD1; NCBI Gene ID: 5133; CD279, PD-1, PD1) is selected from the group consisting of zimberelimab (AB122, GLS-010, WBP-3055), pembrolizumab (KEYTRUDA®, MK-3475, SCH900475), nivolumab 30 (OPDIVO®, BMS-936558, MDX-1106), cemiplimab (LIBTAYO®; cemiplimab-rwlc, REGN-2810), pidilizumab (CT-011), AMG-404, MEDI0680 (AMP-514), spartalizumab (PDR001), tislelizumab (BGB-A317), toripalimab (JS-001), genolimzumab (CBT-501, APL-501, GB 226), SHR-1201, camrelizumab (SHR-1210), sintilimab (TYVYT®; IBI-308), dostarlimab (TSR-042, WBP-285), lambrolizumab (MK-3475); sasanlimab (PF-06801591), cetrelimab (JNJ-63723283), 35 serplulimab (HLX-10), retifanlimab (MGA-012), balstilimab (AGEN2034), prolgolimab (BCD 2024202988   06 May 2024 100), budigalimab (ABBV-181), vopratelimab (JTX-4014), AK-103 (HX-008), AK-105, CS 1003, BI-754091, LZM-009, Sym-021, BAT-1306, PD1-PIK, tebotelimab (MGD013; PD-l / LAG-3), RO-7247669 (PD-l / LAG-3), FS-118 (LAG-3 / PD-L1), RO-7121661 (PD l / TIM-3), RG7769 (PD-l / TIM-3), PF-06936308 (PD 1 / CTLA4), MGD-019 (PD-1 / CTLA4), KN-046 (PD 5   1 / CTLA4), XmAb-20717 (PD 1 / CTLA4), AK-104 (CTLA4 / PD-1) and MEDI-5752 (CTLA4 / PD-1). In some embodiments, the proteinaceous (e.g., antibody) inhibitor of CD274 molecule (NCBI Gene ID: Gene ID: 29126; B7-H, B7H1, PD-L1) is selected from the group consisting of atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®; MSB0010718C), envafolimab (ASC22), durvalumab (IMFINZI®; MEDI-4736), BMS-936559 (MDX1105), 10 cosibelimab (CK-301), lodapolimab (LY 3300054), garivulimab (BGB A333), envafolimab (KN035), opucolimab (HLX 20), manelimab (BCD 135), CX-072, CBT-502 (TQB2450), MSB-2311, SHR-1316, sugemalimab (CS-1001; WBP3155), A167 (KL-A167, HBM 9167), STI-A1015 (IMC-001), FAZ-053, BMS-936559 (MDX1105), INCB086550, GEN-1046 (PD-L1 / 4-1BB), FPT-155 (CTLA4 / PD-L1 / CD28), M7824 (PD-Ll / TGFp-EC domain), CA-170 (PD- 15 L1 / VISTA), CDX-527 (CD27 / PD-L1), LY-3415244 (TIM-3 / PDL1), INBRX-105 (4-1BB / PDL1) and GNS-1480 (PD-L1 / EGFR). In some embodiments, the one or more immune checkpoint inhibitors comprises a small molecule inhibitor of CD274 (PDL1, PD-L1), programmed cell death 1 (PDCD1, PD1, PD-1) or CTLA4. In some embodiments, the small molecule inhibitor of CD274 or PDCD1 is selected from the group consisting of GS-4224, GS- 20   4416, INCB086550 and MAX10181. In some embodiments, the small molecule inhibitor of CTLA4 comprises BPI-002. In some embodiments, the immunotherapy comprises coadministering one or more agents that selectively deplete regulatory T (Treg) cells. In some embodiments, the one or more agents that selectively deplete effector regulatory T (Treg) cells comprise an antibody or antigen-binding fragment thereof that selectively binds to a cell surface 25 receptor selected from the group consisting of C-C motif chemokine receptor 4 (CCR4), C-C motif chemokine receptor 7 (CCR7), C-C motif chemokine receptor 8 (CCR8), C-X-C motif chemokine receptor 4 (CXCR4; CD 184), TNFRSF4 (OX40), TNFRSF18 (GITR, CD357), TNFRSF9 (4-1BB, CD137), cytotoxic T-lymphocyte associated protein 4 (CTLA4, CD152), programmed cell death 1 (PDCD1, PD-1), Sialyl Lewis x (CD15s), CD27, ectonucleoside 30 triphosphate diphosphohydrolase 1 (ENTPD1; CD39), protein tyrosine phosphatase receptor type C (PTPRC; CD45), neural cell adhesion molecule 1 (NCAM1; CD56), selectin L (SELL; CD62L), integrin subunit alpha E (ITGAE; CD 103), interleukin 7 receptor (IL7R; CD 127), CD40 ligand (CD40LG; CD 154), folate receptor alpha (FOLRI), folate receptor beta (FOLR2), leucine rich repeat containing 32 (LRRC32; GARP), IKAROS family zinc finger 2 (IKZF2; 35 HELIOS), inducible T cell costimulatory (ICOS; CD278), lymphocyte activating 3 (LAG3; 2024202988   06 May 2024 CD223), transforming growth factor beta 1 (TGFB1), hepatitis A virus cellular receptor 2 (HAVCR2; CD366; TIM3), T cell immunoreceptor with Ig and ITIM domains (TIGIT), TNF receptor superfamily member IB (CD 120b; TNFR2), IL-2RA (CD25), and combinations thereof. In some embodiments, the immunotherapy comprises co-administering one or more 5 agents that selectively deplete suppressive myeloid cells. In some embodiments, the suppressive myeloid cells are selected from tumor-associated macrophages (TAM) and myeloid derived suppressor cells (MDSC). In some embodiments, the one or more agents that selectively deplete suppressive myeloid cells comprise an antibody or antigen-binding fragment thereof that selectively binds to a cell surface receptor selected from the group consisting of colony 10 stimulating factor 1 receptor (CSF1R), C-C motif chemokine receptor 2 (CCR2), C-C motif chemokine ligand 2 (CCL2), triggering receptor expressed on myeloid cells 2 (TREM2), complement C5a receptor 1 (C5AR1), and mixtures thereof. In some embodiments, the one or more agents that selectively deplete suppressive myeloid cells comprise an agent that inhibits nuclear receptor subfamily 1 group H member 3 (NR1H3; LXRA) or nuclear receptor subfamily 15   1 group H member 2 (NR1H2; LXRB). In some embodiments, the one or more additional therapeutic agents comprise an inhibitor or antagonist of: mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1) (also called Hematopoietic Progenitor Kinase 1 (HPK1)), phosphatidylinositol-4,5-bisphosphate 3-kinase, including catalytic subunit alpha (PIK3CA), catalytic subunit beta (PIK3CB), catalytic subunit gamma (PIK3CG) and catalytic subunit delta 20 (PIK3CD), diacylglycerol kinase alpha (DGKA, DAGK, DAGK1 or DGK-alpha), T cell immunoreceptor with Ig and ITIM domains (TIGIT), X-linked inhibitor of apoptosis (XIAP, BIRC4, IAP-3), baculoviral LAP repeat containing 2 (BIRC2, cIAPl), baculoviral IAP repeat containing 3 (BIRC3, cIAP2), baculoviral IAP repeat containing 5 (BIRC5, survivin), or cytokine inducible SH2 containing protein (CISH). In some embodiments, the one or more 25 additional therapeutic agents comprise an activator or agonist of: a toll-like receptor (TLR); a stimulator of interferon genes (STING) receptor; inducible T cell costimulator (ICOS, CD278); and / or a TNF receptor superfamily (TNFRSF) member. In some embodiments, the TNF receptor superfamily (TNFRSF) member is selected from the group consisting of: TNFRSF 1 A, TNFRSFIB, TNFRSF4 (OX40), TNFRSF5 (CD40), TNFRSF6 (FAS), TNFRSF7 (CD27), 30 TNFRSF8 (CD30), TNFRSF9 (4-1BB, CD137), TNFRSF10A (CD261, DR4, TRAILRI), TNFRSF10B (CD262, DR5, TRAILR2), TNFRSF10C (CD263, TRAILR3), TNFRSF10D (CD264, TRAILR4), TNFRSF11A (CD265, RANK), TNFRSF11B, TNFRSF12A (CD266), TNFRSF13B (CD267), TNFRSF13C (CD268), TNFRSF16 (NGFR, CD271), TNFRSF17 (BCMA, CD269), TNFRSF18 (GITR, CD357), TNFRSF19, TNFRSF21 (CD358, DR6), and 35 TNFRSF25 (DR3). In some embodiments, the TNFRSF4 (OX40 or CD 134) activator or agonist 2024202988   06 May 2024 comprises INCAGN1949, tavolimab (MEDI0562), pogalizumab (MOXR0916 / RG7888), MEDI6469, BMS 986178, PF-04518600, GSK3174998, IBI101, ATOR-1015, ABBV-368 or SL-279252; the TNFRSF9 (4-IBB or CD 137) activator or agonist comprises urelumab, BMS-663513, utomilumab (PF-05082566), CTX-471, MP-0310, ADG-106, ATOR-1017, AGEN2373 5 or QL1806; and / or the TNFRSF18 (GITR or CD357) activator or agonist comprises GWN323, MEDI1873, MK-1248, MK-4166, TRX518, INCAGN1876, BMS-986156, BMS-986256, AMG-228, ASP1951 (PTZ 522), FPA-154 or OMP-336B11. In some embodiments, the methods comprise co-administering a molecule that concurrently binds to TNF receptor superfamily member 4 (TNFRSF4, OX40 or CD134) and TNF receptor superfamily member 18 10 (TNFRSF18, GITR or CD357). In some embodiments, the methods comprise co-administering a molecule selected from the group consisting of AGEN 1884 (zalifrelimab), AGEN1181, AGEN 2034 (balstilimab), AGEN1307, AGEN1327, AGEN1777, AGEN2373, AGEN1223 and GS-1423.

[0019] With respect to the antiviral, anticancer and vaccine enhancement methods, in 15 some embodiments, in some embodiments, the IL-2v, the Fc-IL-2v fusion protein, the homodimer, the heterodimer, the conjugate, the polynucleotide, the vector, the lipoplex (e.g., LNP) and / or the pharmaceutical composition are administered systemically or locally, e.g., via a route selected from intravenous, subcutaneous, intramuscular, intradermal, intratumoral and mucosal (e.g. buccal, intranasal, intrarectal, intravaginal). In various embodiments, the IL-2v, 20 the Fc-IL-2v fusion protein, the homodimer, the heterodimer, the conjugate, the polynucleotide, the vector, the lipoplex (e.g., LNP) and / or the pharmaceutical composition and the one or more additional therapeutic agents are administered by the same or by different routes of administration. In various embodiments, the IL-2v, the Fc-IL-2v fusion protein, the homodimer, the heterodimer, the conjugate, the polynucleotide, the vector, the lipoplex (e.g., LNP) and / or the 25 pharmaceutical composition and the one or more additional therapeutic agents are coadministered according to the same schedule (e.g., co-administered at the same time intervals), or according to different schedules (e.g., co-administered at different time intervals). In some embodiments, the IL-2v, the Fc-IL-2v fusion protein, the homodimer, the heterodimer, the conjugate, the polynucleotide, the vector, the lipoplex (e.g., LNP) and / or the pharmaceutical 30 composition is administered at a dose in the range of 0.5 pg / kg to 1000 pg / kg, e.g., in the range of from 1 pg / kg to 500 pg / kg, e.g., in the range of from 10 pg / kg to 300 pg / kg, e.g., in the range of from 30 pg / kg to 600 pg / kg, e.g., at least 0.5 pg / kg per dose and up to 0.2 pg / kg, 0.3 pg / kg, 0.4 pg / kg, 0.5 pg / kg, 0.6 pg / kg, 0.7 pg / kg, 0.8 pg / kg, 0.9 pg / kg, 1 pg / kg, 1.5 pg / kg, 2pg / kg, 2.5 pg / kg, 3 pg / kg, 3.5 pg / kg, 4 pg / kg, 4.5 pg / kg, 5 pg / kg, 6 pg / kg, 7 pg / kg, 8 pg / kg, 9 pg / kg, 10 2024202988   06 May 2024 pg / kg, 15 pg / kg, 20 pg / kg, 25 pg / kg, 30 pg / kg, 40 pg / kg, 50 pg / kg, 60 pg / kg, 70 pg / kg, 80 pg / kg, 90 pg / kg, 100 pg / kg, 110 pg / kg, 120 pg / kg, 130 pg / kg, 140 pg / kg, 150 pg / kg, 200 pg / kg, 250 pg / kg, 300 pg / kg, 400 pg / kg, 500 pg / kg, 600 pg / kg, 700 pg / kg, 800 pg / kg, 900 pg / kg, 1000 pg / kg per dose. In some embodiments, the IL-2v, the Fc-IL-2v fusion protein, the homodimer, 5 the heterodimer, the conjugate, the polynucleotide, the vector, the lipoplex (e.g., LNP) and / or the pharmaceutical composition is administered at a dose in the range of 0.02 mg to 100 mg, e.g., 0.04 mg to 80 mg, e.g., at least 0.02 mg per dose and up to 0.03 mg, 0.04 mg, 0.05 mg, 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 12 mg, 15 mg, 20 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg or 100 mg per dose. In various embodiments, the methods comprise multiple 10 administrations of the IL-2v, the Fc-IL-2v fusion protein, the homodimer, the heterodimer, the conjugate, the polynucleotide, the vector, the lipoplex (e.g., LNP) and / or the pharmaceutical composition, optionally with one or more additional therapeutic agents, at predetermined intervals. In various embodiments, the methods comprise multiple administrations of the IL-2v, the Fc-IL-2v fusion protein, the homodimer, the heterodimer, the conjugate, the polynucleotide, 15 the vector, the lipoplex (e.g., LNP) and / or the pharmaceutical composition, optionally with one or more additional therapeutic agents, over a time period of at least 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, or longer. In some 20 embodiments, the methods comprise administering the IL-2v, the Fc-IL-2v fusion protein, the homodimer, the heterodimer, the conjugate, the polynucleotide, the vector, the lipoplex (e.g., LNP) and / or the pharmaceutical composition, optionally with one or more additional therapeutic agents, one or more times at predetermined intervals spaced at least 1 week and up to at least 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months or 6 months apart. In some 25 embodiments, the IL-2v, the Fc-IL-2v fusion protein, the homodimer, the heterodimer, the conjugate, the polynucleotide, the vector, the lipoplex (e.g., LNP) and / or the pharmaceutical composition is administered once weekly (i.e., QW), once bi-weekly (i.e. once every other week, or once every two weeks or Q2W), once thrice-weekly (i.e. once every three weeks or Q3W), once monthly (i.e., QM) or once bi-monthly dosing (i.e. once every other month, or once every 30 two months or Q2M), once every three months (Q3M), once every four months (Q4M), once every five months (Q5M), once every six months (Q6M), or less often. In some embodidments, the IL-2v, the Fc-IL-2v fusion protein, the homodimer, the heterodimer, the conjugate, the polynucleotide, the vector, the lipoplex (e.g., LNP) and / or the pharmaceutical composition is administered two or more times subcutaneously at an interval or at intervals between once bi- 35 weekly (i.e. once every other week, or once every two weeks or Q2W) to once thrice-weekly 2024202988   06 May 2024 (i.e. once every three weeks or Q3W). In some embodiments, the IL-2v, the Fc-IL-2v fusion protein, the homodimer, the heterodimer or the conjugate have a serum half-life in a human of at least 6, 9, 12, 15, 18, 21, 24 hours, e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 days, or longer. In some embodiments, the subject or the mammal is a human. 5

[0020] In another aspect, provided is a kit. In various embodiments, the kit comprises one or more unitary doses of the the IL-2v, the Fc-IL-2v fusion protein, the homodimer, the heterodimer, the conjugate, the polynucleotide, the vector, the lipoplex (e.g., LNP) and / or the pharmaceutical composition, described above and herein. In some embodiments, the one or more unitary doses are in a single container, or are in two or more separate containers. In some 10 embodiments, the kit comprises one or more containers selected from the group consisting of vials, ampules and pre-loaded syringes. In some embodiments, the kit comprises one or more containers comprising the fusion protein and / or the homodimer in an aqueous solution. In some embodiments, the aqueous solution comprises the IL-2v, the Fc-IL-2v fusion protein, the homodimer, the heterodimer, the conjugate, the polynucleotide, the vector, the lipoplex (e.g., 15 LNP) and / or the pharmaceutical composition at a concentration in the range of 0.05 mg / ml to 50 mg / ml, e.g., from 0.05 mg / ml to 20 mg / ml, e.g., from 0.1 mg / ml to 40 mg / ml, e.g., from 1.0 mg / ml to 30 mg / ml, e.g., from 0.05 mg / ml to 0.06 mg / ml, 0.07 mg / ml, 0.08 mg / ml, 0.09 mg / ml, 0.1 mg / ml, 0.2 mg / ml, 0.3 mg / ml, 0.4 mg / ml, 0.5 mg / ml, 0.6 mg / ml, 0.7 mg / ml, 0.8 mg / ml, 0.9 mg / ml, 1.0 mg / ml, 1.5 mg / ml, 2.0 mg / ml, 2.5 mg / ml, 3.0 mg / ml, 3.5 mg / ml, 4.0 mg / ml, 4.5 20 mg / ml, 5.0 mg / ml, 6 mg / ml, 7 mg / ml, 8 mg / ml, 9 mg / ml, lOmg / ml, 11 mg / ml, 12 mg / ml, 13 mg / ml, 14 mg / ml, 15 mg / ml, 16 mg / ml, 17 mg / ml, 18 mg / ml, 19 mg / ml, 20 mg / ml, 25 mg / ml, 30 mg / ml, 35 mg / ml, 40 mg / ml, 45 mg / ml or 50 mg / ml. In various embodiments, the one or more unitary doses are the same or are different. In some embodiments, each unitary dose is in the range of 0.5 pg / kg to 1000 pg / kg, e.g., in the range of from 1 pg / kg to 500 pg / kg, e.g., in the 25 range of from 10 pg / kg to 300 pg / kg, e.g., in the range of from 30 pg / kg to 600 pg / kg, e.g., at least 0.5 pg / kg per dose and up to 0.2 pg / kg, 0.3 pg / kg, 0.4 pg / kg, 0.5 pg / kg, 0.6 pg / kg, 0.7 pg / kg, 0.8 pg / kg, 0.9 pg / kg, 1 pg / kg, 1.5 pg / kg, 2pg / kg, 2.5 pg / kg, 3 pg / kg, 3.5 pg / kg, 4 pg / kg, 4.5 pg / kg, 5 pg / kg, 6 pg / kg, 7 pg / kg, 8 pg / kg, 9 pg / kg, 10 pg / kg, 15 pg / kg, 20 pg / kg, 25 pg / kg, 30 pg / kg, 40 pg / kg, 50 pg / kg, 60 pg / kg, 70 pg / kg, 80 pg / kg, 90 pg / kg, 100 pg / kg, 110 pg / kg, 30   120 pg / kg, 130 pg / kg, 140 pg / kg, 150 pg / kg, 200 pg / kg, 250 pg / kg, 300 pg / kg, 400 pg / kg, 500 pg / kg, 600 pg / kg, 700 pg / kg, 800 pg / kg, 900 pg / kg, 1000 pg / kg per dose. In some embodiments, each unitary dose is in the range of 0.02 mg to 100 mg, e.g., 0.04 mg to 80 mg, e.g., at least 0.02 mg per dose and up to 0.03 mg, 0.04 mg, 0.05 mg, 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 12 mg, 15 mg, 20 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg or 100 mg 2024202988   06 May 2024 per dose. In some embodiments, the kit further comprises one or more unitary doses of one or more additional therapeutic agents. In some embodiments, the kit comprises one or more unitary doses of one or more antiviral agents, e.g., against HBV, HIV, HSV or coronavirus. In some embodiments, the kit comprises one or more agonists or activators of one or more toll-like 5 receptors (TLRs). In some embodiments, the TLR agonist or activator is selected from the group consisting of a TLR2 agonist, a TLR3 agonist, a TLR4 agonist, a TLR5 agonist, a TLR7 agonist, a TLR8 agonist and a TLR9 agonist. In some embodiments, the TLR7 agonist is selected from the group consisting of GS 9620 (vesatolimod), R848 (Resiquimod), DS-0509, LHC-165, TMX-101 (imiquimod), RO7020531 and JNJ-4964, and / or wherein the TLR8 agonist 10 is selected from the group consisting of selgantolimod (GS-9688), R848 (Resiquimod) and NKTR-262 (dual TLR7 / TLR8 agonist). In some embodiments, the kit comprises one or more immunostimulatory cytokines or chemokines that promote or increase the proliferation or activation of a / p T cells, y / 5 T cells, NK-T cells, NK cells, and / or dendritic cells. In some embodiments, the one or more immunostimulatory cytokines or chemokines are selected from 15 the group consisting of: IL-10, IL-12, IL-18, gamma chain-dependent cytokines (e.g., IL-4, IL-7, IL-9, IL-15 and IL-21), fms related tyrosine kinase 3 (FLT3) ligand (FLT3L; FLT3LG; NCBI Gene ID: 2323), interferon (IFN)-a, IFN-P, a PEGylated interferon (e.g., PEG-IFN-a2a and / or PEG-IFN-a2b), IFN-y, CXCL9 / Mig (monokine induced by interferon-y), CXCL10 / IP10 (interferon-y-inducible 10 kDa protein) and CXCL11 / I-TAC (interferon-inducible T cell a- 20 chemoattractant), CXCL4 / PF4 (platelet factor 4), monocyte chemoattractant protein 2 (MCP-2), macrophage inflammatory protein 1 alpha (MIP-la), macrophage inflammatory protein 1 beta (MIP-ip) and regulated on activation normal T expressed and secreted protein (RANTES). In some embodiments, the kit comprises one or more interleukin receptor agonists of an interleukin receptor selected from IL-10, IL-12, IL-18 and gamma chain-dependent cytokines (e.g., IL-4, 25   IL-7, IL-9, IL-15 and IL-21). In some embodiments, the kit comprises one or more cytokines selected from the group consisting of IL-10, IL-12, IL-18, gamma chain-dependent cytokines (e.g., IL-4, IL-7, IL-9, IL-15 and IL-21), IFN-a, IFN-p, a PEGylated interferon (e.g., PEG-IFN-a2a and / or PEG-IFN-a2b), IFN-y, and variants thereof. In some embodiments, the kit comprises one or more innate immune activators. In some embodiments, the kit comprises an agonist of a 30 receptor selected from the group consisting of fms related tyrosine kinase 3 (FLT3, a.k.a., CD135, FLK-2, FLK2, STK1), stimulator of interferon genes (STING) receptor, DExD / H-box helicase 58 (DDX58; a.k.a., RIG-I), NLR family pyrin domain containing 3 (NLRP3) and nucleotide binding oligomerization domain containing 2 (NOD2). In some embodiments, the kit comprises one or both of GS-3583 and GS-9992. In some embodiments, the kit comprises one 35 or more antagonists or inhibitors of an inhibitory immune checkpoint protein or receptor and / or 2024202988   06 May 2024 one or more activators or agonists of a stimulatory immune checkpoint protein or receptor. In some embodiments, the one or more immune checkpoint proteins or receptors are selected from the group consisting of: CD27, CD70; CD40, CD40LG; CD47, CD48 (SLAMF2), transmembrane and immunoglobulin domain containing 2 (TMIGD2, CD28H), CD84 (LY9B, 5 SLAMF5), CD96, CD160 (NK1, NK28, BY55), MS4A1 (CD20), CD244 (SLAMF4); CD276 (B7H3); V-set domain containing T cell activation inhibitor 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); natural killer cell cytotoxicity receptor 3 ligand 1 (NCR3LG1, B7H6); HERV-H LTR-associating 2 (HHLA2, B7H7); inducible T cell co-stimulator (ICOS, CD278); 10 inducible T cell costimulator ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF8 (CD30), TNFSF8 (CD30L); TNFRSF10A (CD261, DR4, TRAILRI), TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF10B (CD262, DR5, TRAILR2), TNFRSF10 (TRAIL); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte associated (BTLA)); 15 TNFRSF17 (BCMA, CD269), TNFSF13B (BAFF); TNFRSF18 (GITR), TNFSF18 (GITRL); MHC class I polypeptide-related sequence A (MICA); MHC class I polypeptide-related sequence B (MICB); CD274 (CD274, PDL1, PD-L1); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T-lymphocyte associated protein 4 (CTLA4, CD152); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); Poliovirus receptor 20 (PVR) cell adhesion molecule (PVR, CD 155); PVR related immunoglobulin domain containing (PVRIG, CD112R); T cell immunoreceptor with Ig and ITIM domains (TIGIT); T cell immunoglobulin and mucin domain containing 4 (TIMD4; TIM4); hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3); galectin 9 (LGALS9); lymphocyte activating 3 (LAG3, CD223); signaling lymphocytic activation molecule family member 1 (SLAMF1, SLAM, 25   CD150); lymphocyte antigen 9 (LY9, CD229, SLAMF3); SLAM family member 6 (SLAMF6, CD352); SLAM family member 7 (SLAMF7, CD319); sialic acid binding Ig like lectin 7 (SIGLEC7); sialic acid binding Ig like lectin 9 (SIGLEC9); ULI6 binding protein 1 (ULBP1); ULI6 binding protein 2 (ULBP2); ULI6 binding protein 3 (ULBP3); retinoic acid early transcript IE (RAET1E; ULBP4); retinoic acid early transcript IG (RAET1G; ULBP5); retinoic 30 acid early transcript IL (RAET1L; ULBP6); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); CD160; killer cell lectin like receptor Bl (KLRB1, CD161); killer cell lectin like receptor Cl (KLRC1, NKG2A, CD159A); killer cell lectin like receptor KI (KLRK1, NKG2D, CD314); killer cell lectin like receptor C2 (KLRC2, CD 159c, NKG2C); killer cell lectin like receptor C3 (KLRC3, NKG2E); killer cell lectin like 35 receptor C4 (KLRC4, NKG2F); killer cell immunoglobulin like receptor, two Ig domains and 2024202988   06 May 2024 long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin like receptor DI (KLRD1); 5 killer cell lectin like receptor G1 (KLRG1; CLEC15A, MAFA, 2F1); sialic acid binding Ig like lectin 7 (SIGLEC7); and sialic acid binding Ig like lectin 9 (SIGLEC9). In some embodiments, the kit comprises one or more blockers or inhibitors of one or more T-cell inhibitory immune checkpoint proteins or receptors. In some embodiments, the T-cell inhibitory immune checkpoint proteins or receptors are selected from the group consisting of CD274 (CD274, 10 PDL1, PD-L1); programmed cell death 1 ligand 2 (PDCD1LG2, PD-L2, CD273); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T-lymphocyte associated protein 4 (CTLA4, CD 152); CD276 (B7H3); V-set domain containing T cell activation inhibitor 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B 15 and T lymphocyte associated (BTLA)); PVR related immunoglobulin domain containing (PVRIG, CD112R); T cell immunoreceptor with Ig and ITIM domains (TIGIT); lymphocyte activating 3 (LAG3, CD223); hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3); galectin 9 (LGALS9); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin like receptor, two Ig domains 20 and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); and killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1). In some embodiments, the kit comprises one or more agonists or activators of one or more T-cell stimulatory immune 25 checkpoint proteins or receptors. In some embodiments, the T-cell stimulatory immune checkpoint proteins or receptors are selected from the group consisting of CD27, CD70; CD40, CD40LG; inducible T cell costimulator (ICOS, CD278); inducible T cell costimulator ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF18 (GITR), 30 TNFSF18 (GITRL); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); Poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155). In some embodiments, the kit comprises one or more blockers or inhibitors of one or more NK-cell inhibitory immune checkpoint proteins or receptors. In some embodiments, the NK-cell inhibitory immune checkpoint proteins or receptors are selected from the group consisting of 35 killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, 2024202988   06 May 2024 CD158E1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); killer cell immunoglobulin like receptor, three Ig domains and long 5 cytoplasmic tail 1 (KIR3DL1); CD160; killer cell lectin like receptor Bl (KLRB1, CD161); killer cell lectin like receptor Cl (KLRC1, NKG2A, CD159A); killer cell lectin like receptor DI (KLRD1, CD94); killer cell lectin like receptor G1 (KLRG1; CLEC15A, MAFA, 2F1); sialic acid binding Ig like lectin 7 (SIGLEC7); and sialic acid binding Ig like lectin 9 (SIGLEC9). In some embodiments, the kit comprises one or more agonists or activators of one or more NK-cell 10 stimulatory immune checkpoint proteins or receptors. In some embodiments, the NK-cell stimulatory immune checkpoint proteins or receptors are selected from CD 16, CD226 (DNAM-1); killer cell lectin like receptor KI (KLRK1, NKG2D, CD314); and SLAM family member 7 (SLAMF7). In some embodiments, the kit comprises a proteinaceous (e.g., antibody) inhibitor of PD-L1 (CD274), PD-1 (PDCD1) or CTLA4. In some embodiments, the kit comprises a 15 proteinaceous (e.g., antibody) inhibitor of PD-L1 (CD274) or PD-1 (PDCD1). In some embodiments, the proteinaceous (e.g., antibody) inhibitor of CTLA4 is selected from the group consisting of ipilimumab, tremelimumab, BMS-986218, AGEN1181, AGEN1884 (zalifrelimab), BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002, BCD-145, APL-509, JS-007, BA-3071, ONC-392, AGEN2041, JHL-1155, KN-044, CG-0161, ATOR-1144, 20 PBL5D3H5, FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-019 (PD-I / CTLA4), KN-046 (PD-1 / CTLA4), MEDI-5752 (CTLA4 / PD-1), XmAb-20717 (PD-1 / CTLA4) and AK-104 (CTLA4 / PD-1). In some embodiments, the proteinaceous (e.g., antibody) inhibitor of programmed cell death 1 (PDCD1; NCBI Gene ID: 5133; CD279, PD-1, PD1) is selected from the group consisting of zimberelimab (AB122, GLS-010, WBP-3055), pembrolizumab 25 (KEYTRUDA®, MK-3475, SCH900475), nivolumab (OPDIVO®, BMS-936558, MDX-1106), cemiplimab (LIBTAYO®; cemiplimab-rwlc, REGN-2810), pidilizumab (CT-011), AMG-404, MEDI0680 (AMP-514), spartalizumab (PDR001), tislelizumab (BGB-A317), toripalimab (JS-001), genolimzumab (CBT-501, APL-501, GB 226), SHR-1201, camrelizumab (SHR-1210), sintilimab (TYVYT®; IBI-308), dostarlimab (TSR-042, WBP-285), lambrolizumab (MK-3475); 30 sasanlimab (PF-06801591), cetrelimab (JNJ-63723283), serplulimab (HLX-10), retifanlimab (MGA-012), balstilimab (AGEN2034), prolgolimab (BCD 100), budigalimab (ABBV-181), vopratelimab (JTX-4014), AK-103 (HX-008), AK-105, CS 1003, BI-754091, LZM-009, Sym-021, BAT-1306, PD1-PIK, tebotelimab (MGD013; PD-l / LAG-3), RO-7247669 (PD-l / LAG-3), FS-118 (LAG-3 / PD-L1), RO-7121661 (PD l / TIM-3), RG7769 (PD-l / TIM-3), PF-06936308 35 (PD 1 / CTLA4), MGD-019 (PD-1 / CTLA4), KN-046 (PD 1 / CTLA4), XmAb-20717 (PD 2024202988   06 May 2024 1 / CTLA4), AK-104 (CTLA4 / PD-1) and MEDI-5752 (CTLA4 / PD-1). In some embodiments, the proteinaceous (e.g., antibody) inhibitor of CD274 molecule (NCBI Gene ID: Gene ID: 29126; B7-H, B7H1, PD-L1) is selected from the group consisting of atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®; MSB0010718C), envafolimab (ASC22), 5 durvalumab (IMFINZI®; MEDI-4736), BMS-936559 (MDX1105), cosibelimab (CK-301), lodapolimab (LY 3300054), garivulimab (BGB A333), envafolimab (KN035), opucolimab (HLX 20), manelimab (BCD 135), CX-072, CBT-502 (TQB2450), MSB-2311, SHR-1316, sugemalimab (CS-1001; WBP3155), A167 (KL-A167, HBM 9167), STI-A1015 (IMC-001), FAZ-053, BMS-936559 (MDX1105), INCB086550, GEN-1046 (PD-L1 / 4-1BB), FPT-155 10   (CTLA4 / PD-L1 / CD28), M7824 (PD-Ll / TGFp-EC domain), CA-170 (PD-L1 / VISTA), CDX- 527 (CD27 / PD-L1), LY-3415244 (TIM-3 / PDL1), INBRX-105 (4-1BB / PDL1) and GNS-1480 (PD-L1 / EGFR). In some embodiments, the kit comprises a small molecule inhibitor of CD274 (PDL1, PD-L1), programmed cell death 1 (PDCD1, PD1, PD-1) or CTLA4. In some embodiments, the small molecule inhibitor of CD274 or PDCD1 is selected from the group 15 consisting of GS-4224, GS-4416, INCB086550 and MAX10181. In some embodiments, the small molecule inhibitor of CTLA4 comprises BPI-002. In some embodiments, the kit comprises one or more agents that selectively deplete regulatory T (Treg) cells. In some embodiments, the one or more agents that selectively deplete effector regulatory T (Treg) cells comprise an antibody or antigen-binding fragment thereof that selectively binds to a cell surface 20 receptor selected from the group consisting of C-C motif chemokine receptor 4 (CCR4), C-C motif chemokine receptor 7 (CCR7), C-C motif chemokine receptor 8 (CCR8), C-X-C motif chemokine receptor 4 (CXCR4; CD 184), TNFRSF4 (OX40), TNFRSF18 (GITR, CD357), TNFRSF9 (4-1BB, CD137), cytotoxic T-lymphocyte associated protein 4 (CTLA4, CD152), programmed cell death 1 (PDCD1, PD-1), Sialyl Lewis x (CD15s), CD27, ectonucleoside 25 triphosphate diphosphohydrolase 1 (ENTPD1; CD39), protein tyrosine phosphatase receptor type C (PTPRC; CD45), neural cell adhesion molecule 1 (NCAM1; CD56), selectin L (SELL; CD62L), integrin subunit alpha E (ITGAE; CD 103), interleukin 7 receptor (IL7R; CD 127), CD40 ligand (CD40LG; CD 154), folate receptor alpha (FOLRI), folate receptor beta (FOLR2), leucine rich repeat containing 32 (LRRC32; GARP), IKAROS family zinc finger 2 (IKZF2; 30 HELIOS), inducible T cell costimulatory (ICOS; CD278), lymphocyte activating 3 (LAG3; CD223), transforming growth factor beta 1 (TGFB1), hepatitis A virus cellular receptor 2 (HAVCR2; CD366; TIM3), T cell immunoreceptor with Ig and ITIM domains (TIGIT), TNF receptor superfamily member IB (CD 120b; TNFR2), IL-2RA (CD25), and combinations thereof. In some embodiments, the kit comprises one or more additional therapeutic agents 35 comprising an inhibitor or antagonist of: mitogen-activated protein kinase kinase kinase kinase 2024202988   06 May 2024 1 (MAP4K1) (also called Hematopoietic Progenitor Kinase 1 (HPK1)), phosphatidylinositol-4,5-bisphosphate 3-kinase, including catalytic subunit alpha (PIK3CA), catalytic subunit beta (PIK3CB), catalytic subunit gamma (PIK3CG) and catalytic subunit delta (PIK3CD), diacylglycerol kinase alpha (DGKA, DAGK, DAGK1 or DGK-alpha), T cell immunoreceptor 5 with Ig and ITIM domains (TIGIT), X-linked inhibitor of apoptosis (XIAP, BIRC4, IAP-3), baculoviral LAP repeat containing 2 (BIRC2, cIAPl), baculoviral LAP repeat containing 3 (BIRC3, cIAP2), baculoviral IAP repeat containing 5 (BIRC5, survivin), or cytokine inducible SH2 containing protein (CISH). In some embodiments, the kit comprises one or more additional therapeutic agents comprising an activator or agonist of: a toll-like receptor (TLR); a stimulator 10   of interferon genes (STING) receptor; inducible T cell costimulator (ICOS, CD278); and / or a TNF receptor superfamily (TNFRSF) member. In some embodiments, the the TNF receptor superfamily (TNFRSF) member is selected from the group consisting of: TNFRSF 1 A, TNFRSF IB, TNFRSF4 (OX40), TNFRSF5 (CD40), TNFRSF6 (FAS), TNFRSF7 (CD27), TNFRSF8 (CD30), TNFRSF9 (4-1BB, CD137), TNFRSF10A (CD261, DR4, TRAILRI), 15 TNFRSF10B (CD262, DR5, TRAILR2), TNFRSF10C (CD263, TRAILR3), TNFRSF10D (CD264, TRAILR4), TNFRSF11A (CD265, RANK), TNFRSF11B, TNFRSF12A (CD266), TNFRSF13B (CD267), TNFRSF13C (CD268), TNFRSF16 (NGFR, CD271), TNFRSF17 (BCMA, CD269), TNFRSF18 (GITR, CD357), TNFRSF19, TNFRSF21 (CD358, DR6), and TNFRSF25 (DR3). In some embodiments, the kit comprises: aTNFRSF4 (OX40 or CD 134) 20 activator or agonist selected from INCAGN1949, tavolimab (MEDI0562), pogalizumab (MOXR0916 / RG7888), MEDI6469, BMS 986178, PF-04518600, GSK3174998, IBI101, ATOR-1015, ABBV-368 or SL-279252; a TNFRSF9 (4-1BB or CD137) activator or agonist selected from urelumab, BMS-663513, utomilumab (PF-05082566), CTX-471, MP-0310, ADG-106, ATOR-1017, AGEN2373 or QL1806; and / or a TNFRSF18 (GITR or CD357) activator or 25 agonist selected from GWN323, MEDI1873, MK-1248, MK-4166, TRX518, INCAGN1876, BMS-986156, BMS-986256, AMG-228, ASP1951 (PTZ 522), FPA-154 or OMP-336B11. In some embodiments, the kit comprises a molecule that concurrently binds to TNF receptor superfamily member 4 (TNFRSF4, OX40 or CD134) and TNF receptor superfamily member 18 (TNFRSF 18, GITR or CD357). In some embodiments, the kit comprises a molecule selected 30 from the group consisting of AGEN 1884 (zalifrelimab), AGEN 1181, AGEN 2034 (balstilimab), AGEN1307, AGEN2373, AGEN1223 and GS-1423.

[0021] With respect to kits comprising therapeutic agents for anti-HBV combination therapies, in some embodiments, the one or more antiviral agents are selected from the group consisting of lamivudine (LAM), adefovir dipivoxil (ADV), entecavir (ETV), telbivudine (LdT), 2024202988   06 May 2024 tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF or VEMLIDY®), ledipasvir + sofosbuvir (HARVONI®) and a PEGylated interferon (e.g., PEG-IFN-a2a and / or PEG-IFN-a2b). In some embodiments, the kit further comprises one or more unitary doses of one or more therapeutic agents selected from the group consisting of HBV antigen inhibitors (e.g., HBV core 5 antigen (HBcAg) inhibitors, HBV surface antigen (HBsAg) inhibitors, HBx inhibitors, HBV E antigen inhibitors), anti-HBV antigen antibodies, inhibitory nucleic acids targeting HBV (e.g., antisense oligonucleotide, short interfering RNA (siRNA), DNA-directed RNA interference (ddRNAi)), gene editors targeting HBV (e.g., CRISPR-Cas (e.g., Cas9, Cas 12, Cascade, Cas 13), zinc finger nucleases, homing endonucleases, homing meganucleases (e.g., ARCUS), synthetic 10 nucleases, TALENs), covalently closed circular DNA (cccDNA) inhibitors, HBsAg secretion or assembly inhibitors, HBV viral entry inhibitors, and CAR-T and T cell bispecific (redirected T cells) for specific killing of HBV-infected cells.

[0022] With respect to kits comprising therapeutic agents for anti-HBV combination therapies, in some embodiments, the kit comprises one or more unitary doses of one or more 15 antiretroviral agents. In some embodiments, the kit comprises one or more anti-HIV broadly neutralizing antibodies. In some embodiments, the one or more anti-HIV broadly neutralizing antibodies bind to an epitope or region of gpl20 selected from the group consisting of: (i) third variable loop (V3) and / or high mannose patch comprising a N332 oligomannose glycan; (ii) second variable loop (V2) and / or Env trimer apex; (iii) CD4 binding site (CD4bs); (iv) 20 gpl20 / gp41 interface; or (v) silent face of gpl20. In some embodiments, the one or more antiHIV broadly neutralizing antibodies bind to an epitope or region of gpl20 in the third variable loop (V3) and / or high mannose patch comprising a N332 oligomannose glycan and competes with or comprises VH and VL regions from an antibody selected from the group consisting of GS-9722, PGT-121, PGT-121.414, PGT-122, PGT-123, PGT-124, PGT-125, PGT-126, PGT- 25   128, PGT-130, PGT-133, PGT-134, PGT-135, PGT-136, PGT-137, PGT-138, PGT-139, 10 1074, 10-1074-J, VRC24, 2G12, BG18, 354BG8, 354BG18, 354BG42, 354BG33, 354BG129, 354BG188, 354BG411, 354BG426, DH270.1, DH270.6, PGDM12, VRC41.01, PGDM21, PCDN-33A, BF520.1 and VRC29.03. In some embodiments, the one or more anti-HIV broadly neutralizing antibodies bind to an epitope or region of gpl20 in the second variable loop (V2) 30 and / or Env trimer apex and competes with or comprises VH and VL regions from an antibody selected from the group consisting of PG9, PG16, PGC14, PGG14, PGT-142, PGT-143, PGT-144, PGT-145, CHOI, CH59, PGDM1400, CAP256, CAP256-VRC26.08, CAP256-VRC26.09, CAP256-VRC26.25, PCT64-24E and VRC38.01. In some embodiments, the one or more antiHIV broadly neutralizing antibodies bind to an epitope or region of gpl20 in the CD4 binding 2024202988   06 May 2024 site (CD4bs) and competes with or comprises VH and VL regions from an antibody selected from the group consisting of 3BNC117, GS-9723, 3BNC60, b 12, F105, VRC01, VRC07, VRC07-523, VRC03, VRC06, VRC06b01 VRC08, VRC0801, NIH45-46, VRC-PG04, PGV04; CH103,44-VRC13.01, 1NC9, 12A12, N6, N49-P7, NC-Cowl, I0MA, CH235 andCH235.12, 5   N49P6, N49P7, N49P11, N49P9 and N60P25. In some embodiments, the one or more anti-HIV broadly neutralizing antibodies bind to an epitope or region of gpl20 in the gpl20 / gp41 interface and competes with or comprises VH and VL regions from an antibody selected from the group consisting of PGT-151, CAP248-2B, 35022, 8ANC195, ACS202, VRC34 and VRC34.01. In some embodiments, the one or more anti-HIV broadly neutralizing antibodies 10 bind to an epitope or region of the gpl20 silent face and competes with or comprises VH and VL regions from an antibody selected from VRC-PG05 and SF12. In some embodiments, the one or more anti-HIV broadly neutralizing antibodies bind to an epitope or region of gp41 in the membrane proximal region (MPER). In some embodiments, the one or more anti-HIV broadly neutralizing antibodies bind to an epitope or region of gp41 in the membrane proximal region 15   (MPER) and competes with or comprises VH and VL regions from an antibody selected from the group consisting of 10E8, 10E8v4, 10E8-5R-100cF, 4E10, DH511.11P, 2F5, 7b2, andLNOl. In some embodiments, the one or more anti-HIV broadly neutralizing antibodies bind to an epitope or region of the gp41 fusion peptide and competes with or comprises VH and VL regions from an antibody selected from the group consisting of VRC34 and ACS202. 20

[0023] With respect to kits comprising therapeutic agents for vaccine enhancement combination therapies, in some embodiments, the kit comprises one or more unitary doses of a vaccine. In some embodiments, the vaccine is selected from the group consisting of an antiviral vaccine, an antibacterial vaccine and an anticancer vaccine. In some embodiments, the vaccine comprises an antiviral vaccine against a virus selected from the group consisting of hepatitis A 25 virus (HAV), hepatitis B virus (HBV), human immunodeficiency virus (HIV), cytomegalovirus (CMV), a herpes simplex virus (HSV), Epstein-Barr virus (EBV), human orthopneumovirus or human respiratory syncytial virus (RSV), human papillomavirus (HPV), varicella-zoster virus, measles virus, mumps virus, poliovirus vaccine, influenza virus, paramyxovirus, rotavirus, Zika virus, Dengue virus, Ebola virus and coronavirus (e.g., betacoronavirus, e.g., severe acute 30 respiratory syndrome-related coronavirus, e.g., SARS-CoV2). In some embodiments, the vaccine comprises an antibacterial vaccine against a bacterium selected from the group consisting of mycobacterium tuberculosis, pertussis, tetanus, diphtheria, meningococcus, pneumococcus, Haemophilus influenza, cholera, typhoid, and anthrax. 2024202988   06 May 2024

[0024] With respect to kits comprising therapeutic agents for anticancer combination therapies, in some embodiments, the kit comprises one or more unitary doses of one or more anti-neoplastic or chemotherapeutic agents. In some embodiments, the kit comprises one or more unitary doses of one or more anti-neoplastic or chemotherapeutic agents are selected from 5 the group consisting of a nucleoside analog (e.g., 5-fluorouracil, gemcitabine, cytarabine, cladribine, pentostatin, fludarabine), ataxane (e.g., paclitaxel, nab-paclitaxel, docetaxel, cabazitaxel), a platinum coordination complex (cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, satraplatin, dicycloplatin, eptaplatin, lobaplatin, miriplatin), a dihydrofolate reductase (DHFR) inhibitor (e.g., methotrexate, 10 trimetrexate, pemetrexed), a topoisomerase inhibitor (e.g., doxorubicin, daunorubicin, dactinomycin, eniposide, epirubicin, etoposide, idarubicin, irinotecan, mitoxantrone, pixantrone, sobuzoxane, topotecan, irinotecan, MM-398 (liposomal irinotecan), vosaroxin and GPX-150, aldoxorubicin, AR-67, mavelertinib, AST-2818, avitinib (ACEA-0010), irofulven (MGI-114)), an alkylating agent (e.g., a nitrogen mustard (e.g., cyclophosphamide, chlormethine, uramustine 15 or uracil mustard, melphalan, chlorambucil, ifosfamide, bendamustine, temozolomide, carmustine), a nitrosourea (e.g., carmustine, lomustine, streptozocin), an alkyl sulfonate (e.g., busulfan)), and mixtures thereof. In some embodiments, the kit comprises one or more unitary doses of one or more antibodies or antigen-binding antibody fragments thereof, or antibody-drug conjugates thereof, CD3-targeting multi-specific molecules, NK cell-activating receptor- 20 targeting multi-specific molecules, or non-immunoglobulin antigen-binding domains or antibody mimetic proteins directed against one or more targets or tumor associated antigens (TAAs) selected from the group consisting of: CD 19; membrane spanning 4-domains Al (MS4A1; CD20); CD22 (SIGLEC2); CD27 (TNFRSF7); TNFRSF8 (CD30); CD33 (SIGLEC3); CD37; CD38; CD40 (TNFRSF5), CD44; CD47; CD48 (SLAMF2); CD52; CD70 (TNFSF7; CD27L); 25   5'-nucleotidase ecto (NT5E; CD73), ectonucleoside triphosphate diphosphohydrolase 1 (CD39), CD74; CD79B; CD80; CD86; interleukin 3 receptor subunit alpha (IL3RA), prominin 1 (PROM1; CD133); TNFRSF9 (CD137); syndecan 1 (SDC1; CD138); CD200 molecule (CD200); alpha fetoprotein (AFP), BAG cochaperone 6 (BAG6); MET proto-oncogene, receptor tyrosine kinase (MET); KIT proto-oncogene, receptor tyrosine kinase (KIT); C-type lectin 30 domain family 12 member A (CLEC12A; CD371); C-type lectin domain containing 9A (CLEC9A; CD370); cadherin 3 (CDH3); carbonic anhydrase 6 (CA6); carbonic anhydrase 9 (CA9); carcinoembryonic antigen related cell adhesion molecule 3 (CEACAM3); carcinoembryonic antigen related cell adhesion molecule 5 (CEACAM5); carcinoembryonic antigen related cell adhesion molecule 6 (CEACAM6); chorionic somatomammotropin hormone 35   1 (CSH1); coagulation factor III, tissue factor (F3); collectin subfamily member 10 (COLEC10; 2024202988   06 May 2024 CLL1); delta like canonical Notch ligand 3 (DLL3); ectonucleotide pyrophosphatase / phosphodiesterase 3 (ENPP3); ephrin Al (EFNA1); epidermal growth factor receptor (EGFR; ERBB; HER1); EGFR variant III (EGFRvIII); EPH receptor A2 (EPHA2); epithelial cell adhesion molecule (EPCAM); erb-b2 receptor tyrosine kinase 2 (ERBB2; HER-2 / neu); 5 fibroblast activation protein alpha (FAP); fibroblast growth factor receptor 2 (FGFR2); fibroblast growth factor receptor 3 (FGFR3); folate hydrolase 1 (FOLH1); folate receptor 1 (FOLRI); GD2 ganglioside; glycoprotein NMB (GPNMB; osteoactivin); guanylate cyclase 2C (GUCY2C); human papillomavirus (HPV) E6; HPV E7; major histocompatibility complex (MHC) class I-presented neoantigens, major histocompatibility complex (MHC) class II- 10 presented neoantigens, major histocompatibility complex, class I, E (HLA-E); major histocompatibility complex, class I, F (HLA-F); major histocompatibility complex, class I, G (HLA-G); MHC class I polypeptide-related sequence A (MICA); MHC class I polypeptide-related sequence B (MICB); integrin subunit beta 7 (ITGB7); leukocyte immunoglobulin like receptor Bl (LILRB1; ILT2); leukocyte immunoglobulin like receptor B2 (LILRB2; ILT4); 15 LY6 / PLAUR domain containing 3 (LYPD3); glypican 3 (GPC3); KRAS proto-oncogene, GTPase (KRAS); MAGE family member Al (MAGEA1); MAGE family member A3 (MAGEA3); MAGE family member A4 (MAGEA4); MAGE family member All (MAGEA11); MAGE family member Cl (MAGECI); MAGE family member C2 (MAGEC2); MAGE family member C3 (MAGEC3); MAGE family member DI (MAGED1); MAGE family 20 member D2 (MAGED2); mesothelin (MSLN); mucin 1 (MUC1) and splice variants thereof (e.g., including MUC1 / A, C, D, X, Y, Z and REP); mucin 16 (MUC16; CA125); natural killer cell cytotoxicity receptor 3 ligand 1 (NCR3LG1; B7-H6); necdin, MAGE family member (NDN); nectin cell adhesion molecule 2 (NECTIN2); nectin cell adhesion molecule 4 (NECTIN4); SLIT and NTRK like family member 6 (SLITRK6); promyelocytic leukemia 25 (PML); protein tyrosine kinase 7 (inactive) (PTK7); Poliovirus receptor (PVR) cell adhesion molecule (PVR); SLAM family member 6 (SLAMF6); SLAM family member 7 (SLAMF7); sialic acid binding Ig like lectin 7 (SIGLEC7); sialic acid binding Ig like lectin 9 (SIGLEC9); sialic acid binding Ig like lectin 10 (SIGLEC10); signal regulatory protein alpha (SIRPA) solute carrier family 34 (sodium phosphate), member 2 (SLC34A2); solute carrier family 39 member 6 30   (SLC39A6); STEAP family member 1 (STEAP1); suppression of tumorigenicity 2 (ST2); TNF receptor superfamily member 4 (TNFRSF4; OX40); TNF superfamily member 9 (TNFSF9; 4-1BB-L, CD137L); TNFRSF10A (DR4, TRAILRI); TNFRSF10B (DR5, TRAILR2); TNFRSF13B (BAFF); TNFRSF17 (BCMA); TNFRSF18 (GITR); transferrin (TF); transforming growth factor beta 1 (TGFB1) and isoforms thereof; triggering receptor expressed on myeloid 35 cells 1 (TREM1); triggering receptor expressed on myeloid cells 2 (TREM2); trophoblast 2024202988   06 May 2024 glycoprotein (TPBG); trophinin (TRO); tumor associated calcium signal transducer 2 (TACSTD2); Fucosyl GM1; sialyl Lewis adhesion molecule (sLe); and Lewis Y antigen. In some embodiments, the kit comprises one or more antibodies or antigen-binding antibody fragments thereof, or antibody-drug conjugates thereof, CD3-targeting multi-specific molecules, 5 NK cell-activating receptor-targeting multi-specific molecules, or non-immunoglobulin antigen binding domains or antibody mimetic proteins binds to an epitope of a target or tumor associated antigen (TAA) presented in a major histocompatibility complex (MHC) molecule. In some embodiments, the NK cell-activating receptor is selected from the group consisting of CD 16, NKp30, NKp44, NKp46, NKp80 and NKG2D. In some embodiments, the kit comprises one or 10   more populations of immune cells selected from the group consisting of: natural killer (NK) cells, NK-T cells, T cells, cytokine-induced killer (CIK) cells, macrophage (MAC) cells, tumor infiltrating lymphocytes (TILs) and dendritic cells (DCs). In some embodiments, the kit comprises a population of T cells selected from the group consisting of: alpha / beta TCR T cells, gamma / delta TCR T cells, regulatory T (Treg) cells and TRuC™ T cells. In some embodiments, 15 the one or more cellular therapies comprise a NK cell therapy comprising NK-92 cells. In some embodiments, the cells are allogeneic to an intended recipient. In some embodiments, the one or more populations of immune cells comprise one or more chimeric antigen receptors (CARs). In some embodiments, the one or more CARs bind to a target or tumor associated antigen (TAA) selected from the group consisting of selected from the group consisting of: CD 19; membrane 20 spanning 4-domains Al (MS4A1; CD20); CD22 (SIGLEC2); CD27 (TNFRSF7); TNFRSF8 (CD30); CD33 (SIGLEC3); CD37; CD38; CD40 (TNFRSF5), CD44; CD47; CD48 (SLAMF2); CD52; CD70 (TNFSF7; CD27L); 5'-nucleotidase ecto (NT5E; CD73), ectonucleoside triphosphate diphosphohydrolase 1 (CD39), CD74; CD79B; CD80; CD86; interleukin 3 receptor subunit alpha (IL3RA), prominin 1 (PROM1; CD133); TNFRSF9 (CD137); syndecan 1 (SDC1; 25 CD 138); CD200 molecule (CD200); alpha fetoprotein (AFP), BAG cochaperone 6 (BAG6); MET proto-oncogene, receptor tyrosine kinase (MET); KIT proto-oncogene, receptor tyrosine kinase (KIT); C-type lectin domain family 12 member A (CLEC12A; CD371); C-type lectin domain containing 9A (CLEC9A; CD370); cadherin 3 (CDH3); carbonic anhydrase 6 (CA6); carbonic anhydrase 9 (CA9); carcinoembryonic antigen related cell adhesion molecule 3 30 (CEACAM3); carcinoembryonic antigen related cell adhesion molecule 5 (CEACAM5); carcinoembryonic antigen related cell adhesion molecule 6 (CEACAM6); chorionic somatomammotropin hormone 1 (CSH1); coagulation factor III, tissue factor (F3); collectin subfamily member 10 (COLEC10; CLL1); delta like canonical Notch ligand 3 (DLL3); ectonucleotide pyrophosphatase / phosphodiesterase 3 (ENPP3); ephrin Al (EFNA1); epidermal 35 growth factor receptor (EGFR; ERBB; HER1); EGFR variant III (EGFRvIII); EPH receptor A2 2024202988   06 May 2024 (EPHA2); epithelial cell adhesion molecule (EPCAM); erb-b2 receptor tyrosine kinase 2 (ERBB2; HER-2 / neu); fibroblast activation protein alpha (FAP); fibroblast growth factor receptor 2 (FGFR2); fibroblast growth factor receptor 3 (FGFR3); folate hydrolase 1 (FOLH1); folate receptor 1 (FOLRI); GD2 ganglioside; glycoprotein NMB (GPNMB; osteoactivin); 5 guanylate cyclase 2C (GUCY2C); human papillomavirus (HPV) E6; HPV E7; major histocompatibility complex (MHC) class I-presented neoantigens, major histocompatibility complex (MHC) class Il-presented neoantigens, major histocompatibility complex, class I, E (HLA-E); major histocompatibility complex, class I, F (HLA-F); major histocompatibility complex, class I, G (HLA-G); MHC class I polypeptide-related sequence A (MICA); MHC class 10 I polypeptide-related sequence B (MICB); integrin subunit beta 7 (ITGB7); leukocyte immunoglobulin like receptor Bl (LILRB1; ILT2); leukocyte immunoglobulin like receptor B2 (LILRB2; ILT4); LY6 / PLAUR domain containing 3 (LYPD3); glypican 3 (GPC3); KRAS proto-oncogene, GTPase (KRAS); MAGE family member Al (MAGEA1); MAGE family member A3 (MAGEA3); MAGE family member A4 (MAGEA4); MAGE family member All 15 (MAGEA11); MAGE family member Cl (MAGECI); MAGE family member C2 (MAGEC2); MAGE family member C3 (MAGEC3); MAGE family member DI (MAGED1); MAGE family member D2 (MAGED2); mesothelin (MSLN); mucin 1 (MUC1) and splice variants thereof (e.g., including MUCl / A, C, D, X, Y, Z and REP); mucin 16 (MUC16; CA125); natural killer cell cytotoxicity receptor 3 ligand 1 (NCR3LG1; B7-H6); necdin, MAGE family member 20 (NDN); nectin cell adhesion molecule 2 (NECTIN2); nectin cell adhesion molecule 4 (NECTIN4); SLIT and NTRK like family member 6 (SLITRK6); promyelocytic leukemia (PML); protein tyrosine kinase 7 (inactive) (PTK7); Poliovirus receptor (PVR) cell adhesion molecule (PVR); SLAM family member 6 (SLAMF6); SLAM family member 7 (SLAMF7); sialic acid binding Ig like lectin 7 (SIGLEC7); sialic acid binding Ig like lectin 9 (SIGLEC9); 25 sialic acid binding Ig like lectin 10 (SIGLEC10); signal regulatory protein alpha (SIRPA) solute carrier family 34 (sodium phosphate), member 2 (SLC34A2); solute carrier family 39 member 6 (SLC39A6); STEAP family member 1 (STEAP1); suppression of tumorigenicity 2 (ST2); TNF receptor superfamily member 4 (TNFRSF4; OX40); TNF superfamily member 9 (TNFSF9; 4-1BB-L, CD137L); TNFRSF10A (DR4, TRAILRI); TNFRSF10B (DR5, TRAILR2); 30 TNFRSF13B (BAFF); TNFRSF17 (BCMA); TNFRSF18 (GITR); transferrin (TF); transforming growth factor beta 1 (TGFB1) and isoforms thereof; triggering receptor expressed on myeloid cells 1 (TREM1); triggering receptor expressed on myeloid cells 2 (TREM2); trophoblast glycoprotein (TPBG); trophinin (TRO); tumor associated calcium signal transducer 2 (TACSTD2); Fucosyl GM1; sialyl Lewis adhesion molecule (sLe); and Lewis Y antigen. In 35 some embodiments, the one or more CARs bind to an epitope of a target or tumor associated 2024202988   06 May 2024 antigen (TAA) presented in a major histocompatibility complex (MHC) molecule. In some embodiments, the TAA is a cancer testis antigen. In some embodiments, the cancer testis antigen is selected from the group consisting of acrosin binding protein (ACRBP), alpha fetoprotein (AFP), A-kinase anchoring protein 4 (AKAP4), ATPase family AAA domain 5 containing 2 (ATAD2), kinetochore scaffold 1 (KNL1; a.ka., CASC5), centrosomal protein 55 (CEP55), cancer / testis antigen 1A (CTAG1A; a.k.a., ESO1; CT6.1; LAGE-2; LAGE2A; NY-ESO-1), cancer / testis antigen IB (CTAG1B; a.k.a., CT6.1, CTAG, CTAG1, ESO1, LAGE-2, LAGE2B, NY-ESO-1), cancer / testis antigen 2 (CTAG2; a.k.a., CAMEL, CT2, CT6.2, CT6.2a, CT6.2b, ESO2, LAGE-1, LAGE2B), CCCTC-binding factor like (CTCFL), catenin alpha 2 10 (CTNNA2), cancer / testis antigen 83 (CT83), cyclin Al (CCNA1), DEAD-box helicase 43 (DDX43), developmental pluripotency associated 2 (DPPA2), fetal and adult testis expressed 1 (FATE1), FMRI neighbor (FMR1NB), HORMA domain containing 1 (HORMAD1), insulin like growth factor 2 mRNA binding protein 3 (IGF2BP3), leucine zipper protein 4 (LUZP4), lymphocyte antigen 6 family member K (LY6K), maelstrom spermatogenic transposon silencer 15 (MAEL), MAGE family member Al (MAGEA1); MAGE family member A3 (MAGEA3); MAGE family member A4 (MAGEA4); MAGE family member Al 1 (MAGEA11); MAGE family member Cl (MAGECI); MAGE family member C2 (MAGEC2); MAGE family member DI (MAGED1); MAGE family member D2 (MAGED2), kinesin family member 20B (KIF20B; a.k.a., MPHOSPH1), NUF2 component of NDC80 kinetochore complex (NUF2), nuclear RNA 20 export factor 2 (NXF2), PAS domain containing repressor 1 (PASD1), PDZ binding kinase (PBK), piwi like RNA-mediated gene silencing 2 (PIWIL-2), preferentially expressed antigen in melanoma (PRAME), sperm associated antigen 9 (SPAG9), sperm protein associated with the nucleus, X-linked, family member Al (SPANXA1), SPANX family member A2 (SPANXA2), SPANX family member C (SPANXC), SPANX family member D (SPANXD), SSX family 25 member 1 (SSX1), SSX family member 2 (SSX2), synaptonemal complex protein 3 (SYCP3), testis expressed 14, intercellular bridge forming factor (TEX14), transcription factor Dp family member 3 (TFDP3), serine protease 50 (PRSS50, a.k.a., TSP50), TTK protein kinase (TTK) and zinc finger protein 165 (ZNF165). In some embodiments, the kit comprises one or more unitary doses of a targeted E3 ligase ligand conjugate. In some embodiments, the kit comprises one or 30 more unitary doses of an inhibitor or antagonist of: protein tyrosine phosphatase, non-receptor type 11 (PTPN11 or SHP2), myeloid cell leukemia sequence 1 (MCL1) apoptosis regulator, 5'-nucleotidase ecto (NT5E or CD73), ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1 or CD39), transforming growth factor beta 1 (TGFB1 or TGF0), heme oxygenase 1 (HM0X1, HO-1 or HOI), heme oxygenase 2 (HM0X2, HO-2 or HO2), vascular endothelial 35 growth factor A (VEGFA or VEGF), erb-b2 receptor tyrosine kinase 2 (ERBB2, HER2, 2024202988   06 May 2024 HER2 / neu or CD340), epidermal growth factor receptor (EGFR, ERBB, ERBB1 or HER1), ALK receptor tyrosine kinase (ALK, CD246), poly(ADP-ribose) polymerase 1 (PARP1), poly(ADP-ribose) polymerase 2 (PARP2), TCDD inducible poly(ADP-ribose) polymerase (TIPARP, PARP7), cyclin dependent kinase 4 (CDK4), cyclin dependent kinase 6 (CDK6), TNF 5 receptor superfamily member 14 (TNFRSF14, HVEM, CD270), C-C motif chemokine receptor 2 (CCR2, CD192), C-C motif chemokine receptor 5 (CCR5, CD195), C-C motif chemokine receptor 8 (CCR8, CDwl98), C-X-C motif chemokine receptor 2 (CXCR2, CD182), C-X-C motif chemokine receptor 3 (CXCR3, CD 182, CD 183), C-X-C motif chemokine receptor 4 (CXCR4, CD 184), cytokine inducible SH2 containing protein (CISH), arginase (ARG1, ARG2), 10 carbonic anhydrase (CAI, CA2, CA3, CA4, CA5A, CA5B, CA6, CA7, CA8, CA9, CAIO, CA11, CA12, CAB, CAM), prostaglandin-endoperoxide synthase 1 (PTGS1, COX-1), prostaglandin-endoperoxide synthase 2 (PTGS2, COX-2), secreted phospholipase A2, prostaglandin E synthase (PTGES, PGES), arachidonate 5-lipoxygenase (ALOX5, 5-LOX), soluble epoxide hydrolase 2 (EPHX2), indoleamine 2,3-dioxygenase 1 (IDO1), indoleamine 15 2,3-dioxygenase 2 (IDO2), hypoxia inducible factor 1 subunit alpha (HIF1A), angiopoietin 1 (ANGPT1), Endothelial TEK tyrosine kinase (TIE-2, TEK), Janus kinase 1 (JAKI), catenin beta 1 (CTNNB1), histone deacetylase 9 (HDAC9), 5'-3' exoribonuclease 1 (XRN1), and / or WRN RecQ like helicase (WRN). In some embodiments, the inhibitor of 5'-nucleotidase ecto (NT5E or CD73) is selected from the group consisting of MEDI9447 (oleclumab), CPI-006, 20   BMS-986179, IPH5301, TJ4309 (TJD5), NZV-930, AB-680, PSB-12379, PSB-12441, PSB- 12425, CB-708 and PBF-1662. In some embodiments, the inhibitor of CCR2 and / or CCR5 is selected from the group consisting of BMS-813160, PF-04136309 and CCX-872. In some embodiments, the inhibitor of MCL1 is selected from the group consisting of GS-9716, tapotoclax (AMG-176), AMG-397, S-64315, AZD-5991, 483-LM, A 1210477, UMI-77, JKY-5-25   037 and PRT-1419. In some embodiments, the inhibitor of PTPN11 or SHP2 is selected from the group consisting of TNO155 (SHP-099), RMC-4550, JAB-3068 and RMC-4630. In some embodiments, the inhibitor of Janus kinase 1 (JAKI) is selected from the group consisting of fdgotinib, tofacitinib, baricitinib and ABT-494.

[0025] Unless otherwise defined, all technical and scientific terms used herein have the 30 same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the exemplary methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, 2024202988   06 May 2024 the present application, including definitions, will control. The materials, methods, and examples are illustrative only and not intended to be limiting.

[0026] Other features and advantages of the invention will be apparent from the following detailed description and from the claims. 5                 BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figures 1A-L illustrate graphics showing the (A) IL-2 receptor quaternary complex, (B) IL-2 Interface with key residues selected for mutation and (C-L) interaction of these key residues with surrounding residues from IL-2Ra and IL-2.

[0028] Figure 2 illustrates a ribbon diagram of the designed heterodimeric Fc-IL-2v 10 fusion proteins, described herein. Chain 1 is a variant IgG4 Fc subunit fused to IL-2v via a flexible polypeptide linker. Chain 2 is a complementary variant IgG4 Fc subunit that preferentially heterodimerizes with chain 1.

[0029] Figure 3 illustrates in vitro potency of Fc-IL-2 variant fusion proteins with single substitutions in IL-2 at IL-2Ra binding interface on CTLL-2 cells. 15

[0030] Figures 4A-4R illustrate Biacore binding responses obtained following injection of different concentrations of Fc-IL-2 variant fusion proteins over an IL-2Ra surface. Binding was tested at concentrations up to 20.0 pM in a two-fold concentration series for all samples except 104.46 (F), 111.46 (M) and 113.46 (0) which were studied up to 12.3 pM, 14.8 pM and 16.1 pM, respectively. 20

[0031] Figure 5 illustrates in vitro potency of Fc-IL-2 variant fusion proteins with two or three amino acid substitutions in IL-2 at IL-2Ra binding interface on CTLL-2 cells.

[0032] Figures 6A-6B illustrate in vitro potency of Fc-IL-2 variant fusion proteins with two or three amino acid substitutions in IL-2 at IL-2Ra binding interface on CD 8+ T cell (A) and Treg (B) cell STAT5 activation. 25

[0033] Figure 7 illustrates in vitro potency of Fc-IL-2 variant fusion proteins with two or three amino acid substitutions in IL-2 at IL-2Ra binding interface on KHYG-1 NK cells.

[0034] Figures 8A-8B illustrate in vitro potency of Fc-IL-2 variant fusion proteins with two or three amino acid substitutions in IL-2 at IL-2Ra binding interface on CD 8+ T cell (A) and NK cell (B) proliferation. 30

[0035] Figures 9A-9B illustrate in vitro potency of Fc-IL-2 variant fusion proteins on cynomolgus macaque CD 8+ T cell (A) and Treg cell (B) STAT5 activation. 2024202988   06 May 2024

[0036] Figure 10 illustrates in vitro potency of mouse surrogate Fc-IL-2 variant fusion proteins on CTLL-2 cells.

[0037] Figure 11 illustrates in vitro potency of mouse surrogate Fc-IL-2 variant fusion proteins on Ba / F3 cells. 5

[0038] Figure 12 illustrates single dose pharmacokinetic (PK) curves for Fc-IL-2v heterodimers 107.46 (circle), 108.46 (X), 113.46 (triangle) and 114.46 (square) in cynomolgus macaques.

[0039] Figures 13A-13B illustrate repeat dose PK Values for Fc-IL-2v heterodimers 107.46 (A) and 114.46 (B) following repeat subcutaneous administrations to cynomolgus 10 macaques.

[0040] Figures 14A-14B illustrate the effect of repeat dose subcutaneous administration of Fc-IL-2v heterodimers 107.46 and 114.46 on number of cynomolgus macaque CD8+ T cells (A) and Treg cells (B).

[0041] Figures 15A-15B illustrate in vitro effect of an Fc-IL-2v heterodimer 114.46 on 15 HBV-specific IFN-y+ CD8+ T cells (A) and Ki67+ CD8+ T cells (B).

[0042] Figure 16 illustrates survival of mice with B16-F10 tumors treated with murine surrogate Fc-IL-2v heterodimer 168.250.

[0043] Figure 17 illustrates individual B16-F10 tumor volumes in mice treated with murine surrogate Fc-IL-2v heterodimer 168.250. 20

[0044] Figure 18 illustrates mean CT26 tumor volumes in mice treated with murine surrogate Fc-IL-2v heterodimer 171.250 alone and in combination with anti-PD-1 antibody.

[0045] Figure 19 illustrates survival of mice with CT26 tumors treated with murine surrogate Fc-IL-2v heterodimer 171.250 alone and in combination with anti-PD-1 antibody.

[0046] Figures 20A-20C illustrate in vivo antiviral effect of murine surrogate Fc-IL-2v 25 heterodimer 171.250 alone and in combination with aPD-Ll in mice infected with LCMV. Liver LCMV titer (A). Liver memory CD8+T cells in LCMV mice (B). Serum LCMV titer (C).

[0047] Figures 21A-21C illustrate HBsAg (A), HBeAg (B) and HBV DNA (C) levels after treatment of AAV-HBV infected mice with murine Fc-IL-2v heterodimer 167.250 and anti-PD-L1 antibody. 2024202988   06 May 2024

[0048] Figure 22 illustrates number of HBcAg-specific and HBsAg-specific IFN-y+ HBV-specific T cells in AAV-HBV infected mice after treatment with murine Fc-IL-2v heterodimer 167.250 and anti-PD-Ll antibody. DETAILED DESCRIPTION 5       1. Introduction

[0049] Provided are fusion proteins comprising a serum half-life extending polypeptide operably linked to a variant or mutant or non-naturally occurring IL-2 (IL-2v). In various embodiments, the IL-2v of the fusion protein is truncated at the N-terminus by at least 5 amino acids relative to wild-type IL-2 (i.e., does not comprise amino acid residues corresponding to 10 amino acid residues 1-5 of mature wild-type IL-2 (wt IL-2)); and binds to the interleukin-2 receptor alpha subunit (IL-2RA; CD25) with reduced binding affinity in comparison to wt IL-2. The IL-2 variant fusion proteins described herein have several structural features that enhance its safety and therapeutic efficacy while significantly reducing the frequency of dosing. In addition, these features contribute to improved manufacturability through high level production of a 15   soluble product using expression and purification platforms that are typically employed for monoclonocal antibody manufacturing. For example, Fc-IL-2v fusion proteins described herein were engineered to have negligible affinity for the IL-2Ra highly expressed on Treg cells by the introduction of point mutations in IL-2 at the IL-2 / IL-2Ra interface. In addition, use of a heterodimeric Fc enabled fusion of a single copy of the IL-2v to dimeric Fc. This fusion design 20 mimics the monovalent nature of native IL-2 and avoids the potential for avidity-driven binding to IL-2 receptors. One feature that enhances manufacturability is the introduction of mutations to one subunit of the Fc heterodimer to disrupt protein A binding and avoid co-purification of the corresponding homodimer contaminant with the desired heterodimer product. The use of an IgG4-derived Fc, which naturally lacks the ability to activate complement and has decreased Fc 25 gamma receptor (FcyR) binding relative to IgGl, combined with additional mutations to further minimize FcyR binding eliminated the potential for antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) or complementdependent cytotoxicity (CDC). These Fc modifications are combined with additional changes in the IL-2v proteins to further enhance manufacturability, namely, substitution of an unpaired 30 cysteine residue with serine to prevent unwanted aggregation or modification that might otherwise occur at this unpaired cysteine residue. Unpaired cysteines within the Fc domain can also be substituted, e.g., with a serine (e.g., the position corresponding to position 136 of any one of SEQ ID NOs: 45-56 or 141-143). Furthermore, deletion of the first five residues of the mature native IL-2 sequence eliminated a potential O-glycosylation site on threonine (T3) to 2024202988   06 May 2024 improve manufacturing control. Deletion of the first five residues of mature native IL-2 does not require substitution of T3 to a residue that cannot be O-glycsolyated (e.g., T3A) to reduce the potential for sequence-dependent immunogenicity. The herein described serum half-life extended IL-2v molecules described herein provide a safer, more efficacious, less frequently 5 dosed IL-2-based therapeutic that can be applied to treating a wider variety of diseases than is currently the case.

[0050] Among other things, the present disclosure identifies the source of a problem of determining a minimal combination of amino acid substitutions in wild-type (wt) IL-2 that can abrogate binding to IL-2Ra to a sufficient degree so as to minimize preferential stimulation of 10 immunosuppressive Treg cells over effector CD4+ and CD8+ T cells as well as NK cells. Various literature reports describing studies of IL-2 substitutions fail to provide a comprehensive analysis of the contribution of individual amino acid side chains to IL-2a binding, either due to the limited set of IL-2 residues evaluated in any single study or due to the drastic nature of substitutions reported in such studies, for instance, where replacing an amino 15   acid with a charged side chain to an amino acid with a side chain carrying the opposite charge. The present disclosure, among other things, provides particularly useful and effective constructs including a variant IL-2 moiety. The present disclosure provides IL-2v constructs combining a minimal number of substitutions that could elicit the desired biology (i.e., minimize preferential stimulation of immunosuppressive Treg cells over effector immune cells, while also restricting 20 substitutions to either of alanine or glycine). For example, the present disclosure provides a heterodimeric Fc-IL-2v fusion protein comprising amino acid substitutions of R38G, F42A, and E62A in IL-2. In some embodiments, a provided heterodimeric Fc-IL-2v fusion protein can further comprise: (i) an amino acid substitution of C125S; and / or (ii) deletion of first five residues of mature native IL-2 sequence. Without wishing to be bound by any particular theory, 25 the present disclosure notes that such a C125S substitution may be particularly useful and / or effective to reduce aggregation. Analogously, without wishing to be bound by any particular theory, the present disclosure notes that deletion of first five residues removes a potential O-glycosylation site on a threonine (T3), which may, in some embodiments, be useful and / or effective to improve manufacturing control as well as reduce the risk of sequence-dependent 30 immunogenicity.

[0051] In some embodiments, a heterodimeric Fc-IL-2v fusion protein described herein comprising R38G, F42A, and E62A is characterized by one, two, three, four, five, or more (e.g., all) of: (i) extremely weak or essentially undetectable binding to IL-2Ra, while retaining binding to IL-2RPy compared to an Fc-IL-2 fusion protein with a native IL-2Ra binding interface (See 2024202988   06 May 2024 Example 8); (ii) lower potency in STAT5 activation of CTLL-2 cells expressing IL-2RaPy compared to an Fc-IL-2 fusion protein with a native IL-2Ra binding interface or to Fc-IL-2v heterodimers with R38G and E62A or F42A and E62A substitutions (see Example 9); (iii) lower potency of STAT5 activation in human Treg cells relative to activation by an Fc-IL-2 fusion 5 protein with a native IL-2Ra binding interface (See Example 10); (iv) comparable potency of STAT5 activation in human CD8+ T cells relative to activation by an Fc-IL-2 fusion protein with a native IL-2Ra binding interface (See Example 10); (v) similar proliferation of human CD8+ T cells and NK cells as an Fc-IL-2 fusion protein with a native IL-2Ra binding interface (See, Example 12); (vi) lower potency of STAT5 activation in non-human primate Treg cells 10 relative to activation by an Fc-IL-2 fusion protein with a native IL-2Ra binding interface (See, Example 13); (vii) comparable potency of STAT5 activation in non-human primate CD8+ T cells relative to activation by an Fc-IL-2 fusion protein with a native IL-2Ra binding interface (See, Example 13); (viii) Increased in vivo drug exposure in non-human primates relative to equivalent doses of Fc-IL-2v heterodimer with F42A and E62A substitutions (See Examples 17 15 and 18); or (ix) lower in vivo expansion of Treg cells relative to an Fc-IL-2v heterodimer with F42A and E62A (Example 19).

[0052] IL-2 variants have been the subject of significant research for more than two decades, with much effort focused on developing variants with reduced affinity (relative to wild type IL-2, for example as set forth in SEQ ID NO: 216) for IL-2Ra as part of the trimeric IL 20 2RaPy. Positions of particular focus have included R38, F42, K43, Y45, E61, and E62, which were determined in studies of analogs that utilized binding assays for IL-2Ra (see, for example, Ju, et al. (1990) in The Biology and Clinical Applications of Interleukin-2, ed. Rees, R. C. (Oxford Univ. Press, Oxford), pp. 7-14). Various reports describe substitutions at one or more of these positions, and assess their impact on IL-2Ra binding, however, these studies often made 25 use of drastic substitutions to native side chains, for instance, replacing a native amino acid with a charged side chain to an amino acid with a side chain carrying the opposite charge or, for instance, replacing a native amino acid with an uncharged side chain to an amino acid with a charged side chain (see, Sauve et al., Proc. Natl. Acad. Sci. U.S.A., 88:4636, 1991, Heaton, et al, Cancer Res. 53(11):2597-602, 1993, Wang, et al. Eur J Immunol. 25(5):1212-6, 1995, Vazquez- 30 Lombardi, et al., Nat Commun. 12;8:15373, 2017). Such drastic changes may appear favorable with respect to binding disruption, but could increase the risk of introducing sequence-dependent immunogenicity. IL-2 variant molecules can be immunogenic in the clinic (see, Satyanarayana, C&EN Magazine, “IL-2 treatment can be dangerous. Here’s how drug firms are trying to fix it,” Apr. 4 2021, 99(12) (cen.acs.org / pharmaceuticals / biologics / safer-IL2-cancer-immunotherapy- 2024202988   06 May 2024 autoimmunity / 99 / il2)). Thus, it is advantageous to reduce the risk of immunogenicity by incorporating fewer amino acid substitutions in the IL-2 molecule. In addition, no one study systemically compared the effect of a large panel of single point substitutions and / or combinations thereof, making it challenging to design a minimally substituted IL-2 variant that 5 achieved the dual goals of limiting preferential stimulation of immunosuppressive Treg cells over effector CD4+ and CD8+ T cells and NK cells, while simultaneously limiting the total number and nature of substitutions so as to reduce the possibility of said variant being immunogenic in humans.

[0053] Among other things, the present disclosure surprisingly demonstrates that 10 multiple substitutions of IL-2 of G at position 38, A at position F42, and A at position E62 are particularly useful and / or effective. Indeed, results of prior studies that assessed multiple substitutions in IL-2 variants have indicated that at least four substitutions are necessary with different positions and / or substitutions than G at position 38, A at position F42, or A at position E62. Indeed, studies of multiple substitutions of IL-2 variants indicate that substitution of at 15 least 4 substitutions is required to significantly reduce Treg expansion and IL-2Ra binding relative to wt IL-2 while maintaining CD8+ T cell and NK cell proliferation similar to wt IL-2.

[0054] For example, an assessment of an IL-2 variant made a combination of substitutions, including A at positions 38, 42, 45, and 62 (Carmenate et al., J Immunol. 190 (12) 6230-6238, 2013), and determined its ability to stimulate CD8+ T cells and NK cell 20 proliferation, decrease Treg expansion, and reduce IL-2Ra binding. The results showed that an IL-2 variant including R38A, F42A, Y45A, and E62A stimulated CD8+ T cells and NK cell proliferation similar to wt IL-2, while significantly reducing Treg expansion and IL 2Ra binding relative to wtIL-2. Thus, at least four substitutions including a substitution of A at position 45 were apparently required to stimulate CD8+ T cells and NK cell proliferation, while 25 significantly reducing Treg expansion and IL-2Ra binding. In contrast, the present disclosure provides IL-2 variants that include G at position 38, A at position 42, and A at position E62 and do not include a substitution of A at position 45.

[0055] In another example, an IL-2 variant described above including A at positions 38, 42, 45, and 62 in combination (Carmenate, et a / ., 2013, supra) was further assessed to determine 30 the contribution of each substitution to impairment of IL-2Ra binding (Rojas, et al., J Mol Recognit. 28(4):261-8, 2015). The results of binding assays showed that single IL-2 substitutions of R38A and Y45A still bound IL-2Ra (34 % and 4% of wt IL-2, respectively), while single IL-2 substitutions of F42A and E62A resulted in negligible IL-2Ra binding (<1% of wtIL-2 for each). The results of proliferation assays showed that single IL-2 substitutions of 2024202988   06 May 2024 R38A and Y45A still caused proliferation in IL-2Ra expressing CTLL-2 cells (48.2% and 7.1% of wt, respectively), while single IL-2 substitutions of F42A and E62A resulted in negligible proliferation in CTLL-2 cells (2.0% and 1.3%, respectively), and the combination of all four IL-2 substitutions (R38A, F42A, Y45A, and E62A) resulted in non-detectable CTLL-2 cell 5 proliferation. These results indicate that: (i) at least four mutations are required to reduce IL-2Ra binding sufficiently for non-detectable proliferation of IL-2Ra-expressing CTLL-2 cells; and (ii) among these four mutations, R38A is the least helpful with the most residual binding to IL-2Ra and highest proliferation in CTLL-2 cells. Unlike the Carmenate et al. work, the present disclosure demonstrated that R38G was a more effective single mutation to reduce IL-2Ra 10 binding than R38A, and thus an IL-2 variant with only three substitutions comprising R38G combined with F42A and E62A was sufficient to attenuate STAT5 activation of CTLL-2 cells by over 30,000-fold relative to the equivalent molecule with a native IL-2Ra binding interface, and elicit the desired biology on primary human immune cells by minimizing preferential stimulation of immunosuppressive Treg cells over effector T and NK cells. 15

[0056] Additionally, work by Roche (see, for example, WO2012 / 107417), has described the development of IL-2 variants in the context of heterodimer IgG fusion molecules with antigen binding domains specific for antigens including, for example, tumor antigens. This work indicates, among other things: (i) substitution of position L72 in IL-2 to G is necessary for the desired abolishment of IL-2Ra binding and reduction of human Treg activation in the context of 20 substitutions F42A and Y45A; (ii) desirable IgG IL-2 fusions have a T3A substitution in IL-2 to eliminate the O-glycosylation site; and (iii) desirable IgG IL-2 fusions have a C125A substitution to avoid inter-molecular disulfide bridges. The present discolosure demonstrates that IL-2 variants that contain substitutions at positions R38G, F42A, and E62A reduce STAT5 activation of CTLL-2 cells by over 30,000-fold while IL-2 variants with substitutions at F42A, 25   Y45A, and L72G reduce STAT5 activation of CTLL-2 cells by only 3,800-fold relative to the equivalent molecule with a native IL-2Ra binding interface. In addition, as shown in Example 10, IL-2 variants containing the native IL-2Ra binding interface, or either of R38G / F42A / E62A or F42A / Y45A / L72G triple substitutions had comparable activities to each other in activating CD8+ T cells. However, while both of these triple substitution variants had significantly 30 reduced activity on Treg cells, the R38G / F42A / E62A-containing variant was superior in exhibiting a more modest difference between activity on Treg versus effector CD8 cells (EC50 values of 3.0 nM and 10.7 nM respectively) as compared to the F42A / Y45A / L72G-containing variant (EC50 values of 1.2 and 9.8 nM respectively). Furthermore, this present disclosure demonstrates that deletion the first five N-terminal amino acids of IL-2 can be used as a 2024202988   06 May 2024 preferred strategy to eliminate the O-glycosylsation site, as this avoids any mutagenesis of native IL-2 sequence for this purpose which could otherwise increase the risk of potential immunogenicity in humans.

[0057] Furthermore, recent work reported by Cugene (see, for example, 5   WO2020 / 252418), has described development of IL-2 variants in the context of bivalent IL-2 homodimer Fc fusions and indicates, among other things: (i) at position R38, none of A, F, or G substitutions dramatically improved specificity for IL-2R0y as compared with IL-2RaPy, comparably fused; (ii) among the tested substitutions, R38A was more helpful (EC50 of 3.23) than either of the others (EC50 of 2.0 and 0.42 for R38G and R38F, respectively) at improving 10 such specificity; (iii) at position E62, all substitutions of F, H, L, and A did improve specificity for IL-2RPy as compared with IL-2RaPy, comparably fused; (iv) among the tested substitutions, E62F was more helpful (EC50 of 151) than any of the others (EC50 of 2.57, 2.38, and 60.5 for E26H, E62L, and E62A, respectively) at improving such specificity; and (iii) desirable IL-2-Fc fusions do not have an S residue at position 125. In fact, the reference IL-2 used in Cugene’s 15 work apparently naturally included an S125 residue; Cugene recommends substituting away from S (specifically, using an S125I substitution), whereas the present disclosure substitutes to S (specifically, using a C125S substitution). In contrast to this recent work by Cugene, the present disclosure provides IL-2 Fc fusion protein variants that include G at position 38, A at position 42, A at position 62, and S at position 125. 20

[0058] Whether taken individually or together, it is clear that, the teachings available prior to the present disclosure would have led one skilled in the art to develop IL-2 variants different from those described herein, particularly in the context of Fc fusions. 2. Variant Interleukin-2 (IL-2v) Proteins a. Variant IL-2 (IL-2v) with Reduced Binding Affinity to IL-2 Receptor Alpha 25               Subunit (IL-2RA)

[0059] With respect to functional attributes, generally, the variant IL-2 (IL-2v) domain, e.g., of the herein described fusion proteins, binds to the alpha subunit of IL-2 receptor (IL-2RA) with reduced affinity, e.g., with a KD of at least 60 pM. The alpha subunit of IL-2 receptor can be human, non-human primate or mouse. Human IL-2RA (a.k.a., CD25; IDDM10, IL-2R, 30 IMD41, TCGFR, p55) is assigned NCBI Gene ID: 3559. Mouse il2ra (a.k.a., CD25; I12r; Ly-43) is assigned NCBI Gene ID: 16184. Rhesus monkey IL-2RA is assigned NCBI Gene ID: 574300. Macaca fascicularis (cynomolgus or crab-eating macaque) IL-2RA is assigned NCBI Gene ID: 102123605. In some embodiments, the IL-2v binds to IL-2RA with an equilibrium 2024202988   06 May 2024 dissociation constant (Kd) of at least 60 pM (e.g., 60 pM or higher). Further, in some embodiments, the variant IL-2 (IL-2v) domain, e.g., of the herein described fusion proteins, binds to a complex of interleukin 2 receptor subunit beta (IL-2RB; CD 122) and interleukin 2 receptor subunit gamma (IL-2RG; CD132) with a Kd of less than 150 nM, e.g., less than 1.5 5 nM, e.g., less than 120 pM, e.g., less than 100 pM, e.g., less than 80 pM, e.g., less than 75 pM, e.g., less than 70 pM, e.g., as determined determined in a cell line having an artificial Fc-fused IL2Rp / IL2Ry heterodimer, described herein, in some embodiments, the variant IL-2 (IL-2v) domain, e.g., of the herein described fusion proteins, binds to a complex of interleukin 2 receptor subunit beta (IL-2RB; CD 122) and interleukin 2 receptor subunit gamma (IL-2RG; 10   CD 132) with a Kd within 10-fold, e.g., within 9-fold, 8-fold, 7-fold, 6-fold, 5-fold, 4-fold, 3 fold, 2-fold, or less, of the Kd of wild-type IL-2 under equivalent conditions. The complex of interleukin 2 receptor subunit beta (IL-2RB; CD 122) and interleukin 2 receptor subunit gamma (IL-2RG; CD 132) can be human, non-human primate or mouse. Human IL-2RB (a.k.a., CD122, IL15RB, IMD63, P70-75) is assigned NCBI Gene ID: 3560 and human IL-2RG (a.k.a., 15   P64; CIDX; IMD4; CD132; SCIDX; IL-2RG; SCIDX1) is assigned NCBI Gene ID: 3561. Mouse il2rb (a.k.a., p70; CD122; IL15Rbeta; Il-2Rbeta; IL-15Rbeta; Il-2 / 15Rbeta) is assigned NCBI Gene ID: 16185 and mouse il2rg (a.k.a., gc; p64; [g]c; CD132; gamma(c)) is assigned NCBI Gene ID: 16186. Rhesus monkey IL-2RB is assigned NCBI Gene ID: 696331 and rhesus monkey IL-2RG is assigned NCBI Gene ID: 641338. Cynomolgus monkey IL-2RB is assigned 20 NCBI Gene ID: 102138714 and rhesus monkey IL-2RG is assigned NCBI Gene ID: 102144912. Binding affinity can be determined according to any method in the art. One method for determining binding affinity is surface plasmon resonance (SPR).

[0060] In various embodiments, the variant IL-2 (IL-2v) domain, e.g., of the herein described fusion proteins, promotes or induces equivalent or greater proliferation of CD8+ T 25 cells relative to wt IL-2, an IL-2v of any one of SEQ ID NOs: 43 and 44. Additionally, in some embodiments, the concentration at which the IL-2v, e.g., of the herein described fusion proteins, elicits 50% of maximal (ECso) signal transducer and activator of transcription 5 (STAT5) activation or signaling of regulatory T (Treg) cells is at least 1000-fold, e.g., at least 1500-fold, e.g., at least 1700-fold, e.g., at least 2000-fold, e.g., at least 2500-fold higher, relative to the 30 ECso for STAT5 activation or signaling of wt IL-2, or an IL-2v of any one of SEQ ID NOs: 43 and 44. See, e.g., Gilmour, etal., Proc Natl Acad Sci USA (1995) 92(23): 10772-6; Gaffen, Cytokine (2001) 14(2):63-77; Varker, et al., Clin Cancer Res (2006) 12(19):5850-8. “Regulatory T cells” (Tregs; Treg cells), also known as “suppressor T cells,” are a subpopulation of T cells that are immunosuppressive and generally suppress or downregulate induction and 2024202988   06 May 2024 proliferation of effector T cells. Tregs express the surface biomarkers CD4 and CD25 (IL-2 receptor a-chain) and intracellular DNA binding biomarker FOXP3. Human Foxp3+CD4+ T cells have been divided into three subfractions based upon the expression level of Foxp3 and the cell surface molecules CD25 and CD45RA. The Foxp3hiCD45RA- CD25hi and 5 Foxp31oCD45RA+CD251o phenotypes correspond to suppressive Treg cells, whereas the Foxp31oCD45RA-CD251o fraction marks activated T effector (Teff) cells without suppressive activity. In addition, Treg cells from cancer patients, as compared to those in healthy subjects, are usually characterized by a distinct expression profile of chemokine receptors, such as CCR4, CXCR4, and CCR5, which facilitates their migration into tumors in response to the 10 corresponding chemokine ligands derived from tumor microenvironment. See, e.g., Liu, et al., FEBS J. (2016) 283(14):2731-48 and Miyara, et al., Immunity (2009) 30, 899-911.

[0061] In some embodiments, the concentration at which the IL-2v, e.g., of the herein described fusion proteins, elicits 50% of maximal (ECso) of IL-2RaPy-mediated STAT5 activation or signaling (e.g., measured as STAT5 activation of CTLL2 cells) is at least 250015 fold, e.g., at least 5000-fold, e.g., at least 7500-fold, e.g., at least 10,000-fold, e.g., at least 15,000-fold, e.g., at least 20,000-fold higher, relative to the ECso for STAT5 activation or signaling of wt IL-2, or an IL-2v of any one of SEQ ID NOs: 43 and 44. See, e.g., Gilmour, et al., Proc Natl Acad Sci USA (1995) 92(23): 10772-6; Gaffen, Cytokine (2001) 14(2):63-77; Ortega, et al., J Immunol. (1984) 133(4): 1970-5; Gillis, etal., J Immunol. (1978) 120(6):2027-20   32.

[0062] In some embodiments, the concentration at which the IL-2v, e.g., of the herein described fusion proteins, elicits 50% of maximal (ECso) proliferation of natural killer (NK) cells is at least 10-fold, e.g., at least 12-fold, e.g., at least 15-fold, e.g., at least 16-fold, e.g., at least 18-fold, e.g., at least 20-fold higher, e.g., as measured using KHYG-1 cells, relative to the 25 ECso for proliferation of wt IL-2, or an IL-2v of any one of SEQ ID NOs: 43 and 44. See, e.g., Suck, et al., Exp Hematol (2005) Oct;33(l0): 1160-71; Yagita, et al., Leukemia (2000) 14(5):922-30; Cell line KHYG-1 has DSMZ no.: ACC 725; ExPASy Cellosaurus KHYG-1 (CVCL 2976); CellBank Australia CODE: JCRB0156.

[0063] A “polypeptide variant,” as the term is used herein, is a polypeptide that typically 30 differs from a polypeptide specifically disclosed herein in one or more substitutions, deletions, additions and / or insertions. Such variants may be naturally occurring or may be synthetically generated, for example, by modifying one or more of the above polypeptide sequences described herein and evaluating one or more biological activities of the polypeptide as described herein and / or using any of a number of techniques well known in the art. 2024202988   06 May 2024

[0064] The term “variant” may also refer to any naturally occurring or engineered molecule comprising one or more nucleotide or amino acid mutations. In one embodiment, the multi-specific antigen binding molecule is a bispecific antigen binding molecule. In one embodiment, the multi-specific antigen binding molecule is a bispecific antibody. For example, 5 somatic variants may encompass all related naturally occurring antibodies that are part of or derived from the same B-cell lineage. Engineered variants may encompass all single mutations or combinatorial mutations made to an antibody.

[0065] With respect to structural attributes, generally, the IL-2v domain, e.g., of the herein described fusion proteins, do not comprise the first five amino acid residues 10 corresponding to amino acid positions 1-5 of wt IL-2 (e.g., do not comprise the amino acid sequence APTSS (SEQ ID NO: 163)). As used herein, numbering of a given amino acid polymer or nucleic acid polymer “corresponds to”, is “corresponding to” or is “relative to” the numbering of a selected or reference amino acid polymer or nucleic acid polymer when the position of any given polymer component (e.g., amino acid, nucleotide, also referred to 15   generically as a “residue”) is designated by reference to the same or to an equivalent position (e.g., based on an optimal alignment or a consensus sequence) in the selected amino acid or nucleic acid polymer, rather than by the actual numerical position of the component in the given polymer. Stated another way, in the IL-2v domain, e.g., of the herein described IL-2v and IL-2v fusion proteins, the first five amino acids corresponding to a wild-type or native mature IL-2 are 20 truncated. For fusion proteins based on human IL-2, the numbering of IL-2 positions is with reference to mature human IL-2 (NCBI Gene ID: 3558), shown below, or with reference to SEQ ID NO:44 (IL-2v having a serine at position 125 (C125S): APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELK PLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSI 25 ISTLT (SEQ ID NO: 216).

[0066] In various embodiments, the IL-2v domain is from (e.g., based on or derived from) a human wild-type IL-2 or a wild-type IL-2 of a non-human primate. For fusion proteins based on rhesus monkey IL-2, the numbering of IL-2 positions is with reference to mature rhesus monkey IL-2 (NCBI Gene ID: 708017), shown below: 30 APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELK PLEEVLNLAQSKNFHLRDTKDLISNINVIVLELKGSETTLMCEYADETATIVEFLNRWITFCQS IISTLT (SEQ ID NO: 217). 2024202988   06 May 2024

[0067] For fusion proteins based on cynomolgus monkey IL-2, the numbering of IL-2 positions is with reference to mature cynomolgus monkey IL-2 (NCBI Gene ID: 102129830), shown below: APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELRHLQCLEEELK 5 PLEEVLNLAQSKSFHLRDTKDLISNINVIVLELKGSETTLMCEYADETATIVEFLNRWITFCQS IISTLT (SEQ ID NO: 262).

[0068] In some embodiments, the IL-2v comprises a serine at position 125 (C125) and at least two, or at least three, substitutions (e.g., to glycine or alanine) at amino acid positions selected from the group consisting of R38, F42, Y45, E61, E62 and L72. In some embodiments, 10 the IL-2v comprises a serine at position 125 (C125) and at least two, or at least three, no more than three, no more than two, substitutions (e.g., to glycine or alanine) at amino acid positions selected from the group consisting of R38, F42, Y45, E61 and E62. In some embodiments, the IL-2v comprises a serine at position 125 (C125) and at least two, or at least three, no more than three, no more than two, substitutions (e.g., to glycine or alanine) at amino acid positions 15 selected from the group consisting of R38, F42, Y45 and E62. In some embodiments, the IL-2v comprises a serine at position 125 (Cl25) and at least two, or at least three, no more than three, no more than two, substitutions (e.g., to glycine or alanine) at amino acid positions selected from the group consisting of R38, F42 and E62. In some embodiments, the IL-2v comprises a serine at position 125 (C125) and at least two, or at least three, no more than three, no more than two, 20 substitutions at amino acid positions selected from the group consisting of R38G, F42A, Y45G, E61A, E62A and L72G. In some embodiments, the IL-2v comprises a serine at position 125 (C125) and at least two, or at least three, no more than three, no more than two, substitutions at amino acid positions selected from the group consisting of R38G, F42A, Y45G, E61A and E62A. In some embodiments, the IL-2v comprises a serine at position 125 (C125) and at least 25 two, or at least three, no more than three, no more than two, substitutions at amino acid positions selected from the group consisting of R38G, F42A, Y45G and E62A. In some embodiments, the IL-2v comprises a serine at position 125 (C125) and at least two, or at least three, no more than three, no more than two, substitutions at amino acid positions selected from the group consisting of R38G, F42A and E62A. The foregoing position numbers are with respect to an IL-2v of SEQ 30 ID NO:44. In some embodiments, the IL-2v does not comprise an amino acid substitution at one or more, or all, of positions selected from the group consisting of D20, Y45, E61, E68, V69, L72, A73, L80, R81, L85, L86,187,192 and Q126. In some embodiments, the IL-2v does not comprise an amino acid substitution at one or more, or all, of positions selected from the group consisting of H16, D20, E61, N88 and V91. 2024202988   06 May 2024

[0069] In some embodiments, the IL-2v comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-42 or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence 5 selected from the group consisting of SEQ ID NOs: 1-42. Illustrative IL-2v sequences based on wild-type human IL-2, including SEQ ID Nos: 1-44, are provided in Table A. TABLE A: variant IL-2 with reduced binding to interleukin-2 receptor subunit alpha (IL-2RA; CD25) PROTEIN NO: SEQ ID NO: Features Polypeptide Sequence 1 Al-5_R38Xi_ T41X2_F42X3_ Y45X4_E61X5_ E62X6_E68X7_ L72X8_Q74X9_ Y107X10_C125S X2 is R, S, G or A X2 is T, G or A X3 is F, G or A X4 is Y, G or A X5 is E, G or A Xs is E, G or A X7 is E, G or A X8 is L, G or A X9 is Q, G or A X10 is Y, G or A stkktqlqlehllldlqmilnginnyknpkltx1mlx2x3kfx4mpkkatelkhlqclex5x6lkp lex7vlnx8ax9sknfhlrprdlisninvivlelkgsettfmcex10adetativeflnrwitfs QSIISTLT 2 A1-5_R38X2_ F42X3_Y45X4_ E61X5_E62X6_ L72X8_C125S X2 is R, S, G or A X3 is F, G or A stkktqlqlehllldlqmilnginnyknpkltx1mltx3kfx4mpkkatelkhlqclex5x6lkp LEEVLNX8AQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSI ISTLT TABLE A: variant IL-2 with reduced binding to interleukin-2 receptor subunit alpha (IL-2RA; CD25) PROTEIN NO: SEQ ID NO: Features Polypeptide Sequence X4 is Y, G or A X5 is E, G or A X6 is E, G or A X8 is L, G or A 3 Al-5_ R38X!_F42X3_ Y45X4_E61X5_ E62X6_C125S Xx is R, S, G or A X3 is F, G or A X4 is Y, G or A X5 is E, G or A X6 is E, G or A STKKTQLQLEHLLLDLQMILNGINNYKNPKLTXiMLTXsKFX^PKKATELKHLQCLEXsXgLKP LEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSII STLT 4 Al- 5_R38Xi_F42X3_Y4 5X4_E62X6_C125S X3 is R, S, G or A X3 is F, G or A X4 is Y, G or A X6 is E, G or A STKKTQLQLEHLLLDLQMILNGINNYKNPKLTXiMLTXsKFX^PKKATELKHLQCLEEXgLKPL EEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIIS TLT TABLE A: variant IL-2 with reduced binding to interleukin-2 receptor subunit alpha (IL-2RA; CD25) PROTEIN NO: SEQ ID NO: Features Polypeptide Sequence 5 Al-5_ R38X!_F42X2_ E62X5_C125S X2 is R, S, G or A X3 is F, G or A X6 is E, G or A STKKTQLQLEHLLLDLQMILNGINNYKNPKLTXiMLTXaKFYMPKKATELKHLQCLEEXgLKPLE EVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIIST LT 6 Al-5_ R38Xi_F42A_E62A _C125S X2 is R, S, G or A STKKTQLQLEHLLLDLQMILNGINNYKNPKLTXiMLTAKFYMPKKATELKHLQCLEEALKPLEE VLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTL T 7 A1-5_R38G_C125S STKKTQLQLEHLLLDLQMILNGINNYKNPKLTGMLTFKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 8 A1-5_R38A_C125S STKKTQLQLEHLLLDLQMILNGINNYKNPKLTAMLTFKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 9 A1-5_T41G_C125S STKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLGFKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 10 A1-5_T41A_C125S STKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLAFKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 11 A1-5_F42G_C125S STKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTGKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 12 A1-5_F42A_C125S STKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT TABLE A: variant IL-2 with reduced binding to interleukin-2 receptor subunit alpha (IL-2RA; CD25) PROTEIN NO: SEQ ID NO: Features Polypeptide Sequence 13 A1-5_Y45G_C125S STKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFGMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 14 A1-5_Y45A_C125S STKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFAMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 15 A1-5_E61A_C125S STKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEAELKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 16 A1-5_E62A_C125S STKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEALKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 17 A1-5_E68A_C125S STKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEAV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 18 A1-5_L72G_C125S STKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEV LNGAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 19 A1-5_Q74G_C125S STKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEV LNLAGSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 20 Al-5_ Y107G_C125S STKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEGADETATIVEFLNRWITFSQSIISTLT 21 Al-5_ Y107A_C125S STKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEAADETATIVEFLNRWITFSQSIISTLT 22 Al-5_ Y45G_E61A_C125S STKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFGMPKKATELKHLQCLEAELKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 23 Al-5_ Y45G_E62A_C125S STKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFGMPKKATELKHLQCLEEALKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 24 Al-5_ R38G_Y45G_C125S STKKTQLQLEHLLLDLQMILNGINNYKNPKLTGMLTFKFGMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT TABLE A: variant IL-2 with reduced binding to interleukin-2 receptor subunit alpha (IL-2RA; CD25) PROTEIN NO: SEQ ID NO: Features Polypeptide Sequence 25 Al-5_ R38G_E61A_C125S STKKTQLQLEHLLLDLQMILNGINNYKNPKLTGMLTFKFYMPKKATELKHLQCLEAELKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 26 Al-5_ F42A_E61A_C125S STKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEAELKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 27 Al-5_ F42A_Y45G_C125S STKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFGMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 28 A1-5_Y45G_ E61A_E62A_C125S STKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFGMPKKATELKHLQCLEAALKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 29 A1-5_E61A_ E62A_C125S STKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEAALKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 30 A1-5_R38G_ F42A_C125S STKKTQLQLEHLLLDLQMILNGINNYKNPKLTGMLTAKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 31 A1-5_F42A_Y45A_ L72G_C125S STKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFAMPKKATELKHLQCLEEELKPLEEV LNGAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 32 A1-5_R38G_F42A_ Y45G_C125S STKKTQLQLEHLLLDLQMILNGINNYKNPKLTGMLTAKFGMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 33 A1-5_F42A_ E62A_C125S STKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEALKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 34 A1-5_F42A_Y45G_ E62A_C125S STKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFGMPKKATELKHLQCLEEALKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 35 A1-5_F42A_Y45G_ E61A_C125S STKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFGMPKKATELKHLQCLEAELKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 36 A1-5_R38G_Y45G_ E61A_C125S STKKTQLQLEHLLLDLQMILNGINNYKNPKLTGMLTFKFGMPKKATELKHLQCLEAELKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT TABLE A: variant IL-2 with reduced binding to interleukin-2 receptor subunit alpha (IL-2RA; CD25) PROTEIN NO: SEQ ID NO: Features Polypeptide Sequence 37 A1-5_R38G_F42A_ E61A_C125S STKKTQLQLEHLLLDLQMILNGINNYKNPKLTGMLTAKFYMPKKATELKHLQCLEAELKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 38 A1-5_R38G_Y45G_ E62A_C125S STKKTQLQLEHLLLDLQMILNGINNYKNPKLTGMLTFKFGMPKKATELKHLQCLEEALKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 39 A1-5_R38G_ E62A_C125S STKKTQLQLEHLLLDLQMILNGINNYKNPKLTGMLTFKFYMPKKATELKHLQCLEEALKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 40 A1-5_R38G_F42A_ E62A_C125S STKKTQLQLEHLLLDLQMILNGINNYKNPKLTGMLTAKFYMPKKATELKHLQCLEEALKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 41 A1-5_F42A_E61A_ E62A_C125S STKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEAALKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 42 A1-5_R38G_E61A_ E62A_C125S STKKTQLQLEHLLLDLQMILNGINNYKNPKLTGMLTFKFYMPKKATELKHLQCLEAALKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 43 A1-5_C125S STKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEV LNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 44 T3A_C125S APASSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELK PLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSI ISTLT 2024202988   06 May 2024

[0070] Modifications may be made in the structure of the IL-2v, and IL-2v fusion polynucleotides and polypeptides, described herein and still obtain a functional molecule that encodes a variant or derivative polypeptide with desirable characteristics. When it is desired to alter the amino acid sequence of a polypeptide to create an equivalent, or even an 5 improved, variant or portion of a polypeptide described herein, one skilled in the art will typically change one or more of the codons of the encoding DNA sequence.

[0071] For example, certain amino acids may be substituted for other amino acids in a protein structure without appreciable loss of its ability to bind other polypeptides (e.g., antigens) or cells. Since it is the binding capacity and nature of a protein that defines that 10 protein's biological functional activity, certain amino acid sequence substitutions can be made in a protein sequence, and, of course, its underlying DNA coding sequence, and nevertheless obtain a protein with like properties. It is thus contemplated that various changes may be made in the polypeptide sequences of the disclosed antibodies and antigenbinding fragments thereof, or corresponding DNA sequences that encode said polypeptides 15    without appreciable loss of their biological utility or activity.

[0072] In many instances, a polypeptide variant will contain one or more conservative substitutions. A “conservative substitution” is one in which an amino acid is substituted for another amino acid that has similar properties, such that one skilled in the art of peptide chemistry would expect the secondary structure and hydropathic nature of the 20 polypeptide to be substantially unchanged.

[0073] As used herein, “identity” means the percentage of identical nucleotide or amino acid residues at corresponding positions in two or more sequences when the sequences are aligned to maximize sequence matching, i.e., taking into account gaps and insertions. Sequences are generally aligned for maximum correspondence over a designated 25 region, e.g., a region at least 20, 25, 30, 35, 40, 45, 50, 55, 60, 65 or more amino acids or nucleotides in length, and can be up to the full length of the reference polypeptide or polynucleotide sequence. For sequence comparison, typically one sequence acts as a reference sequence, to which test sequences are compared. When using a sequence comparison algorithm, test and reference sequences are input into a computer program, 30 subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. Otherwise, standard parameters can be used. The sequence comparison algorithm then calculates the percent sequence identity for the test sequence(s) relative to the reference sequence, based on the designated program parameters. 2024202988   06 May 2024

[0074] When comparing polynucleotide and polypeptide sequences, two sequences are said to be “identical” if the sequence of nucleotides or amino acids in the two sequences is the same when aligned for maximum correspondence, as described below. Comparisons between two sequences are typically performed by comparing the sequences over a 5 comparison window to identify and compare local regions of sequence similarity. A “comparison window” as used herein, refers to a segment of at least 20 contiguous positions, usually 30 to 75 contiguous positions, 40 to 50 contiguous positions, or over the full length of a sequence, in which a sequence may be compared to a reference sequence of the same number of contiguous positions after the two sequences are optimally aligned. 10

[0075] Optimal alignment of sequences for comparison may be conducted using the Megalign program in the Lasergene suite of bioinformatics software (DNASTAR, Inc., Madison, WI), using default parameters. This program embodies several alignment schemes described in the following references: Dayhoff, M.O. (1978) A model of evolutionary change in proteins - Matrices for detecting distant relationships. In Dayhoff, M.O. (ed.) 15 Atlas of Protein Sequence and Structure, National Biomedical Research Foundation, Washington DC Vol. 5, Suppl. 3, pp. 345-358; Hein J. (1990) Unified Approach to Alignment and Phylogenes pp. 626-645 Methods in Enzymology vol. 183, Academic Press, Inc., San Diego, CA; Higgins, D.G. and Sharp, P.M. (1989) CABIOS 5: 151-153; Myers, E.W. and Muller W. (1988) CABIOS 4:11-17; Robinson, E.D. (1971) Comb. Theor 77: 20   105; Santou, N. Nes, M. (1987) Mol. Biol. Evol. 4:406-425; Sneath, P.H.A. and Sokal, R.R. (1973) Numerical Taxonomy - the Principles and Practice of Numerical Taxonomy, Freeman Press, San Francisco, CA; Wilbur, W.J. and Lipman, D.J. (1983) Proc. Natl. Acad., Sci. USA 80:726-730.

[0076] Alternatively, optimal alignment of sequences for comparison may be 25 conducted by the local identity algorithm of Smith and Waterman (1981) Add. APL. Math 2:482, by the identity alignment algorithm of Needleman and Wunsch (1970) J. Mol. Biol. 48:443, by the search for similarity methods of Pearson and Lipman (1988) Proc. Natl. Acad. Sci. USA 85: 2444, by computerized implementations of these algorithms (GAP, BESTFIT, BLAST, FASTA, and TFASTA in the Wisconsin Genetics Software Package, 30 Genetics Computer Group (GCG), 575 Science Dr., Madison, WI), or by inspection.

[0077] One example of algorithms that are suitable for determining percent sequence identity and sequence similarity are the BLAST and BLAST 2.0 algorithms, which are described in Altschul et al. (1977) Nucl. Acids Res. 25:3389-3402 and Altschul et al. (1990) J. Mol. Biol. 215:403-410, respectively. BLAST and BLAST 2.0 can be used, for 2024202988   06 May 2024 example with the parameters described herein, to determine percent sequence identity for the polynucleotides and polypeptides described herein. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information (blast, ncbi. nlm. nih. gov / B last, cgi). 5

[0078] In one illustrative example, cumulative scores can be calculated using, for nucleotide sequences, the parameters M (reward score for a pair of matching residues; always >0) and N (penalty score for mismatching residues; always <0). Extension of the word hits in each direction are halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, 10 due to the accumulation of one or more negative-scoring residue alignments; or the end of either sequence is reached. The BLAST algorithm parameters W, T and X determine the sensitivity and speed of the alignment. The BLASTN program (for nucleotide sequences) uses as defaults a word length (W) of 11, and expectation (E) of 10, and the BLOSUM62 scoring matrix (see Henikoff and Henikoff (1989) Proc. Natl. Acad. Sci. USA 89: 10915) 15 alignments, (B) of 50, expectation (E) of 10, M=5, N=-4 and a comparison of both strands.

[0079] For amino acid sequences, a scoring matrix can be used to calculate the cumulative score. Extension of the word hits in each direction are halted when: the cumulative alignment score falls off by the quantity X from its maximum achieved value; the cumulative score goes to zero or below, due to the accumulation of one or more 20 negative-scoring residue alignments; or the end of either sequence is reached. The BLAST algorithm parameters W, T and X determine the sensitivity and speed of the alignment.

[0080] In one approach, the “percentage of sequence identity” is determined by comparing two optimally aligned sequences over a window of comparison of at least 20 positions, wherein the portion of the polynucleotide or polypeptide sequence in the 25 comparison window may comprise additions or deletions (i.e., gaps) of 20 percent or less, usually 5 to 15 percent, or 10 to 12 percent, as compared to the reference sequences (which does not comprise additions or deletions) for optimal alignment of the two sequences. The percentage is calculated by determining the number of positions at which the identical nucleic acid bases or amino acid residues occur in both sequences to yield the number of 30 matched positions, dividing the number of matched positions by the total number of positions in the reference sequence (i.e., the window size) and multiplying the results by 100 to yield the percentage of sequence identity.

[0081] In some embodiments, the IL-2v, serum half-life extended IL-2v, e.g., Fc-IL-2v fusion proteins, and homodimers and heterodimers thereof, do not comprise a signal 2024202988   06 May 2024 peptide. In some embodiments, the IL-2v, serum half-life extended IL-2v, e.g., Fc-IL-2v fusion proteins, and homodimers and heterodimers thereof comprise an N-terminal signal peptide. The signal peptide can be an endogenous signal peptide (e.g., from a native or wild-type IL-2 protein), or from a heterologous polypeptide. In various embodiments, the 5 signal peptide or leader sequence is from a source protein selected from a serum protein, an immunoglobulin, a cytokine, a chemokine, a chaperone protein, an invariant protein, and a protein that directs proteins to the lysosomal compartment. In various embodiments, the signal peptide or leader sequence is from a source protein selected from colony stimulating factor 2 (CSF2, GM-CSF), tissue type plasminogen activator (PLAT, t-PA), C-C motif 10 chemokine ligand 7 (CCL7, MCP-3), C-X-C motif chemokine ligand 10 (CXCL10, IP-10), CD74 (p33; DHLAG; HLADG; immunoglobulin Kappa; la-GAMMA, invariant chain), serum albumin (ALB), SPARC (osteonectin), cwcv and kazal like domains proteoglycan 1 (SPOCK1); SPARC (osteonectin), cwcv and kazal like domains proteoglycan 2 (SPOCK2); polyubiquitin B / C (UBB / UBC), calreticulin (CALR) and vesicular stomatitis virus G 15 protein (VSV-G). In various embodiments, the signal peptide or leader sequence is from a source protein selected from colony stimulating factor 2 (CSF2, GM-CSF), immunoglobulin Kappa; la-GAMMA, invariant chain), and serum albumin (ALB). In some embodiments, the signal peptide is from a serum albumin signal peptide (e.g., comprising the amino acid sequence KWVTFISLLFLFSSAYS (SEQ ID NO: 218). In various embodiments, the 20 signal peptide or leader sequence is selected from an amino acid sequence of any one of SEQ ID NOs: 218-231, or a sequence that is at least 95%, 96%, 97%, 98%, or 99% identical to any one of SEQ ID NOs: 218-231. Illustrative signal sequences that can be used in the present IL-2v, serum half-life extended IL-2v, e.g., Fc-IL-2v fusion proteins, and homodimers and heterodimers thereof are provided in Table B. TABLE B - illustrative signal sequences SEQ ID NO: source protein name SEQUENCE 218 albumin KWVTFISLLFLFSSAYS 219 IL-2 MYRMQLLSCIALSLALVTNS 220 SPOCK1 MPAIAVLAAAAAAWCFLQVES 221 SPOCK2 MRAPGCGRLVLPLLLLAAAALA 222 Ig Kappa MDMRVPAQLLGLLLLWLSGARC 223 CSF2, GM-CSF MWLQSLLLLGTVACSISV 224 PLAT, t-PA MDAMKRGLCCVLLLCGAVFVSAR 225 CD74 MHRRRSRSCREDQKPV 226 p-catenin MRKAAVSHWQQQSYLDSGIHSGATTTAPSLS 227 CCL7, MCP-3 MKASAALLCLLLTAAAFSPQGLA 2024202988   06 May 2024 TABLE B - illustrative signal sequences SEQ ID NO: source protein name SEQUENCE 228 ubiquitin MQIFVKTLTGKTITLEVEPSDTIENVKAKIQDKEGIPPDQQR LIFAGKQLEDGRTLSDYNIQKESTLHLVLRLRGG 229 calreticulin MLLSVPLLLGLLGLAVA 230 VSV-G MKCLLYLAFLFIGVNC 231 CXCL10, IP-10 MNQTAILICCLIFLTLSGIQG

[0082] The signal peptide can be designed to be cleaved off, e.g., after secretion from the cell, to form a mature fusion protein. A modified human serum albumin signal peptide to secrete proteins in cells that can find use in expressing the present fusion proteins 5 is described, e.g., in Attallah, et al., Protein Expr Purif. (2017) 132:27-33. Additional signal peptide sequences for use in expressing the herein described fusion proteins are described, e.g., in Kober, et al., BiotechnolBioeng. (2013) 110(4): 1164-73.

[0083] In certain embodiments, the IL-2v domain comprises or is derived from a mouse or murine IL-2 sequence. Mus musculus IL-2 is identified as NCBI Gene ID 16183. 10 For fusion proteins based on mouse IL-2, the numbering of IL-2 positions is with reference to mature mouse IL-2, shown below: APTSSSTSSSTAEAQQQQQQQQQQQQHLEQLLMDLQELLSRMENYRNLKLPRMLTFKFYLP KQATELKDLQCLEDELGPLRHVLDLTQSKSFQLEDAENFISNIRVTWKLKGSDNTFECQF DDESATWDFLRRWIAFCQSIISTSPQ (SEQ ID NO: 234) . 15

[0084] Illustrative IL-2v domains based on or derived from a wild-type mouse IL-2 having reduced binding to a mouse IL-2RA (a.k.a., il2ra, CD25; I12r; Ly-43; NCBI Gene ID: 16184) are provided in Table D. Generally, the IL-2v domain of the herein described fusion proteins do not comprise the first 23 amino acid residues of the mature wild type mouse IL-2 sequence (e.g., do not comprise the amino acid sequence 20 APTSSSTSSSTAEAQQQQQQQQQ (SEQ ID NO: 235)). In some embodiments, the mouse IL-2v comprises an alanine at position 140 (C140) and at least one, two, or at least three, substitutions at amino acid positions selected from the group consisting of R52, F56, Y59, E76, L86, wherein the position numbers are with respect to the sequence of mature mouse IL-2 represented by SEQ ID NO: 234. In some embodiments, the mouse IL-2v 25 comprises an alanine at position 140 (C140) and at least one, two, or at least three, substitutions to alanine or glycine at amino acid positions selected from the group consisting of R52, F56, Y59, E76, L86, wherein the position numbers are with respect to the 2024202988   06 May 2024 sequence of mature mouse IL-2 represented by SEQ ID NO: 234. In some embodiments, the mouse IL-2v comprises an amino acid sequence corresponding to residues 250-375 of an amino acid sequence selected from the group consisting of SEQ ID NOs: 166-171, or comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 5   91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence corresponding to residues 250-375 of an amino acid sequence selected from the group consisting of SEQ ID NOs: 166-171.

[0085] As appropriate or desired, the IL-2v polypeptides described herein can be 10   PEGylated or not PEGylated. b. Serum Half-Life Extending Polypeptide

[0086] The herein described fusion proteins comprise a variant IL-2 that binds to IL-2RA with reduced binding affinity, and a serum half-life extending polypeptide. In some embodiments, the fusion protein comprises in sequential order fromN-terminus to C- 15 terminus, the serum half-life extending polypeptide (e.g., the Fc region) and the IL-2v. In some embodiments, the fusion protein comprises in sequential order from N-terminus to C-terminus, the IL-2v and the serum half-life extending polypeptide (e.g., the Fc region). Polypeptides that can used to extend the serum half-life of another polypeptide, e.g., via linking or fusion, are known in the art and can be used in the present fusion proteins. 20 Illustrative serum half-life extending polypeptides that can be linked or fused with the herein described IL-2v include without limitation an immunoglobulin fragment crystallizable region (Fc region), one or more serum albumin moieties, an albumin binding protein or peptide, an IgG, an XTEN polypeptide, a proline / alanine / serine-rich (PAS) polypeptide, an elastin-like polypeptide. IL-2v linked or fused to one or more serum 25 albumin moieties, an albumin binding protein or peptide, an IgG, an XTEN polypeptide, a proline / alanine / serine-rich (PAS) polypeptide, an elastin-like polypeptide need not dimerize (e.g., need not form homodimers or heterodimers). The one or more serum albumin moieties, an albumin binding protein or peptide, an IgG, an XTEN polypeptide, a proline / alanine / serine-rich (PAS) polypeptide, an elastin-like polypeptide can be linked or 30 fused to either or both of the N-terminus or the C-terminus of the IL-2v. Illustrative XTEN protein polymers that can be used in the present IL-2v fusion proteins are described, e.g., in Schellenberger, et al., Nat Biotechnol. 2009 Dec;27(12):l 186-90; Podust, et al., Journal of Controlled Release 240 (2016) 52-66; WO2010091122, WO2011123813, WO2013130683, WO2016077505 and WO2017197048. Illustrative proline / alanine / serine-rich (PAS) 2024202988   06 May 2024 polypeptides that can be used in the present IL-2v fusion proteins are described, e.g., in Schlapschy, et al., Protein Eng Des Sei. (2013) 26(8):489-501 and Breibeck, et al., Biopolymers. (2018) Jan;109(l). doi: 10.1002 / bip.23069, WO2016122806 and WO2016130451. The foregoing references are which are hereby incorporated herein by 5 reference in their entirety for all purposes.

[0087] In some embodiments, the serum half-life extending polypeptide is an immunoglobulin fragment crystallizable region (Fc region). Generally, the Fc domain is comprised of or derived from the same species as the IL-2v domain (e.g., human, dog, cat, mouse or monkey). In some embodiments, the Fc region is from a human IgGl, IgG2, 10 IgG3 or IgG4. In some embodiments, the Fc region is from a human IgGl or IgG4.

[0088] In some embodiments, the Fc modifications can promote one or more of increased serum half-life or decreased antibody effector function of the molecule. In other embodiments, certain of these modifications, decrease antibody effector function and increase half-life of the antibody. In some embodiments, the Fc-IL-2v fusion proteins 15   described herein comprise two or more, three or more, four or more, five or more, six or more, six or fewer, five or fewer, four or fewer, three or fewer, two or fewer, or one modified Fc amino acid residue(s). Exemplary amino acid substitutions are described below.

[0089] In some embodiments, the Fc domain of the fusion protein does not comprise 20 a hinge region; it is truncated or deleted, in whole or in part. The structural hinge region of human IgGl, IgG2 and IgG4 antibodies is a peptide linker of 19 to 23 amino acids containing two to four cysteine residues, is genetically encoded on the hinge exon together with the 5’-end of the CH2 exon, and allows for disulfide bridges between first and second Fc domains (Roux, et al., J. Immunol. (1998) 161:4083). The structural hinge region is 25 comprised of amino acid residue positions 216-238 (EU numbering) or 226-251 (Kabat numbering) (identified on imgt.org). In some embodiments, the Fc region comprises or is derived from a human IgG4 isotype and does not comprise the amino acid sequence ESKYGPPCPPCP (SEQ ID NO: 236). In some embodiments, the Fc region comprises or is derived from a human IgG 1 isotype and does not comprise the amino acid sequence 30 EPKSCDKTHTCPPCP (SEQ ID NO: 237) or EPKSCDKTHTCPPCPAPELL (SEQ ID NO: 238). Fc Mutations that Increase Serum Half-Life

[0090] In some embodiments, the Fc region comprises amino acid modifications that promote an increased serum half-life of the fusion protein. Mutations that increase the 2024202988   06 May 2024 half-life of an antibody have been described. In one embodiment, the constant region of a Fc-IL-2v fusion proteins described herein comprise a methionine to tyrosine substitution at position 252 (EU numbering), a serine to threonine substitution at position 254 (EU numbering), and a threonine to glutamic acid substitution at position 256 (EU numbering). 5 See, e.g., U.S. Patent No. 7,658,921. This type of mutant, designated as a “YTE mutant” exhibits a four-fold increased half-life relative to wild-type versions of the same antibody (Dall’Acqua, et al., J Biol Chern, 281: 23514-24 (2006); Robbie, et al., Antimicrob Agents Chemotherap., 57(12):6147-6153 (2013)). In certain embodiments, the Fc-IL-2v fusion proteins described herein comprise an IgG constant domain comprising one, two, three or 10 more amino acid substitutions of amino acid residues at positions 251-257, 285-290, 308 314, 385-389, and 428-436 (EU numbering). Alternatively, M428L andN434S (“LS”) substitutions can increase the pharmacokinetic half-life of the fusion protein. In other embodiments, the Fc-IL-2v fusion proteins described herein comprise a M428L and N434S substitution (EU numbering). In other embodiments, the Fc-IL-2v fusion proteins described 15 herein comprise T250Q and M428L (EU numbering) mutations. In other embodiments, the Fc-IL-2v fusion proteins described herein comprise H433K and N434F (EU numbering) mutations. Fc Mutations that Reduce or Eliminate Effector Activity

[0091] In some embodiments, the Fc-IL-2v fusion proteins described herein can 20 have an Fc domain with amino acid substitutions that reduce or eliminate Fc effector function (including, e.g., antibody-dependent cellular cytotoxicity (ADCC), antibodydependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC)).

[0092] In some embodiments, the Fc region is altered by replacing at least one amino acid residue with a different amino acid residue to reduce or eliminate effector 25 function(s) of the antibody. For example, one or more amino acids selected from amino acid residues 234, 235, 236, 237, 297, 318, 320 and 322 (EU numbering) can be replaced with a different amino acid residue such that the fusion protein has decreased affinity for an effector ligand. The effector ligand to which affinity is altered can be, for example, an Fc receptor (e.g., at residue positions 234, 235, 236, 237, 297 (EU numbering)) or the Cl 30 component of complement (e.g., at residue positions 297, 318, 320, 322 (EU numbering)). U.S. Pat. Nos. 5,624,821 and 5,648,260, both by Winter et al.

[0093] Fc modifications reducing or eliminating effector function include substitutions, insertions, and deletions, e.g., at one or more positions including 234, 235, 236, 237, 267, 269, 325, and 328, e.g., 234G, 235G, 236R, 237K, 267R, 269R, 325L, and 2024202988   06 May 2024 328R (EU numbering). Further, an Fc variant may comprise 236R / 328R. Other modifications for reducing FcyR and complement interactions include substitutions at positions 297A, 234A, 235A, 318A, 228P, 236E, 268Q, 309L, 329G, 330S, 33IS, 220S, 226S, 229S, 238S, 233P, and 234V (EU numbering). These and other modifications are 5 reviewed in Strohl (2009) Current Opinion in Biotechnology 20:685-691; see also, Schlothauer, et al., Protein Eng Des Sei. (2016) 29(10):457-466. Effector functions (both ADCC and complement activation) can be reduced, while maintaining neonatal FcR binding (maintaining half-life), by mutating IgG residues at one or more of positions 233236 and 327-331, such as E233P, L234V, L235A, optionally G236A, A327G, A330S and 10   P331S in IgGl; E233P, F234V, L235A, optionally G236A, in IgG4; and A330S and P331S in IgG2 (EU numbering). See Armour et al. (1999) Eur. J. Immunol. 29:2613; WO 99 / 58572. Other mutations that reduce effector function include L234A and L235A in IgGl (Alegre etal. (1994) Transplantation 57:1537); V234A and G237A in IgG2 (Cole et al. (1997) J. Immunol. 159:3613; see also U.S. Pat. No. 5,834,597); and S228P and L235E 15 for IgG4 (Reddy et al. (2000) J. Immunol. 164:1925). Another combination of mutations for reducing effector function in a human IgGl include L234F, L235E and P331S. Oganesyan et al. (2008) Acta Crystallogr. D. Biol. Crystallogr. 64:700. See generally Labrijn et gal. (2008) Curr. Op. Immunol. 20:479. Additional mutations found to decrease effector function in the context of an Fc (IgGl) fusion protein (abatacept) include C226S, 20   C229S and P238S (EU numbering). Davis et al. (2007) J. Immunol. 34:2204.

[0094] ADCC activity may be reduced by modifying the Fc region. In certain embodiments, sites that affect binding to Fc receptors may be removed, e.g., sites other than salvage receptor binding sites. In other embodiments, an Fc region may be modified to remove an ADCC site. Exemplary ADCC sites have been described with respect to ADCC 25 sites in IgGl (Sarmay, et al, (1992) Molec. Immunol. 29 (5): 633-9). In one embodiment, the G236R and L328R variant of human IgGl effectively eliminates FcyR binding (Horton, etal. (2011) J. Immunol. 186:4223 and Chu, etal. (2008) Mol. Immunol. 45:3926). In other embodiments, the Fc having reduced binding to FcyRs comprises the amino acid substitutions L234A, L235E and G237A. Gross, et al. (2001) Immunity 15:289. 30 Modifications in the IgG Fc region to decrease binding to FcyRI to decrease ADCC (e.g., 234A; 235E; 236A; G237A) identified in WO 88 / 007089 can be used in the present fusion proteins. See also Duncan & Winter (1988) Nature 332:563; Chappel et al. (1991) Proc. Nat'l Acad. Sci. (USA) 88:9036; and Sondermann et al. (2000) Nature 406:267 (discussing the effects of these mutations on FcyRIII binding). 2024202988   06 May 2024

[0095] CDC activity may also be reduced by modifying the Fc region. Mutations at IgGl positions D270, K322, P329 and P331, specifically alanine mutations D270A, K322A, P329A and P331A, significantly reduce the ability of the corresponding antibody to bind Clq and activate complement (Idusogie et al. (2000) J. Immunol. 164:4178; WO 99 / 51642. 5 Modification of position 331 of IgGl (e.g. P331S) has been shown to reduce complement binding (Tao et al. (1993)1 Exp. Med. 178:661; Xu Y, et al. J Biol Chern. 1994. 269:346974; and Canfield & Morrison (1991) J. Exp. Med. 173:1483). In another example, one or more amino acid residues within amino acid positions 231 to 239 are altered to thereby reduce the ability of the antibody to fix complement (WO 94 / 29351). Modifications in the 10 IgG Fc region identified in WO 88 / 007089 that reduce or eliminate binding to complement component Clq, and therefore reduce or eliminate CDC (e.g., E318A or V / K320A and K322A / Q) can be used in the present fusion proteins.

[0096] In some embodiments, the Fc with reduced complement fixation has the amino acid substitutions A330S and P331S. Gross et al. (2001) Immunity 15:289. 15

[0097] Other Fc variants having reduced ADCC and / or CDC are disclosed at Glaesner etal. (2010) Diabetes Metab. Res. Rev. 26:287 (F234A and L235A to decrease ADCC and ADCP in an IgG4); Hutchins et al. (1995) Proc. Nat'1 Acad. Sci. (USA) 92:11980 (F234A, G237A and E318A in an IgG4); An et al. (2009) MAbs 1:572 and U.S. Pat. App. Pub. 2007 / 0148167 (H268Q, V309L, A330S and P331S in an IgG2); McEarchem 20 et al. (2007) Blood 109:1185 (C226S, C229S, E233P, L234V, L235A in an IgGl); Vafa et al. (2014) Methods 65:114 (V234A, G237A, P238S, H268A, V309L, A330S, P331S in an IgG2) (EU numbering).

[0098] In certain embodiments, the fusion protein has an Fc having essentially no effector function, e.g., the Fc has reduced or eliminated binding to FcyRs and reduced or 25 eliminated complement fixation, e.g., is effectorless. An exemplary IgGl Fc that is effectorless comprises the following five mutations: L234A, L235E, G237A, A330S and P331S (EU numbering) (Gross et al. (2001) Immunity 15:289). These five substitutions may be combined with N297A to eliminate glycosylation as well. Mutations that Facilitate Heterodimerization 30

[0099] In some embodiments, first and second Fc domains have mutations to facilitate heterodimerization. Mutations in Fc domain pairs that facilitate or promote heterodimerization are reviewed in Ha, et al., Front. Immunol. (2016) 7:394. In some embodiments, the first Fc domain and the second Fc domain comprise the following amino acid substitutions (EU numbering), respectively (or vice versa): T366W and 2024202988   06 May 2024 T366S / L368A / Y407V; T366W / S354C and T366S / L368A / Y407V / Y349C; S364H / F405A and Y349T / T394F; T350V / L351Y / F405A / Y407V and T350V / T366L / K392L / T394W; K360D / D399M / Y407A and E345R / Q347R / T366V / K409V; K409D / K392D and D399K / E356K; K360E / K409W and Q347R / D399V / F405T; K360E / K409W / Y349C and 5   Q347R / D399V / F405T / S354C; F405L and K409R; or K370E / K409W and E357N / D399V / F405T.

[0100] In some embodiments, Fc region heterodimerization of the two different heavy chain-containing species can be facilitated by so-called ‘knobs-into-holes’ mutations (Atwell et al. 1997. JMB 270:26-35). The ‘hole’ mutations (T366S, L368A and Y407V) 10 are incorporated into one Fc-containing chain, the T366W ‘knob’ mutation is incorporated into the other chain. In addition, a C220S mutation can be incorporated into an IgGl hinge region of a scFv-containing arm to eliminate a free cysteine that otherwise forms a disulfide bond with a corresponding cysteine in the light chain in a wild-type IgGl. Co-transfection of such constructs leads to preferential formation of a heterodimeric Fc, with low levels of 15 homodimer contaminants. Additionally, incorporating a S354C mutation can be incorporated into the Fc containing the ‘knob’ mutations and a Y349C mutation into the Fc containing the ‘hole’ mutations can optionally be used to generate a covalent bond between the two halves of the heterodimeric Fc if additional thermodynamic stability is desired (Merchant et al. 1998. Nat. Biotechnol. 16: 677-81). 20

[0101] To facilitate purification of the heterodimeric molecule away from contaminating homodimeric products, the H435R or H435R+Y436F mutations to reduce or eliminate protein A binding can be introduced into one but not both of the Fc-containing chains (Jendeberg, L. et al. 1997 J. Immunol. Methods 201:25-34). This reduces or eliminates protein A binding of the homodimer contaminant containing these mutations, and 25 greatly simplifies purification of the desired heterodimer away from remaining homodimer contaminant via additional chromatography steps (e.g. ion exchange, e.g., anion exchange). In embodiments incorporating H435R (or H435R+Y436F) mutations in the first or second Fc region of a heavy chain, if the VH region in the same heavy chain is from a VH3 family variable region, this VH region can also include amino acid substitutions, as described 30 herein, to reduce or eliminate Protein A binding of the entire heavy chain. IgGl Isotype Fc

[0102] In one embodiment, the Fc region comprises or is derived from a human IgGl. In some embodiments, the antibody has a chimeric heavy chain constant region (e.g., having the CHI, hinge, CH2 regions of IgG4 and CH3 region of IgGl). 2024202988   06 May 2024

[0103] IgGl antibodies exist in various allotypes and isoallotypes. In particular embodiments, the Fc-IL-2v fusion proteins described herein include an IgGl heavy chain having an allotype of Glml; nGlm2; Glm3; Glml7,l; Glml7,l,2; Glm3,l; or Glml7. Each of these allotypes or isoallotypes is characterized by the following amino acid residues 5 at the indicated positions within the IgGl heavy chain constant region (Fc) (EU numbering): Glml:D356, L358; nGlml: E356, M358; Glm3: R214, E356, M358, A431; Glml7,l: K214, D356, L358, A431; 10         Glml7,l,2: K214, D356, L358, G431; Glm3,l: R214, D356, L358, A431; and Glml7: K214, E356, M358, A431.

[0104] In a specific embodiment, the IL-2v domain, or truncated fragment thereof, is directly linked to, or linked via an intervening amino acid sequence (e.g., a G-S linker), to 15 a wild type IgGlm3 sequence, or fragment thereof, provided below. EPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTIS KAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVL DSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 20   74) . For example, in various embodiments, the IgGlm3 fragment has the first five residues (EPKSC; SEQ ID NO: 232) removed, having the following sequence: DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDG VEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQ PREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGS 25 FFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 233) .

[0105] In certain embodiments, the Fc-IL-2v fusion protein has an IgGl isotype. In some embodiments, the Fc-IL-2v fusion protein contains a human IgGl constant region. In some embodiments, the human IgGl Fc region contains one or more modifications. For 30 example, in some embodiments, the Fc region contains one or more amino acid substitutions (e.g., relative to a wild-type Fc region of the same isotype). In some embodiments, the one or more amino acid substitutions are selected from N297A, N297Q (Bolt S et al. (1993) Eur J Immunol 23:403-411), D265A, L234A, L235A (McEarchem et al., (2007) Blood, 109:1185-1192), C226S, C229S (McEarchem et al., (2007) Blood. 2024202988   06 May 2024 109:1185-1192), P238S (Davis et al., (2007) J Rheumatol, 34:2204-2210), E233P, L234V (McEarchern etaL, (2007) Blood, 109:1185-1192), P238A, A327Q, A327G, P329A (Shields R L. et al., (2001) J Biol Chem. 276(9):6591-604), P329G (Schlothauer, et al., Protein Eng Des Sei. (2016) 29(10):457-466); K322A, L234F, L235E (Hezareh, et al., 5   (2001) J Virol 75, 12161-12168; Oganesyan et al., (2008). Acta Crystallographica 64, 700 704), P331S (Oganesyan et al., (2008) Acta Crystallographica 64, 700-704), T394D (Wilkinson et al. (2013) MAbs 5(3): 406-417), A330L, M252Y, S254T, and / or T256E, where the amino acid position is according to the EU numbering convention. In certain embodiments, the Fc region further includes an amino acid deletion at a position 10 corresponding to glycine 236 according to the EU numbering convention.

[0106] In some embodiments, the Fc-IL-2v fusion protein has an IgGl isotype with a heavy chain constant region that contains a C220S amino acid substitution according to the EU numbering convention.

[0107] In some embodiments, the Fc region comprises a human IgGl isotype and 15 comprises one or more amino acid substitutions in the Fc region at a residue position selected from the group consisting of: N297A, N297G, N297Q, N297G, D265A, L234A, L235A, C226S, C229S, P238S, E233P, L234V, P238A, A327Q, A327G, P329A, P329G, K322A, L234F, L235E, P331S, T394D, A330L, M252Y, S254T, T256E, M428L, N434S, T366W, T366S, L368A, Y407V, H435R, Y436F, and any combination thereof, wherein the 20 numbering of the residues is according to EU numbering. In some embodiments, the Fc region comprises a human IgGl isotype and comprises one or more amino acid substitutions in the Fc region at a residue position selected from the group consisting of: L234A, L234V, L234F, L235A, L235E, P329G, A330L, P331S, and any combination thereof, wherein the numbering of the residues is according to EU numbering. 25 IgG4 Isotype Fc

[0108] For uses where effector function is to be avoided altogether, e.g. when antigen binding alone is sufficient to generate the desired therapeutic benefit, and effector function only leads to (or increases the risk of) undesired side effects, IgG4 antibodies may be used, or antibodies or fragments lacking the Fc region or a substantial portion thereof can 30 be devised, or the Fc may be mutated to eliminate glycosylation altogether (e.g. N297A). Alternatively, a hybrid construct of human IgG2 (CHI domain and hinge region) and human IgG4 (CH2 and CH3 domains) has been generated that is devoid of effector function, lacking the ability to bind the FcyRs (like IgG2) and unable to activate complement (like IgG4). (see, Rother et al. (2007) Nat. Biotechnol. 25:1256; Mueller et al. 2024202988   06 May 2024 (1997) Mol. Immunol. 34:441; and Labrijn et al. (2008) Curr. Op. Immunol. 20:479, discussing Fc modifications to reduce effector function generally).

[0109] In certain embodiments, the Fc-IL-2v fusion protein has an IgG4 isotype. In some embodiments, the Fc-IL-2v fusion protein contains a human IgG4 constant region. In 5 some embodiments, the human IgG4 constant region includes an Fc region. In some embodiments, the Fc region contains one or more modifications. For example, in some embodiments, the Fc region contains one or more amino acid substitutions (e.g., relative to a wild-type Fc region of the same isotype). In some embodiments, the one or more amino acid substitutions are selected from E233P, F234V, F234A, L235A, G237A, E318A, 10   S228P, L235E, T394D, M252Y, S254T, T256E, N297A, N297G, N297Q, T366W, T366S, L368A, Y407V, M428L, N434S, H435R, Y436F, and any combination thereof, where the amino acid position is according to the EU numbering convention. See, e.g., Hutchins et al. (1995) Proc Natl Acad Sei USA, 92:11980-11984; Reddy etal., (2000) J Immunol, 164:1925-1933; Angal etal., (1993) Mol Immunol. 30(l):105-8; U.S. Pat. No. 8,614,299 15   B2; Vafa O. et al., (2014) Methods 65:114-126; and Jacobsen et. al., J. Biol. Chem.(2Qll) 292(5):1865-1875. In some embodiments, the Fc region comprises a human IgG4 isotype and comprises one or more amino acid substitutions in the Fc region at a residue position selected from the group consisting of: F234V, F234A, L235A, L235E, S228P, and any combination thereof, wherein the numbering of the residues is according to EU numbering. 20

[0110] In some embodiments, an IgG4 variant of the present disclosure may be combined with an S228P mutation according to the EU numbering convention (Angal et al., (1993) Mol Immunol, 30:105-108) and / or with one or more mutations described in Peters et al., (2012) J Biol Chern. 13; 287(29):24525-33) to enhance antibody stabilization. IgG2 Isotype Fc 25

[0111] In certain embodiments, the Fc-IL-2v fusion protein has an IgG2 isotype. In some embodiments, the Fc-IL-2v fusion protein contains a human IgG2 constant region. In some embodiments, the human IgG2 constant region includes an Fc region. In some embodiments, the Fc region contains one or more modifications. For example, in some embodiments, the Fc region contains one or more amino acid substitutions (e.g., relative to 30 a wild-type Fc region of the same isotype). In some embodiments, the one or more amino acid substitutions are selected from P238S, V234A, G237A, H268A, H268Q, H268E, V309L, N297A, N297G, N297Q, V309L, A330S, P331 S, C232S, C233S, M252Y, S254T, and / or T256E, where the amino acid position is according to the EU numbering convention (Vafa, et al., (2014) Methods 65:114-126). 2024202988   06 May 2024

[0112] In certain embodiments, the Fc-IL-2v fusion proteins described herein comprise the L234F, L235E, D265A mutations, which are collectively referred to as “FEA.” The FEA mutations decrease or abrogate effector function. In certain embodiments, the Fc-IL-2v fusion proteins described herein comprise the L234F, L235E, 5   D265A, and F405L mutations, which are collectively referred to as “FEAL.” In certain embodiments, the Fc-IL-2v fusion proteins described herein comprise the L234F, L235E, D265A, and a mutation selected from the group consisting of F405L, F405A, F405D, F405E, F405H, F405I, F405K, F405M, F405N, F405Q, F405S, F405T, F405V, F405W, and F405Y. In certain embodiments, the Fc-IL-2v fusion proteins described herein 10 comprise the L234F, L235E, D265A, and K409R mutations, which are collectively referred to as “FEAR.” In certain embodiments, FEAL and FEAR are comprised in a fusion protein described herein. In certain embodiments, the Fc-IL-2v fusion proteins described herein additionally comprise the M428L and N434S mutations, which are collectively referred to as LS. In certain embodiments, the Fc-IL-2v fusion proteins described herein comprise the 15   L234F, L235E, D265A, F405L, M428L, and N434S mutations, which are collectively referred to as “FEALLS.” In certain embodiments, the Fc-IL-2v fusion proteins described herein comprise the L234F, L235E, D265A, M428L, and N434S mutations along with one further mutation selected from the group consisting of F405L, F405A, F405D, F405E, F405H, F405I, F405K, F405M, F405N, F405Q, F405S, F405T, F405V, F405W, and 20   F405Y. In certain embodiments, the Fc-IL-2v fusion proteins described herein comprise the L234F, L235E, D265A, K409R, M428L, and N434S mutations which are collectively referred to as “FEARLS.” In certain embodiments, FEALLS and FEARLS are comprised in a fusion protein described herein. By reducing or abrogating effector function on the Fc domains of the Fc-IL-2v fusion protein, cells bound by the molecule are not killed by innate 25 effector cells e.g., NK cells, macrophages.

[0113] In certain embodiments, the one or more modifications are selected from the following Fc amino acid substitutions (EU numbering) or combinations thereof: L234F; L235E; G236A; S239D; F243L; D265E; D265A; S267E; H268F; R292P; N297Q; N297G, N297A; S298A; S324T; I332E; S239D; A330L; L234F; L235E; P331S; F243L; Y300L; 30   V305I; P396L; S298A; E333A; K334A; E345R; L235V; F243L; R292P; Y300L; P396L; M428L; E430G; N434S; G236A, S267E, H268F, S324T, and I332E; G236A, S239D, and I332E; S239D, A330L, I332E; L234F, L235E, and P331S; F243L, R292P, Y300L, V305I, and P396L; G236A, H268F, S324T, and I332E; S239D, H268F, S324T, and I332E; S298A, E333A, and K334A; L235V, F243L, R292P, Y300L, and P396L; S239D, I332E; S239D, 35   S298A, and I332E; G236A, S239D, I332E, M428L, and N434S; G236A, S239D, A330L, 2024202988   06 May 2024 I332E, M428L, and N434S; S239D, I332E, G236A and A330L; M428L and N4343S; M428L, N434S; G236A, S239D, A330L, and I332E; and G236A and I332E. In certain embodiments, the one or more modifications is selected from the group consisting of: D265A, L234F, L235E, N297A, N297G, N297Q, and P331S. In certain embodiments, the 5 one or more modifications are selected from N297A and D265A. In certain embodiments, the one or more modifications are selected from L234F and L235E. In certain embodiments, the one or more modifications are selected from L234F, L234E, and D265A. In certain embodiments, the one or more modifications are selected from L234F, L234E, and N297Q. In certain embodiments, the one or more modifications are selected from 10   L234F, L235E, and P331S. In certain embodiments, the one or more modifications are selected from D265A and N297Q. In certain embodiments, the one or more modifications are selected from L234F, L235E, D265A, N297A, N297G, N297Q, and P331S.

[0114] Mutations that reduce Fc-receptor binding and find use in the herein described fusion proteins include, for example, N297A; N297G; N297Q; D265A; 15   L234F / L235E; L234F / L235E / N297Q; L234F / L235E / P331S; D265A / N297Q; and L234F / L235E / D265A / N297Q / P331S (all EU numbering). In certain embodiments the Fc-IL-2v fusion proteins described herein described herein comprise L234F and L235E mutations. In certain embodiments the Fc-IL-2v fusion proteins described herein described herein comprise L234F, L235E, and D265A mutations. In certain embodiments the Fc-IL- 20 2v fusion proteins described herein described herein comprise L234F, L235E, and N297Q mutations. In certain embodiments the Fc-IL-2v fusion proteins described herein described herein comprise an N297A or N297Q mutation. In certain embodiments the Fc-IL-2v fusion proteins described herein described herein comprise an N297A, N297G or N297Q mutation as well as L234F, L235E, and D265A mutations. In certain embodiments, one, 25 two, three, four, or more amino acid substitutions are introduced into a Fc region to alter the effector function of the antigen binding molecule. For example, these substitutions are located at positions selected from the group consisting of amino acid residues 234, 235, 236, 237, 265, 297, 318, 320, and 322, (according to EU numbering). These positions can be replaced with a different amino acid residue such that the antigen binding molecule has an 30 altered (e.g., reduced) affinity for an effector ligand (e.g., an Fc receptor or the C1 component of complement), but retains the antigen binding ability of the parent antibody. In certain embodiments, the Fc-IL-2v fusion proteins described herein described herein comprise E233P, L234V, L235A, and / or G236A mutations (EU numbering). In some embodiments, the Fc-IL-2v fusion proteins described herein comprise A327G, A330S, 35 and / or P331S mutations (EU numbering). In some embodiments, the Fc-IL-2v fusion 2024202988   06 May 2024 proteins described herein comprise K322A mutations (EU numbering). In some embodiments the Fc-IL-2v fusion proteins described herein comprise E318A, K320A, and K322A (EU numbering) mutations. In certain embodiments, the Fc-IL-2v fusion proteins described herein comprise a L235E (EU numbering) mutation. 5

[0115] In some embodiments, the Fc portion of the fusion protein comprises an amino acid sequence having at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%, identical to an amino acid sequence of GGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY 10 NSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREE MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 239); GGPSVFLFPPKPKDTLYITREPEVTCVWDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQY NSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREE 15 MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQ QGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 240); ESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSQEDPEVQFNWYV DGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAK GQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD 20 GSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 241) ; ESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSQEDPEVQFNWYV DGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAK GQPREPQVYTLPPSQEEMTKNQVSLSCAVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD 25 GSFFLVSRLTVDKSRWQEGNVFSCSVMHEALHNRFTQKSLSLSLGK (SEQ ID NO: 4 6) ; ESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSQEDPEVQFNWYV DGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAK GQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD 30 GSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 242); or ESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLYITREPEVTCVWDVSQEDPEVQFNWYV DGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAK GQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSD 2024202988   06 May 2024 1005242139 GSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 243) .

[0116] In some embodiments, the terminal Fc amino acid residue (e.g., K447) is removed or eliminated. In some embodiments, the Fc region comprises an amino acid 5 sequence selected from the group consisting of SEQ ID NOs: 45-72, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 4572. In some embodiments, the Fc region comprises an amino acid sequence selected from 10 the group consisting of SEQ ID NOs: 45, 47, 49, 52, 54, 56, 57, 59, 61, 63, 65, 67, 69 and 71, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 45, 47, 49, 52, 54, 56, 57, 59, 61, 63, 65, 67, 69 and 71. In some 15 embodiments, the Fc region comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 46, 48, 50, 51, 53, 55, 58, 60 and 62, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 46, 48, 50, 51, 20   53, 55, 58, 60 and 62. c. Linker

[0117] In various embodiments, the IL-2v domain, or truncated fragment thereof, is directly linked or contiguously linked or abutted to the serum half-life extending polypeptide (e.g., Fc domain). In some embodiments, the IL-2v domain, or truncated 25 fragment thereof, is operably linked to the serum half-life extending polypeptide (e.g., Fc domain) via a linker, e.g., the linker is positioned between the serum half-life extending polypeptide (e.g., Fc domain) and the IL-2v. As appropriate, the linker can be a flexible linker. For example, the linker can be an amino acid sequence comprising 1 to 10 repeats or units, e.g., 1 to 5 repeats or units, e.g., 3 to 5 repeats or units, e.g., 3 or 4 or 5 repeats of a 30 GGGS motif (SEQ ID NO: 265), e.g., 3 or 4 or 5 repeats of a GGGGS motif (SEQ ID NO: 264), or mixtures thereof (“G-S linker”) (Desplancq et al. 1994, Protein Engineering 7:1027-1033). In some embodiments, the linker has a length of from 4 to 50 amino acids, e.g., from 5 amino acids to 25 amino acids, e.g., from 12 amino acids to 15, 16, 20 or 25 2024202988   06 May 2024 amino acids. In some embodiments, the linker comprises 4 repeats of a GGGGS motif (SEQ ID NO: 246).

[0118] In certain embodiments the IL-2v domain, or truncated fragment thereof, is directly linked to, or linked via an intervening amino acid sequence (e.g., a G-S linker), to a 5 human IgGl (e.g., mutant IgGlm3 sequence), IgG2, IgG3 or IgG4 with 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) amino acid substitutions. d. Illustrative Fc-IL-2v Fusion Proteins

[0119] Further provided are Fc-IL-2v fusion proteins, comprising an IL-2v domain, as described above and herein, and an Fc domain, as described above and herein. 10

[0120] Functionally, in various embodiments, the Fc-IL-2v fusion protein binds to IL-2RA with an equilibrium dissociation constant (Kd) of at least 60 pM (e.g., 60 pM or higher), e.g., at least 70 pM, 80 pM, 90 pM, 100 pM, or higher (indicative of a weaker binding affinity or Kd). In some embodiments, the Fc-IL-2v fusion protein binds to a complex of interleukin 2 receptor subunit beta (IL-2RB; CD 122) and interleukin 2 receptor 15 subunit gamma (IL-2RG; CD132) with a Kd of less than 150 nM, e.g., less than 1.5 nM, e.g., less than 120 pM, e.g., less than 100 pM, e.g., less than 80 pM, e.g., less than 75 pM, e.g., less than 70 pM. In some embodiments, the Fc-IL-2v fusion protein promotes equivalent or greater proliferation of CD8+ T cells relative to an IL-2v of any one of SEQ ID NOs: 43 and 44, a fusion protein comprising Fc operably linked to wt IL-2, or a fusion 20 protein of any one of SEQ ID NOs. 117, 118, 161 and 162. In some embodiments, the concentration at which the IL-2v fusion protein elicits 50% of maximal (ECso) signal transducer and activator of transcription 5 (STAT5) activation or signaling of regulatory T (Treg) cells is at least 1000-fold, e.g., at least 1500-fold, e.g., at least 1700-fold, e.g., at least 2000-fold, e.g., at least 2500-fold higher, relative to the ECso for STAT5 activation or 25 signaling of wt IL-2, or an IL-2v of any one of SEQ ID NOs: 43 and 44, a fusion protein comprising Fc operably linked to wt IL-2, or a fusion protein of any one of SEQ ID NOs. 117, 118, 161 or 162. In some embodiments, the concentration at which the IL-2v fusion protein elicits ECso of IL-2RaPy-mediated STAT5 activation or signaling (e.g., measured as STAT5 activation of CTLL2 cells) is at least 2500-fold, e.g., at least 5000-fold, e.g., at least 30    7500-fold, e.g., at least 10,000-fold, e.g., at least 15,000-fold, e.g., at least 20,000-fold higher, relative to the ECso for STAT5 activation or signaling of wt IL-2, or an IL-2v of any one of SEQ ID NOs: 43 and 44, a fusion protein comprising Fc operably linked to wt IL-2, or a fusion protein of any one of SEQ ID NOs. 117, 118, 161 or 162. In some embodiments, the concentration at which the IL-2v fusion protein elicits 50% of maximal 2024202988   06 May 2024 (ECso) proliferation of natural killer (NK) cells is at least 10-fold, e.g., at least 12-fold, e.g., at least 15-fold, e.g., at least 16-fold, e.g., at least 18-fold, e.g., at least 20-fold higher, e.g., as measured using KHYG-1 cells, relative to the ECso for proliferation of wt IL-2, or an IL-2v of any one of SEQ ID NOs: 43 and 44, a fusion protein comprising Fc operably linked to 5 wt IL-2, or a fusion protein of any one of SEQ ID NOs. 117, 118, 161 or 162.

[0121] Structurally, in various embodiments, the Fc-IL-2v fusion protein comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 75-116 and 119-160, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at 10 least 98%, or at least 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 75-116 and 119-160. Illustrative Fc-IL-2v fusion proteins based on or derived from human wild-type Fc and human wild-type IL-2 are provided in Table C.

[0122] In various embodiments, the Fc-IL-2v fusion protein is based on or derived from mouse wild-type Fc and mouse wild-type IL-2, comprises an amino acid sequence 15 selected from the group consisting of SEQ ID NOs: 166-171, or comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 166-171. Illustrative Fc-IL-2v fusion proteins based on or derived from mouse wild-type Fc 20 and mouse wild-type IL-2 are provided in Table D. In various embodiments, the mouse Fc- IL-2v fusion proteins are in the form of a heterodimer, e.g., with an Fc domain comprising an amino acid sequence of SEQ ID NO: 250, or comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to an 25 amino acid sequence of SEQ ID NOs: 250. GPTIKPCPPCKCPAPNAAGGPSVFIFPPKIKDVLMISLSPIVTCVWDVSEDDPDVQISWF VNNVEVHTAQTQTHREDYNSTLRWSALPIQHQDWMSGKEFKCKVNNKDLGAPIERTISKP KGSVRAPQVYVLPPPEEEMTKKQVTLSCAVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDS DGSYFMVSKLRVEKKNWVERNSYSCSWHEGLHNHHTTKSFSRTPGK (SEQ ID NO: 30   250)

[0123] Generally, the Fc-IL-2v fusion proteins described herein, are not fused to a second cytokine. For example, the Fc-IL-2v fusion proteins described herein are not fused to a second interleukin, including a second IL-2, or an interferon. 2024202988   06 May 2024

[0124] In some embodiments, the Fc-IL-2v fusion proteins are not glycosylated. In some embodiments, the IL-2v in the Fc-IL-2v fusion proteins is not glycosylated. In some embodiments, the Fc region or Fc domain of the Fc-IL-2v fusion proteins is glycosylated, e.g., has a single N-linked glycan at position N297 in one or both of the Fc regions or Fc 5 domains (EU numbering) of the herein described Fc-IL-2v heterodimers. TABLE C: Illustrative human Fc-IL-2v fusion proteins PROTEIN NO: SEQ ID NO: Features Polypeptide Sequence (Fc domain is underlined) IgG4 variants 75 higG4 S228P / F234A / L235A T366W ESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGV EVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP QVYTLPPSQEEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRL hIL-2v_Al-5_R38X1_ T41X2_F42X3_ Y45X4_E61X5_ E62X6_E68X7_ L72X8_Q74X9_ Y107X10_C125S X2 is R, S, G or A X2 is T, G or A X3 is F, G or A X4 is Y, G or A X5 is E, G or A X6 is E, G or A X7 is E, G or A X8 is L, G or A X9 is Q, G or A X10 is Y, G or A TVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGSGGGGSGGGGSGGGGSSTKKTQLQ lehllldlqmilnginnyknpkltx1mlx2x3kfx4mpkkatelkhlqclex5x6lkplex7vlnx 8ax9sknfhlrprdlisninvivlelkgsettfmcex10adetativeflnrwitfsqsiistlt 76 higG4 S228P / F234A / L235A T366W ESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGV EVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP QVYTLPPSQEEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRL TVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGSGGGGSGGGGSGGGGSSTKKTQLQ TABLE C: Illustrative human Fc-IL-2v fusion proteins PROTEIN NO: SEQ ID NO: Features Polypeptide Sequence (Fc domain is underlined) hIL-2v_Al-5_R38X1_ F42X2_Y4 5X3_E61X4_ E62X5_L72X6_C125S X2 is R, S, G or A X2 is F, G or A X3 is Y, G or A X4 is E, G or A X5 is E, G or A Xs is L, G or A lehllldlqmilnginnyknpkltx1mltx2kfx3mpkkatelkhlqclex4x5lkpleevlnx6a QSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 77 hIgG4 S228P / F234A / L235A ESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGV EVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP T366W QVYTLPPSQEEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRL hIL-2v_Al-5_R38X1_ F42X2_Y4 5X3_E61X4_ E62X5_C125S X2 is R, S, G or A X2 is F, G or A X3 is Y, G or A X4 is E, G or A X5 is E, G or A TVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGSGGGGSGGGGSGGGGSSTKKTQLQ LEHLLLDLQMILNGINNYKNPKLTX1MLTX2KFX3MPKKATELKHLQCLEX4X5LKPLEEVLNLA QSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 78 higG4 S228P / F234A / L235A T366W ESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGV EVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP QVYTLPPSQEEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRL TVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGSGGGGSGGGGSGGGGSSTKKTQLQ TABLE C: Illustrative human Fc-IL-2v fusion proteins PROTEIN NO: SEQ ID NO: Features Polypeptide Sequence (Fc domain is underlined) hIL-2v_Al-5_ R38X!_F42X2_ Y45X3_E62X5_C125S X2 is R, S, G or A X2 is F, G or A X3 is Y, G or A X5 is E, G or A lehllldlqmilnginnyknpkltx1mltx2kfx3mpkkatelkhlqcleex5lkpleevlnlaq SKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 79 h!gG4 S228P / F234A / L235A T366W ESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGV EVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP QVYTLPPSQEEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRL hIL-2v_Al-5_ R38X2_F42X2_ E62X5_C125S X2 is R, S, G or A X2 is F, G or A X5 is E, G or A TVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGSGGGGSGGGGSGGGGSSTKKTQLQ lehllldlqmilnginnyknpkltx1mltx2kfympkkatelkhlqcleex5lkpleevlnlaqs KNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 80 h!gG4 S228P / F234A / L235A T366W ESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGV EVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP QVYTLPPSQEEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRL hIL-2v_Al-5_R38X1_ F42A_E62A_C125S X2 is R, S, G or A TVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGSGGGGSGGGGSGGGGSSTKKTQLQ LEHLLLDLQMILNGINNYKNPKLTXiMLTAKFYMPKKATELKHLQCLEEALKPLEEVLNLAQSK NFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT TABLE C: Illustrative human Fc-IL-2v fusion proteins PROTEIN NO: SEQ ID NO: Features Polypeptide Sequence (Fc domain is underlined) 81 h!gG4 S228P / F234A / L235A T366W ESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGV EVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP QVYTLPPSQEEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRL hIL-2v_Al-5_ R38G_C125S TVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGSGGGGSGGGGSGGGGSSTKKTQLQ LEHLLLDLQMILNGINNYKNPKLTGMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKN FHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 82 h!gG4 S228P / F234A / L235A ESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGV EVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP T366W QVYTLPPSQEEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRL hIL-2v_Al-5_ R38A_C125S TVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGSGGGGSGGGGSGGGGSSTKKTQLQ LEHLLLDLQMILNGINNYKNPKLTAMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKN FHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 83 hIgG4 S228P / F234A / L235A ESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGV EVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP T366W QVYTLPPSQEEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRL hIL-2v_Al-5_ T41G_C125S TVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGSGGGGSGGGGSGGGGSSTKKTQLQ LEHLLLDLQMILNGINNYKNPKLTRMLGFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKN FHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 84 hIgG4 S228P / F234A / L235A T366W ESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGV EVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP QVYTLPPSQEEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRL hIL-2v_Al-5_ T41A_C125S TVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGSGGGGSGGGGSGGGGSSTKKTQLQ LEHLLLDLQMILNGINNYKNPKLTRMLAFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKN FHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT TABLE C: Illustrative human Fc-IL-2v fusion proteins PROTEIN NO: SEQ ID NO: Features Polypeptide Sequence (Fc domain is underlined) 85 h!gG4 S228P / F234A / L235A T366W ESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGV EVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP QVYTLPPSQEEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRL hIL-2v_Al-5_ F42G_C125S TVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGSGGGGSGGGGSGGGGSSTKKTQLQ LEHLLLDLQMILNGINNYKNPKLTRMLTGKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKN FHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 86 hIgG4 S228P / F234A / L235A ESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGV EVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP T366W QVYTLPPSQEEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRL hIL-2v_Al-5_ F42A_C125S TVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGSGGGGSGGGGSGGGGSSTKKTQLQ LEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKN FHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 87 hIgG4 S228P / F234A / L235A ESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGV EVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP T366W QVYTLPPSQEEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRL hIL-2v_Al-5_ Y45G_C125S TVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGSGGGGSGGGGSGGGGSSTKKTQLQ LEHLLLDLQMILNGINNYKNPKLTRMLTFKFGMPKKATELKHLQCLEEELKPLEEVLNLAQSKN FHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 88 hIgG4 S228P / F234A / L235A T366W ESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGV EVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP QVYTLPPSQEEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRL hIL-2v_Al-5_ Y45A_C125S TVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGSGGGGSGGGGSGGGGSSTKKTQLQ LEHLLLDLQMILNGINNYKNPKLTRMLTFKFAMPKKATELKHLQCLEEELKPLEEVLNLAQSKN FHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT TABLE C: Illustrative human Fc-IL-2v fusion proteins PROTEIN NO: SEQ ID NO: Features Polypeptide Sequence (Fc domain is underlined) 89 h!gG4 S228P / F234A / L235A T366W ESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGV EVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP QVYTLPPSQEEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRL hIL-2v_Al-5_ E61A_C125S TVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGSGGGGSGGGGSGGGGSSTKKTQLQ LEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEAELKPLEEVLNLAQSKN FHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 90 h!gG4 S228P / F234A / L235A ESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGV EVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP T366W QVYTLPPSQEEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRL hIL-2v_Al-5_ E62A_C125S TVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGSGGGGSGGGGSGGGGSSTKKTQLQ LEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEALKPLEEVLNLAQSKN FHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 91 hIgG4 S228P / F234A / L235A ESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGV EVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP T366W QVYTLPPSQEEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRL hIL-2v_Al-5_ E68A_C125S TVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGSGGGGSGGGGSGGGGSSTKKTQLQ LEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEAVLNLAQSKN FHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 92 hIgG4 S228P / F234A / L235A T366W ESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGV EVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP QVYTLPPSQEEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRL hIL-2v_Al-5_ L72G_C125S TVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGSGGGGSGGGGSGGGGSSTKKTQLQ LEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNGAQSKN FHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT TABLE C: Illustrative human Fc-IL-2v fusion proteins PROTEIN NO: SEQ ID NO: Features Polypeptide Sequence (Fc domain is underlined) 93 h!gG4 S228P / F234A / L235A T366W ESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGV EVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP QVYTLPPSQEEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRL hIL-2v_Al-5_ Q74G_C125S TVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGSGGGGSGGGGSGGGGSSTKKTQLQ LEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAGSKN FHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 94 hIgG4 S228P / F234A / L235A ESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGV EVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP T366W QVYTLPPSQEEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRL hIL-2v_Al-5_ Y107G_C125S TVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGSGGGGSGGGGSGGGGSSTKKTQLQ LEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKN FHLRPRDLISNINVIVLELKGSETTFMCEGADETATIVEFLNRWITFSQSIISTLT 95 hIgG4 S228P / F234A / L235A ESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGV EVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP T366W QVYTLPPSQEEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRL hIL-2v_Al-5_ Y107A_C125S TVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGSGGGGSGGGGSGGGGSSTKKTQLQ LEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKN FHLRPRDLISNINVIVLELKGSETTFMCEAADETATIVEFLNRWITFSQSIISTLT 96 hIgG4 S228P / F234A / L235A T366W ESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGV EVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP QVYTLPPSQEEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRL hIL-2v_Al-5_ Y45G_E61A_C125S TVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGSGGGGSGGGGSGGGGSSTKKTQLQ LEHLLLDLQMILNGINNYKNPKLTRMLTFKFGMPKKATELKHLQCLEAELKPLEEVLNLAQSKN FHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT TABLE C: Illustrative human Fc-IL-2v fusion proteins PROTEIN NO: SEQ ID NO: Features Polypeptide Sequence (Fc domain is underlined) 97 h!gG4 S228P / F234A / L235A T366W ESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGV EVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP QVYTLPPSQEEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRL hIL-2v_Al-5_ Y45G_E62A_C125S TVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGSGGGGSGGGGSGGGGSSTKKTQLQ LEHLLLDLQMILNGINNYKNPKLTRMLTFKFGMPKKATELKHLQCLEEALKPLEEVLNLAQSKN FHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 98 h!gG4 S228P / F234A / L235A T366W ESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGV EVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP QVYTLPPSQEEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRL hIL-2v_Al-5_ R38G_Y45G_C125S TVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGSGGGGSGGGGSGGGGSSTKKTQLQ LEHLLLDLQMILNGINNYKNPKLTGMLTFKFGMPKKATELKHLQCLEEELKPLEEVLNLAQSKN FHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 99 hIgG4 S228P / F234A / L235A ESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGV EVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP T366W QVYTLPPSQEEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRL hIL-2v_Al-5_ R38G_E61A_C125S TVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGSGGGGSGGGGSGGGGSSTKKTQLQ LEHLLLDLQMILNGINNYKNPKLTGMLTFKFYMPKKATELKHLQCLEAELKPLEEVLNLAQSKN FHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 100 hIgG4 S228P / F234A / L235A ESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGV EVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP T366W QVYTLPPSQEEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRL hIL-2v_Al-5_ F42A_E61A_C125S TVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGSGGGGSGGGGSGGGGSSTKKTQLQ TABLE C: Illustrative human Fc-IL-2v fusion proteins PROTEIN NO: SEQ ID NO: Features Polypeptide Sequence (Fc domain is underlined) LEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEAELKPLEEVLNLAQSKN FHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 101 h!gG4 S228P / F234A / L235A T366W ESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGV EVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP QVYTLPPSQEEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRL hIL-2v_Al-5_ F42A_Y45G_C125S TVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGSGGGGSGGGGSGGGGSSTKKTQLQ LEHLLLDLQMILNGINNYKNPKLTRMLTAKFGMPKKATELKHLQCLEEELKPLEEVLNLAQSKN FHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 102 h!gG4 S228P / F234A / L235A T366W ESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGV EVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP QVYTLPPSQEEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRL hIL-2v_Al-5_Y45G_ E61A_E62A_C125S TVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGSGGGGSGGGGSGGGGSSTKKTQLQ LEHLLLDLQMILNGINNYKNPKLTRMLTFKFGMPKKATELKHLQCLEAALKPLEEVLNLAQSKN FHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 103 h!gG4 S228P / F234A / L235A ESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGV EVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP T366W QVYTLPPSQEEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRL hIL-2v_Al-5_ E61A_E62A_C125S TVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGSGGGGSGGGGSGGGGSSTKKTQLQ LEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEAALKPLEEVLNLAQSKN FHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 104 h!gG4 S228P / F234A / L235A ESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGV EVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP T366W QVYTLPPSQEEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRL TABLE C: Illustrative human Fc-IL-2v fusion proteins PROTEIN NO: SEQ ID NO: Features Polypeptide Sequence (Fc domain is underlined) hIL-2v_Al-5_ R38G_F42A_C125S TVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGSGGGGSGGGGSGGGGSSTKKTQLQ LEHLLLDLQMILNGINNYKNPKLTGMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKN FHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 105 h!gG4 S228P / F234A / L235A T366W ESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGV EVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP QVYTLPPSQEEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRL hIL-2v_Al-5_F42A_ Y45A_L72G_C125S TVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGSGGGGSGGGGSGGGGSSTKKTQLQ LEHLLLDLQMILNGINNYKNPKLTRMLTAKFAMPKKATELKHLQCLEEELKPLEEVLNGAQSKN FHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 106 h!gG4 S228P / F234A / L235A ESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGV EVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP T366W QVYTLPPSQEEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRL hIL-2v_Al-5_R38G_ F42A_Y45G_C125S TVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGSGGGGSGGGGSGGGGSSTKKTQLQ LEHLLLDLQMILNGINNYKNPKLTGMLTAKFGMPKKATELKHLQCLEEELKPLEEVLNLAQSKN FHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 107 h!gG4 S228P / F234A / L235A ESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGV EVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP T366W QVYTLPPSQEEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRL hIL-2v_Al-5_ F42A_E62A_C125S TVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGSGGGGSGGGGSGGGGSSTKKTQLQ LEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEALKPLEEVLNLAQSKN FHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT TABLE C: Illustrative human Fc-IL-2v fusion proteins PROTEIN NO: SEQ ID NO: Features Polypeptide Sequence (Fc domain is underlined) 108 h!gG4 S228P / F234A / L235A T366W ESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGV EVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP QVYTLPPSQEEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRL hIL-2v_Al-5_ F42A_ Y45G_E62A_C125S TVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGSGGGGSGGGGSGGGGSSTKKTQLQ LEHLLLDLQMILNGINNYKNPKLTRMLTAKFGMPKKATELKHLQCLEEALKPLEEVLNLAQSKN FHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 109 h!gG4 S228P / F234A / L235A T366W ESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGV EVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP QVYTLPPSQEEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRL hIL-2v_Al-5_F42A_ Y45G_E61A_C125S TVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGSGGGGSGGGGSGGGGSSTKKTQLQ LEHLLLDLQMILNGINNYKNPKLTRMLTAKFGMPKKATELKHLQCLEAELKPLEEVLNLAQSKN FHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 110 h!gG4 S228P / F234A / L235A ESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGV EVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP T366W QVYTLPPSQEEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRL hIL-2v_Al-5_R38G_ Y45G_E61A_C125S TVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGSGGGGSGGGGSGGGGSSTKKTQLQ LEHLLLDLQMILNGINNYKNPKLTGMLTFKFGMPKKATELKHLQCLEAELKPLEEVLNLAQSKN FHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 111 h!gG4 S228P / F234A / L235A ESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGV EVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP T366W QVYTLPPSQEEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRL hIL-2v_Al-5_R38G_ F42A_E61A_C125S TVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGSGGGGSGGGGSGGGGSSTKKTQLQ TABLE C: Illustrative human Fc-IL-2v fusion proteins PROTEIN NO: SEQ ID NO: Features Polypeptide Sequence (Fc domain is underlined) LEHLLLDLQMILNGINNYKNPKLTGMLTAKFYMPKKATELKHLQCLEAELKPLEEVLNLAQSKN FHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 112 h!gG4 S228P / F234A / L235A T366W ESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGV EVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP QVYTLPPSQEEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRL hIL-2v_Al-5_R38G_ Y45G_E62A_C125S TVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGSGGGGSGGGGSGGGGSSTKKTQLQ LEHLLLDLQMILNGINNYKNPKLTGMLTFKFGMPKKATELKHLQCLEEALKPLEEVLNLAQSKN FHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 113 h!gG4 S228P / F234A / L235A T366W ESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGV EVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP QVYTLPPSQEEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRL hIL-2v_Al-5_ R38G_E62A_C125S TVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGSGGGGSGGGGSGGGGSSTKKTQLQ LEHLLLDLQMILNGINNYKNPKLTGMLTFKFYMPKKATELKHLQCLEEALKPLEEVLNLAQSKN FHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 114 h!gG4 S228P / F234A / L235A ESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGV EVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP T366W QVYTLPPSQEEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRL hIL-2v_Al-5_R38G_ F42A_E62A_C125S TVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGSGGGGSGGGGSGGGGSSTKKTQLQ LEHLLLDLQMILNGINNYKNPKLTGMLTAKFYMPKKATELKHLQCLEEALKPLEEVLNLAQSKN FHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 115 h!gG4 S228P / F234A / L235A ESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGV EVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP T366W QVYTLPPSQEEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRL TABLE C: Illustrative human Fc-IL-2v fusion proteins PROTEIN NO: SEQ ID NO: Features Polypeptide Sequence (Fc domain is underlined) hIL-2v_Al-5_F42A_ E61A_E62A_C125S TVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGSGGGGSGGGGSGGGGSSTKKTQLQ LEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEAALKPLEEVLNLAQSKN FHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 116 h!gG4 S228P / F234A / L235A T366W ESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGV EVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP QVYTLPPSQEEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRL hIL-2v_Al-5_R38G_ E61A_E62A_C125S TVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGSGGGGSGGGGSGGGGSSTKKTQLQ LEHLLLDLQMILNGINNYKNPKLTGMLTFKFYMPKKATELKHLQCLEAALKPLEEVLNLAQSKN FHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 117 hIgG4 S228P / F234A / L235A T366W hIL-2v_Al-5_C125S ESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGV EVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP QVYTLPPSQEEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRL TVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGSGGGGSGGGGSGGGGSSTKKTQLQ LEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKN FHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 118 hIgG4 S228P / F234A / L235A T366W hIL-2v_T3A_C125S ESKYGPPCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSQEDPEVQFNWYVDGV EVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREP QVYTLPPSQEEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRL TVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGGGGGSGGGGSGGGGSGGGGSAPASSSTK KTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNL AQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT TABLE C: Illustrative human Fc-IL-2v fusion proteins PROTEIN NO: SEQ ID NO: Features Polypeptide Sequence (Fc domain is underlined) IgGl variants 119 hlgGl L234A / L235A / P331S / T366W hIL-2v_Al-5_R38X2_ T41X2_F42X3_ Y45X4_E61X5_ E62X6_E68X7_ L72X8_Q74X9_ Y107X10_C125S X2 is R, S, G or A X2 is T, G or A X3 is F, G or A X4 is Y, G or A X5 is E, G or A X6 is E, G or A X7 is E, G or A X8 is L, G or A X9 is Q, G or A X10 is Y, G or A EPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQP REPQVYTLPPSREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGSSTKKT qlqlehllldlqmilnginnyknpkltx1mlx2x3kfx4mpkkatelkhlqclex5x6lkplex7v lnx8ax9sknfhlrprdlisninvivlelkgsettfmcex10adetativeflnrwitfsqsiis TLT 120 hlgGl L234A / L235A / P331S / T366W EPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQP REPQVYTLPPSREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGSS TKKT TABLE C: Illustrative human Fc-IL-2v fusion proteins PROTEIN NO: SEQ ID NO: Features Polypeptide Sequence (Fc domain is underlined) hIL-2v_Al-5_ R38Xi_F42X2_ Y4 5X3_E61X4_E62X5_ L72X6_C125S X2 is R, S, G or A X2 is F, G or A X3 is Y, G or A X4 is E, G or A X5 is E, G or A X6 is L, G or A qlqlehllldlqmilnginnyknpkltx1mltx2kfx3mpkkatelkhlqclex4x5lkpleevl nx6aqsknfhlrprdlisninvivlelkgsettfmceyadetativeflnrwitfsqsiistlt 121 hlgGl L234A / L235A / P331S / EPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQP T366W REPQVYTLPPSREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY hIL-2v_Al-5_ R38X2_F42X2_ Y4 5X3_E61X4_E62X5_ C125S X2 is R, S, G or A X2 is F, G or A X3 is Y, G or A X4 is E, G or A X5 is E, G or A SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGSSTKKT QLQLEHLLLDLQMILNGINNYKNPKLTX1MLTX2KFX3MPKKATELKHLQCLEX4X5LKPLEEVL NLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT TABLE C: Illustrative human Fc-IL-2v fusion proteins PROTEIN NO: SEQ ID NO: Features Polypeptide Sequence (Fc domain is underlined) 122 hlgGl L234A / L235A / P331S / T366W EPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQP REPQVYTLPPSREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY hIL-2v_Al-5_ R38X2_F42X2_ Y45X3_E62X5_C125S X2 is R, S, G or A X2 is F, G or A X3 is Y, G or A X5 is E, G or A SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGSSTKKT qlqlehllldlqmilnginnyknpkltx1mltx2kfx3mpkkatelkhlqcleex5lkpleevln LAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 123 hlgGl L234A / L235A / P331S / T366W EPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQP REPQVYTLPPSREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY hIL-2v_Al-5_R38X!_ F42X2_E62X5_C125S X2 is R, S, G or A X2 is F, G or A X5 is E, G or A SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGSSTKKT qlqlehllldlqmilnginnyknpkltx1mltx2kfympkkatelkhlqcleex5lkpleevlnl AQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 124 hlgGl L234A / L235A / P331S / T366W EPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQP REPQVYTLPPSREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY hIL-2v_Al-5_R38X2_ F42A_E62A_C125S SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGSSTKKT QLQLEHLLLDLQMILNGINNYKNPKLTXiMLTAKFYMPKKATELKHLQCLEEALKPLEEVLNLA QSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT TABLE C: Illustrative human Fc-IL-2v fusion proteins PROTEIN NO: SEQ ID NO: Features Polypeptide Sequence (Fc domain is underlined) Xx is R, S, G or A 125 hlgGl L234A / L235A / P331S / T366W EPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQP REPQVYTLPPSREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY hIL-2v_Al-5_ R38G_C125S SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGSSTKKT QLQLEHLLLDLQMILNGINNYKNPKLTGMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQ SKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 126 hlgGl L234A / L235A / P331S / T366W EPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQP REPQVYTLPPSREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY hIL-2v_Al-5_ R38A_C125S SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGSSTKKT QLQLEHLLLDLQMILNGINNYKNPKLTAMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQ SKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 127 hlgGl L234A / L235A / P331S / EPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQP T366W REPQVYTLPPSREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY hIL-2v_Al-5_ T41G_C125S SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGSSTKKT QLQLEHLLLDLQMILNGINNYKNPKLTRMLGFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQ SKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 128 hlgGl L234A / L235A / P331S / T366W EPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQP REPQVYTLPPSREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY hIL-2v_Al-5_ T41A_C125S SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGSSTKKT TABLE C: Illustrative human Fc-IL-2v fusion proteins PROTEIN NO: SEQ ID NO: Features Polypeptide Sequence (Fc domain is underlined) QLQLEHLLLDLQMILNGINNYKNPKLTRMLAFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQ SKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 129 hlgGl L234A / L235A / P331S / EPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQP T366W REPQVYTLPPSREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY hIL-2v_Al-5_ F42G_C125S SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGSSTKKT QLQLEHLLLDLQMILNGINNYKNPKLTRMLTGKFYMPKKATELKHLQCLEEELKPLEEVLNLAQ SKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 130 hlgGl L234A / L235A / P331S / T366W EPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQP REPQVYTLPPSREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY hIL-2v_Al-5_ F42A_C125S SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGSSTKKT QLQLEHLLLDLQMILNGINNYKNPKLTRMLTAKFYMPKKATELKHLQCLEEELKPLEEVLNLAQ SKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 131 hlgGl L234A / L235A / P331S / EPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQP T366W REPQVYTLPPSREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY hIL-2v_Al-5_ Y45G_C125S SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGSSTKKT QLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFGMPKKATELKHLQCLEEELKPLEEVLNLAQ SKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 132 hlgGl L234A / L235A / P331S / EPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQP T366W REPQVYTLPPSREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGS GGGG S GGGG SS TKKT TABLE C: Illustrative human Fc-IL-2v fusion proteins PROTEIN NO: SEQ ID NO: Features Polypeptide Sequence (Fc domain is underlined) hIL-2v_Al-5_ Y45A_C125S QLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFAMPKKATELKHLQCLEEELKPLEEVLNLAQ SKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 133 hlgGl L234A / L235A / P331S / EPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQP T366W REPQVYTLPPSREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY hIL-2v_Al-5_ E61A_C125S SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGSSTKKT QLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEAELKPLEEVLNLAQ SKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 134 hlgGl L234A / L235A / P331S / T366W EPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQP REPQVYTLPPSREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY hIL-2v_Al-5_ E62A_C125S SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGSSTKKT QLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEALKPLEEVLNLAQ SKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 135 hlgGl L234A / L235A / P331S / EPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQP T366W REPQVYTLPPSREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY hIL-2v_Al-5_ E68A_C125S SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGSSTKKT QLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEAVLNLAQ SKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 136 hlgGl L234A / L235A / P331S / EPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQP T366W REPQVYTLPPSREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGS GGGG S GGGG SS TKKT TABLE C: Illustrative human Fc-IL-2v fusion proteins PROTEIN NO: SEQ ID NO: Features Polypeptide Sequence (Fc domain is underlined) hIL-2v_Al-5_ L72G_C125S QLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNGAQ SKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 137 hlgGl L234A / L235A / P331S / EPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQP T366W REPQVYTLPPSREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY hIL-2v_Al-5_ Q74G_C125S SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGSSTKKT QLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAG SKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT 138 hlgGl L234A / L235A / P331S / T366W EPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQP REPQVYTLPPSREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY hIL-2v_Al-5_ Y107G_C125S SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGSSTKKT QLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQ SKNFHLRPRDLISNINVIVLELKGSETTFMCEGADETATIVEFLNRWITFSQSIISTLT 139 hlgGl L234A / L235A / P331S / EPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQP T366W REPQVYTLPPSREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY hIL-2v_Al-5_ Y107A_C125S SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGGGGSSTKKT QLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQ SKNFHLRPRDLISNINVIVLELKGSETTFMCEAADETATIVEFLNRWITFSQSIISTLT 140 hlgGl L234A / L235A / P331S / EPKSSDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVWDVSHEDPEVKFNWYV DGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQP T366W REPQVYTLPPSREEMTKNQVSLWCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLY SKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGS GGGG S GGGG SS TKKT TABLE C: Illustrative human Fc-IL-2v fusion proteins PROTEIN NO: SEQ ID NO: Features Polypeptide Sequence (Fc domain is underlined) hIL-2v_Al-5_ Y45G_E61A_C125S QLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFGMPKKATELKHLQCLEAELKPLEEVLNLAQ SKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSII...

Claims

What is claimed is;1.     An interleukin-2 variant (IL-2v), wherein the IL-2v:i. is truncated at the N-terminus by at least 5 amino acids relative to5                        wild-type IL-2; andii. binds to the interleukin-2 receptor alpha subunit (IL-2RA; CD25) with reduced binding affinity in comparison to wild-type IL-2 (wt IL-2).

2. The IL-2v of claim 1, wherein the IL-2v binds to IL-2RA with an 10   equilibrium dissociation constant (Kd) of at least 60 pM (e.g., 60 pM or higher).

3. The IL-2v of any one of claims 1 to 2, wherein the IL-2v binds to a complex of interleukin 2 receptor subunit beta (IL-2RB; CD 122) and interleukin 2 receptor subunit gamma (IL-2RG; CD 132) with a Kd of less than 150 nM, e.g., less than 1.5 nM, e.g., less than 120 pM, e.g., less than 100 pM, e.g., less than 80 pM, e.g., less than 75 pM, 15   e.g., less than 70 pM.

4. The IL-2v of any one of claims 1 to 3, wherein the IL-2v promotes equivalent or greater proliferation of CD8+ T cells relative to wild-type (wt) IL-2, or an IL-2v of any one of SEQ ID NOs: 43 and 44.

5. The IL-2v of any one of claims 1 to 4, wherein the concentration at 20 which the IL-2v elicits 50% of maximal (ECso) signal transducer and activator of transcription 5 (STAT5) activation or signaling of regulatory T (Treg) cells is at least 1000fold, e.g., at least 1500-fold, e.g., at least 1700-fold, e.g., at least 2000-fold, e.g., at least 2500-fold higher, relative to the ECso for STAT5 activation or signaling of wt IL-2, or an IL-2v of any one of SEQ ID NOs: 43 and 44.25                 6. The IL-2v of any one of claims 1 to 5, wherein the concentration atwhich the IL-2v elicits ECso of IL-2RaPy-mediated STAT5 activation or signaling (e.g., measured as STAT5 activation of CTLL2 cells) is at least 2500-fold, e.g., at least 5000-fold, e.g., at least 7500-fold, e.g., at least 10,000-fold, e.g., at least 15,000-fold, e.g., at least 20,000-fold higher, relative to the ECso for STAT5 activation or signaling of wt IL-2, or an30 IL-2v of any one of SEQ ID NOs: 43 and 44.2024202988   06 May 20247.     The IL-2v of any one of claims 1 to 6, wherein the concentration atwhich the IL-2v elicits 50% of maximal (ECso) proliferation of natural killer (NK) cells is at least 10-fold, e.g., at least 12-fold, e.g., at least 15-fold, e.g., at least 16-fold, e.g., at least 18-fold, e.g., at least 20-fold higher, e.g., as measured using KHYG-1 cells, relative to the5 ECso for proliferation of wt IL-2, or an IL-2v of any one of SEQ ID NOs: 43 and 44.

8. The IL-2v of any one of claims 1 to 7, wherein the IL-2v comprises a serine at position 125 (Cl25) and at least two, or at least three, substitutions at amino acid positions selected from the group consisting of R38, F42, Y45, E61 and E62, wherein the position numbers are with respect to an IL-2v of SEQ ID NO:44.10                 9. The IL-2v of any one of claims 1 to 8, wherein the IL-2v comprises aserine at position 125 (Cl25) and at least two, or at least three, substitutions at amino acid positions selected from the group consisting of R38, F42, Y45 and E62, wherein the position numbers are with respect to an IL-2v of SEQ ID NO:44.

10. The IL-2v of any one of claims 1 to 9, wherein the IL-2v comprises a15 serine at position 125 (Cl25) and at least two, or at least three, substitutions at amino acid positions selected from the group consisting of R38, F42 and E62, wherein the position numbers are with respect to an IL-2v of SEQ ID NO:44.

11. The IL-2v of claim 10, wherein the IL-2v does not comprise amino acid substitutions at one or more positions selected from the group consisting of Y45, E61, 20   E68 and L72.

12. The IL-2v of any one of claims 1 to 11, wherein the IL-2v does not comprise an amino acid substitution at one or more, or all, of positions selected from the group consisting of D20, Y45, E61, E68, V69, L72, A73, L80, R81, L85, L86,187,192 and Q126.25                  13. The IL-2v of any one of claims 1 to 11, wherein the IL-2v does notcomprise an amino acid substitution at one or more, or all, of positions selected from the group consisting of H16, D20, E61, N88 and V91.

14. The IL-2v of any one of claims 1 to 13, wherein the IL-2v is PEGylated.2024202988   06 May 202415. A fusion protein comprising: a serum half-life extending polypeptide operably linked to an interleukin-2 variant (IL-2v), wherein the IL-2v:i. is truncated at the N-terminus by at least 5 amino acids relative to wild-type IL-2; and5                    ii. binds to the interleukin-2 receptor alpha subunit (IL-2RA; CD25)with reduced binding affinity in comparison to wild-type IL-2 (wt IL-2).

16. The fusion protein of claim 15, wherein the serum half-life extending polypeptide is selected from the group consisting of: an immunoglobulin fragment10 crystallizable region (Fc region), a serum albumin, an albumin binding protein or peptide, an IgG, an XTEN polypeptide, aproline / alanine / serine-rich (PAS) polypeptide, an elastinlike polypeptide.

17. The fusion protein of any one of claims 15 to 16, wherein the serum half-life extending polypeptide is an immunoglobulin fragment crystallizable region (Fc 15 region).

18. The fusion protein of any one of claims 15 to 17, wherein the fusion protein binds to IL-2RA with an equilibrium dissociation constant (Kd) of at least 60 pM (e.g., 60 pM or higher).

19. The fusion protein of any one of claims 15 to 18, wherein the IL-2v20 binds to a complex of interleukin 2 receptor subunit beta (IL-2RB; CD 122) and interleukin2 receptor subunit gamma (IL-2RG; CD132) with a Kd of less than 150 nM, e.g., less than1.5 nM, e.g., less than 120 pM, e.g., less than 100 pM, e.g., less than 80 pM, e.g., less than 75 pM, e.g., less than 70 pM.

20. The fusion protein of any one of claims 15 to 19, wherein the fusion25 protein promotes equivalent or greater proliferation of CD8+ T cells relative to an IL-2v of any one of SEQ ID NOs: 43 and 44, a fusion protein comprising Fc operably linked to wt IL-2, or a fusion protein of any one ofSEQ ID NOs. 117, 118, 161 and 162.

21. The fusion protein of any one of claims 15 to 20, wherein the concentration at which the IL-2v fusion protein elicits 50% of maximal (ECso) signal30 transducer and activator of transcription 5 (STAT5) activation or signaling of regulatory T (Treg) cells is at least 1000-fold, e.g., at least 1500-fold, e.g., at least 1700-fold, e.g., at least 2000-fold, e.g., at least 2500-fold higher, relative to the ECso for STAT5 for activation or2024202988   06 May 2024signaling of wt IL-2, or an IL-2v of any one of SEQ ID NOs: 43 and 44, a fusion protein comprising Fc operably linked to wt IL-2, or a fusion protein of any one of SEQ ID NOs. 117, 118, 161 or 162.

22. The fusion protein of any one of claims 15 to 21, wherein the5 concentration at which the IL-2v fusion protein elicits ECso of IL-2RaPy-mediated STAT5 activation or signaling (e.g., measured as STAT5 activation of CTLL2 cells) is at least 2500-fold, e.g., at least 5000-fold, e.g., at least 7500-fold, e.g., at least 10,000-fold, e.g., at least 15,000-fold, e.g., at least 20,000-fold higher, relative to the ECso for STAT5 activation or signaling of wt IL-2, or an IL-2v of any one of SEQ ID NOs: 43 and 44, a fusion protein 10 comprising Fc operably linked to wt IL-2, or a fusion protein of any one of SEQ ID NOs.117, 118, 161 or 162.

23. The fusion protein of any one of claims 15 to 22, wherein the concentration at which the IL-2v fusion protein elicits 50% of maximal (ECso) proliferation of natural killer (NK) cells is at least 10-fold, e.g., at least 12-fold, e.g., at least 15-fold, e.g., 15 at least 16-fold, e.g., at least 18-fold, e.g., at least 20-fold higher, e.g., as measured using KHYG-1 cells, relative to the ECso for proliferation of wt IL-2, or an IL-2v of any one of SEQ ID NOs: 43 and 44, a fusion protein comprising Fc operably linked to wt IL-2, or a fusion protein of any one of SEQ ID NOs. 117, 118, 161 or 162.

24. The fusion protein of any one of claims 15 to 23, wherein the IL-2v 20 comprises a serine at position 125 (C125) and at least two, or at least three, substitutions at amino acid positions selected from the group consisting of R38, F42, Y45, E61 and E62, wherein the position numbers are with respect to an IL-2v of SEQ ID NO:44.

25. The fusion protein of any one of claims 15 to 24, wherein the IL-2v comprises a serine at position 125 (C125) and at least two, or at least three, substitutions at 25 amino acid positions selected from the group consisting of R38, F42, Y45 and E62, wherein the position numbers are with respect to an IL-2v of SEQ ID NO:44.

26. The fusion protein of any one of claims 15 to 25, wherein the IL-2v comprises a serine at position 125 (C125) and at least two, or at least three, substitutions at amino acid positions selected from the group consisting of R38, F42 and E62, wherein the30 position numbers are with respect to an IL-2v of SEQ ID NO:44.2024202988   06 May 202427. The fusion protein of claim 26, wherein the IL-2v does not comprise amino acid substitutions at one or more positions selected from the group consisting of Y45, E61,E68 and L72.

28. The fusion protein of any one of claims 15 to 27, wherein the IL-2v 5 does not comprise the amino acid sequence APTSS (SEQ ID NO: 163).

29. The fusion protein of any one of claims 15 to 28, wherein the IL-2v is from a human wild-type IL-2.

30. The fusion protein of any one of claims 15 to 29, wherein the IL-2v comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-42 10 or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-42.

31. The fusion protein of any one of claims 15 to 30, wherein the Fc 15 region is from a human IgGl, IgG2, IgG3 or IgG4.

32. The fusion protein of any one of claims 15 to 31, wherein the Fc region is from a human IgGl or IgG4.

33. The fusion protein of any one of claims 15 to 32, wherein the Fc region comprises a human IgGl isotype and comprises one or more amino acid substitutions 20 in the Fc region at a residue position selected from the group consisting of: N297A, N297G, N297Q, N297G, D265A, L234A, L235A, C226S, C229S, P238S, E233P, L234V, P238A, A327Q, A327G, P329A, P329G, K322A, L234F, L235E, P331S, T394D, A330L, M252Y, S254T, T256E, M428L, N434S, T366W, T366S, L368A, F405L, Y407V, K409R, H435R, Y436F, and any combination thereof, wherein the numbering of the residues is according to 25 EU numbering.

34. The fusion protein of claim 33, wherein the Fc region comprises a human IgGl isotype and comprises one or more amino acid substitutions in the Fc region at a residue position selected from the group consisting of: L234A, L234V, L234F, L235A, L235E, D265A, P329G, P33 IS, and any combination thereof, wherein the numbering of the 30 residues is according to EU numbering.2024202988   06 May 202435. The fusion protein of any one of claims 15 to 32, wherein the Fc region comprises a human IgG4 isotype and comprises one or more amino acid substitutions in the Fc region at a residue position selected from the group consisting of: E233P, F234V, F234A, L235A, G237A, E318A, S228P, L235E, T394D, M252Y, S254T, T256E, N297A,5  N297G, N297Q, T366W, T366S, L368A, F405L, Y407V, K409R, M428L, N434S, H435R,Y436F, and any combination thereof, wherein the numbering of the residues is according to EU numbering.

36. The fusion protein of claim 35, wherein the Fc region comprises a human IgG4 isotype and comprises one or more amino acid substitutions in the Fc region at 10 a residue position selected from the group consisting of: F234V, F234A, L235A, L235E, S228P, and any combination thereof, wherein the numbering of the residues is according to EU numbering.

37. The fusion protein of any one of claims 15 to 36, wherein the Fc region comprises the following amino acids at the indicated positions (EU index15 numbering):i. Tyrosine at position 252, threonine at position 254 and glutamic acid at position 256 (YTE); orii. Leucine at position 428 and serine at position 434 (LS).

38. The fusion protein of any one of claims 15 to 37, wherein the Fc 20 region comprises the following amino acids at the indicated positions (EU index numbering): an arginine at position 435 and a phenylalanine at position 436.

39. The fusion protein of any one of claims 15 to 38, wherein the terminal Fc amino acid residue (e.g., K447) is removed or eliminated.

40. The fusion protein of any one of claims 15 to 39, wherein the Fc25 region comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 45-72, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 45-72.30                 41. The fusion protein of any one of claims 15 to 40, wherein the Fcregion comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 45, 47, 49, 52, 54, 56, 57, 59, 61, 63, 65, 67, 69 and 71, or an amino acid sequence2024202988   06 May 2024that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 45, 47, 49, 52, 54, 56, 57, 59, 61, 63, 65, 67, 69 and 71.5                 42. The fusion protein of any one of claims 15 to 41, comprising insequential order from N-terminus to C-terminus, the Fc region and the IL-2v.

43. The fusion protein of any one of claims 15 to 42, comprising a flexible linker between the Fc region and the IL-2v.

44. The fusion protein of claim 43, wherein the linker has a length of10 from 4 to 50 amino acids, e.g., from 5 amino acids to 25 amino acids, e.g., from 15 amino acids to 25 amino acids.

45. The fusion protein of any one of claims 43 to 44, wherein the linker comprises from 1 to 10 units, e.g., 1 to 5 units, e.g., 3 to 5 units, of a poly-glycine serine linker selected from GGGS (SEQ ID NO: 265), GGGGS (SEQ ID NO: 264) and15   combinations thereof.

46. The fusion protein of any one of claims 15 to 45, comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 75-116 and 119160, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least20   98%, or at least 99% identical to an amino acid sequence selected from the group consistingof SEQ ID NOs: 75-116 and 119-160.

47. A fusion protein comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 166-171, or comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 25   94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to anamino acid sequence selected from the group consisting of SEQ ID NOs: 166-171.

48. The fusion protein of any one of claims 15 to 47, wherein the fusion protein does not specifically bind any antigen other than an Fc receptor or a complex of interleukin 2 receptor subunit beta (IL-2RB; CD 122) and interleukin 2 receptor subunit30 gamma (IL-2RG; CD132).2024202988   06 May 202449. The fusion protein of any one of claims 15 to 48, comprising an N-terminal signal peptide or leader sequence.

50. The fusion protein of any one of claims 15 to 49, wherein the IL-2v is not PEGylated.5                51.    A homodimer comprising two Fc-IL-2v fusion proteins of any one ofclaims 15 to 50.

52. A heterodimer comprising: (i) a first Fc-IL-2v fusion protein of anyone of claims 15 to 50 comprising a first Fc domain, and (ii) a second Fc-IL-2v fusion protein of any one of claims 15 to 50 comprising a second Fc domain.10                  53. A heterodimer comprising: (i) an (i.e., one) Fc-IL-2v fusion proteinof any one of claims 15 to 50 comprising a first Fc domain, and (ii) a second Fc domain.

54. The heterodimer of any one of claims 52 to 53, wherein the first Fc domain and the second Fc domain comprise the following amino acid substitutions (EU numbering), respectively:15                 a) T366W and T366S / L368A / Y407V;b) T366S / L368A / Y407V and T366W;c) T366W / S354C and T366S / L368A / Y407V / Y349C;d) T366S / L368A / Y407V / Y349C and T366W / S354C;e) S364H / F405A and Y349T / T394F;20                  f) Y349T / T394F and S364H / F405A;g) T350V / L351Y / F405A / Y407V and T350V / T366L / K392L / T394W;h) T350V / T366L / K392L / T394W and T350V / L351Y / F405A / Y407V;i) K360D / D399M / Y407A and E345R / Q347R / T366V / K409V;j) E345R / Q347R / T366V / K409V and K360D / D399M / Y407A;25                 k) K409D / K392D and D399K / E356K;1) D399K / E356K and K409D / K392D;m) K360E / K409W and Q347R / D399V / F405T;n) Q347R / D399V / F405T and K360E / K409W;o) K360E / K409W / Y349C and Q347R / D399V / F405T / S354C;30                 p) Q347R / D399V / F405T / S354C and K360E / K409W / Y349C;q) K370E / K409W and E357N / D399V / F405T; orr) E357N / D399V / F405T and K370E / K409W.2024202988   06 May 202455. The heterodimer of any one of claims 52 to 54, wherein one or both of the first Fc domain and the second Fc domain comprise the following amino acids at the indicated positions (EU index numbering):i. Tyrosine at position 252, threonine at position 254 and glutamic acid5                        at position 256 (YTE); orii. Leucine at position 428 and serine at position 434 (LS).

56. The heterodimer of any one of claims 52 to 55, wherein one or both of the first Fc domain and the second Fc domain comprise the following amino acids at the indicated positions (EU index numbering): an arginine at position 435 and a phenylalanine 10 at position 436.

57. The heterodimer of any one of claims 52 to 56, wherein one or both of the first Fc domain and the second Fc domain comprise a human IgG4 isotype and comprises one or more amino acid substitutions in the Fc region at a residue position selected from the group consisting of: F234V, F234A, L235A, L235E, S228P, and any15   combination thereof, wherein the numbering of the residues is according to EU numbering.

58. The heterodimer of any one of claims 52 to 56, wherein one or both of the first Fc domain and the second Fc domain comprise a human IgGl isotype and comprises one or more amino acid substitutions in the Fc region at a residue position selected from the group consisting of: L234A, L234V, L234F, L235A, L235E, P331S, and20 any combination thereof, wherein the numbering of the residues is according to EU numbering.

59. The heterodimer of any one of claims 52 to 58, wherein the terminal Fc amino acid residue (e.g., K447) is removed or eliminated from one or both of the first Fc domain and the second Fc domain.25                 60. The heterodimer of any one of claims 52 to 59, wherein the first Fcdomain and the second Fc domain comprise amino acid sequences set forth, respectively, below, or comprise amino acid sequences that are at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the amino acid sequences set forth, respectively,30 below:a) SEQIDNOs.: 45 and 46;b) SEQIDNOs.: 47 and 48;2024202988   06 May 2024c) SEQ ID NOs. 49 and 46; d) SEQ ID NOs. 45 and 51; e) SEQ ID NOs. 49 and 51; 0 SEQ ID NOs. 52 and 48; 5 g) SEQ ID NOs. 47 and 53; h) SEQ ID NOs. 52 and 53; i) SEQ ID NOs. 54 and 46; j) SEQ ID NOs. 45 and 55; k) SEQ ID NOs. 54 and 55; 10 1) SEQ ID NOs. 56 and 48; m) SEQ ID NOs. 47 and 50; n) SEQ ID NOs. 56 and 50; o) SEQ ID NOs. 57 and 58; P) SEQ ID NOs. 59 and 60; 15 q) SEQ ID NOs. 61 and 58; r) SEQ ID NOs. 57 and 62; s) SEQ ID NOs. 63 and 64; t) SEQ ID NOs. 65 and 60; u) SEQ ID NOs. 59 and 66; 20 V) SEQ ID NOs. 67 and 68; w) SEQ ID NOs. 69 and 58; x) SEQ ID NOs. 57 and 70; y) SEQ ID NOs. 69 and 70; z) SEQ ID NOs. 71 and 60; 25 aa) SEQ ID NOs. 59 and 72; or bb) SEQ ID NOs. 71 and 72.

61. The heterodimer of any one of claims 52 to 60, comprising a human IgG4 Fc-IL-2v fusion protein comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 75-116, or an amino acid sequence that is at least 80%, at least30   85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, atleast 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 75-116; and a second Fc region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 46, 51 and 55, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least35   91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at2024202988   06 May 2024least 98%, or at least 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 46, 51 and 55.

62. The heterodimer of claim 61, comprising a human IgG4 Fc-IL-2v fusion protein comprising (i) a first amino acid sequence as set forth below, or an amino5 acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to a first amino acid sequence set forth below; and (ii) a second Fc region comprising a second amino acid sequence set forth below, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least10   94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to asecond amino acid sequence set forth below, respectively:1) SEQ ID NO 75 and SEQ ID NO: 46; 2) SEQ ID NO 76 and SEQ ID NO: 46; 3) SEQ ID NO 77 and SEQ ID NO: 46; 15                  4) SEQ ID NO 78 and SEQ ID NO: 46; 5) SEQ ID NO 79 and SEQ ID NO: 46; 6) SEQ ID NO 80 and SEQ ID NO: 46; 7) SEQ ID NO 81 and SEQ ID NO: 46; 8) SEQ ID NO 82 and SEQ ID NO: 46; 20                 9) SEQ ID NO 83 and SEQ ID NO: 46; 10) SEQ ID NO 84 and SEQ ID NO: 46; H) SEQ ID NO 85 and SEQ ID NO: 46; 12) SEQ ID NO 86 and SEQ ID NO: 46; 13) SEQ ID NO 87 and SEQ ID NO: 46; 25                  14) SEQ ID NO 88 and SEQ ID NO: 46; 15) SEQ ID NO 89 and SEQ ID NO: 46; 16) SEQ ID NO 90 and SEQ ID NO: 46; 17) SEQ ID NO 91 and SEQ ID NO: 46; 18) SEQ ID NO 92 and SEQ ID NO: 46; 30                 19) SEQ ID NO 93 and SEQ ID NO: 46; 20) SEQ ID NO 94 and SEQ ID NO: 46; 21) SEQ ID NO 95 and SEQ ID NO: 46; 22) SEQ ID NO 96 and SEQ ID NO: 46; 23) SEQ ID NO 97 and SEQ ID NO: 46; 35                 24) SEQ ID NO 98 and SEQ ID NO: 46;2024202988   06 May 202425) SEQ ID NO 99 and SEQ ID NO: 46; 26) SEQ ID NO 100 and SEQ ID NO: 46; 27) SEQ ID NO 101 and SEQ ID NO: 46; 28) SEQ ID NO 102 and SEQ ID NO: 46; 5 29) SEQ ID NO 103 and SEQ ID NO: 46; 30) SEQ ID NO 104 and SEQ ID NO: 46; 31) SEQ ID NO 105 and SEQ ID NO: 46; 32) SEQ ID NO 106 and SEQ ID NO: 46; 33) SEQ ID NO 107 and SEQ ID NO: 46; 10 34) SEQ ID NO 108 and SEQ ID NO: 46; 35) SEQ ID NO 109 and SEQ ID NO: 46; 36) SEQ ID NO 110 and SEQ ID NO: 46; 37) SEQ ID NO 111 and SEQ ID NO: 46; 38) SEQ ID NO 112 and SEQ ID NO: 46; 15 39) SEQ ID NO 113 and SEQ ID NO: 46; 40) SEQ ID NO 114 and SEQ ID NO: 46; 41) SEQ ID NO 115 and SEQ ID NO: 46; or 42) SEQ ID NO 116 and SEQ ID NO: 46.

63. The heterodimer of any one of claims 52 to 62, comprising a human20 IgG4 Fc-IL-2v fusion protein comprising (i) a first amino acid sequence as set forth below, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to a first amino acid sequence set forth below; and (ii) a second Fc region comprising a second amino acid sequence set forth below, or an amino acid sequence25 that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to a second amino acid sequence set forth below, respectively:1) SEQ ID NO: 80 and SEQ ID NO: 46;2) SEQ ID NO: 107 and SEQ ID NO: 46; or30                  3) SEQ ID NO: 114 and SEQ ID NO: 46.

64. The heterodimer of any one of claims 52 to 62, comprising a human IgG4 Fc-IL-2v fusion protein comprising (i) a first amino acid sequence of SEQ ID NO: 114, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least2024202988   06 May 202498%, or at least 99% identical to SEQ ID NO: 114; and (ii) a second Fc region comprising an amino acid sequence of SEQ ID NO: 46, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 46.5                65. The heterodimer of any one of claims 52 to 60, comprising a humanIgGl Fc-IL-2v fusion protein comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 119-160, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence10 selected from the group consisting of SEQ ID NOs: 119-160; and a second Fc region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 58, 62 and 70, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to an amino acid sequence selected from the group15 consisting of SEQ ID NOs: 58, 62 and 70.

66. The heterodimer of claim 65, comprising a human IgGl Fc-IL-2v fusion protein comprising (i) a first amino acid sequence as set forth below, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least20   99% identical to a first amino acid sequence set forth below; and (ii) a second Fc regioncomprising a second amino acid sequence set forth below, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to a second amino acid sequence set forth below, respectively:251)    SEQ ID NO: 119 and SEQ ID NO: 58;2)    SEQ ID NO: 120 and SEQ ID NO: 58;3)    SEQ ID NO: 121 and SEQ ID NO: 58;4)    SEQ ID NO: 122 and SEQ ID NO: 58;5)    SEQ ID NO: 123 and SEQ ID NO: 58;6)    SEQ ID NO: 124 and SEQ ID NO: 58;7)    SEQ ID NO: 125 and SEQ ID NO: 58;8)    SEQ ID NO: 126 and SEQ ID NO: 58;9)    SEQ ID NO: 127 and SEQ ID NO: 58;10)   SEQ ID NO: 128 and SEQ ID NO: 58;2024202988   06 May 202411) SEQ ID NO 129 and SEQ ID NO: 58; 12) SEQ ID NO 130 and SEQ ID NO: 58; 13) SEQ ID NO 131 and SEQ ID NO: 58; 14) SEQ ID NO 132 and SEQ ID NO: 58; 5                    15) SEQ ID NO 133 and SEQ ID NO: 58; 16) SEQ ID NO 134 and SEQ ID NO: 58; 17) SEQ ID NO 135 and SEQ ID NO: 58; 18) SEQ ID NO 136 and SEQ ID NO: 58; 19) SEQ ID NO 137 and SEQ ID NO: 58; 10                 20) SEQ ID NO 138 and SEQ ID NO: 58; 21) SEQ ID NO 139 and SEQ ID NO: 58; 22) SEQ ID NO 140 and SEQ ID NO: 58; 23) SEQ ID NO 141 and SEQ ID NO: 58; 24) SEQ ID NO 142 and SEQ ID NO: 58; 15                 25) SEQ ID NO 143 and SEQ ID NO: 58; 26) SEQ ID NO 144 and SEQ ID NO: 58; 27) SEQ ID NO 145 and SEQ ID NO: 58; 28) SEQ ID NO 146 and SEQ ID NO: 58; 29) SEQ ID NO 147 and SEQ ID NO: 58; 20                30) SEQ ID NO 148 and SEQ ID NO: 58; 31) SEQ ID NO 149 and SEQ ID NO: 58; 32) SEQ ID NO 150 and SEQ ID NO: 58; 33) SEQ ID NO 151 and SEQ ID NO: 58; 34) SEQ ID NO 152 and SEQ ID NO: 58; 25                 35) SEQ ID NO 153 and SEQ ID NO: 58; 36) SEQ ID NO 154 and SEQ ID NO: 58; 37) SEQ ID NO 155 and SEQ ID NO: 58; 38) SEQ ID NO 156 and SEQ ID NO: 58; 39) SEQ ID NO 157 and SEQ ID NO: 58; 30                40) SEQ ID NO 158 and SEQ ID NO: 58; 41) SEQ ID NO 159 and SEQ ID NO: 58; or 42) SEQ ID NO 160 and SEQ ID NO:

58.

67. The heterodimer of any one of claims 65 to 66, comprising a humanIgGl Fc-IL-2v fusion protein comprising (i) a first amino acid sequence as set forth below, 35 or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at2024202988   06 May 2024least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to a first amino acid sequence set forth below; and (ii) a second Fc region comprising a second amino acid sequence set forth below, or an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at5 least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical toa second amino acid sequence set forth below, respectively:1) SEQ ID NO: 124 and SEQ ID NO: 58;2) SEQ ID NO: 151 and SEQ ID NO: 58; or3) SEQ ID NO: 158 and SEQ ID NO: 58.10                 68. The heterodimer of any one of claims 52 to 67, wherein thepolypeptide comprising the first Fc domain comprises a first N-terminal signal peptide or leader sequence and the polypeptide comprising the second Fc domain comprises a second N-terminal signal peptide or leader sequence.

69. The heterodimer of claim 68, wherein the first N-terminal signal15 peptide or leader sequence and the second first N-terminal signal peptide or leader sequence are the same.

70. The heterodimer of claim 68, wherein the first N-terminal signal peptide or leader sequence and the second first N-terminal signal peptide or leader sequence are different.20                 71. The heterodimer of any one of claims 52 to 70, wherein theheterodimer does not specifically bind any antigen other than an Fc receptor or a complex of interleukin 2 receptor subunit beta (IL-2RB; CD 122) and interleukin 2 receptor subunit gamma (IL-2RG; CD 132).

72. The heterodimer of any one of claims 52 to 71, wherein the second25 Fc domain is not fused to an antigen binding domain.

73. The heterodimer of any one of claims 52 to 72, wherein neither the first Fc domain nor the second Fc domain is fused to an antigen binding domain.

74. The heterodimer of any one of claims 52 to 73, wherein the heterodimer comprises a serum half-life in a human of at least 6, 9, 12, 15, 18, 21, 24 hours, 30    e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 days, or longer.2024202988   06 May 202475.    The heterodimer of any one of claims 52 to 71, wherein the secondFc domain is fused to an antigen binding domain.

76. The heterodimer of claim 75, wherein the antigen binding domain binds to CD 8.5                77. The heterodimer of claim 75, wherein the antigen binding domainbinds to an immune checkpoint protein.

78. The heterodimer of claim 77, wherein the immune checkpoint protein is selected from the group consisting of: CD27, CD70; CD40, CD40LG; CD47, CD48 (SLAMF2), transmembrane and immunoglobulin domain containing 2 (TMIGD2, CD28H), 10 CD84 (LY9B, SLAMF5), CD96, CD160 (NK1, NK28, BY55), MS4A1 (CD20), CD244 (SLAMF4); CD276 (B7H3); V-set domain containing T cell activation inhibitor 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); natural killer cell cytotoxicity receptor 3 ligand 1 (NCR3LG1, B7H6); HERV-H LTR-associating 2 (HHLA2, B7H7); inducible T cell co-15 stimulator (ICOS, CD278); inducible T cell costimulator ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF8 (CD30), TNFSF8 (CD30L); TNFRSF10A (CD261, DR4, TRAILRI), TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF10B (CD262, DR5, TRAILR2), TNFRSF10 (TRAIL); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and20 T lymphocyte associated (BTLA)); TNFRSF17 (BCMA, CD269), TNFSF13B (BAFF); TNFRSF18 (GITR), TNFSF18 (GITRL); MHC class I polypeptide-related sequence A (MICA); MHC class I polypeptide-related sequence B (MICB); CD274 (CD274, PDL1, PD-L1); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T-lymphocyte associated protein 4 (CTLA4, CD152); CD80 (B7-1), CD28; nectin cell adhesion molecule25   2 (NECTIN2, CD112); CD226 (DNAM-1); Poliovirus receptor (PVR) cell adhesionmolecule (PVR, CD155); PVR related immunoglobulin domain containing (PVRIG, CD112R); T cell immunoreceptor with Ig and ITIM domains (TIGIT); T cell immunoglobulin and mucin domain containing 4 (TIMD4; TIM4); hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3); galectin 9 (LGALS9); lymphocyte activating 330 (LAG3, CD223); signaling lymphocytic activation molecule family member 1 (SLAMF1, SLAM, CD150); lymphocyte antigen 9 (LY9, CD229, SLAMF3); SLAM family member 6 (SLAMF6, CD352); SLAM family member 7 (SLAMF7, CD319); sialic acid binding Ig like lectin 7 (SIGLEC7); sialic acid binding Ig like lectin 9 (SIGLEC9); ULI6 binding2024202988   06 May 2024protein 1 (ULBP1); ULI6 binding protein 2 (ULBP2); ULI6 binding protein 3 (ULBP3); retinoic acid early transcript IE (RAET1E; ULBP4); retinoic acid early transcript 1G (RAET1G; ULBP5); retinoic acid early transcript IL (RAET1L; ULBP6); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR,5   CD158E1); CD160; killer cell lectin like receptor Bl (KLRB1, CD161); killer cell lectinlike receptor Cl (KLRC1, NKG2A, CD159A); killer cell lectin like receptor KI (KLRK1, NKG2D, CD314); killer cell lectin like receptor C2 (KLRC2, CD159c, NKG2C); killer cell lectin like receptor C3 (KLRC3, NKG2E); killer cell lectin like receptor C4 (KLRC4, NKG2F); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic10 tail 1 (KIR2DL1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin like receptor DI (KLRD1); killer cell lectin like receptor G1 (KLRG1; CLEC15A, MAFA, 2F1); sialic acid15 binding Ig like lectin 7 (SIGLEC7); and sialic acid binding Ig like lectin 9 (SIGLEC9).

79. The heterodimer of claim 77, wherein the immune checkpoint protein is selected from the group consisting of: CD274 (CD274, PDL1, PD-L1) and programmed cell death 1 (PDCD1, PD1, PD-1).

80. The heterodimer of claim 75, wherein the antigen binding domain20 binds to a target selected from the group consisting of: asialoglycoprotein receptor 1 (ASGR1), asialoglycoprotein receptor 2 (ASGR2), ATP binding cassette (ABC) family transporter (e.g., ATP binding cassette subfamily B member 1 (ABCB1; P-GP), ATP binding cassette subfamily B member 4 (ABCB4; MDR3), ATP binding cassette subfamily C member 1 (ABCC1; MRP1), ATP binding cassette subfamily C member 2 (ABCC2;25 MRP2), ATP binding cassette subfamily C member 3 (ABCC3; MRP3), ATP binding cassette subfamily C member 4 (ABCC4; MRP4), ATP binding cassette subfamily G member 2 (Junior blood group; ABCG2; BCRP), and ATP binding cassette subfamily B member 11 (ABCB11; a.k.a., Bile Salt Export Pump (BSEP)); a solute carrier (SLC) family transporter (e.g., solute carrier family 10 member 1 (SLC10A1; a.k.a., Sodium-taurocholate30 Co-transporting Polypeptide (NTCP)); solute carrier family 16 member 1 (SLC16A1; MCT1), solute carrier family 22 member 1 (SLC22A1; OCTI), solute carrier family 22 member 3 (SLC22A3; OCT3), solute carrier family 22 member 7 (SLC22A7; OAT2), solute carrier family 27 member 5 (SLC27A5; FATP5), solute carrier organic anion transporter family member 1B1 (SLCO1B1; OATP1B1), solute carrier organic anion2024202988   06 May 2024transporter family member 1B3 (SLCO1B3; OATP1B3), and solute carrier organic anion transporter family member 2B1 (SLCO2B1; OATP2B1)), transferrin receptor 2 (TFR2, TFRC2) and an HBV epitope (e.g., HBV core 18-27; envl81-193; env 335-343; pol 575583) presented in major histocompatibility complex (MHC) molecule (pMHC).5                 81. The heterodimer of claim 75, wherein the antigen binding domainbinds to a target selected from the group consisting of human immunodeficiency virus (HIV) gpl20, HIV gp41, human CD4, and human interleukin 7 receptor (IL7R; CD127).

82. The heterodimer of claim 75, wherein the antigen binding domain binds to a target selected from the group consisting of herpes simple virus (HSV)10 glycoprotein B (gB), glycoprotein C (gC), glycoprotein D (gD) and glycoprotein E (gE).

83. The heterodimer of claim 75, wherein the antigen binding domain binds to a target or tumor associated antigen (TAA) selected from the group consisting of: CD19; membrane spanning 4-domains Al (MS4A1; CD20); CD22 (SIGLEC2); CD27 (TNFRSF7); TNFRSF8 (CD30); CD33 (SIGLEC3); CD37; CD38; CD40 (TNFRSF5),15   CD44; CD47; CD48 (SLAMF2); CD52; CD70 (TNFSF7; CD27L); 5'-nucleotidase ecto(NT5E; CD73), ectonucleoside triphosphate diphosphohydrolase 1 (CD39), CD74; CD79B; CD80; CD86; interleukin 3 receptor subunit alpha (IL3RA), prominin 1 (PROM1; CD133); TNFRSF9 (CD137); syndecan 1 (SDC1; CD138); CD200 molecule (CD200); alpha fetoprotein (AFP), BAG cochaperone 6 (BAG6); MET proto-oncogene, receptor tyrosine20 kinase (MET); KIT proto-oncogene, receptor tyrosine kinase (KIT); C-type lectin domain family 12 member A (CLEC12A; CD371); C-type lectin domain containing 9A (CLEC9A; CD370); cadherin 3 (CDH3); carbonic anhydrase 6 (CA6); carbonic anhydrase 9 (CA9); carcinoembryonic antigen related cell adhesion molecule 3 (CEACAM3); carcinoembryonic antigen related cell adhesion molecule 5 (CEACAM5); carcinoembryonic antigen related25 cell adhesion molecule 6 (CEACAM6); chorionic somatomammotropin hormone 1 (CSH1); coagulation factor III, tissue factor (F3); collectin subfamily member 10 (COLEC10;CLL1); delta like canonical Notch ligand 3 (DLL3); ectonucleotide pyrophosphatase / phosphodiesterase 3 (ENPP3); ephrin Al (EFNA1); epidermal growth factor receptor (EGFR; ERBB; HER1); EGFR variant III (EGFRvIII); EPH receptor A2 (EPHA2);30 epithelial cell adhesion molecule (EPCAM); erb-b2 receptor tyrosine kinase 2 (ERBB2; HER-2 / neu); fibroblast activation protein alpha (FAP); fibroblast growth factor receptor 2 (FGFR2); fibroblast growth factor receptor 3 (FGFR3); folate hydrolase 1 (FOLH1); folate receptor 1 (FOLRI); GD2 ganglioside; glycoprotein NMB (GPNMB; osteoactivin);2024202988   06 May 2024guanylate cyclase 2C (GUCY2C); human papillomavirus (HPV) E6; HPV E7; major histocompatibility complex (MHC) class I-presented neoantigens, major histocompatibility complex (MHC) class Il-presented neoantigens, major histocompatibility complex, class I, E (HLA-E); major histocompatibility complex, class I, F (HLA-F); major histocompatibility5 complex, class I, G (HLA-G); MHC class I polypeptide-related sequence A (MICA); MHC class I polypeptide-related sequence B (MICB); integrin subunit beta 7 (ITGB7); leukocyte immunoglobulin like receptor Bl (LILRB1; ILT2); leukocyte immunoglobulin like receptor B2 (LILRB2; ILT4); LY6 / PLAUR domain containing 3 (LYPD3); glypican 3 (GPC3);KRAS proto-oncogene, GTPase (KRAS); MAGE family member Al (MAGEA1); MAGE10 family member A3 (MAGEA3); MAGE family member A4 (MAGEA4); MAGE family member Al 1 (MAGEA11); MAGE family member Cl (MAGECI); MAGE family member C2 (MAGEC2); MAGE family member C3 (MAGEC3); MAGE family member DI (MAGED1); MAGE family member D2 (MAGED2); mesothelin (MSLN); mucin 1 (MUC1) and splice variants thereof (e.g., including MUC1 / A, C, D, X, Y, Z and REP);15 mucin 16 (MUC16; CA125); natural killer cell cytotoxicity receptor 3 ligand 1 (NCR3LG1;B7-H6); necdin, MAGE family member (NDN); nectin cell adhesion molecule 2 (NECTIN2); nectin cell adhesion molecule 4 (NECTIN4); SLIT and NTRK like family member 6 (SLITRK6); promyelocytic leukemia (PML); protein tyrosine kinase 7 (inactive) (PTK7); Poliovirus receptor (PVR) cell adhesion molecule (PVR); SLAM family member 620 (SLAMF6); SLAM family member 7 (SLAMF7); sialic acid binding Ig like lectin 7 (SIGLEC7); sialic acid binding Ig like lectin 9 (SIGLEC9); sialic acid binding Ig like lectin 10 (SIGLEC10); signal regulatory protein alpha (SIRPA) solute carrier family 34 (sodium phosphate), member 2 (SLC34A2); solute carrier family 39 member 6 (SLC39A6); STEAP family member 1 (STEAP 1); suppression of tumorigenicity 2 (ST2); TNF receptor25 superfamily member 4 (TNFRSF4; OX40); TNF superfamily member 9 (TNFSF9; 4-1BB-L, CD137L); TNFRSF10A (DR4, TRAILRI); TNFRSF10B (DR5, TRAILR2);TNFRSF13B (BAFF); TNFRSF17 (BCMA); TNFRSF18 (GITR); transferrin (TF); transforming growth factor beta 1 (TGFB1) and isoforms thereof; triggering receptor expressed on myeloid cells 1 (TREM1); triggering receptor expressed on myeloid cells 2 30 (TREM2); trophoblast glycoprotein (TPBG); trophinin (TRO); tumor associated calciumsignal transducer 2 (TACSTD2); Fucosyl GM1; sialyl Lewis adhesion molecule (sLe); and Lewis Y antigen.

84. The heterodimer of claim 75, wherein the antigen binding domain binds to an epitope of a target or tumor associated antigen (TAA) presented in a major35 histocompatibility complex (MHC) molecule.

85. The heterodimer of claim 84, wherein the TAA is a cancer testis2024202988   06 May 2024antigen.

86. The heterodimer of claim 85, wherein the cancer testis antigen isselected from the group consisting of acrosin binding protein (ACRBP), alpha fetoprotein5 (AFP), A-kinase anchoring protein 4 (AKAP4), ATPase family AAA domain containing 2 (ATAD2), kinetochore scaffold 1 (KNL1; a.k.a., CASC5), centrosomal protein 55 (CEP55), cancer / testis antigen 1A (CTAG1A; a.k.a., ESO1; CT6.1; LAGE-2; LAGE2A; NY-ESO-1), cancer / testis antigen IB (CTAG1B; a.k.a., CT6.1, CTAG, CTAG1, ESO1, LAGE-2, LAGE2B, NY-ESO-1), cancer / testis antigen 2 (CTAG2; a.k.a., CAMEL, CT2, CT6.2,10   CT6.2a, CT6.2b, ESO2, LAGE-1, LAGE2B), CCCTC-binding factor like (CTCFL), cateninalpha 2 (CTNNA2), cancer / testis antigen 83 (CT83), cyclin Al (CCNA1), DEAD-box helicase 43 (DDX43), developmental pluripotency associated 2 (DPPA2), fetal and adult testis expressed 1 (FATE 1), FMRI neighbor (FMR1NB), HORMA domain containing 1 (HORMAD1), insulin like growth factor 2 mRNA binding protein 3 (IGF2BP3), leucine15 zipper protein 4 (LUZP4), lymphocyte antigen 6 family member K (LY6K), maelstrom spermatogenic transposon silencer (MAEL), MAGE family member Al (MAGEA1); MAGE family member A3 (MAGEA3); MAGE family member A4 (MAGEA4); MAGE family member Al 1 (MAGEA11); MAGE family member Cl (MAGECI); MAGE family member C2 (MAGEC2); MAGE family member DI (MAGED1); MAGE family member20 D2 (MAGED2), kinesin family member 20B (KIF20B; a.k.a., MPHOSPH1), NUF2 component of NDC80 kinetochore complex (NUF2), nuclear RNA export factor 2 (NXF2), PAS domain containing repressor 1 (PASD1), PDZ binding kinase (PBK), piwi like RNA-mediated gene silencing 2 (PIWIL-2), preferentially expressed antigen in melanoma (PRAME), sperm associated antigen 9 (SPAG9), sperm protein associated with the nucleus,25 X-linked, family member Al (SPANXA1), SPANX family member A2 (SPANXA2), SPANX family member C (SPANXC), SPANX family member D (SPANXD), SSX family member 1 (SSX 1), SSX family member 2 (SSX2), synaptonemal complex protein 3 (SYCP3), testis expressed 14, intercellular bridge forming factor (TEX14), transcription factor Dp family member 3 (TFDP3), serine protease 50 (PRSS50, a.k.a., TSP50), TTK30 protein kinase (TTK) and zinc finger protein 165 (ZNF165).

87. A conjugate comprising: the IL-2v of any one of claims 1 to 14, the fusion protein of any one of claims 15 to 50, the homodimer of claim 51, or the heterodimer of any one of claims 52 to 86; attached to a therapeutic agent.2024202988   06 May 202488. The conjugate of claim 87, wherein the therapeutic agent is covalently linked.

89. The conjugate of any one of claims 87 to 88, wherein the therapeutic agent is a small organic compound.5                 90. The conjugate of claim 89, where the therapeutic agent is selectedfrom GS-4224 and GS-4416.

91. The conjugate of any one of claims 87 to 90, wherein the therapeutic agent is an agonist or activator of a pattern recognition receptor (PRR), e.g., a Toll-like receptor (TLR), a RIG-I-like receptor (RLRs), a NOD-like receptors (NLR), an AIM2-like10 receptors (ALR), a C-type lectin receptors (CLR), a DNA receptor or an RNA receptor.

92. The conjugate of any one of claims 87 to 91, wherein the therapeutic agent is an agonist or activator of a toll-like receptor (TLR), DExD / H-box helicase 58 (DDX58; a.k.a., RIG-I) or a stimulator of interferon genes (STING) receptor.

93. The conjugate of claim 92, wherein the TLR agonist or activator is15   selected from the group consisting of a TLR2 agonist, a TLR3 agonist, a TLR4 agonist, aTLR5 agonist, a TLR7 agonist, a TLR8 agonist and a TLR9 agonist.

94. The conjugate of claim 93, wherein the TLR7 agonist is selected from the group consisting of vesatolimod (GS-9620), DS-0509, LHC-165, TMX-101 (imiquimod), RO7020531 and JNJ-4964, and / or wherein the TLR8 agonist is selected from20 the group consisting of selgantolimod (GS-9688) and NKTR-262 (dual TLR7 / TLR8 agonist).

95. A polynucleotide encoding the IL-2v of any one of claims 1 to 11, or the fusion protein of any one of claims 15 to 50 or the homodimer of claim 51.

96. The polynucleotide of claim 95, comprising a nucleic acid selected25 from the group consisting of SEQ ID NOs: 175-212, or a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 175-212.

97. A polynucleotide or multiple polynucleotides encoding the Fc-IL-2v30 fusion protein and the second Fc region of the heterodimer of any one of claims 52 to 86.2024202988   06 May 202498. The polynucleotide or polynucleotides according to claim 97, wherein the polynucleotide encoding the Fc-IL-2v fusion protein comprises a nucleic acid selected from the group consisting of SEQ ID NOs: 175-212, or a nucleic acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least5   94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to anucleic acid sequence selected from the group consisting of SEQ ID NOs: 175-212.

99. The polynucleotide or polynucleotides according to any one of claims97 to 98, wherein the polynucleotide encoding the second Fc region comprises a nucleic acid selected from the group consisting of SEQ ID NOs: 214-215, or a nucleic acid10 sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to a nucleic acid sequence selected from the group consisting of SEQ ID NOs: 214-215.

100. The polynucleotide or polynucleotides of any one of claims 95 to 99, 15   wherein the polynucleotide or polynucleotides are selected from the group consisting ofDNA, cDNA, RNA or mRNA.

101. An expression cassette or multiple expression cassettes comprising one or more regulatory sequences operably linked to the polynucleotide or polynucleotides of any one of claims 95 to 100.20                 102. A vector comprising the polynucleotide or polynucleotides of any oneof claims 95 to 100, or the expression cassette of claim 101.

103. The vector of claim 102, wherein the vector is a plasmid vector or a viral vector.

104. The vector of claim 103, wherein the viral vector comprises an25 oncolytic viral vector.

105. The vector of any one of claims 103 to 104, wherein the viral vector comprises a DNA virus or an RNA virus.

106. The vector of any one of claims 103 to 105, wherein the viral vectoris from a viral family selected from the group consisting of: Adenoviridae (e.g., 30 Adenovirus), Arenaviridae (e.g., lymphocytic choriomeningitis mammarenavirus, Cali2024202988   06 May 2024mammarenavirus (a.k.a., Pichinde mammarenavirus), Poxviridae (e.g., Vaccinia virus), Herpesviridae (e.g., Herpesvirus, e.g., HSV-1), Parvoviridae (e.g., Parvovirus Hl), Reoviridae (e.g., Reovirus), Retroviridae (e.g., Lentivirus), Picornaviridae (e.g., Coxsackievirus, Seneca Valley Virus, Poliovirus), Paramyxoviridae (e.g., Measles virus, 5 Newcastle disease virus (NDV)), Rhabdoviridae (e.g., Vesicular stomatitis virus (VSV)), Togaviridae (e.g., Alphavirus, Sindbis virus) and Enteroviridae (e.g., Echovirus).

107. A lipoplex, e.g., lipid nanoparticle (LNP), comprising the polynucleotide or polynucleotides of any one of claims 95 to 100, the expression cassette of claim 101 or the vector of any one of claims 102 to 106.10                 108. A cell or population of cells comprising the polynucleotide orpolynucleotides of any one of claims 95 to 100, the expression cassette of claim 101 or the vector of any one of claims 102 to 106, wherein the cell or population of cells expresses the IL-2v of any one of claims 1 to 11, the fusion protein of any one of claims 15 to 50, the homodimer of claim 51, or the heterodimer of any one of claims 52 to 86.15                  109. The cell or population of cells of claim 108, wherein the cell orpopulation of cells is a eukaryotic cell.

110. The cell or population of cells of any one of claims 108 to 109, wherein the cell or population of cells comprises a mammalian cell, an insect cell, a plant cell or a yeast cell.20                  111.   The cell or population of cells of any one of claims 108 to 110,wherein the mammalian cell is a Chinese Hamster Ovary (CHO) cell.

112. The cell or population of cells of any one of claims 108 to 110, wherein the mammalian cell is a human cell.

113. The cell or population of cells of claim 112, wherein the cell is a 25 human embryonic kidney cell.

114. A method of producing an Fc-IL-2 fusion protein heterodimer, the method comprising:a) culturing a cell or population of cells of any one of claims 108 to 113 transformed with the polynucleotide or polynucleotides of any one of claims 95 to 100, or2024202988   06 May 2024the expression cassette or multiple expression cassettes of claim 101, in a cell culture under conditions sufficient to express the Fc-IL-2 fusion protein heterodimer molecules; andb) isolating or purifying the Fc-IL-2 fusion protein heterodimer molecules from the cell culture.5                  115. The method of any claim 114, wherein the Fc-IL-2 fusionpolypeptide and the Fc polypeptide are expressed and assembled in the same cell.

116. The method of any one of claims 114 to 115, wherein the isolating or purifying step comprises Protein A chromatography.

117. The method of claim 116, wherein the isolating or purifying step 10   further comprises in-stream pH neutralization or immediate pH neutralization of Protein Achromatography eluate.

118. The method of any one of claims 116 to 117, wherein the isolating or purifying step further comprises anion exchange chromatography.

119. The method of any one of claims 114 to 118, wherein at least 90%, 15   91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or more, of the Fc-IL-2 fusion proteinheterodimer molecules are isolated or purified.

120. The method of any one of claims 114 to 119, wherein the cell or population of cells are cultured in a culture volume of at least 2L, e.g., at least 5L, 10L, 50L, 100L, 150L, 200L, 250L, or more.20                 121. The method of any one of claims 114 to 120, further comprisingformulating the Fc-IL-2 fusion protein heterodimer molecules into a sterile pharmaceutical composition suitable for administration to a human subject.

122. A pharmaceutical composition comprising the IL-2v of any one of claims 1 to 14, the fusion protein of any one of claims 15 to 50, the homodimer of claim 51, 25 the heterodimer of any one of claims 52 to 86, the conjugate of any one of claims 87 to 94, the polynucleotide or polynucleotides of any one of claims 95 to 100, the expression cassette of claim 101, the vector of any one of claims 102 to 106, or the lipoplex (e.g., LNP) of claim 107, and a pharmaceutically acceptable carrier.

123. The pharmaceutical composition 122, wherein the composition 30 comprises an aqueous formulation.2024202988   06 May 2024124. The pharmaceutical composition of any one of claims 122 to 123, comprising the fusion protein, the homodimer, the heterodimer and / or the conjugate at a concentration in the range of 0.05 mg / ml to 50 mg / ml, e.g., from 0.05 mg / ml to 20 mg / ml, e.g., from 0.1 mg / ml to 40 mg / ml, e.g., from 1.0 mg / ml to 30 mg / ml, e.g., from 0.05 mg / ml 5 to 0.06 mg / ml, 0.07 mg / ml, 0.08 mg / ml, 0.09 mg / ml, 0.1 mg / ml, 0.2 mg / ml, 0.3 mg / ml, 0.4 mg / ml, 0.5 mg / ml, 0.6 mg / ml, 0.7 mg / ml, 0.8 mg / ml, 0.9 mg / ml, 1.0 mg / ml, 1.5 mg / ml, 2.0 mg / ml, 2.5 mg / ml, 3.0 mg / ml, 3.5 mg / ml, 4.0 mg / ml, 4.5 mg / ml, 5.0 mg / ml, 6 mg / ml, 7 mg / ml, 8 mg / ml, 9 mg / ml, lOmg / ml, 11 mg / ml, 12 mg / ml, 13 mg / ml, 14 mg / ml, 15 mg / ml, 16 mg / ml, 17 mg / ml, 18 mg / ml, 19 mg / ml, 20 mg / ml, 25 mg / ml, 30 mg / ml, 10   35 mg / ml, 40 mg / ml, 45 mg / ml or 50 mg / ml.

125. The pharmaceutical composition of 122, wherein the composition is lyophilized.

126. The pharmaceutical composition of any one of claims 122 to 125, further comprising one or more additional therapeutic agents.15                  127. The pharmaceutical composition of any one of claims 122 to 126,further comprising a second therapeutic agent.

128. The pharmaceutical composition of any one of claims 122 to 126, further comprising second and third therapeutic agents.

129. A method for eliciting an immune response to human hepatitis B 20 virus (HBV) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the IL-2v of any one of claims 1 to 14, the fusion protein of any one of claims 15 to 50, the homodimer of claim 51, the heterodimer of any one of claims 52 to 78, the conjugate of any one of claims 87 to 94, the polynucleotide or polynucleotides of any one of claims 95 to 100, the expression cassette of claim 101, the 25 vector of any one of claims 102 to 106, or the lipop lex (e.g., LNP) of claim 107 or the pharmaceutical composition of any one of claims 122 to 128.

130. A method of treating or preventing human hepatitis B virus (HBV) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the IL-2v of any one of claims 1 to 14, the fusion protein of any one of claims 15 30 to 50, the homodimer of claim 51, the heterodimer of any one of claims 52 to 78, the conjugate of any one of claims 87 to 94, the polynucleotide or polynucleotides of any one of claims 95 to 100, the expression cassette of claim 101, the vector of any one of claims 1022024202988   06 May 2024to 106, or the lipoplex (e.g., LNP) of claim 107 or the pharmaceutical composition of any one of claims 122 to 128.

131. Use of the IL-2v of any one of claims 1 to 14, the fusion protein of any one of claims 15 to 50, the homodimer of claim 51, the heterodimer of any one of 5 claims 52 to 78, the conjugate of any one of claims 87 to 94, the polynucleotide or polynucleotides of any one of claims 95 to 100, the expression cassette of claim 101, the vector of any one of claims 102 to 106, or the lipoplex (e.g., LNP) of claim 107 or the pharmaceutical composition of any one of claims 122 to 128 in a method of eliciting an immune response to human hepatitis B virus (HBV) in a subject in need thereof.10                 132. Use of the IL-2v of any one of claims 1 to 14, the fusion protein ofany one of claims 15 to 50, the homodimer of claim 51, the heterodimer of any one of claims 52 to 78, the conjugate of any one of claims 87 to 94, the polynucleotide or polynucleotides of any one of claims 95 to 100, the expression cassette of claim 101, the vector of any one of claims 102 to 106, or the lipoplex (e.g., LNP) of claim 107 or the15 pharmaceutical composition of any one of claims 122 to 128 in a method of treating or preventing human hepatitis B virus (HBV) in a subject in need thereof.

133. The method of any one of claims 129 to 130 or the use of any one of claims 131 to 132, wherein the subject is infected with HBV, is suspected of being infected with HBV, or is at risk of being infected with HBV.20                 134. The method or use of any one of claims 129 to 133, wherein thesubject is asymptomatic.

135. The method or use of any one of claims 129 to 133, wherein the subject is chronically infected with HBV.

136. The method or use of claim 135, wherein the subject is exhibiting or 25 experiencing one or more symptoms selected from hepatic failure, hepatic cancer, hepatic fibrosis and hepatic cirrhosis.

137. The method or use of any one of claims 129 to 133, wherein the subject is acutely infected with HBV.

138. The method or use of claim 135 to 137, wherein the subject is30 exhibiting or experiencing one or more symptoms selected from jaundice, visible webs of2024202988   06 May 2024swollen blood vessels in the skin, dark-colored (e.g., orange or brown) urine, light-colored feces, fever, persistent fatigue, malaise, abdominal pain, abdominal fluid, loss of appetite, nausea, and vomiting.

139. The method or use of any one of claims 129 to 138, wherein the5 subject is co-infected with hepatitis D virus (HDV).

140. The method or use of any one of claims 129 to 139, wherein the subject is not receiving antiviral therapy or antiviral therapy is discontinued prior to administration of the IL-2v, the fusion protein, the homodimer, the heterodimer, the conjugate, the polynucleotide or polynucleotides, the expression cassette, the vector, or the 10 lipoplex (e.g., LNP) or the pharmaceutical composition.

141. The method or use of any one of claims 129 to 140, wherein antiviral therapy is discontinued after one or more administrations of the fusion protein, the homodimer, the heterodimer, the conjugate, the polynucleotide, the vector, the lipoplex (e.g., LNP) and / or the pharmaceutical composition.15                  142. The method or use of any one of claims 129 to 141, furthercomprising co-administering to the subject one or more antiviral agents.

143. The method or use of 142, wherein the one or more antiviral agents are selected from the group consisting of lamivudine (LAM), adefovir dipivoxil (ADV), entecavir (ETV), telbivudine (LdT), tenofovir disoproxil fumarate (TDF), tenofovir20 alafenamide (TAF or VEMLIDY®), ledipasvir + sofosbuvir (HARVONI®) and a PEGylated interferon (e.g., PEG-IFN-a2a and / or PEG-IFN-a2b).

144. The method or use of claim 143, further comprising co-administering to the subject one or more therapeutic agents selected from the group consisting of HBV antigen inhibitors (e.g., HBV core antigen (HBcAg) inhibitors, HBV surface antigen25 (HBsAg) inhibitors, HBx inhibitors, HBV E antigen inhibitors), anti-HBV antigen antibodies, inhibitory nucleic acids targeting HBV (e.g., antisense oligonucleotide, short interfering RNA (siRNA), DNA-directed RNA interference (ddRNAi)), gene editors targeting HBV (e.g.,_CRISPR-Cas (e.g., Cas9, Cas 12, Cascade, Cas 13), zinc finger nucleases, homing endonucleases, homing meganucleases (e.g., ARCUS), synthetic30 nucleases, TALENs), covalently closed circular DNA (cccDNA) inhibitors, HBsAg secretion or assembly inhibitors, HBV viral entry inhibitors, and CAR-T and T cell bispecific (redirected T cells) for specific killing of HBV-infected cells.2024202988   06 May 2024145. A method of activating a latent viral reservoir in a subject infected with human immunodeficiency virus (HIV), comprising administering to the subject a therapeutically effective amount of the IL-2v of any one of claims 1 to 14, the fusion protein of any one of claims 15 to 50, the homodimer of claim 51, the heterodimer of any one of 5 claims 52 to 75 and 81, the conjugate of any one of claims 87 to 94, the polynucleotide or polynucleotides of any one of claims 95 to 100, the expression cassette of claim 101, the vector of any one of claims 102 to 106, or the lipop lex (e.g., LNP) of claim 107 or the pharmaceutical composition of any one of claims 122 to 128.

146. A method of treating or preventing human immunodeficiency virus 10 (HIV) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the IL-2v of any one of claims 1 to 14, the fusion protein of any one of claims 15 to 50, the homodimer of claim 51, the heterodimer of any one of claims 52 to 75 and 81, the conjugate of any one of claims 87 to 94, the polynucleotide or polynucleotides of any one of claims 95 to 100, the expression cassette of claim 101, the vector of any one 15 of claims 102 to 106, or the lipoplex (e.g., LNP) of claim 107 or the pharmaceutical composition of any one of claims 122 to 128.

147. Use of the IL-2v of any one of claims 1 to 14, the fusion protein of any one of claims 15 to 50, the homodimer of claim 51, the heterodimer of any one of claims 52 to 75 and 81, the conjugate of any one of claims 87 to 94, the polynucleotide or 20 polynucleotides of any one of claims 95 to 100, the expression cassette of claim 101, the vector of any one of claims 102 to 106, or the lipoplex (e.g., LNP) of claim 107 or the pharmaceutical composition of any one of claims 122 to 128 in a method of activating a latent viral reservoir in a subject infected with human immunodeficiency virus (HIV).

148. Use of the IL-2v of any one of claims 1 to 14, the fusion protein of 25 any one of claims 15 to 50, the homodimer of claim 51, the heterodimer of any one of claims 52 to 75 and 81, the conjugate of any one of claims 87 to 94, the polynucleotide or polynucleotides of any one of claims 95 to 100, the expression cassette of claim 101, the vector of any one of claims 102 to 106, or the lipoplex (e.g., LNP) of claim 107 or the pharmaceutical composition of any one of claims 122 to 128 in a method of treating or 30 preventing human immunodeficiency virus (HIV) in a subject in need thereof.

149. The method of any one of claims 145 to 146 or the use of any one of claims 147 to 148, further comprising administering to the subject an additional therapeutic agent.2024202988   06 May 2024150. The method or use of claim 149, further comprising administering to the subject one or more anti-HIV broadly neutralizing antibodies.

151. The method or use of claim 150, wherein the one or more anti-HIVbroadly neutralizing antibodies bind to an epitope or region of gpl20 selected from the 5 group consisting of:third variable loop (V3) and / or high mannose patch comprising a N332 oligomannose glycan;second variable loop (V2) and / or Env trimer apex;CD4 binding site (CD4bs);gpl20 / gp41 interface; orsilent face of gpl20.152.The method or use of any one of claims 150 to 151, wherein the oneor more anti-HIV broadly neutralizing antibodies bind to an epitope or region of gpl20 in the third variable loop (V3) and / or high mannose patch comprising a N332 oligomannose15 glycan and competes with or comprises VH and VL regions from an antibody selected fromthe group consisting of GS-9722, PGT-121, PGT-121.414, PGT-122, PGT-123, PGT-124, PGT-125, PGT-126, PGT-128, PGT-130, PGT-133, PGT-134, PGT-135, PGT-136, PGT-137, PGT-138, PGT-139, 10-1074, 10-1074-J, VRC24, 2G12, BG18, 354BG8, 354BG18, 354BG42, 354BG33, 354BG129, 354BG188, 354BG411, 354BG426, DH270.1, DH270.6, 20 PGDM12, VRC41.01, PGDM21, PCDN-33A, BF520.1 and VRC29.03.

153. The method or use of any one of claims 150 to 152, wherein the oneor more anti-HIV broadly neutralizing antibodies bind to an epitope or region of gpl20 in the second variable loop (V2) and / or Env trimer apex and competes with or comprises VH and VL regions from an antibody selected from the group consisting of PG9, PG16, PGC14,25 PGG14, PGT-142, PGT-143, PGT-144, PGT-145, CHOI, CH59, PGDM1400, CAP256, CAP256-VRC26.08, CAP256-VRC26.09, CAP256-VRC26.25, PCT64-24E and VRC38.01.

154. The method or use of any one of claims 150 to 153, wherein the oneor more anti-HIV broadly neutralizing antibodies bind to an epitope or region of gpl20 in 30 the CD4 binding site (CD4bs) and competes with or comprises VH and VL regions from anantibody selected from the group consisting of 3BNC117, GS-9723, 3BNC60, bl2, F105,VRC01, VRC07, VRC07-523, VRC03, VRC06, VRC06b01 VRC08, VRC0801, NIH45-46,2024202988   06 May 2024VRC-PG04, PGV04; CH103, 44-VRC13.01, 1NC9, 12A12, N6, N49-P7, NC-Cowl, IOMA, CH235 and CH235.12, N49P6, N49P7, N49P11, N49P9 andN60P25.

155. The method or use of any one of claims 150 to 154, wherein the one or more anti-HIV broadly neutralizing antibodies bind to an epitope or region of gpl20 in5 the gpl20 / gp41 interface and competes with or comprises VH and VL regions from an antibody selected from the group consisting of PGT-151, CAP248-2B, 35022, 8ANC195, ACS202, VRC34 and VRC34.01.

156. The method or use of any one of claims 150 to 155, wherein the one or more anti-HIV broadly neutralizing antibodies bind to an epitope or region of the gpl2010   silent face and competes with or comprises VH and VL regions from an antibody selectedfrom VRC-PG05 and SF12.

157. The method or use of any one of claims 150 to 156, wherein the one or more anti-HIV broadly neutralizing antibodies bind to an epitope or region of gp41 in the membrane proximal region (MPER).15                 158. The method or use of any one of claims 150 to 157, wherein the oneor more anti-HIV broadly neutralizing antibodies bind to an epitope or region of gp41 in the membrane proximal region (MPER) and competes with or comprises VH and VL regions from an antibody selected from the group consisting of 10E8, 10E8v4, 10E8-5R-100cF, 4E10, DH511.11P, 2F5, 7b2, andLNOl.20                 159. The method or use of any one of claims 150 to 158, wherein the oneor more anti-HIV broadly neutralizing antibodies bind to an epitope or region of the gp41 fusion peptide and competes with or comprises VH and VL regions from an antibody selected from the group consisting of VRC34 and ACS202.

160. The method or use of any one of claims 149 to 159, wherein the25 subject is not receiving antiretroviral therapy (ART) or ART is discontinued prior to administration of the fusion protein, the homodimer, the heterodimer, the conjugate, the polynucleotide or polynucleotides, the expression cassette, the vector, the lipoplex (e.g., LNP) or the pharmaceutical composition.

161. The method or use of any one of claims 149 to 160, wherein ART is 30 discontinued after one or more administrations of the fusion protein, the homodimer, the2024202988   06 May 2024heterodimer, the conjugate, the polynucleotide or polynucleotides, the expression cassette, the vector, the lipoplex (e.g., LNP) or the pharmaceutical composition.

162. The method or use of any one of claims 149 to 159, further comprising administering one or more antiretroviral therapy (ART) agents to the subject.5                 163. The method or use of any one of claims 145 to 162, wherein thesubject is chronically infected with HIV.

164. A method of enhancing, improving, and / or increasing the response to a vaccine therapy in a subject in need thereof, comprising co-administering to the subject (1) an effective amount of the IL-2v of any one of claims 1 to 14, the fusion protein of any 10 one of claims 15 to 50, the homodimer of claim 51, the heterodimer of any one of claims 52 to 86, the conjugate of any one of claims 87 to 94, the polynucleotide or polynucleotides of any one of claims 95 to 100, the expression cassette of claim 101, the vector of any one of claims 102 to 106, or the lipoplex (e.g., LNP) of claim 107 or the pharmaceutical composition of any one of claims 122 to 128; and (2) an effective amount of a vaccine.15                  165. Use of the IL-2v of any one of claims 1 to 14, the fusion protein ofany one of claims 15 to 50, the homodimer of claim 51, the heterodimer of any one of claims 52 to 86, the conjugate of any one of claims 87 to 94, the polynucleotide or polynucleotides of any one of claims 95 to 100, the expression cassette of claim 101, the vector of any one of claims 102 to 106, or the lipoplex (e.g., LNP) of claim 107 or the 20 pharmaceutical composition of any one of claims 122 to 128 in combination with a vaccine in a method of enhancing, improving, and / or increasing the response to a vaccine therapy in a subject in need thereof.

166. The method of claim 164 or the use of claim 165, wherein the vaccine is selected from the group consisting of an antiviral vaccine, an antibacterial 25 vaccine and an anticancer vaccine.

167. The method or use of any one of claims 164 to 166, wherein the vaccine comprises an antiviral vaccine against a virus selected from the group consisting of hepatitis A virus (HAV), hepatitis B virus (HBV), human immunodeficiency virus (HIV), cytomegalovirus (CMV), a herpes simplex virus (HSV), Epstein-Barr virus (EBV), human 30   orthopneumovirus or human respiratory syncytial virus (RSV), human papillomavirus(HPV), varicella-zoster virus, measles virus, mumps virus, poliovirus vaccine, influenza virus, paramyxovirus, rotavirus, Zika virus, Dengue virus, Ebola virus and coronavirus (e.g.,2024202988   06 May 2024betacoronavirus, e.g., severe acute respiratory syndrome-related coronavirus, e.g., SARS-CoV2).

168. The method or use of any one of claims 164 to 166, wherein the vaccine comprises an antibacterial vaccine against a bacterium selected from the group 5 consisting of mycobacterium tuberculosis, pertussis, tetanus, diphtheria, meningococcus, pneumococcus, Haemophilus influenza, cholera, typhoid, and anthrax.

169. The method or use of any one of claims 164 to 168, comprising a prime-boost regimen comprising administering a priming composition at a first time point and administering one or more boosting compositions at one or more subsequent time 10 points.

170. The method or use of claim 169, wherein the priming composition comprises the IL-2v of any one of claims 1 to 14, the fusion protein of any one of claims 15 to 50, the homodimer of claim 51, the heterodimer of any one of claims 52 to 86, the conjugate of any one of claims 87 to 94, the polynucleotide or polynucleotides of any one of 15 claims 95 to 100, the expression cassette of claim 101, the vector of any one of claims 102 to 106, or the lipoplex (e.g., LNP) of claim 107 or the pharmaceutical composition of any one of claims 122 to 128.

171. The method or use of claim 169, wherein the one or more boostingcompositions comprise the IL-2v of any one of claims 1 to 14, the fusion protein of any one 20 of claims 15 to 50, the homodimer of claim 51, the heterodimer of any one of claims 52 to 86, the conjugate of any one of claims 87 to 94, the polynucleotide or polynucleotides of any one of claims 95 to 100, the expression cassette of claim 101, the vector of any one of claims 102 to 106, or the lipoplex (e.g., LNP) of claim 107 or the pharmaceutical composition of any one of claims 122 to 128.25                 172. The method or use of any one of claims 169 to 171, wherein thepriming composition and the boosting composition are the same.

173. The method or use of any one of claims 169 to 171, wherein the priming composition and the boosting composition are different.

174. A method of preventing, reducing and / or inhibiting the recurrence, 30 growth, proliferation, migration and / or metastasis of a cancer cell or population of cancer cells in a subject in need thereof, comprising administering to the subject an effective2024202988   06 May 2024amount of the IL-2v of any one of claims 1 to 14, the fusion protein of any one of claims 15 to 50, the homodimer of claim 51, the heterodimer of any one of claims 52 to 78 and 83 to 86, the conjugate of any one of claims 87 to 94, the polynucleotide or polynucleotides of any one of claims 95 to 100, the expression cassette of claim 101, the vector of any one of5 claims 102 to 106, or the lipoplex (e.g., LNP) of claim 107 or the pharmaceutical composition of any one of claims 122 to 128.

175. Use of the IL-2v of any one of claims 1 to 14, the fusion protein ofany one of claims 15 to 50, the homodimer of claim 51, the heterodimer of any one of claims 52 to 78 and 83 to 86, the conjugate of any one of claims 87 to 94, the10 polynucleotide or polynucleotides of any one of claims 95 to 100, the expression cassette of claim 101, the vector of any one of claims 102 to 106, or the lipoplex (e.g., LNP) of claim 107 or the pharmaceutical composition of any one of claims 122 to 128 in a method of preventing, reducing and / or inhibiting the recurrence, growth, proliferation, migration and / or metastasis of a cancer cell or population of cancer cells in a subject in need thereof.15                  176. The method of claim 174 or the use of claim 175, wherein the fusionprotein, the homodimer, the heterodimer, the conjugate, the polynucleotide, the vector, the lipoplex (e.g., LNP) and / or the pharmaceutical composition is co-administered with one or more anti-neoplastic or chemotherapeutic agents.

177. The method or use of claim 176, wherein the one or more anti-20 neoplastic or chemotherapeutic agents are selected from the group consisting of a nucleoside analog (e.g., 5-fluorouracil, gemcitabine, cytarabine, cladribine, pentostatin, fludarabine), a taxane (e.g., paclitaxel, nab-paclitaxel, docetaxel, cabazitaxel), a platinum coordination complex (cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, satraplatin, dicycloplatin, eptaplatin, lobaplatin, miriplatin), a25 dihydrofolate reductase (DHFR) inhibitor (e.g., methotrexate, trimetrexate, pemetrexed), a topoisomerase inhibitor (e.g., doxorubicin, daunorubicin, dactinomycin, eniposide, epirubicin, etoposide, idarubicin, irinotecan, mitoxantrone, pixantrone, sobuzoxane, topotecan, irinotecan, MM-398 (liposomal irinotecan), vosaroxin and GPX-150, aldoxorubicin, AR-67, mavelertinib, AST-2818, avitinib (ACEA-0010), irofulven (MGL30    114)), an alkylating agent (e.g., a nitrogen mustard (e.g., cyclophosphamide, chlormethine,uramustine or uracil mustard, melphalan, chlorambucil, ifosfamide, bendamustine, temozolomide, carmustine), a nitrosourea (e.g., carmustine, lomustine, streptozocin), an alkyl sulfonate (e.g., busulfan)), and mixtures thereof.2024202988   06 May 2024178. The method or use of any one of claims 174 to 177, wherein the fusion protein, the homodimer, the heterodimer, the conjugate, the polynucleotide, the vector, the lipoplex (e.g., LNP) and / or the pharmaceutical composition is co-administered with a FOLFOX regimen, a FOLFIRI regimen, a FOLFOXIRI regimen or a FOLFIRINOX 5 regimen.

179. The method or use of any one of claims 174 to 178, wherein the fusion protein, the homodimer, the heterodimer, the conjugate, the polynucleotide, the vector, the lipoplex (e.g., LNP) and / or the pharmaceutical composition is co-administered with an immunotherapy comprising one or more antibodies or antigen-binding antibody 10 fragments thereof, or antibody-drug conjugates thereof, CD3-targeting multi-specific molecules, NK cell-activating receptor-targeting multi-specific molecules, or nonimmunoglobulin antigen-binding domains or antibody mimetic proteins directed against one or more targets or tumor associated antigens (TAAs) selected from the group consisting of: CD19; membrane spanning 4-domains Al (MS4A1; CD20); CD22 (SIGLEC2); CD2715 (TNFRSF7); TNFRSF8 (CD30); CD33 (SIGLEC3); CD37; CD38; CD40 (TNFRSF5), CD44; CD47; CD48 (SLAMF2); CD52; CD70 (TNFSF7; CD27L); 5'-nucleotidase ecto (NT5E; CD73), ectonucleoside triphosphate diphosphohydrolase 1 (CD39), CD74; CD79B; CD80; CD86; interleukin 3 receptor subunit alpha (IL3RA), prominin 1 (PROM1; CD133); TNFRSF9 (CD137); syndecan 1 (SDC1; CD138); CD200 molecule (CD200); alpha20 fetoprotein (AFP), BAG cochaperone 6 (BAG6); MET proto-oncogene, receptor tyrosine kinase (MET); KIT proto-oncogene, receptor tyrosine kinase (KIT); C-type lectin domain family 12 member A (CLEC12A; CD371); C-type lectin domain containing 9A (CLEC9A; CD370); cadherin 3 (CDH3); carbonic anhydrase 6 (CA6); carbonic anhydrase 9 (CA9); carcinoembryonic antigen related cell adhesion molecule 3 (CEACAM3); carcinoembryonic25 antigen related cell adhesion molecule 5 (CEACAM5); carcinoembryonic antigen related cell adhesion molecule 6 (CEACAM6); chorionic somatomammotropin hormone 1 (CSH1); coagulation factor III, tissue factor (F3); collectin subfamily member 10 (COLEC10;CLL1); delta like canonical Notch ligand 3 (DLL3); ectonucleotide pyrophosphatase / phosphodiesterase 3 (ENPP3); ephrin Al (EFNA1); epidermal growth factor receptor 30 (EGFR; ERBB; HER1); EGFR variant III (EGFRvIII); EPH receptor A2 (EPHA2);epithelial cell adhesion molecule (EPCAM); erb-b2 receptor tyrosine kinase 2 (ERBB2; HER-2 / neu); fibroblast activation protein alpha (FAP); fibroblast growth factor receptor 2 (FGFR2); fibroblast growth factor receptor 3 (FGFR3); folate hydrolase 1 (FOLH1); folate receptor 1 (FOLRI); GD2 ganglioside; glycoprotein NMB (GPNMB; osteoactivin);35 guanylate cyclase 2C (GUCY2C); human papillomavirus (HPV) E6; HPV E7; major2024202988   06 May 2024histocompatibility complex (MHC) class I-presented neoantigens, major histocompatibility complex (MHC) class Il-presented neoantigens, major histocompatibility complex, class I, E (HLA-E); major histocompatibility complex, class I, F (HLA-F); major histocompatibility complex, class I, G (HLA-G); MHC class I polypeptide-related sequence A (MICA); MHC 5 class I polypeptide-related sequence B (MICB); integrin subunit beta 7 (ITGB7); leukocyteimmunoglobulin like receptor Bl (LILRB1; ILT2); leukocyte immunoglobulin like receptor B2 (LILRB2; ILT4); LY6 / PLAUR domain containing 3 (LYPD3); glypican 3 (GPC3);KRAS proto-oncogene, GTPase (KRAS); MAGE family member Al (MAGEA1); MAGE family member A3 (MAGEA3); MAGE family member A4 (MAGEA4); MAGE family10 member Al 1 (MAGEA11); MAGE family member Cl (MAGECI); MAGE family member C2 (MAGEC2); MAGE family member C3 (MAGEC3); MAGE family member DI (MAGED1); MAGE family member D2 (MAGED2); mesothelin (MSLN); mucin 1 (MUC1) and splice variants thereof (e.g., including MUC1 / A, C, D, X, Y, Z and REP); mucin 16 (MUC16; CA125); natural killer cell cytotoxicity receptor 3 ligand 1 (NCR3LG1;15   B7-H6); necdin, MAGE family member (NDN); nectin cell adhesion molecule 2(NECTIN2); nectin cell adhesion molecule 4 (NECTIN4); SLIT and NTRK like family member 6 (SLITRK6); promyelocytic leukemia (PML); protein tyrosine kinase 7 (inactive) (PTK7); Poliovirus receptor (PVR) cell adhesion molecule (PVR); SLAM family member 6 (SLAMF6); SLAM family member 7 (SLAMF7); sialic acid binding Ig like lectin 720 (SIGLEC7); sialic acid binding Ig like lectin 9 (SIGLEC9); sialic acid binding Ig like lectin 10 (SIGLEC10); signal regulatory protein alpha (SIRPA) solute carrier family 34 (sodium phosphate), member 2 (SLC34A2); solute carrier family 39 member 6 (SLC39A6); STEAP family member 1 (STEAP 1); suppression of tumorigenicity 2 (ST2); TNF receptor superfamily member 4 (TNFRSF4; OX40); TNF superfamily member 9 (TNFSF9; 4-1BB-25 L, CD137L); TNFRSF10A (DR4, TRAILRI); TNFRSF10B (DR5, TRAILR2); TNFRSF13B (BAFF); TNFRSF17 (BCMA); TNFRSF18 (GITR); transferrin (TF); transforming growth factor beta 1 (TGFB1) and isoforms thereof; triggering receptor expressed on myeloid cells 1 (TREM1); triggering receptor expressed on myeloid cells 2 (TREM2); trophoblast glycoprotein (TPBG); trophinin (TRO); tumor associated calcium30 signal transducer 2 (TACSTD2); Fucosyl GM1; sialyl Lewis adhesion molecule (sLe); and Lewis Y antigen.

180. The method or use of claim 179, wherein the one or more antibodies or antigen-binding antibody fragments thereof, or antibody-drug conjugates thereof, CD3-targeting multi-specific molecules, NK cell-activating receptor-targeting multi-specific35 molecules, or non-immunoglobulin antigen-binding domains or antibody mimetic proteins2024202988   06 May 2024binds to an epitope of a target or tumor associated antigen (TAA) presented in a major histocompatibility complex (MHC) molecule.

181. The method or use of any one of claims 179 to 180, wherein the NK cell-activating receptor is selected from the group consisting of CD 16, NKp30, NKp44,5 NKp46, NKp80 and NKG2D.

182. The method or use of any one of claims 174 to 180, wherein the fusion protein, the homodimer, the heterodimer, the conjugate, the polynucleotide, the vector, the lipoplex (e.g., LNP) and / or the pharmaceutical composition is co-administered with one or more cellular therapies selected from the group consisting of: natural killer10 (NK) cells, NK-T cells, T cells, cytokine-induced killer (CIK) cells, macrophage (MAC) cells, tumor infdtrating lymphocytes (TILs) and dendritic cells (DCs).

183. The method or use of claim 182, wherein the one or more cellular therapies comprise a T cell therapy selected from the group consisting of: alpha / beta TCR T cells, gamma / delta TCR T cells, regulatory T (Treg) cells and TRuC™ T cells.15                  184. The method or use of claim 182, wherein the one or more cellulartherapies comprise aNK cell therapy, e.g., comprisingNK-92 cells.

185. The method or use of any one of claims 182 to 184, wherein the one or more cellular therapies comprise cells that are autologous, syngeneic or allogeneic to the subject.20                 186. The method or use of any one of claims 182 to 185, wherein the oneor more cellular therapies comprise cells comprising chimeric antigen receptors (CARs).

187. The method or use of any one of claims 182 to 186, wherein the cells in the cellular therapy bind to a target or tumor associated antigen (TAA) selected from the group consisting of selected from the group consisting of: CD 19; membrane spanning 425 domains Al (MS4A1; CD20); CD22 (SIGLEC2); CD27 (TNFRSF7); TNFRSF8 (CD30); CD33 (SIGLEC3); CD37; CD38; CD40 (TNFRSF5), CD44; CD47; CD48 (SLAMF2); CD52; CD70 (TNFSF7; CD27L); 5'-nucleotidase ecto (NT5E; CD73), ectonucleoside triphosphate diphosphohydrolase 1 (CD39), CD74; CD79B; CD80; CD86; interleukin 3 receptor subunit alpha (IL3RA), prominin 1 (PROM1; CD 133); TNFRSF9 (CD 137);30 syndecan 1 (SDC1; CD138); CD200 molecule (CD200); alpha fetoprotein (AFP), BAG cochaperone 6 (BAG6); MET proto-oncogene, receptor tyrosine kinase (MET); KIT proto-2024202988   06 May 2024oncogene, receptor tyrosine kinase (KIT); C-type lectin domain family 12 member A (CLEC12A; CD371); C-type lectin domain containing 9A (CLEC9A; CD370); cadherin 3 (CDH3); carbonic anhydrase 6 (CA6); carbonic anhydrase 9 (CA9); carcinoembryonic antigen related cell adhesion molecule 3 (CEACAM3); carcinoembryonic antigen related5 cell adhesion molecule 5 (CEACAM5); carcinoembryonic antigen related cell adhesion molecule 6 (CEACAM6); chorionic somatomammotropin hormone 1 (CSH1); coagulation factor III, tissue factor (F3); collectin subfamily member 10 (COLEC10; CLL1); delta like canonical Notch ligand 3 (DLL3); ectonucleotide pyrophosphatase / phosphodiesterase 3 (ENPP3); ephrin Al (EFNA1); epidermal growth factor receptor (EGFR; ERBB; HER1);10 EGFR variant III (EGFRvIII); EPH receptor A2 (EPHA2); epithelial cell adhesion molecule (EPCAM); erb-b2 receptor tyrosine kinase 2 (ERBB2; HER-2 / neu); fibroblast activation protein alpha (FAP); fibroblast growth factor receptor 2 (FGFR2); fibroblast growth factor receptor 3 (FGFR3); folate hydrolase 1 (FOLH1); folate receptor 1 (FOLRI); GD2 ganglioside; glycoprotein NMB (GPNMB; osteoactivin); guanylate cyclase 2C (GUCY2C);15 human papillomavirus (HPV) E6; HPV E7; major histocompatibility complex (MHC) class I-presented neoantigens, major histocompatibility complex (MHC) class Il-presented neoantigens, major histocompatibility complex, class I, E (HLA-E); major histocompatibility complex, class I, F (HLA-F); major histocompatibility complex, class I, G (HLA-G); MHC class I polypeptide-related sequence A (MICA); MHC class I20 polypeptide-related sequence B (MICB); integrin subunit beta 7 (ITGB7); leukocyte immunoglobulin like receptor Bl (LILRB1; ILT2); leukocyte immunoglobulin like receptor B2 (LILRB2; ILT4); LY6 / PLAUR domain containing 3 (LYPD3); glypican 3 (GPC3);KRAS proto-oncogene, GTPase (KRAS); MAGE family member Al (MAGEA1); MAGE family member A3 (MAGEA3); MAGE family member A4 (MAGEA4); MAGE family25 member Al 1 (MAGEA11); MAGE family member Cl (MAGECI); MAGE family member C2 (MAGEC2); MAGE family member C3 (MAGEC3); MAGE family member DI (MAGED1); MAGE family member D2 (MAGED2); mesothelin (MSLN); mucin 1 (MUC1) and splice variants thereof (e.g., including MUC1 / A, C, D, X, Y, Z and REP);mucin 16 (MUC16; CA125); natural killer cell cytotoxicity receptor 3 ligand 1 (NCR3LG1;30   B7-H6); necdin, MAGE family member (NDN); nectin cell adhesion molecule 2(NECTIN2); nectin cell adhesion molecule 4 (NECTIN4); SLIT and NTRK like family member 6 (SLITRK6); promyelocytic leukemia (PML); protein tyrosine kinase 7 (inactive) (PTK7); Poliovirus receptor (PVR) cell adhesion molecule (PVR); SLAM family member 6 (SLAMF6); SLAM family member 7 (SLAMF7); sialic acid binding Ig like lectin 735 (SIGLEC7); sialic acid binding Ig like lectin 9 (SIGLEC9); sialic acid binding Ig like lectin2024202988   06 May 202410 (SIGLEC10); signal regulatory protein alpha (SIRPA) solute carrier family 34 (sodium phosphate), member 2 (SLC34A2); solute carrier family 39 member 6 (SLC39A6); STEAP family member 1 (STEAP 1); suppression of tumorigenicity 2 (ST2); TNF receptor superfamily member 4 (TNFRSF4; OX40); TNF superfamily member 9 (TNFSF9; 4-1BB-5 L, CD137L); TNFRSF10A (DR4, TRAILRI); TNFRSF10B (DR5, TRAILR2); TNFRSF13B (BAFF); TNFRSF17 (BCMA); TNFRSF18 (GITR); transferrin (TF); transforming growth factor beta 1 (TGFB1) and isoforms thereof; triggering receptor expressed on myeloid cells 1 (TREM1); triggering receptor expressed on myeloid cells 2 (TREM2); trophoblast glycoprotein (TPBG); trophinin (TRO); tumor associated calcium10 signal transducer 2 (TACSTD2); Fucosyl GM1; sialyl Lewis adhesion molecule (sLe); and Lewis Y antigen.

188. The method or use of any one of claims 182 to 187, wherein the cells in the cellular therapy bind to an epitope of a target or tumor associated antigen (TAA) presented in a major histocompatibility complex (MHC) molecule.15                 189. The method or use of claim 180 or claim 188, wherein the TAA is acancer testis antigen.

190. The method or use of claim 189, wherein the cancer testis antigen is selected from the group consisting of acrosin binding protein (ACRBP), alpha fetoprotein (AFP), A-kinase anchoring protein 4 (AKAP4), ATPase family AAA domain containing 220 (ATAD2), kinetochore scaffold 1 (KNL1; a.k.a., CASC5), centrosomal protein 55 (CEP55), cancer / testis antigen 1A (CTAG1A; a.k.a., ESO1; CT6.1; LAGE-2; LAGE2A; NY-ESO-1), cancer / testis antigen IB (CTAG1B; a.k.a., CT6.1, CTAG, CTAG1, ESO1, LAGE-2, LAGE2B, NY-ESO-1), cancer / testis antigen 2 (CTAG2; a.k.a., CAMEL, CT2, CT6.2, CT6.2a, CT6.2b, ESO2, LAGE-1, LAGE2B), CCCTC-binding factor like (CTCFL), catenin25 alpha 2 (CTNNA2), cancer / testis antigen 83 (CT83), cyclin Al (CCNA1), DEAD-box helicase 43 (DDX43), developmental pluripotency associated 2 (DPPA2), fetal and adult testis expressed 1 (FATE 1), FMRI neighbor (FMR1NB), HORMA domain containing 1 (H0RMAD1), insulin like growth factor 2 mRNA binding protein 3 (IGF2BP3), leucine zipper protein 4 (LUZP4), lymphocyte antigen 6 family member K (LY6K), maelstrom30 spermatogenic transposon silencer (MAEL), MAGE family member Al (MAGEA1); MAGE family member A3 (MAGEA3); MAGE family member A4 (MAGEA4); MAGE family member Al 1 (MAGEA11); MAGE family member Cl (MAGECI); MAGE family member C2 (MAGEC2); MAGE family member DI (MAGED1); MAGE family member2024202988   06 May 2024D2 (MAGED2), kinesin family member 20B (KIF20B; a.k.a., MPHOSPH1), NUF2 component of NDC80 kinetochore complex (NUF2), nuclear RNA export factor 2 (NXF2), PAS domain containing repressor 1 (PASD1), PDZ binding kinase (PBK), piwi like RNA-mediated gene silencing 2 (PIWIL-2), preferentially expressed antigen in melanoma5 (PRAME), sperm associated antigen 9 (SPAG9), sperm protein associated with the nucleus, X-linked, family member Al (SPANXA1), SPANX family member A2 (SPANXA2), SPANX family member C (SPANXC), SPANX family member D (SPANXD), SSX family member 1 (SSX 1), SSX family member 2 (SSX2), synaptonemal complex protein 3 (SYCP3), testis expressed 14, intercellular bridge forming factor (TEX14), transcription10 factor Dp family member 3 (TFDP3), serine protease 50 (PRSS50, a.k.a., TSP50), TTK protein kinase (TTK) and zinc finger protein 165 (ZNF165).

191. The method or use of any one of claims 174 to 190, wherein the fusion protein, the homodimer, the heterodimer, the conjugate, the polynucleotide, the vector, the lipoplex (e.g., LNP) and / or the pharmaceutical composition is co-administered15   with a targeted E3 ligase ligand conjugate.

192. The method or use of any one of claims 174 to 191, wherein the fusion protein, the homodimer, the heterodimer, the conjugate, the polynucleotide, the vector, the lipoplex (e.g., LNP) and / or the pharmaceutical composition is co-administered with one or more additional therapeutic agents comprising an inhibitor or antagonist of:20                 • protein tyrosine phosphatase, non-receptor type 11 (PTPN11 or SHP2),• myeloid cell leukemia sequence 1 (MCL1) apoptosis regulator,• 5'-nucleotidase ecto (NT5E or CD73),• ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1 or CD39),• transforming growth factor beta 1 (TGFB1 or TGF0),25               • heme oxygenase 1 (HM0X1, HO-1 or HOI),• heme oxygenase 2 (HM0X2, HO-2 or HO2),• vascular endothelial growth factor A (VEGFA or VEGF),• erb-b2 receptor tyrosine kinase 2 (ERBB2, HER2, HER2 / neu or CD340),• epidermal growth factor receptor (EGFR, ERBB, ERBB1 or HER1),30                • ALK receptor tyrosine kinase (ALK, CD246),• poly(ADP-ribose) polymerase 1 (PARP1),• poly(ADP-ribose) polymerase 2 (PARP2),• TCDD inducible poly(ADP-ribose) polymerase (TIPARP, PARP7),2024202988   06 May 2024• cyclin dependent kinase 4 (CDK4),• cyclin dependent kinase 6 (CDK6),• TNF receptor superfamily member 14 (TNFRSF14, HVEM, CD270),• C-C motif chemokine receptor 2 (CCR2, CD 192),5                • C-C motif chemokine receptor 5 (CCR5, CD 195),• C-C motif chemokine receptor 8 (CCR8, CDwl98),• C-X-C motif chemokine receptor 2 (CXCR2, CD 182),• C-X-C motif chemokine receptor 3 (CXCR3, CD 182, CD 183),• C-X-C motif chemokine receptor 4 (CXCR4, CD 184),10                • arginase (ARG 1, ARG2),• carbonic anhydrase (CAI, CA2, CA3, CA4, CA5A, CA5B, CA6, CA7, CA8, CA9, CAIO, CA11, CA12, CAB, CAM),• prostaglandin-endoperoxide synthase 1 (PTGS1, COX-1),• prostaglandin-endoperoxide synthase 2 (PTGS2, COX-2),15                 • secreted phospholipase A2,• prostaglandin E synthase (PTGES, PGES),• arachidonate 5-lipoxygenase (ALOX5, 5-LOX),• soluble epoxide hydrolase 2 (EPHX2),• indoleamine 2,3-dioxygenase 1 (IDO1),20                 • indoleamine 2,3-dioxygenase 2 (IDO2),• hypoxia inducible factor 1 subunit alpha (HIF1A),• angiopoietin 1 (ANGPT1),• Endothelial TEK tyrosine kinase (TIE-2, TEK),• Janus kinase 1 (JAKI),25                • catenin beta 1 (CTNNB1),• histone deacetylase 9 (HDAC9),• 5'-3' exoribonuclease 1 (XRN1), and / or• WRN RecQ like helicase (WRN).

193. The method or use of claim 192, wherein the inhibitor comprises an30 antibody or an antigen-binding fragment thereof, or antibody-drug conjugate thereof, CD3-targeting multi-specific molecule, NK cell-activating receptor-targeting multi-specific molecule, non-immunoglobulin antigen binding molecule or antibody mimetic protein.2024202988   06 May 2024194. The method or use of claim 192, wherein the inhibitor comprises an inhibitory nucleic acid.

195. The method or use of claim 192, wherein the inhibitor comprises a small organic molecule.5                 196. The method or use of any one of claims 192 to 195, wherein theinhibitor of 5'-nucleotidase ecto (NT5E or CD73) is selected from the group consisting of MEDI9447 (oleclumab), CPI-006, BMS-986179, IPH5301, TJ4309 (TJD5), NZV-930, AB-680, PSB-12379, PSB-12441, PSB-12425, CB-708 and PBF-1662.

197. The method or use of any one of claims 192 to 195, wherein the10   inhibitor of CCR2 and / or CCR5 is selected from the group consisting of BMS-813160, PF-04136309 and CCX-872.

198. The method or use of any one of claims 192 to 195, wherein the inhibitor of MCL1 is selected from the group consisting of GS-9716, tapotoclax (AMG-176), AMG-397, S-64315, AZD-5991, 483-LM, A-1210477, UMI-77, JKY-5-037, APG-15   3526 and PRT-1419.

199. The method or use of any one of claims 192 to 195, wherein the inhibitor of PTPN11 or SHP2 is selected from the group consisting of TNO155 (SHP-099), RMC-4550, JAB-3068 and RMC-4630.

200. The method or use of any one of claims 192 to 195, wherein the20   inhibitor of Janus kinase 1 (JAKI) is selected from the group consisting of fdgotinib,tofacitinib, baricitinib and ABT-494.

201. The method or use of any one of claims 174 to 200, wherein the fusion protein, the homodimer, the heterodimer, the conjugate, the polynucleotide, the vector, the lipoplex (e.g., LNP) and / or the pharmaceutical composition is co-administered 25 with an oncolytic viral vector.

202. The method or use of claim 201, wherein the oncolytic viral vector comprises a DNA virus or a RNA virus.

203. The method or use of any one of claims 201 to 202, wherein the viral vector is from a viral family selected from the group consisting of: Adenoviridae (e.g.,30 Adenovirus), Arenaviridae (e.g., lymphocytic choriomeningitis mammarenavirus, Cali2024202988   06 May 2024mammarenavirus (a.k.a., Pichinde mammarenavirus), Poxviridae (e.g., Vaccinia virus), Herpesviridae (e.g., Herpesvirus, e.g., HSV-1), Parvoviridae (e.g., Parvovirus Hl), Reoviridae (e.g., Reovirus), Picornaviridae (e.g., Coxsackievirus, Seneca Valley Virus, Poliovirus), Paramyxoviridae (e.g., Measles virus, Newcastle disease virus (NDV)), 5 Rhabdoviridae (e.g., Vesicular stomatitis virus (VSV)), Togaviridae (e.g., Alphavirus, Sindbis virus), Enteroviridae (e.g., Echovirus).

204. The method or use of any one of claims 174 to 203, wherein the subject has cancer.

205. The method or use of any one of claims 174 to 204, wherein the10 subject is in cancer remission.

206. The method or use of any one of claims 174 to 205, wherein the subject has a hematological cancer, e.g., a leukemia (e.g., Acute Myelogenous Leukemia (AML), Acute Lymphoblastic Leukemia (ALL), B-cell ALL, Myelodysplastic Syndrome (MDS), myeloproliferative disease (MPD), Chronic Myelogenous Leukemia (CML),15 Chronic Lymphocytic Leukemia (CLL), undifferentiated leukemia), a lymphoma (e.g., small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), follicular lymphoma (FL), T-cell lymphoma, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), marginal zone lymphoma (MZL), Waldenstrom’s macroglobulinemia (WM)) and / or a myeloma (e.g., multiple myeloma (MM)).20                207. The method or use of any one of claims 174 to 206, wherein thesubject has a solid tumor.

208. The method or use of claim 207, wherein the tumor is a malignant tumor.

209. The method or use of any one of claims 207 to 208, wherein the25 tumor is a metastatic tumor.

210. The method or use of any one of claims 207 to 209, wherein the subject has a cancer selected from the group consisting of an epithelial tumor (e.g., a carcinoma, a squamous cell carcinoma, a basal cell carcinoma, a squamous intraepithelial neoplasia), a glandular tumor (e.g., an adenocarcinoma, an adenoma, an adenomyoma), a30 mesenchymal or soft tissue tumor (e.g., a sarcoma, a rhabdomyosarcoma, a leiomyosarcoma, a liposarcoma, a fibrosarcoma, a dermatofibrosarcoma, a2024202988   06 May 2024neurofibrosarcoma, a fibrous histiocytoma, an angiosarcoma, an angiomyxoma, a leiomyoma, a chondroma, a chondrosarcoma, an alveolar soft-part sarcoma, an epithelioid hemangioendothelioma, a Spitz tumor, a synovial sarcoma), and a lymphoma.

211. The method or use of any one of claims 207 to 210, wherein the5 subject has a solid tumor in or arising from a tissue or organ selected from the group consisting of:• bone (e.g., adamantinoma, aneurysmal bone cysts, angiosarcoma, chondroblastoma, chondroma, chondromyxoid fibroma, chondrosarcoma, chordoma, dedifferentiated chondrosarcoma, enchondroma, epithelioid hemangioendothelioma, fibrous dysplasia of10 the bone, giant cell tumour of bone, haemangiomas and related lesions, osteoblastoma, osteochondroma, osteosarcoma, osteoid osteoma, osteoma, periosteal chondroma, Desmoid tumor, Ewing sarcoma);• lips and oral cavity (e.g., odontogenic ameloblastoma, oral leukoplakia, oral squamous cell carcinoma, primary oral mucosal melanoma); salivary glands (e.g., pleomorphic15       salivary gland adenoma, salivary gland adenoid cystic carcinoma, salivary glandmucoepidermoid carcinoma, salivary gland Warthin's tumors);• esophagus (e.g., Barrett's esophagus, dysplasia and adenocarcinoma);• gastrointestinal tract, including stomach (e.g., gastric adenocarcinoma, primary gastric lymphoma, gastrointestinal stromal tumors (GISTs), metastatic deposits, gastric20 carcinoids, gastric sarcomas, neuroendocrine carcinoma, gastric primary squamous cell carcinoma, gastric adenoacanthomas), intestines and smooth muscle (e.g., intravenous leiomyomatosis), colon (e.g., colorectal adenocarcinoma), rectum, anus;• pancreas (e.g., serous neoplasms, including microcystic or macrocystic serous cystadenoma, solid serous cystadenoma, Von Hippel-Landau (VHL)-associated serous25 cystic neoplasm, serous cystadenocarcinoma; mucinous cystic neoplasms (MCN), intraductal papillary mucinous neoplasms (IPMN), intraductal oncocytic papillary neoplasms (IOPN), intraductal tubular neoplasms, cystic acinar neoplasms, including acinar cell cystadenoma, acinar cell cystadenocarcinoma, pancreatic adenocarcinoma, invasive pancreatic ductal adenocarcinomas, including tubular adenocarcinoma,30 adenosquamous carcinoma, colloid carcinoma, medullary carcinoma, hepatoid carcinoma, signet ring cell carcinoma, undifferentiated carcinoma, undifferentiated carcinoma with osteoclast-like giant cells, acinar cell carcinoma, neuroendocrine neoplasms, neuroendocrine microadenoma, neuroendocrine tumors (NET), neuroendocrine carcinoma (NEC), including small cell or large cell NEC, insulinoma,2024202988   06 May 2024gastrinoma, glucagonoma, serotonin-producing NET, somatostatinoma, VIPoma, solid-pseudopapillary neoplasms (SPN), pancreatoblastoma);• gall bladder (e.g. carcinoma of the gallbladder and extrahepatic bile ducts, intrahepatic cholangiocarcinoma);5   • neuro-endocrine (e.g., adrenal cortical carcinoma, carcinoid tumors,phaeochromocytoma, pituitary adenomas);• thyroid (e.g., anaplastic (undifferentiated) carcinoma, medullary carcinoma, oncocytic tumors, papillary carcinoma, adenocarcinoma);• liver (e.g., adenoma, combined hepatocellular and cholangiocarcinoma, fibrolamellar 10       carcinoma, hepatoblastoma, hepatocellular carcinoma, mesenchymal, nested stromalepithelial tumor, undifferentiated carcinoma; hepatocellular carcinoma, intrahepatic cholangiocarcinoma, bile duct cystadenocarcinoma, epithelioid hemangioendothelioma, angiosarcoma, embryonal sarcoma, rhabdomyosarcoma, solitary fibrous tumor, teratoma, York sac tumor, carcinosarcoma, rhabdoid tumor);15   • kidney (e.g., ALK-rearranged renal cell carcinoma, chromophobe renal cell carcinoma,clear cell renal cell carcinoma, clear cell sarcoma, metanephric adenoma, metanephric adenofibroma, mucinous tubular and spindle cell carcinoma, nephroma, nephroblastoma (Wilms tumor), papillary adenoma, papillary renal cell carcinoma, renal oncocytoma, renal cell carcinoma, succinate dehydrogenase-deficient renal cell carcinoma, collecting20 duct carcinoma);• breast (e.g., invasive ductal carcinoma, including without limitation, acinic cell carcinoma, adenoid cystic carcinoma, apocrine carcinoma, cribriform carcinoma, glycogen-rich / clear cell, inflammatory carcinoma, lipid-rich carcinoma, medullary carcinoma, metaplastic carcinoma, micropapillary carcinoma, mucinous carcinoma, 25 neuroendocrine carcinoma, oncocytic carcinoma, papillary carcinoma, sebaceous carcinoma, secretory breast carcinoma, tubular carcinoma; lobular carcinoma, including without limitation, pleomorphic carcinoma, signet ring cell carcinoma,• peritoneum (e.g., mesothelioma; primary peritoneal cancer);• female sex organ tissues, including ovary (e.g., choriocarcinoma, epithelial tumors, 30 germ cell tumors, sex cord-stromal tumors), Fallopian tubes (e.g., serous adenocarcinoma, mucinous adenocarcinoma, endometrioid adenocarcinoma, clear cell adenocarcinoma, transitional cell carcinoma, squamous cell carcinoma, undifferentiated carcinoma, Mullerian tumors, adenosarcoma, leiomyosarcoma, teratoma, germ cell tumors, choriocarcinoma, trophoblastic tumors), uterus (e.g., carcinoma of the cervix, 35 endometrial polyps, endometrial hyperplasia, intraepithelial carcinoma (EIC),2024202988   06 May 2024endometrial carcinoma (e.g., endometrioid carcinoma, serous carcinoma, clear cell carcinoma, mucinous carcinoma, squamous cell carcinoma, transitional carcinoma, small cell carcinoma, undifferentiated carcinoma, mesenchymal neoplasia), leiomyoma (e.g., endometrial stromal nodule, leiomyosarcoma, endometrial stromal sarcoma (ESS), 5 mesenchymal tumors), mixed epithelial and mesenchymal tumors (e.g., adenofibroma, carcinofibroma, adenosarcoma, carcinosarcoma (malignant mixed mesodermal sarcoma - MMMT)), endometrial stromal tumors, endometrial malignant mullerian mixed tumours, gestational trophoblastic tumors (partial hydatiform mole, complete hydatiform mole, invasive hydatiform mole, placental site tumour)), vulva, vagina;10   • male sex organ tissues, including prostate, testis (e.g., germ cell tumors, spermatocyticseminoma), penis;• bladder (e.g., squamous cell carcinoma, urothelial carcinoma, bladder urothelial carcinoma);• brain, (e.g., gliomas (e.g., astrocytomas, including non-infiltrating, low-grade,15 anaplastic, glioblastomas; oligodendrogliomas, ependymomas), meningiomas, gangliogliomas, schwannomas (neurilemmomas), craniopharyngiomas, chordomas, Non-Hodgkin lymphomas (NHLs), indolent non-Hodgkin’s lymphoma (iNHL), refractory iNHL, pituitary tumors;• eye (e.g., retinoma, retinoblastoma, ocular melanoma, posterior uveal melanoma, iris 20 hamartoma);• head and neck (e.g., nasopharyngeal carcinoma, Endolymphatic Sac Tumor (ELST), epidermoid carcinoma, laryngeal cancers including squamous cell carcinoma (SCC) (e.g., glottic carcinoma, supraglottic carcinoma, subglottic carcinoma, transglottic carcinoma), carcinoma in situ, verrucous, spindle cell and basaloid SCC,25 undifferentiated carcinoma, laryngeal adenocarcinoma, adenoid cystic carcinoma, neuroendocrine carcinomas, laryngeal sarcoma), head and neck paragangliomas (e.g., carotid body, jugulotympanic, vagal);• thymus (e.g., thymoma);• heart (e.g., cardiac myxoma);30   • lung (e.g, small cell carcinoma (SCLC), non-small cell lung carcinoma (NSCLC),including squamous cell carcinoma (SCC), adenocarcinoma and large cell carcinoma, carcinoids (typical or atypical), carcinosarcomas, pulmonary blastomas, giant cell carcinomas, spindle cell carcinomas, pleuropulmonary blastoma);• lymph (e.g, lymphomas, including Hodgkin’s lymphoma, non-Hodgkin’s lymphoma35 (NHL), indolent non-Hodgkin’s lymphoma (iNHL), refractory iNHL, Epstein-Barr virus2024202988   06 May 2024(EBV)-associated lymphoproliferative diseases, including B cell lymphomas and T cell lymphomas (e.g., Burkitt lymphoma; large B cell lymphoma, diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, indolent B-cell lymphoma, low grade B cell lymphoma, fibrin-associated diffuse large cell lymphoma; primary effusion5 lymphoma; plasmablastic lymphoma; extranodal NK / T cell lymphoma, nasal type; peripheral T cell lymphoma, cutaneous T cell lymphoma, angioimmunoblastic T cell lymphoma; follicular T cell lymphoma; systemic T cell lymphoma), lymphangioleiomyomatosis);• central nervous system (CNS) (e.g., gliomas including astrocytic tumors (e.g., pilocytic 10       astrocytoma, pilomyxoid astrocytoma, subependymal giant cell astrocytoma,pleomorphic xanthoastrocytoma, diffuse astrocytoma, fibrillary astrocytoma, gemistocytic astrocytoma, protoplasmic astrocytoma, anaplastic astrocytoma, glioblastoma (e.g., giant cell glioblastoma, gliosarcoma, glioblastoma multiforme) and gliomatosis cerebri), oligodendroglial tumors (e.g., oligodendroglioma, anaplastic15 oligodendroglioma), oligoastrocytic tumors (e.g., oligoastrocytoma, anaplastic oligoastrocytoma), ependymal tumors (e.g., subependymom, myxopapillary ependymoma, ependymomas (e.g., cellular, papillary, clear cell, tanycytic), anaplastic ependymoma), optic nerve glioma, and non-gliomas (e.g., choroid plexus tumors, neuronal and mixed neuronal-glial tumors, pineal region tumors, embryonal tumors,20 medulloblastoma, meningeal tumors, primary CNS lymphomas, germ cell tumors, Pituitary adenomas, cranial and paraspinal nerve tumors, stellar region tumors); neurofibroma, meningioma, peripheral nerve sheath tumors, peripheral neuroblastic tumours (including without limitation neuroblastoma, ganglioneuroblastoma, ganglioneuroma), trisomy 19 ependymoma);25   • neuroendocrine tissues (e.g., paraganglionic system including adrenal medulla(pheochromocytomas) and extra-adrenal paraganglia ((extra-adrenal) paragangliomas);• skin (e.g., clear cell hidradenoma, cutaneous benign fibrous histiocytomas, cylindroma, hidradenoma, melanoma (including cutaneous melanoma, mucosal melanoma), pilomatricoma, Spitz tumors); and30   • soft tissues (e.g., aggressive angiomyxoma, alveolar rhabdomyosarcoma, alveolar softpart sarcoma, angiofibroma, angiomatoid fibrous histiocytoma, synovial sarcoma, biphasic synovial sarcoma, clear cell sarcoma, dermatofibrosarcoma protuberans, desmoid-type fibromatosis, small round cell tumor, desmoplastic small round cell tumor, elastofibroma, embryonal rhabdomyosarcoma, Ewing's tumors / primitive35 neurectodermal tumors (PNET), extraskeletal myxoid chondrosarcoma, extraskeletal2024202988   06 May 2024osteosarcoma, paraspinal sarcoma, inflammatory myofibroblastic tumor, lipoblastoma, lipoma, chondroid lipoma, liposarcoma / malignant lipomatous tumors, liposarcoma, myxoid liposarcoma, fibromyxoid sarcoma, lymphangioleiomyoma, malignant myoepithelioma, malignant melanoma of soft parts, myoepithelial carcinoma,5 myoepithelioma, myxoinflammatory fibroblastic sarcoma, undifferentiated sarcoma, pericytoma, rhabdomyosarcoma, non-rhabdomyosarcoma soft tissue sarcoma (NRSTS), soft tissue leiomyosarcoma, undifferentiated sarcoma, well-differentiated liposarcoma.

212. The method or use of any one of claims 207 to 211, wherein the subject has a hematological cancer selected from the group consisting of melanoma,10 leukemia, acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL); lymphoma; B-cell Non-Hodgkin Lymphoma; and multiple myeloma (MM); or a solid tumor cancer selected from the group consisting of melanoma; head and neck; ovarian; mesothelioma; endometrial; prostate; sarcoma; neuroblastoma; liver; lung; breast; esophageal, gastric and pancreatic.15                213. The method or use of any one of claims 207 to 212, wherein thesubject has a cancer selected from the group consisting of a lung cancer, a colorectal cancer, a breast cancer, a prostate cancer, a cervical cancer and a head and neck cancer.

214. The method or use of any one of claims 174 to 213, wherein the subject is naive to or has not received chemotherapy.20                215. The method or use of any one of claims 174 to 214, wherein thesubject has received a lymphodepleting chemotherapy regimen.

216. The method or use of any one of claims 174 to 214, wherein the subject has bone marrow cells, or is not depleted of bone marrow cells.

217. The method or use of any one of claims 129 to 216, wherein the25 fusion protein, the homodimer, the heterodimer, the conjugate, the polynucleotide, the vector, the lipoplex (e.g., LNP) and / or the pharmaceutical composition is co-administered with one or more additional therapeutic agents.

218. The method or use of claim 217, comprising co-administering one or more agonists or activators of one or more toll-like receptors (TLRs).2024202988   06 May 2024219. The method or use of claim 218, wherein the TLR agonist or activator is selected from the group consisting of a TLR2 agonist, a TLR3 agonist, a TLR4 agonist, a TLR5 agonist, a TLR7 agonist, a TLR8 agonist and a TLR9 agonist.

220. The method or use of any one of claims 218 to 219, wherein the5 TLR7 agonist is selected from the group consisting of GS 9620 (vesatolimod), R848 (Resiquimod), DS-0509, LHC-165, TMX-101 (imiquimod), RO7020531 and JNJ-4964, and / or wherein the TLR8 agonist is selected from the group consisting of selgantolimod (GS-9688), R848 (Resiquimod) andNKTR-262 (dual TLR7 / TLR8 agonist).

221. The method or use of any one of claims 129 to 220, wherein the10   cytokine or chemokine therapy comprises co-administering one or more immunostimulatorycytokines or chemokines that promote or increase the proliferation or activation of a / p T cells, y / 5 T cells, NK-T cells, NK cells, and / or dendritic cells.

222. The method or use of claim 221, wherein the one or more immunostimulatory cytokines or chemokines are selected from the group consisting of: IL-15   10, IL-12, IL-18, gamma chain-dependent cytokines (e.g., IL-4, IL-7, IL-9, IL-15 and IL-21), fms related tyrosine kinase 3 (FLT3) ligand (FLT3L), interferon (IFN)-a, IFN-P, a PEGylated interferon (e.g., PEG-IFN-a2a and / or PEG-IFN-a2b), IFN-y, CXCL9 / Mig (monokine induced by interferon-y), CXCL10 / IP10 (interferon-y-inducible 10 kDa protein) and CXCL11 / I-TAC (interferon-inducible T cell a-chemoattractant), CXCL4 / PF4 (platelet20 factor 4), monocyte chemoattractant protein 2 (MCP-2), macrophage inflammatory protein 1 alpha (MIP-la), macrophage inflammatory protein 1 beta (MIP-ip) and regulated on activation normal T expressed and secreted protein (RANTES).

223. The method or use of any one of claims 129 to 222, comprising coadministering one or more interleukin receptor agonists of an interleukin receptor selected25 from IL-10, IL-12, IL-18 and gamma chain-dependent cytokines (e.g., IL-4, IL-7, IL-9, IL-15 and IL-21).

224. The method or use of claim 223, comprising co-administering one or more cytokines selected from the group consisting of IL-10, IL-12, IL-18, gamma chaindependent cytokines (e.g., IL-4, IL-7, IL-9, IL-15 and IL-21), IFN-a, IFN-P, a PEGylated30 interferon (e.g., PEG-IFN-a2a and / or PEG-IFN-a2b), IFN-y, and variants thereof.

225. The method or use of any one of claims 129 to 224, comprising coadministering one or more innate immune activators.2024202988   06 May 2024226. The method or use of claim 225, wherein the one or more innate immune activators comprises an agonist of a receptor selected from the group consisting of fms related tyrosine kinase 3 (FLT3), stimulator of interferon genes (STING) receptor, DExD / H-box helicase 58 (DDX58; a.k.a., RIG-I), NLR family pyrin domain containing 3 5 (NLRP3) and nucleotide binding oligomerization domain containing 2 (NOD2).

227. The method or use of any one of claims 225 to 226, comprising coadministering one or both of GS-3583 and GS-9992.

228. The method or use of any one of claims 129 to 227, wherein the fusion protein, the homodimer, the heterodimer, the conjugate, the polynucleotide, the10 vector, the lipoplex (e.g., LNP) and / or the pharmaceutical composition is co-administered with an immunotherapy, an immunostimulatory therapy, a cytokine therapy, a chemokine therapy, a cellular therapy, a gene therapy, and combinations thereof.

229. The method or use of claim 228, wherein the immunotherapy comprises co-administering one or more antagonists or inhibitors of an inhibitory immune 15 checkpoint protein or receptor and / or one or more activators or agonists of a stimulatory immune checkpoint protein or receptor.

230. The method or use of claim 229, wherein the one or more immune checkpoint proteins or receptors are selected from the group consisting of: CD27, CD70; CD40, CD40LG; CD47, CD48 (SLAMF2), transmembrane and immunoglobulin domain20 containing 2 (TMIGD2, CD28H), CD84 (LY9B, SLAMF5), CD96, CD 160 (NK1, NK28, BY55), MS4A1 (CD20), CD244 (SLAMF4); CD276 (B7H3); V-set domain containing T cell activation inhibitor 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); natural killer cell cytotoxicity receptor 3 ligand 1 (NCR3LG1, B7H6); HERV-H LTR-associating 2 (HHLA2,25   B7H7); inducible T cell co-stimulator (ICOS, CD278); inducible T cell costimulator ligand(ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF8 (CD30), TNFSF8 (CD30L); TNFRSF10A (CD261, DR4, TRAILRI), TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF10B (CD262, DR5, TRAILR2), TNFRSF10 (TRAIL); TNFRSF14 (HVEM,30   CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte associated (BTLA));TNFRSF17 (BCMA, CD269), TNFSF 13B (BAFF); TNFRSF18 (GITR), TNFSF 18 (GITRL); MHC class I polypeptide-related sequence A (MICA); MHC class I polypeptide-related sequence B (MICB); CD274 (CD274, PDL1, PD-L1); programmed cell death 12024202988   06 May 2024(PDCD1, PD1, PD-1); cytotoxic T-lymphocyte associated protein 4 (CTLA4, CD 152);CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); Poliovirus receptor (PVR) cell adhesion molecule (PVR, CD 155); PVR related immunoglobulin domain containing (PVRIG, CD112R); T cell immunoreceptor with Ig and 5 ITIM domains (TIGIT); T cell immunoglobulin and mucin domain containing 4 (TIMD4;TIM4); hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3); galectin 9 (LGALS9); lymphocyte activating 3 (LAG3, CD223); signaling lymphocytic activation molecule family member 1 (SLAMF1, SLAM, CD150); lymphocyte antigen 9 (LY9, CD229, SLAMF3); SLAM family member 6 (SLAMF6, CD352); SLAM family member 7 10 (SLAMF7, CD319); sialic acid binding Ig like lectin 7 (SIGLEC7); sialic acid binding Ig like lectin 9 (SIGLEC9); UL16 binding protein 1 (ULBP1); UL16 binding protein 2 (ULBP2); UL16 binding protein 3 (ULBP3); retinoic acid early transcript IE (RAET1E;ULBP4); retinoic acid early transcript IG (RAET1G; ULBP5); retinoic acid early transcript IL (RAET1L; ULBP6); killer cell immunoglobulin like receptor, three Ig domains and long 15 cytoplasmic tail 1 (KIR, CD158E1); CD160; killer cell lectin like receptor Bl (KLRB1,CD161); killer cell lectin like receptor Cl (KLRC1, NKG2A, CD159A); killer cell lectin like receptor KI (KLRK1, NKG2D, CD314); killer cell lectin like receptor C2 (KLRC2, CD 159c, NKG2C); killer cell lectin like receptor C3 (KLRC3, NKG2E); killer cell lectin like receptor C4 (KLRC4, NKG2F); killer cell immunoglobulin like receptor, two Ig 20 domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin like receptor DI (KLRD1); killer cell lectin like receptor G1 (KLRG1;25 CLEC15A, MAFA, 2F1); sialic acid binding Ig like lectin 7 (SIGLEC7); and sialic acid binding Ig like lectin 9 (SIGLEC9).

231. The method or use of any one of claims 228 to 230, wherein the immunotherapy comprises co-administering one or more blockers or inhibitors of one or more T-cell inhibitory immune checkpoint proteins or receptors.30                 232. The method or use of claim 231, wherein the T-cell inhibitoryimmune checkpoint proteins or receptors are selected from the group consisting of CD274 (CD274, PDL1, PD-L1); programmed cell death 1 ligand 2 (PDCD1LG2, PD-L2, CD273); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T-lymphocyte associated protein 4 (CTLA4, CD152); CD276 (B7H3); V-set domain containing T cell activation inhibitor 12024202988   06 May 2024(VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte associated (BTLA)); PVR relatedimmunoglobulin domain containing (PVRIG, CD112R); T cell immunoreceptor with Ig and5 ITIM domains (TIGIT); lymphocyte activating 3 (LAG3, CD223); hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3); galectin 9 (LGALS9); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1);killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 210 (KIR2DL2); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); and killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1).

233. The method or use of any one of claims 228 to 232, wherein the immunotherapy comprises co-administering one or more agonists or activators of one or15 more T-cell stimulatory immune checkpoint proteins or receptors.

234. The method or use of claim 233, wherein the T-cell stimulatory immune checkpoint proteins or receptors are selected from the group consisting of CD27, CD70; CD40, CD40LG; inducible T cell costimulator (ICOS, CD278); inducible T cell costimulator ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, 20   OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF9 (CD 137), TNFSF9(CD137L); TNFRSF18 (GITR), TNFSF18 (GITRL); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); Poliovirus receptor (PVR) cell adhesion molecule (PVR, CD 155).

235. The method or use of any one of claims 228 to 234, wherein the25 immunotherapy comprises co-administering one or more blockers or inhibitors of one or more NK-cell inhibitory immune checkpoint proteins or receptors.

236. The method or use of claim 235, wherein the NK-cell inhibitory immune checkpoint proteins or receptors are selected from the group consisting of killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR,30   CD158E1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmictail 1 (KIR2DL1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); killer cell immunoglobulin like receptor, three Ig2024202988   06 May 2024domains and long cytoplasmic tail 1 (KIR3DL1); CD 160; killer cell lectin like receptor Bl (KLRB1, CD161); killer cell lectin like receptor Cl (KLRC1, NKG2A, CD159A); killer cell lectin like receptor DI (KLRD1, CD94), killer cell lectin like receptor G1 (KLRG1;CLEC15A, MAFA, 2F1); sialic acid binding Ig like lectin 7 (SIGLEC7); and sialic acid5 binding Ig like lectin 9 (SIGLEC9).

237. The method or use of any one of claims 228 to 236, wherein the immunotherapy comprises co-administering one or more agonists or activators of one or more NK-cell stimulatory immune checkpoint proteins or receptors.

238. The method or use of claim 237, wherein the NK-cell stimulatory10 immune checkpoint proteins or receptors are selected from CD 16, CD226 (DNAM-1); killer cell lectin like receptor KI (KLRK1, NKG2D, CD314); and SLAM family member 7 (SLAMF7).

239. The method or use of any one of claims 229 to 238, wherein the one or more immune checkpoint inhibitors comprises a proteinaceous (e.g., antibody) inhibitor15 of PD-L1 (CD274), PD-1 (PDCD1) or CTLA4.

240. The method or use of any one of claims 229 to 239, wherein the one or more immune checkpoint proteins or receptors are selected from the group consisting of: CD274 (CD274, PDL1, PD-L1) and programmed cell death 1 (PDCD1, PD1, PD-1).

241. The method or use of claim 239, wherein the proteinaceous (e.g.,20   antibody) inhibitor of CTLA4 is selected from the group consisting of ipilimumab,tremelimumab, BMS-986218, AGEN1181, AGEN1884 (zalifrelimab), BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002, BCD-145, APL-509, JS-007, BA-3071, ONC-392, AGEN-2041, JHL-1155, KN-044, CG-0161, ATOR-1144, PBI-5D3H5, FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-019 (PD-1 / CTLA4), KN-04625   (PD-1 / CTLA4), MEDI-5752 (CTLA4 / PD-1), XmAb-20717 (PD-1 / CTLA4) and AK-104(CTLA4 / PD-1).

242. The method or use of claim 239 or claim 240, wherein the proteinaceous (e.g., antibody) inhibitor of programmed cell death 1 (PDCD1; NCBI Gene ID: 5133; CD279, PD-1, PD1) is selected from the group consisting of zimberelimab30   (AB122, GLS-010, WBP-3055), pembrolizumab (KEYTRUDA®, MK-3475, SCH900475),nivolumab (OPDIVO®, BMS-936558, MDX-1106), cemiplimab (LIBTAYO®;cemiplimab-rwlc, REGN-2810), pidilizumab (CT-011), AMG-404, MEDI0680 (AMP-514),2024202988   06 May 2024spartalizumab (PDR001), tislelizumab (BGB-A317), toripalimab (JS-001), genolimzumab (CBT-501, APL-501, GB 226), SHR-1201, camrelizumab (SHR-1210), sintilimab (TYVYT®; IBI-308), dostarlimab (TSR-042, WBP-285), lambrolizumab (MK-3475); sasanlimab (PF-06801591), cetrelimab (JNJ-63723283), serplulimab (HLX-10),5 retifanlimab (MGA-012), balstilimab (AGEN2034), prolgolimab (BCD 100), budigalimab (ABBV-181), vopratelimab (JTX-4014), AK-103 (HX-008), AK-105, CS-1003, BI-754091, LZM-009, Sym-021, BAT-1306, PD1-PIK, tebotelimab (MGD013; PD-l / LAG-3), RO-7247669 (PD-l / LAG-3), FS-118 (LAG-3 / PD-L1), RO-7121661 (PD-l / TIM-3), RG7769 (PD-l / TIM-3), PF-06936308 (PD-1 / CTLA4), MGD-019 (PD-1 / CTLA4), KN-04610   (PD-1 / CTLA4), XmAb-20717 (PD-1 / CTLA4), AK-104 (CTLA4 / PD-1) and MEDI-5752(CTLA4 / PD-1).

243. The method or use of claim 239 or claim 240, wherein the proteinaceous (e.g., antibody) inhibitor of CD274 molecule (NCBI Gene ID: Gene ID: 29126; B7-H, B7H1, PD-L1) is selected from the group consisting of atezolizumab15 (TECENTRIQ®), avelumab (BAVENCIO®; MSB0010718C), envafolimab (ASC22), durvalumab (IMFINZI®; MEDI-4736), BMS-936559 (MDX1105), cosibelimab (CK-301), lodapolimab (LY 3300054), garivulimab (BGB A333), envafolimab (KN035), opucolimab (HLX 20), manelimab (BCD 135), CX-072, CBT-502 (TQB2450), MSB-2311, SHR-1316, sugemalimab (CS-1001; WBP3155), A167 (KL-A167, HBM 9167), STI-A1015 (IMC-001),20   FAZ-053, BMS-936559 (MDX1105), INCB086550, GEN-1046 (PD-L1 / 4-1BB), FPT-155(CTLA4 / PD-L1 / CD28), M7824 (PD-Ll / TGFp-EC domain), CA-170 (PD-L1 / VISTA), CDX-527 (CD27 / PD-L1), LY-3415244 (TIM-3 / PDL1), INBRX-105 (4-1BB / PDL1) and GNS-1480 (PD-L1 / EGFR).

244. The method or use of any one of claims 229 to 238, wherein the one 25 or more immune checkpoint inhibitors comprises a small molecule inhibitor of CD274(PDL1, PD-L1), programmed cell death 1 (PDCD1, PD1, PD-1) or CTLA4.

245. The method or use of claim 244, wherein the small molecule inhibitor of CD274 or PDCD1 is selected from the group consisting of GS-4224, GS-4416, INCB086550 and MAX10181.30                 246. The method or use of claim 244, wherein the small molecule inhibitorof CTLA4 comprises BPI-002.2024202988   06 May 2024247. The method or use of any one of claims 228 to 246, wherein the immunotherapy comprises co-administering one or more agents that selectively deplete regulatory T (Treg) cells.

248. The method or use of claim 247, wherein the one or more agents that5 selectively deplete effector regulatory T (Treg) cells comprise an antibody or antigenbinding fragment thereof that selectively binds to a cell surface receptor selected from the group consisting of C-C motif chemokine receptor 4 (CCR4), C-C motif chemokine receptor 7 (CCR7), C-C motif chemokine receptor 8 (CCR8), C-X-C motif chemokine receptor 4 (CXCR4; CD 184), TNFRSF4 (OX40), TNFRSF18 (GITR, CD357), TNFRSF910   (4-1BB, CD137), cytotoxic T-lymphocyte associated protein 4 (CTLA4, CD152),programmed cell death 1 (PDCD1, PD-1), Sialyl Lewis x (CD 15s), CD27, ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1; CD39), protein tyrosine phosphatase receptor type C (PTPRC; CD45), neural cell adhesion molecule 1 (NCAM1; CD56), selectin L (SELL; CD62L), integrin subunit alpha E (ITGAE; CD 103), interleukin 7 receptor (IL7R;15   CD127), CD40 ligand (CD40LG; CD154), folate receptor alpha (FOLRI), folate receptorbeta (FOLR2), leucine rich repeat containing 32 (LRRC32; GARP), IKAROS family zinc finger 2 (IKZF2; HELIOS), inducible T cell costimulatory (ICOS; CD278), lymphocyte activating 3 (LAG3; CD223), transforming growth factor beta 1 (TGFB1), hepatitis A virus cellular receptor 2 (HAVCR2; CD366; TIM3), T cell immunoreceptor with Ig and ITIM20 domains (TIGIT), TNF receptor superfamily member IB (CD 120b; TNFR2), IL-2RA (CD25), and combinations thereof.

249. The method or use of any one of claims 228 to 248, wherein the immunotherapy comprises co-administering one or more agents that selectively deplete suppressive myeloid cells.25                250. The method or use of claim 249, wherein the suppressive myeloidcells are selected from tumor-associated macrophages (TAM) and myeloid derived suppressor cells (MDSC).

251. The method or use of any one of claims 249 to 250, wherein the one or more agents that selectively deplete suppressive myeloid cells comprise an antibody or 30 antigen-binding fragment thereof that selectively binds to a cell surface receptor selected from the group consisting of colony stimulating factor 1 receptor (CSF1R), C-C motif chemokine receptor 2 (CCR2), C-C motif chemokine ligand 2 (CCL2), triggering receptor2024202988   06 May 2024expressed on myeloid cells 2 (TREM2), complement C5a receptor 1 (C5AR1), and mixtures thereof.

252. The method or use of any one of claims 249 to 251, wherein the one or more agents that selectively deplete suppressive myeloid cells comprise an agent that5 inhibits nuclear receptor subfamily 1 group H member 3 (NR1H3; LXRA) or nuclear receptor subfamily 1 group H member 2 (NR1H2; LXRB).

253. The method or use of any one of claims 129 to 252, wherein the fusion protein, the homodimer, the heterodimer, the conjugate, the polynucleotide, the vector, the lipoplex (e.g., LNP) and / or the pharmaceutical composition is co-administered 10   with one or more additional therapeutic agents comprising an inhibitor or antagonist of:• mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1) (also called Hematopoietic Progenitor Kinase 1 (HPK1)),• phosphatidylinositol-4,5-bisphosphate 3-kinase, including catalytic subunit alpha (PIK3CA), catalytic subunit beta (PIK3CB), catalytic15                    subunit gamma (PIK3CG) and catalytic subunit delta (PIK3CD),• diacylglycerol kinase alpha (DGKA, DAGK, DAGK1 or DGK-alpha),• T cell immunoreceptor with Ig and ITIM domains (TIGIT),• X-linked inhibitor of apoptosis (XIAP, BIRC4, IAP-3),• baculoviral IAP repeat containing 2 (BIRC2, cIAPl),20                 • baculoviral IAP repeat containing 3 (BIRC3, cIAP2),• baculoviral IAP repeat containing 5 (BIRC5, survivin), or• cytokine inducible SH2 containing protein (CISH).

254. The method or use of any one of claims 129 to 253, wherein the fusion protein, the homodimer, the heterodimer, the conjugate, the polynucleotide, the25 vector, the lipoplex (e.g., LNP) and / or the pharmaceutical composition is co-administered with one or more additional therapeutic agents comprising an activator or agonist of:• a toll-like receptor (TLR);• a stimulator of interferon genes (STING) receptor;• inducible T cell costimulator (ICOS, CD278); and / or30                • a TNF receptor superfamily (TNFRSF) member.

255. The method or use of claim 254, wherein the TNF receptor superfamily (TNFRSF) member is selected from the group consisting of: TNFRSF 1 A,2024202988   06 May 2024TNFRSF1B, TNFRSF4 (0X40), TNFRSF5 (CD40), TNFRSF6 (FAS), TNFRSF7 (CD27), TNFRSF8 (CD30), TNFRSF9 (4-1BB, CD137), TNFRSF10A (CD261, DR4, TRAILRI), TNFRSF10B (CD262, DR5, TRAILR2), TNFRSF10C (CD263, TRAILR3), TNFRSF10D (CD264, TRAILR4), TNFRSF11A (CD265, RANK), TNFRSF1 IB, TNFRSF12A (CD266), 5 TNFRSF13B (CD267), TNFRSF13C (CD268), TNFRSF16 (NGFR, CD271), TNFRSF17(BCMA, CD269), TNFRSF18 (GITR, CD357), TNFRSF19, TNFRSF21 (CD358, DR6), and TNFRSF25 (DR3).

256. The method or use of any one of claims 254 to 255, wherein:• the TNFRSF4 (OX40 or CD 134) activator or agonist comprises10                  INCAGN1949, tavolimab (MEDI0562), pogalizumab(MOXR0916 / RG7888), MEDI6469, BMS-986178, PF-04518600, GSK3174998, IBI101, ATOR-1015, ABBV-368 or SL-279252;• the TNFRSF9 (4-IBB or CD 137) activator or agonist comprises urelumab, BMS-663513, utomilumab (PF-05082566), CTX-471, MP-15                  0310, ADG-106, ATOR-1017, AGEN2373 or QL1806; and / or• the TNFRSF18 (GITR or CD357) activator or agonist comprises GWN323, MEDI1873, MK-1248, MK-4166, TRX518, INCAGN1876, BMS-986156, BMS-986256, AMG-228, ASP1951 (PTZ 522), FPA-154 or OMP-336B11.20                257. The method or use of any one of claims 254 to 256, comprising coadministering a molecule that concurrently binds to TNF receptor superfamily member 4 (TNFRSF4, OX40 or CD134) and TNF receptor superfamily member 18 (TNFRSF18, GITR or CD357).

258. The method or use of any one of claims 254 to 257, comprising co-25 administering a molecule selected from the group consisting of AGEN1884 (zalifrelimab), AGEN1181, AGEN 2034 (balstilimab), AGEN1307, AGEN1327, AGEN1777, AGEN2373, AGEN1223 and GS-1423.

259. The method or use of any one of claims 129 to 258, wherein the fusion protein, the homodimer, the heterodimer, the conjugate, the polynucleotide, the30 vector, the lipoplex (e.g., LNP) and / or the pharmaceutical composition are administered systemically or locally.2024202988   06 May 2024260. The method or use of any one of claims 129 to 259, wherein the fusion protein, the homodimer, the heterodimer, the conjugate, the polynucleotide, the vector, the lipoplex (e.g., LNP) and / or the pharmaceutical composition are administered via a route selected from intravenous, subcutaneous, intramuscular, intradermal, intratumoral5 and mucosal (e.g. buccal, intranasal, intrarectal, intravaginal).

261. The method or use of any one of claims 129 to 260, wherein the fusion protein, the homodimer, the heterodimer, the conjugate, the polynucleotide, the vector, the lipoplex (e.g., LNP) and / or the pharmaceutical composition and the one or more additional therapeutic agents are administered by the same routes of administration.10                262. The method or use of any one of claims 129 to 260, wherein thefusion protein, the homodimer, the heterodimer, the conjugate, the polynucleotide, the vector, the lipoplex (e.g., LNP) and / or the pharmaceutical composition and the one or more additional therapeutic agents are administered by different routes of administration.

263. The method or use of any one of claims 129 to 262, wherein the 15 fusion protein, the homodimer, the heterodimer, the conjugate, the polynucleotide, the vector, the lipoplex (e.g., LNP) and / or the pharmaceutical composition and the one or more additional therapeutic agents are co-administered according to the same schedule (e.g., coadministered at the same time intervals).

264. The method or use of any one of claims 129 to 262, wherein the20 fusion protein, the homodimer, the heterodimer, the conjugate, the polynucleotide, the vector, the lipoplex (e.g., LNP) and / or the pharmaceutical composition and the one or more additional therapeutic agents are co-administered according to different schedules (e.g., coadministered at different time intervals).

265. The method or use of any one of any one of claims 129 to 264, 25 wherein the fusion protein, the homodimer, the heterodimer, the conjugate, thepolynucleotide, the vector, the lipoplex (e.g., LNP) and / or the pharmaceutical composition is administered at a dose in the range of 0.5 pg / kg to 1000 pg / kg, e.g., in the range of from 1 pg / kg to 500 pg / kg, e.g., in the range of from 10 pg / kg to 300 pg / kg, e.g., in the range of from 30 pg / kg to 600 pg / kg, e.g., at least 0.5 pg / kg per dose and up to 0.2 pg / kg, 0.3 pg / kg, 30   0.4 pg / kg, 0.5 pg / kg, 0.6 pg / kg, 0.7 pg / kg, 0.8 pg / kg, 0.9 pg / kg, 1 pg / kg, 1.5 pg / kg, 2 pg / kg,2.5 pg / kg, 3 pg / kg, 3.5 pg / kg, 4 pg / kg, 4.5 pg / kg, 5 pg / kg, 6 pg / kg, 7 pg / kg, 8 pg / kg, 9 pg / kg, 10 pg / kg, 15 pg / kg, 20 pg / kg, 25 pg / kg, 30 pg / kg, 40 pg / kg, 50 pg / kg, 60 pg / kg, 702024202988   06 May 2024pg / kg, 80 pg / kg, 90 pg / kg, 100 pg / kg, 110 pg / kg, 120 pg / kg, 130 pg / kg, 140 pg / kg, 150 pg / kg, 200 pg / kg, 250 pg / kg, 300 pg / kg, 400 pg / kg, 500 pg / kg, 600 pg / kg, 700 pg / kg, 800 pg / kg, 900 pg / kg, 1000 pg / kg per dose.

266. The method or use of any one of claims 129 to 264, wherein the5 fusion protein, the homodimer, the heterodimer, the conjugate, the polynucleotide, the vector, the lipoplex (e.g., LNP) and / or the pharmaceutical composition is administered at a dose in the range of 0.02 mg to 100 mg, e.g., 0.04 mg to 80 mg, e.g., at least 0.02 mg per dose and up to 0.03 mg, 0.04 mg, 0.05 mg, 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 12 mg, 15 mg, 20 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg or 100 mg per dose.10                267. The method or use of any one of claims 129 to 266, comprisingmultiple administrations of the fusion protein, the homodimer, the heterodimer, the conjugate, the polynucleotide, the vector, the lipoplex (e.g., LNP) and / or the pharmaceutical composition, optionally with one or more additional therapeutic agents, at predetermined intervals.15                268. The method or use of any one of claims 129 to 267, comprisingadministering over a time period of at least 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, or longer.20                269. The method or use of any one of claims 129 to 268, comprisingadministering one or more times at predetermined intervals spaced at least 1 week and up to at least 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months or 6 months apart.

270. The method or use of any one of claims 129 to 269, wherein the 25 fusion protein, the homodimer, the heterodimer, the conjugate, the polynucleotide, the vector, the lipoplex (e.g., LNP) and / or the pharmaceutical composition is administered once weekly (i.e., QW), once bi-weekly (i.e. once every other week, or once every two weeks or Q2W), once thrice-weekly (i.e. once every three weeks or Q3W), once monthly (i.e., QM) or once bi-monthly dosing (i.e. once every other month, or once every two months or Q2M), 30 once every three months (Q3M), once every four months (Q4M), once every five months (Q5M), once every six months (Q6M), or less often.2024202988   06 May 2024271. The method or use of any one of claims 129 to 270, wherein the fusion protein, the homodimer, the heterodimer, the conjugate, the polynucleotide, the vector, the lipoplex (e.g., LNP) and / or the pharmaceutical composition is administered two or more times subcutaneously at an interval or at intervals between once bi-weekly (i.e.5 once every other week, or once every two weeks or Q2W) to once thrice-weekly (i.e. once every three weeks or Q3W).

272. The method or use of any one of claims 129 to 271, wherein the fusion protein, the homodimer, the heterodimer or the conjugate has a serum half-life in a human of at least 6, 9, 12, 15, 18, 21, 24 hours, e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 10    12, 13, 14 days, or longer.

273. The method or use of any one of claims 129 to 272, wherein the subject or the mammal is a human.

274. A kit comprising one or more unitary doses of the IL-2v of any one of claims 1 to 14, the fusion protein of any one of claims 15 to 50, the homodimer of claim 15   51, the heterodimer of any one of claims 52 to 86, the conjugate of any one of claims 87 to94, the polynucleotide or polynucleotides of any one of claims 95 to 100, the expression cassette of claim 101, the vector of any one of claims 102 to 106, or the lipoplex (e.g., LNP) of claim 107 or the pharmaceutical composition of any one of claims 122 to 128.

275. The kit of claim 274, wherein the one or more unitary doses are in a 20 single container.

276. The kit of claim 274, wherein the one or more unitary doses are in two or more separate containers.

277. The kit of any one of claims 274 to 276, comprising one or more containers selected from the group consisting of vials, ampules and pre-loaded syringes.25                278. The kit of any one of claims 274 to 277, comprising one or morecontainers comprising the fusion protein and / or the homodimer in an aqueous solution.

279. The kit of claim 278, wherein the aqueous solution comprises the fusion protein, the homodimer, the heterodimer, the conjugate, the polynucleotide, the vector, the lipoplex (e.g., LNP) and / or the pharmaceutical composition at a concentration in 30 the range of 0.05 mg / ml to 50 mg / ml, e.g., from 0.05 mg / ml to 20 mg / ml, e.g., from 0.12024202988   06 May 2024mg / ml to 40 mg / ml, e.g., from 1.0 mg / ml to 30 mg / ml, e.g., from 0.05 mg / ml to 0.06 mg / ml, 0.07 mg / ml, 0.08 mg / ml, 0.09 mg / ml, 0.1 mg / ml, 0.2 mg / ml, 0.3 mg / ml, 0.4 mg / ml, 0.5 mg / ml, 0.6 mg / ml, 0.7 mg / ml, 0.8 mg / ml, 0.9 mg / ml, 1.0 mg / ml, 1.5 mg / ml, 2.0 mg / ml, 2.5 mg / ml, 3.0 mg / ml, 3.5 mg / ml, 4.0 mg / ml, 4.5 mg / ml, 5.0 mg / ml, 6 mg / ml, 7 mg / ml, 8 5 mg / ml, 9 mg / ml, lOmg / ml, 11 mg / ml, 12 mg / ml, 13 mg / ml, 14 mg / ml, 15 mg / ml, 16 mg / ml, 17 mg / ml, 18 mg / ml, 19 mg / ml, 20 mg / ml, 25 mg / ml, 30 mg / ml, 35 mg / ml, 40 mg / ml, 45 mg / ml or 50 mg / ml.

280. The kit of any one of claims 274 to 279, wherein the one or more unitary doses are the same.10                281. The kit of any one of claims 274 to 279, wherein the one or moreunitary doses are the different.

282. The kit of any one of claims 274 to 281, wherein each unitary dose is in the range of 0.5 pg / kg to 1000 pg / kg, e.g., in the range of from 1 pg / kg to 500 pg / kg, e.g., in the range of from 10 pg / kg to 300 pg / kg, e.g., in the range of from 30 pg / kg to 600 pg / kg, 15   e.g., at least 0.5 pg / kg per dose and up to 0.2 pg / kg, 0.3 pg / kg, 0.4 pg / kg, 0.5 pg / kg, 0.6pg / kg, 0.7 pg / kg, 0.8 pg / kg, 0.9 pg / kg, 1 pg / kg, 1.5 pg / kg, 2pg / kg, 2.5 pg / kg, 3 pg / kg, 3.5 pg / kg, 4 pg / kg, 4.5 pg / kg, 5 pg / kg, 6 pg / kg, 7 pg / kg, 8 pg / kg, 9 pg / kg, 10 pg / kg, 15 pg / kg, 20 pg / kg, 25 pg / kg, 30 pg / kg, 40 pg / kg, 50 pg / kg, 60 pg / kg, 70 pg / kg, 80 pg / kg, 90 pg / kg, 100 pg / kg, 110 pg / kg, 120 pg / kg, 130 pg / kg, 140 pg / kg, 150 pg / kg, 200 pg / kg, 250 pg / kg, 20   300 pg / kg, 400 pg / kg, 500 pg / kg, 600 pg / kg, 700 pg / kg, 800 pg / kg, 900 pg / kg, 1000 pg / kgper dose.

283. The kit of any one of claims 274 to 282, wherein each unitary dose is in the range of 0.02 mg to 100 mg, e.g., 0.04 mg to 80 mg, e.g., at least 0.02 mg per dose and up to 0.03 mg, 0.04 mg, 0.05 mg, 0.1 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 25 mg, 12 mg, 15 mg, 20 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg or 100 mg per dose.

284. The kit of any one of claims 274 to 283, further comprising one or more unitary doses of one or more additional therapeutic agents.

285. The kit of claim 284, comprising one or more unitary doses of one or more antiviral agents.30                 286. The kit of claim 285, wherein the one or more antiviral agents areselected from the group consisting of lamivudine (LAM), adefovir dipivoxil (ADV),2024202988   06 May 2024entecavir (ETV), telbivudine (LdT), tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF or VEMLIDY®), ledipasvir + sofosbuvir (HARVONI®) and a PEGylated interferon (e.g., PEG-IFN-a2a and / or PEG-IFN-a2b).

287. The kit of any one of claims 284 to 286, further comprising one or5 more unitary doses of one or more therapeutic agents selected from the group consisting of HBV antigen inhibitors (e.g., HBV core antigen (HBcAg) inhibitors, HBV surface antigen (HBsAg) inhibitors, HBx inhibitors, HBV E antigen inhibitors), anti-HBV antigen antibodies, inhibitory nucleic acids targeting HBV (e.g., antisense oligonucleotide, short interfering RNA (siRNA), DNA-directed RNA interference (ddRNAi)), gene editors10 targeting HBV (e.g., CRISPR-Cas (e.g., Cas9, Cas 12, Cascade, Cas 13), zinc finger nucleases, homing endonucleases, homing meganucleases (e.g., ARCUS), synthetic nucleases, TALENs), covalently closed circular DNA (cccDNA) inhibitors, HBsAg secretion or assembly inhibitors, HBV viral entry inhibitors, and CAR-T and T cell bispecific (redirected T cells) for specific killing of HBV-infected cells.15288.   The kit of claim 285, comprising one or more unitary doses of one ormore antiretroviral agents.

289. The kit of any one of claims 284, 285 and 288, comprising one or more anti-HIV broadly neutralizing antibodies.

290. The kit of claim 289, wherein the one or more anti-HIV broadly20 neutralizing antibodies bind to an epitope or region of gpl20 selected from the groupconsisting of:25i. third variable loop (V3) and / or high mannose patch comprising a N332 oligomannose glycan;ii. second variable loop (V2) and / or Env trimer apex;iii. CD4 binding site (CD4bs);iv. gpl20 / gp41 interface; orv. silent face of gpl20.

291. The kit of any one of claims 289 to 290, wherein the one or moreanti-HIV broadly neutralizing antibodies bind to an epitope or region of gpl20 in the third30 variable loop (V3) and / or high mannose patch comprising a N332 oligomannose glycan and competes with or comprises VH and VL regions from an antibody selected from the group consisting of GS-9722, PGT-121, PGT-121.414, PGT-122, PGT-123, PGT-124, PGT-125,2024202988   06 May 2024PGT-126, PGT-128, PGT-130, PGT-133, PGT-134, PGT-135, PGT-136, PGT-137, PGT-138, PGT-139, 10-1074, 10-1074-J, VRC24, 2G12, BG18, 354BG8, 354BG18, 354BG42, 354BG33, 354BG129, 354BG188, 354BG411, 354BG426, DH270.1, DH270.6, PGDM12, VRC41.01, PGDM21, PCDN-33A, BF520.1 and VRC29.03.5                 292. The kit of any one of claims 289 to 291, wherein the one or moreanti-HIV broadly neutralizing antibodies bind to an epitope or region of gpl20 in the second variable loop (V2) and / or Env trimer apex and competes with or comprises VH and VL regions from an antibody selected from the group consisting of PG9, PG16, PGC14, PGG14, PGT-142, PGT-143, PGT-144, PGT-145, CHOI, CH59, PGDM1400, CAP256,10   CAP256-VRC26.08, CAP256-VRC26.09, CAP256-VRC26.25, PCT64-24E andVRC38.01.

293. The kit of any one of claims 289 to 292, wherein the one or more anti-HIV broadly neutralizing antibodies bind to an epitope or region of gpl20 in the CD4 binding site (CD4bs) and competes with or comprises VH and VL regions from an antibody15 selected from the group consisting of 3BNC117, GS-9723, 3BNC60, bl2, F105, VRC01, VRC07, VRC07-523, VRC03, VRC06, VRC06b01 VRC08, VRC0801, NIH45-46, VRC-PG04, PGV04; CH103, 44-VRC13.01, 1NC9, 12A12, N6, N49-P7, NC-Cowl, I0MA, CH235 and CH235.12, N49P6, N49P7, N49P11, N49P9 andN60P25.

294. The kit of any one of claims 289 to 293, wherein the one or more20 anti-HIV broadly neutralizing antibodies bind to an epitope or region of gpl20 in the gpl20 / gp41 interface and competes with or comprises VH and VL regions from an antibody selected from the group consisting of PGT-151, CAP248-2B, 35022, 8ANC195, ACS202, VRC34 and VRC34.01.

295. The kit of any one of claims 289 to 294, wherein the one or more25 anti-HIV broadly neutralizing antibodies bind to an epitope or region of the gpl20 silent face and competes with or comprises VH and VL regions from an antibody selected from VRC-PG05 and SF12.

296. The kit of any one of claims 289 to 295, wherein the one or more anti-HIV broadly neutralizing antibodies bind to an epitope or region of gp41 in the30 membrane proximal region (MPER).

297. The kit of any one of claims 289 to 296, wherein the one or more anti-HIV broadly neutralizing antibodies bind to an epitope or region of gp41 in the2024202988   06 May 2024membrane proximal region (MPER) and competes with or comprises VH and VL regions from an antibody selected from the group consisting of 10E8, 10E8v4, 10E8-5R-100cF, 4E10, DH511.11P, 2F5, 7b2, andLNOl.

298. The kit of any one of claims 289 to 297, wherein the one or more5 anti-HIV broadly neutralizing antibodies bind to an epitope or region of the gp41 fusion peptide and competes with or comprises VH and VL regions from an antibody selected from the group consisting of VRC34 and ACS202.

299. The kit of claim 284, comprising one or more unitary doses of a vaccine.10                 300. The kit of claim 299, wherein the vaccine is selected from the groupconsisting of an antiviral vaccine, an antibacterial vaccine and an anticancer vaccine.

301. The kit of any one of claims 299 to 300, wherein the vaccine comprises an antiviral vaccine against a virus selected from the group consisting of hepatitis A virus (HAV), hepatitis B virus (HBV), human immunodeficiency virus (HIV),15 cytomegalovirus (CMV), a herpes simplex virus (HSV), Epstein-Barr virus (EBV), human orthopneumovirus or human respiratory syncytial virus (RSV), human papillomavirus (HPV), varicella-zoster virus, measles virus, mumps virus, poliovirus vaccine, influenza virus, paramyxovirus, rotavirus, Zika virus, Dengue virus, Ebola virus and coronavirus (e.g., betacoronavirus, e.g., severe acute respiratory syndrome-related coronavirus, e.g., SARS-20 CoV2).

302. The kit of any one of claims 299 to 300, wherein the vaccine comprises an antibacterial vaccine against a bacterium selected from the group consisting of mycobacterium tuberculosis, pertussis, tetanus, diphtheria, meningococcus, pneumococcus, Haemophilus influenza, cholera, typhoid, and anthrax.25                 303. The kit of claim 284, comprising one or more unitary doses of one ormore anti-neoplastic or chemotherapeutic agents.

304. The kit of claim 303, comprising one or more unitary doses of one or more anti-neoplastic or chemotherapeutic agents are selected from the group consisting of a nucleoside analog (e.g., 5-fluorouracil, gemcitabine, cytarabine, cladribine, pentostatin,30 fludarabine), a taxane (e.g., paclitaxel, nab-paclitaxel, docetaxel, cabazitaxel), a platinum coordination complex (cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate,2024202988   06 May 2024phenanthriplatin, picoplatin, satraplatin, dicycloplatin, eptaplatin, lobaplatin, miriplatin), a dihydrofolate reductase (DHFR) inhibitor (e.g., methotrexate, trimetrexate, pemetrexed), a topoisomerase inhibitor (e.g., doxorubicin, daunorubicin, dactinomycin, eniposide, epirubicin, etoposide, idarubicin, irinotecan, mitoxantrone, pixantrone, sobuzoxane,5 topotecan, irinotecan, MM-398 (liposomal irinotecan), vosaroxin and GPX-150, aldoxorubicin, AR-67, mavelertinib, AST-2818, avitinib (ACEA-0010), irofulven (MGI-114)), an alkylating agent (e.g., a nitrogen mustard (e.g., cyclophosphamide, chlormethine, uramustine or uracil mustard, melphalan, chlorambucil, ifosfamide, bendamustine, temozolomide, carmustine), a nitrosourea (e.g., carmustine, lomustine, streptozocin), an 10 alkyl sulfonate (e.g., busulfan)), and mixtures thereof.

305. The kit of any one of claims 284 and 303 to 304, comprising one or more unitary doses of one or more antibodies or antigen-binding antibody fragments thereof, or antibody-drug conjugates thereof, CD3-targeting multi-specific molecules, NK cell-activating receptor-targeting multi-specific molecules, or non-immunoglobulin antigen-15   binding domains or antibody mimetic proteins directed against one or more targets or tumorassociated antigens (TAAs) selected from the group consisting of: CD 19; membrane spanning 4-domains Al (MS4A1; CD20); CD22 (SIGLEC2); CD27 (TNFRSF7); TNFRSF8 (CD30); CD33 (SIGLEC3); CD37; CD38; CD40 (TNFRSF5), CD44; CD47; CD48 (SLAMF2); CD52; CD70 (TNFSF7; CD27L); 5'-nucleotidase ecto (NT5E; CD73), 20 ectonucleoside triphosphate diphosphohydrolase 1 (CD39), CD74; CD79B; CD80; CD86;interleukin 3 receptor subunit alpha (IL3RA), prominin 1 (PROM1; CD133); TNFRSF9 (CD137); syndecan 1 (SDC1; CD138); CD200 molecule (CD200); alpha fetoprotein (AFP), BAG cochaperone 6 (BAG6); MET proto-oncogene, receptor tyrosine kinase (MET); KIT proto-oncogene, receptor tyrosine kinase (KIT); C-type lectin domain family 12 member A 25 (CLEC12A; CD371); C-type lectin domain containing 9A (CLEC9A; CD370); cadherin 3(CDH3); carbonic anhydrase 6 (CA6); carbonic anhydrase 9 (CA9); carcinoembryonic antigen related cell adhesion molecule 3 (CEACAM3); carcinoembryonic antigen related cell adhesion molecule 5 (CEACAM5); carcinoembryonic antigen related cell adhesion molecule 6 (CEACAM6); chorionic somatomammotropin hormone 1 (CSH1); coagulation 30 factor III, tissue factor (F3); collectin subfamily member 10 (COLEC10; CLL1); delta likecanonical Notch ligand 3 (DLL3); ectonucleotide pyrophosphatase / phosphodiesterase 3 (ENPP3); ephrin Al (EFNA1); epidermal growth factor receptor (EGFR; ERBB; HER1); EGFR variant III (EGFRvIII); EPH receptor A2 (EPHA2); epithelial cell adhesion molecule (EPCAM); erb-b2 receptor tyrosine kinase 2 (ERBB2; HER-2 / neu); fibroblast activation35 protein alpha (FAP); fibroblast growth factor receptor 2 (FGFR2); fibroblast growth factor2024202988   06 May 2024receptor 3 (FGFR3); folate hydrolase 1 (FOLH1); folate receptor 1 (FOLRI); GD2 ganglioside; glycoprotein NMB (GPNMB; osteoactivin); guanylate cyclase 2C (GUCY2C);human papillomavirus (HPV) E6; HPV E7; major histocompatibility complex (MHC) class I-presented neoantigens, major histocompatibility complex (MHC) class Il-presented5 neoantigens, major histocompatibility complex, class I, E (HLA-E); major histocompatibility complex, class I, F (HLA-F); major histocompatibility complex, class I, G (HLA-G); MHC class I polypeptide-related sequence A (MICA); MHC class I polypeptide-related sequence B (MICB); integrin subunit beta 7 (ITGB7); leukocyte immunoglobulin like receptor Bl (LILRB1; ILT2); leukocyte immunoglobulin like receptor10 B2 (LILRB2; ILT4); LY6 / PLAUR domain containing 3 (LYPD3); glypican 3 (GPC3); KRAS proto-oncogene, GTPase (KRAS); MAGE family member Al (MAGEA1); MAGE family member A3 (MAGEA3); MAGE family member A4 (MAGEA4); MAGE family member Al 1 (MAGEA11); MAGE family member Cl (MAGECI); MAGE family member C2 (MAGEC2); MAGE family member C3 (MAGEC3); MAGE family member DI15 (MAGED1); MAGE family member D2 (MAGED2); mesothelin (MSLN); mucin 1 (MUC1) and splice variants thereof (e.g., including MUCl / A, C, D, X, Y, Z and REP); mucin 16 (MUC16; CA125); natural killer cell cytotoxicity receptor 3 ligand 1 (NCR3LG1; B7-H6); necdin, MAGE family member (NDN); nectin cell adhesion molecule 2 (NECTIN2); nectin cell adhesion molecule 4 (NECTIN4); SLIT and NTRK like family20 member 6 (SLITRK6); promyelocytic leukemia (PML); protein tyrosine kinase 7 (inactive) (PTK7); Poliovirus receptor (PVR) cell adhesion molecule (PVR); SLAM family member 6 (SLAMF6); SLAM family member 7 (SLAMF7); sialic acid binding Ig like lectin 7 (SIGLEC7); sialic acid binding Ig like lectin 9 (SIGLEC9); sialic acid binding Ig like lectin 10 (SIGLEC10); signal regulatory protein alpha (SIRPA) solute carrier family 34 (sodium25 phosphate), member 2 (SLC34A2); solute carrier family 39 member 6 (SLC39A6); STEAP family member 1 (STEAP 1); suppression of tumorigenicity 2 (ST2); TNF receptor superfamily member 4 (TNFRSF4; OX40); TNF superfamily member 9 (TNFSF9; 4-1BB-L, CD137L); TNFRSF10A (DR4, TRAILRI); TNFRSF10B (DR5, TRAILR2);TNFRSF13B (BAFF); TNFRSF17 (BCMA); TNFRSF18 (GITR); transferrin (TF);30 transforming growth factor beta 1 (TGFB1) and isoforms thereof; triggering receptor expressed on myeloid cells 1 (TREM1); triggering receptor expressed on myeloid cells 2 (TREM2); trophoblast glycoprotein (TPBG); trophinin (TRO); tumor associated calcium signal transducer 2 (TACSTD2); Fucosyl GM1; sialyl Lewis adhesion molecule (sLe); and Lewis Y antigen.2024202988   06 May 2024306. The kit of any one of claims 284 and 303 to 305, comprising one or more antibodies or antigen-binding antibody fragments thereof, or antibody-drug conjugates thereof, CD3-targeting multi-specific molecules, NK cell-activating receptor-targeting multi-specific molecules, or non-immunoglobulin antigen-binding domains or antibody5 mimetic proteins binds to an epitope of a target or tumor associated antigen (TAA) presented in a major histocompatibility complex (MHC) molecule.

307. The kit of any one of claims 305 to 306, wherein the NK cellactivating receptor is selected from the group consisting of CD 16, NKp30, NKp44, NKp46, NKp80 and NKG2D.10                308. The kit of any one of claims 284 and 303 to 307, comprising one ormore populations of immune cells selected from the group consisting of: natural killer (NK) cells, NK-T cells, T cells, cytokine-induced killer (CIK) cells, macrophage (MAC) cells, tumor infdtrating lymphocytes (TILs) and dendritic cells (DCs).

309. The kit of any one of claims 284 and 303 to 308, comprising a15 population of T cells selected from the group consisting of: alpha / beta TCR T cells, gamma / delta TCR T cells, regulatory T (Treg) cells and TRuC™ T cells.

310. The kit of claim 309, wherein the one or more cellular therapies comprise a NK cell therapy comprising NK-92 cells.

311. The kit of any one of claims 284 and 303 to 310, wherein the cells are 20 allogeneic to an intended recipient.

312. The kit of any one of claims 308 to 311, wherein the one or more populations of immune cells comprise one or more chimeric antigen receptors (CARs).

313. The kit of claim 312, wherein the one or more CARs bind to a target or tumor associated antigen (TAA) selected from the group consisting of selected from the25 group consisting of: CD 19; membrane spanning 4-domains Al (MS4A1; CD20); CD22 (SIGLEC2); CD27 (TNFRSF7); TNFRSF8 (CD30); CD33 (SIGLEC3); CD37; CD38; CD40 (TNFRSF5), CD44; CD47; CD48 (SLAMF2); CD52; CD70 (TNFSF7; CD27L); 5'-nucleotidase ecto (NT5E; CD73), ectonucleoside triphosphate diphosphohydrolase 1 (CD39), CD74; CD79B; CD80; CD86; interleukin 3 receptor subunit alpha (IL3RA),30 prominin 1 (PROM1; CD133); TNFRSF9 (CD137); syndecan 1 (SDC1; CD138); CD200 molecule (CD200); alpha fetoprotein (AFP), BAG cochaperone 6 (BAG6); MET proto-2024202988   06 May 2024oncogene, receptor tyrosine kinase (MET); KIT proto-oncogene, receptor tyrosine kinase (KIT); C-type lectin domain family 12 member A (CLEC12A; CD371); C-type lectin domain containing 9A (CLEC9A; CD370); cadherin 3 (CDH3); carbonic anhydrase 6 (CA6); carbonic anhydrase 9 (CA9); carcinoembryonic antigen related cell adhesion 5 molecule 3 (CEACAM3); carcinoembryonic antigen related cell adhesion molecule 5(CEACAM5); carcinoembryonic antigen related cell adhesion molecule 6 (CEACAM6); chorionic somatomammotropin hormone 1 (CSH1); coagulation factor III, tissue factor (F3); collectin subfamily member 10 (COLEC10; CLL1); delta like canonical Notch ligand 3 (DLL3); ectonucleotide pyrophosphatase / phosphodiesterase 3 (ENPP3); ephrin Al10 (EFNA1); epidermal growth factor receptor (EGFR; ERBB; HER1); EGFR variant III (EGFRvIII); EPH receptor A2 (EPHA2); epithelial cell adhesion molecule (EPCAM); erb-b2 receptor tyrosine kinase 2 (ERBB2; HER-2 / neu); fibroblast activation protein alpha (FAP); fibroblast growth factor receptor 2 (FGFR2); fibroblast growth factor receptor 3 (FGFR3); folate hydrolase 1 (FOLH1); folate receptor 1 (FOLRI); GD2 ganglioside;15 glycoprotein NMB (GPNMB; osteoactivin); guanylate cyclase 2C (GUCY2C); human papillomavirus (HPV) E6; HPV E7; major histocompatibility complex (MHC) class I-presented neoantigens, major histocompatibility complex (MHC) class Il-presented neoantigens, major histocompatibility complex, class I, E (HLA-E); major histocompatibility complex, class I, F (HLA-F); major histocompatibility complex, class I, 20 G (HLA-G); MHC class I polypeptide-related sequence A (MICA); MHC class I polypeptide-related sequence B (MICB); integrin subunit beta 7 (ITGB7); leukocyte immunoglobulin like receptor Bl (LILRB1; ILT2); leukocyte immunoglobulin like receptor B2 (LILRB2; ILT4); LY6 / PLAUR domain containing 3 (LYPD3); glypican 3 (GPC3);KRAS proto-oncogene, GTPase (KRAS); MAGE family member Al (MAGEA1); MAGE 25 family member A3 (MAGEA3); MAGE family member A4 (MAGEA4); MAGE family member Al 1 (MAGEA11); MAGE family member Cl (MAGECI); MAGE family member C2 (MAGEC2); MAGE family member C3 (MAGEC3); MAGE family member DI (MAGED1); MAGE family member D2 (MAGED2); mesothelin (MSLN); mucin 1 (MUC1) and splice variants thereof (e.g., including MUCl / A, C, D, X, Y, Z and REP);30 mucin 16 (MUC16; CA125); natural killer cell cytotoxicity receptor 3 ligand 1 (NCR3LG1;B7-H6); necdin, MAGE family member (NDN); nectin cell adhesion molecule 2 (NECTIN2); nectin cell adhesion molecule 4 (NECTIN4); SLIT and NTRK like family member 6 (SLITRK6); promyelocytic leukemia (PML); protein tyrosine kinase 7 (inactive) (PTK7); Poliovirus receptor (PVR) cell adhesion molecule (PVR); SLAM family member 6 35 (SLAMF6); SLAM family member 7 (SLAMF7); sialic acid binding Ig like lectin 72024202988   06 May 2024(SIGLEC7); sialic acid binding Ig like lectin 9 (SIGLEC9); sialic acid binding Ig like lectin 10 (SIGLEC10); signal regulatory protein alpha (SIRPA) solute carrier family 34 (sodium phosphate), member 2 (SLC34A2); solute carrier family 39 member 6 (SLC39A6); STEAP family member 1 (STEAP 1); suppression of tumorigenicity 2 (ST2); TNF receptor5 superfamily member 4 (TNFRSF4; OX40); TNF superfamily member 9 (TNFSF9; 4-1BB-L, CD137L); TNFRSF10A (DR4, TRAILRI); TNFRSF10B (DR5, TRAILR2);TNFRSF13B (BAFF); TNFRSF17 (BCMA); TNFRSF18 (GITR); transferrin (TF); transforming growth factor beta 1 (TGFB1) and isoforms thereof; triggering receptor expressed on myeloid cells 1 (TREM1); triggering receptor expressed on myeloid cells 2 10 (TREM2); trophoblast glycoprotein (TPBG); trophinin (TRO); tumor associated calcium signal transducer 2 (TACSTD2); Fucosyl GM1; sialyl Lewis adhesion molecule (sLe); and Lewis Y antigen.

314. The kit of any one of claims 308 to 313, wherein the one or more CARs bind to an epitope of a target or tumor associated antigen (TAA) presented in a major15 histocompatibility complex (MHC) molecule.

315. The kit of claim 306 or claim 314, wherein the TAA is a cancer testis antigen.

316. The kit of claim 315, wherein the cancer testis antigen is selected from the group consisting of acrosin binding protein (ACRBP), alpha fetoprotein (AFP), A-20 kinase anchoring protein 4 (AKAP4), ATPase family AAA domain containing 2 (ATAD2), kinetochore scaffold 1 (KNL1; a.k.a., CASC5), centrosomal protein 55 (CEP55), cancer / testis antigen 1A (CTAG1A; a.k.a., ESO1; CT6.1; LAGE-2; LAGE2A; NY-ESO-1), cancer / testis antigen IB (CTAG1B; a.k.a., CT6.1, CTAG, CTAG1, ESO1, LAGE-2, LAGE2B, NY-ESO-1), cancer / testis antigen 2 (CTAG2; a.k.a., CAMEL, CT2, CT6.2,25   CT6.2a, CT6.2b, ESO2, LAGE-1, LAGE2B), CCCTC-binding factor like (CTCFL), cateninalpha 2 (CTNNA2), cancer / testis antigen 83 (CT83), cyclin Al (CCNA1), DEAD-box helicase 43 (DDX43), developmental pluripotency associated 2 (DPPA2), fetal and adult testis expressed 1 (FATE 1), FMRI neighbor (FMR1NB), HORMA domain containing 1 (HORMAD1), insulin like growth factor 2 mRNA binding protein 3 (IGF2BP3), leucine30 zipper protein 4 (LUZP4), lymphocyte antigen 6 family member K (LY6K), maelstrom spermatogenic transposon silencer (MAEL), MAGE family member Al (MAGEA1); MAGE family member A3 (MAGEA3); MAGE family member A4 (MAGEA4); MAGE family member Al 1 (MAGEA11); MAGE family member Cl (MAGECI); MAGE family2024202988   06 May 2024member C2 (MAGEC2); MAGE family member DI (MAGED1); MAGE family member D2 (MAGED2), kinesin family member 20B (KIF20B; a.k.a., MPHOSPH1), NUF2 component of NDC80 kinetochore complex (NUF2), nuclear RNA export factor 2 (NXF2), PAS domain containing repressor 1 (PASD1), PDZ binding kinase (PBK), piwi like RNA-5 mediated gene silencing 2 (PIWIL-2), preferentially expressed antigen in melanoma (PRAME), sperm associated antigen 9 (SPAG9), sperm protein associated with the nucleus, X-linked, family member Al (SPANXA1), SPANX family member A2 (SPANXA2), SPANX family member C (SPANXC), SPANX family member D (SPANXD), SSX family member 1 (SSX 1), SSX family member 2 (SSX2), synaptonemal complex protein 310 (SYCP3), testis expressed 14, intercellular bridge forming factor (TEX14), transcription factor Dp family member 3 (TFDP3), serine protease 50 (PRSS50, a.k.a., TSP50), TTK protein kinase (TTK) and zinc finger protein 165 (ZNF165).

317. The kit of any one of claims 284 and 303 to 316, comprising one or more unitary doses of a targeted E3 ligase ligand conjugate.15                318. The kit of any one of claims 284 and 303 to 317, comprising one ormore unitary doses of an inhibitor or antagonist of:• protein tyrosine phosphatase, non-receptor type 11 (PTPN11 or SHP2),• myeloid cell leukemia sequence 1 (MCL1) apoptosis regulator,• 5'-nucleotidase ecto (NT5E or CD73),20                • ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1 orCD39),• transforming growth factor beta 1 (TGFB1 or TGF0),• heme oxygenase 1 (HM0X1, HO-1 or HOI),• heme oxygenase 2 (HM0X2, HO-2 or HO2),• vascular endothelial growth factor A (VEGFA or VEGF),25                • erb-b2 receptor tyrosine kinase 2 (ERBB2, HER2, HER2 / neu or CD340),• epidermal growth factor receptor (EGFR, ERBB, ERBB1 or HER1),• ALK receptor tyrosine kinase (ALK, CD246),• poly(ADP-ribose) polymerase 1 (PARP1),• poly(ADP-ribose) polymerase 2 (PARP2),30                • TCDD inducible poly(ADP-ribose) polymerase (TIPARP, PARP7),• cyclin dependent kinase 4 (CDK4),• cyclin dependent kinase 6 (CDK6),• TNF receptor superfamily member 14 (TNFRSF14, HVEM, CD270),2024202988   06 May 2024• C-C motif chemokine receptor 2 (CCR2, CD 192),• C-C motif chemokine receptor 5 (CCR5, CD 195),• C-C motif chemokine receptor 8 (CCR8, CDwl98),• C-X-C motif chemokine receptor 2 (CXCR2, CD 182),5                • C-X-C motif chemokine receptor 3 (CXCR3, CD 182, CD 183),• C-X-C motif chemokine receptor 4 (CXCR4, CD 184),• cytokine inducible SH2 containing protein (CISH),• arginase (ARG 1, ARG2),• carbonic anhydrase (CAI, CA2, CA3, CA4, CA5A, CA5B, CA6, CA7,10                 CA8, CA9, CAIO, CA11, CA12, CAB, CAM),• prostaglandin-endoperoxide synthase 1 (PTGS1, COX-1),• prostaglandin-endoperoxide synthase 2 (PTGS2, COX-2),• secreted phospholipase A2,• prostaglandin E synthase (PTGES, PGES),15                • arachidonate 5-lipoxygenase (ALOX5, 5-LOX),• soluble epoxide hydrolase 2 (EPHX2),• indoleamine 2,3-dioxygenase 1 (IDO1),• indoleamine 2,3-dioxygenase 2 (IDO2),• hypoxia inducible factor 1 subunit alpha (HIF1A),20                • angiopoietin 1 (ANGPT1),• Endothelial TEK tyrosine kinase (TIE-2, TEK),• Janus kinase 1 (JAKI),• cateninbeta 1 (CTNNB1),• histone deacetylase 9 (HDAC9),25                 • 5'-3' exoribonuclease 1 (XRN1), and / or• WRN RecQ like helicase (WRN).

319. The kit of claim 318, wherein the inhibitor of 5'-nucleotidase ecto (NT5E or CD73) is selected from the group consisting of MEDI9447 (oleclumab), CPI-006, BMS-986179, IPH5301, TJ4309 (TJD5), NZV-930, AB-680, PSB-12379, PSB-12441,30   PSB-12425, CB-708 and PBF-1662.

320. The kit of claim 318, wherein the inhibitor of CCR2 and / or CCR5 is selected from the group consisting of BMS-813160, PF-04136309 and CCX-872.2024202988   06 May 2024321. The kit of claim 318, wherein the inhibitor of MCL1 is selected from the group consisting of GS-9716, tapotoclax (AMG-176), AMG-397, S-64315, AZD-5991, 483-LM, A-1210477, UMI-77, JKY-5-037 and PRT-1419.

322. The kit of claim 318, wherein the inhibitor of PTPN11 or SHP2 is5 selected from the group consisting of TNO155 (SHP-099), RMC-4550, JAB-3068 and RMC-4630.

323. The kit of claim 318, wherein the inhibitor of Janus kinase 1 (JAKI) is selected from the group consisting of fdgotinib, tofacitinib, baricitinib and ABT-494.

324. The kit of any one of claims 284 to 323, comprising one or more10 agonists or activators of one or more toll-like receptors (TLRs).

325. The kit of claim 324, wherein the TLR agonist or activator is selected from the group consisting of a TLR2 agonist, a TLR3 agonist, a TLR4 agonist, a TLR5 agonist, a TLR7 agonist, a TLR8 agonist and a TLR9 agonist.

326. The kit of any one of claims 324 to 325, wherein the TLR7 agonist is 15 selected from the group consisting of GS 9620 (vesatolimod), R848 (Resiquimod), DS-0509, LHC-165, TMX-101 (imiquimod), RO7020531 and JNJ-4964, and / or wherein the TLR8 agonist is selected from the group consisting of selgantolimod (GS-9688), R848 (Resiquimod) and NKTR-262 (dual TLR7 / TLR8 agonist).

327. The kit of any one of claims 284 to 326, comprising one or more20 immunostimulatory cytokines or chemokines that promote or increase the proliferation or activation of a / p T cells, y / 5 T cells, NK-T cells, NK cells, and / or dendritic cells.

328. The kit of claim 327, wherein the one or more immunostimulatory cytokines or chemokines are selected from the group consisting of: IL-10, IL-12, IL-18, gamma chain-dependent cytokines (e.g., IL-4, IL-7, IL-9, IL-15 and IL-21), fms related25 tyrosine kinase 3 (FLT3) ligand (FLT3L; FLT3LG), interferon (IFN)-a, IFN-P, a PEGylated interferon (e.g., PEG-IFN-a2a and / or PEG-IFN-a2b), IFN-y, CXCL9 / Mig (monokine induced by interferon-y), CXCL10 / IP10 (interferon-y-inducible 10 kDa protein) and CXCL11 / I-TAC (interferon-inducible T cell a-chemoattractant), CXCL4 / PF4 (platelet factor 4), monocyte chemoattractant protein 2 (MCP-2), macrophage inflammatory protein30   1 alpha (MIP-la), macrophage inflammatory protein 1 beta (MIP-ip) and regulated onactivation normal T expressed and secreted protein (RANTES).2024202988   06 May 2024329. The kit of any one of claims 284 to 328, comprising one or more interleukin receptor agonists of an interleukin receptor selected from IL-10, IL-12, IL-18 and gamma chain-dependent cytokines (e.g., IL-4, IL-7, IL-9, IL-15 and IL-21).

330. The kit of claim 329, comprising one or more cytokines selected from 5   the group consisting of IL-10, IL-12, IL-18, gamma chain-dependent cytokines (e.g., IL-4,IL-7, IL-9, IL-15 and IL-21), IFN-a, IFN-p, a PEGylated interferon (e.g., PEG-IFN-a2a and / or PEG-IFN-a2b), IFN-y, and variants thereof.

331. The kit of any one of claims 284 to 330, comprising one or more innate immune activators.10                 332. The kit of claim 331, comprising an agonist of a receptor selectedfrom the group consisting of fms related tyrosine kinase 3 (FLT3), stimulator of interferon genes (STING) receptor, DExD / H-box helicase 58 (DDX58; a.k.a., RIG-I), NLR family pyrin domain containing 3 (NLRP3) and nucleotide binding oligomerization domain containing 2 (NOD2).15                 333. The kit of any one of claims 225 to 226, comprising one or both ofGS-3583 and GS-9992.

334. The kit of any one of claims 284 to 333, comprising one or more antagonists or inhibitors of an inhibitory immune checkpoint protein or receptor and / or one or more activators or agonists of a stimulatory immune checkpoint protein or receptor.20                335. The kit of claim 334, wherein the one or more immune checkpointproteins or receptors are selected from the group consisting of: CD27, CD70; CD40, CD40LG; CD47, CD48 (SLAMF2), transmembrane and immunoglobulin domain containing 2 (TMIGD2, CD28H), CD84 (LY9B, SLAMF5), CD96, CD 160 (NK1, NK28, BY55), MS4A1 (CD20), CD244 (SLAMF4); CD276 (B7H3); V-set domain containing T25 cell activation inhibitor 1 (VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); natural killer cell cytotoxicity receptor 3 ligand 1 (NCR3LG1, B7H6); HERV-H LTR-associating 2 (HHLA2, B7H7); inducible T cell co-stimulator (ICOS, CD278); inducible T cell costimulator ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF30 superfamily member 4 (TNFSF4, OX40L); TNFRSF8 (CD30), TNFSF8 (CD30L); TNFRSF10A (CD261, DR4, TRAILRI), TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF10B (CD262, DR5, TRAILR2), TNFRSF10 (TRAIL); TNFRSF14 (HVEM,2024202988   06 May 2024CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte associated (BTLA)); TNFRSF17 (BCMA, CD269), TNFSF13B (BAFF); TNFRSF18 (GITR), TNFSF18 (GITRL); MHC class I polypeptide-related sequence A (MICA); MHC class I polypeptide-related sequence B (MICB); CD274 (CD274, PDL1, PD-L1); programmed cell death 15 (PDCD1, PD1, PD-1); cytotoxic T-lymphocyte associated protein 4 (CTLA4, CD 152); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); Poliovirus receptor (PVR) cell adhesion molecule (PVR, CD 155); PVR related immunoglobulin domain containing (PVRIG, CD112R); T cell immunoreceptor with Ig and ITIM domains (TIGIT); T cell immunoglobulin and mucin domain containing 4 (TIMD4;10 TIM4); hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3); galectin 9 (LGALS9); lymphocyte activating 3 (LAG3, CD223); signaling lymphocytic activation molecule family member 1 (SLAMF1, SLAM, CD150); lymphocyte antigen 9 (LY9, CD229, SLAMF3); SLAM family member 6 (SLAMF6, CD352); SLAM family member 7 (SLAMF7, CD319); sialic acid binding Ig like lectin 7 (SIGLEC7); sialic acid binding Ig15 like lectin 9 (SIGLEC9); ULI6 binding protein 1 (ULBP1); ULI6 binding protein 2 (ULBP2); UL16 binding protein 3 (ULBP3); retinoic acid early transcript IE (RAET1E; ULBP4); retinoic acid early transcript IG (RAET1G; ULBP5); retinoic acid early transcript IL (RAET1L; ULBP6); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); CD160; killer cell lectin like receptor Bl (KLRB1,20   CD161); killer cell lectin like receptor Cl (KLRC1, NKG2A, CD159A); killer cell lectinlike receptor KI (KLRK1, NKG2D, CD314); killer cell lectin like receptor C2 (KLRC2, CD 159c, NKG2C); killer cell lectin like receptor C3 (KLRC3, NKG2E); killer cell lectin like receptor C4 (KLRC4, NKG2F); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin like receptor,25 two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin like receptor DI (KLRD1); killer cell lectin like receptor G1 (KLRG1; CLEC15A, MAFA, 2F1); sialic acid binding Ig like lectin 7 (SIGLEC7); and sialic acid30 binding Ig like lectin 9 (SIGLEC9).

336. The kit of any one of claims 334 to 335, comprising one or more blockers or inhibitors of one or more T-cell inhibitory immune checkpoint proteins or receptors.2024202988   06 May 2024337. The kit of claim 336, wherein the T-cell inhibitory immune checkpoint proteins or receptors are selected from the group consisting of CD274 (CD274, PDL1, PD-L1); programmed cell death 1 ligand 2 (PDCD1LG2, PD-L2, CD273); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T-lymphocyte associated protein 5   4 (CTLA4, CD152); CD276 (B7H3); V-set domain containing T cell activation inhibitor 1(VTCN1, B7H4); V-set immunoregulatory receptor (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte associated (BTLA)); PVR related immunoglobulin domain containing (PVRIG, CD112R); T cell immunoreceptor with Ig and 10 ITIM domains (TIGIT); lymphocyte activating 3 (LAG3, CD223); hepatitis A virus cellular receptor 2 (HAVCR2, TIMD3, TIM3); galectin 9 (LGALS9); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 215 (KIR2DL2); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 3 (KIR2DL3); and killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1).

338. The kit of any one of claims 334 to 337, comprising one or more agonists or activators of one or more T-cell stimulatory immune checkpoint proteins or 20 receptors.

339. The kit of claim 338, wherein the T-cell stimulatory immune checkpoint proteins or receptors are selected from the group consisting of CD27, CD70; CD40, CD40LG; inducible T cell costimulator (ICOS, CD278); inducible T cell costimulator ligand (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, 25   OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF9 (CD 137), TNFSF9(CD137L); TNFRSF18 (GITR), TNFSF18 (GITRL); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); Poliovirus receptor (PVR) cell adhesion molecule (PVR, CD 155).

340. The kit of any one of claims 334 to 339, comprising one or more 30 blockers or inhibitors of one or more NK-cell inhibitory immune checkpoint proteins or receptors.

341. The kit of claim 340, wherein the NK-cell inhibitory immune checkpoint proteins or receptors are selected from the group consisting of killer cell2024202988   06 May 2024immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 1 (KIR2DL1); killer cell immunoglobulin like receptor, two Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin like receptor, two Ig domains and5 long cytoplasmic tail 3 (KIR2DL3); killer cell immunoglobulin like receptor, three Ig domains and long cytoplasmic tail 1 (KIR3DL1); CD 160; killer cell lectin like receptor Bl (KLRB1, CD161); killer cell lectin like receptor Cl (KLRC1, NKG2A, CD159A); killer cell lectin like receptor DI (KLRD1, CD94); killer cell lectin like receptor G1 (KLRG1; CLEC15A, MAFA, 2F1); sialic acid binding Ig like lectin 7 (SIGLEC7); and sialic acid10 binding Ig like lectin 9 (SIGLEC9).

342. The kit of any one of claims 334 to 341, comprising one or more agonists or activators of one or more NK-cell stimulatory immune checkpoint proteins or receptors.

343. The kit of claim 342, wherein the NK-cell stimulatory immune15 checkpoint proteins or receptors are selected from CD 16, CD226 (DNAM-1); killer cell lectin like receptor KI (KLRK1, NKG2D, CD314); and SLAM family member 7 (SLAMF7).

344. The kit of any one of claims 334 to 342, comprising a proteinaceous (e.g., antibody) inhibitor of PD-L1 (CD274), PD-1 (PDCD1) or CTLA4.20                 345. The kit of any one of claims 334 to 344, comprising a proteinaceous(e.g., antibody) inhibitor of PD-L1 (CD274) or PD-1 (PDCD1).

346. The kit of claim 344, wherein the proteinaceous (e.g., antibody) inhibitor of CTLA4 is selected from the group consisting of ipilimumab, tremelimumab, BMS-986218, AGEN1181, AGEN1884 (zalifrelimab), BMS-986249, MK-1308, REGN-25   4659, ADU-1604, CS-1002, BCD-145, APL-509, JS-007, BA-3071, ONC-392,AGEN2041, JHL-1155, KN-044, CG-0161, ATOR-1144, PBL5D3H5, FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-019 (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4), MEDI-5752 (CTLA4 / PD-1), XmAb-20717 (PD-1 / CTLA4) and AK-104 (CTLA4 / PD-1).30                  347. The kit of claim 344, wherein the proteinaceous (e.g., antibody)inhibitor of programmed cell death 1 (PDCD1; NCBI Gene ID: 5133; CD279, PD-1, PD1) is selected from the group consisting of zimberelimab (AB122, GLS-010, WBP-3055),2024202988   06 May 2024pembrolizumab (KEYTRUDA®, MK-3475, SCH900475), nivolumab (OPDIVO®, BMS-936558, MDX-1106), cemiplimab (LIBTAYO®; cemiplimab-rwlc, REGN-2810), pidilizumab (CT-011), AMG-404, MEDI0680 (AMP-514), spartalizumab (PDR001), tislelizumab (BGB-A317), toripalimab (JS-001), genolimzumab (CBT-501, APL-501, GB 5   226), SHR-1201, camrelizumab (SHR-1210), sintilimab (TYVYT®; IBI-308), dostarlimab(TSR-042, WBP-285), lambrolizumab (MK-3475); sasanlimab (PF-06801591), cetrelimab (JNJ-63723283), serplulimab (HLX-10), retifanlimab (MGA-012), balstilimab (AGEN2034), prolgolimab (BCD 100), budigalimab (ABBV-181), vopratelimab (JTX-4014), AK-103 (HX-008), AK-105, CS-1003, BI-754091, LZM-009, Sym-021, BAT-1306, 10 PD1-PIK, tebotelimab (MGD013; PD-l / LAG-3), RO-7247669 (PD-l / LAG-3), FS-118 (LAG-3 / PD-L1), RO-7121661 (PD-l / TIM-3), RG7769 (PD-l / TIM-3), PF-06936308 (PD-1 / CTLA4), MGD-019 (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4), XmAb-20717 (PD-1 / CTLA4), AK-104 (CTLA4 / PD-1) and MEDI-5752 (CTLA4 / PD-1).

348. The kit of claim 344, wherein the proteinaceous (e.g., antibody) 15 inhibitor of CD274 molecule (NCBI Gene ID: Gene ID: 29126; B7-H, B7H1, PD-L1) is selected from the group consisting of atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®; MSB0010718C), envafolimab (ASC22), durvalumab (IMFINZI®; MEDI-4736), BMS-936559 (MDX1105), cosibelimab (CK-301), lodapolimab (LY 3300054), garivulimab (BGB A333), envafolimab (KN035), opucolimab (HLX 20), manelimab (BCD 20   135), CX-072, CBT-502 (TQB2450), MSB-2311, SHR-1316, sugemalimab (CS-1001;WBP3155), A167 (KL-A167, HBM 9167), STI-A1015 (IMC-001), FAZ-053, BMS-936559 (MDX1105), INCB086550, GEN-1046 (PD-L1 / 4-1BB), FPT-155 (CTLA4 / PD-L1 / CD28), M7824 (PD-Ll / TGFp-EC domain), CA-170 (PD-L1 / VISTA), CDX-527 (CD27 / PD-L1), LY-3415244 (TIM-3 / PDL1), INBRX-105 (4-1BB / PDL1) and GNS-1480 (PD-L1 / EGFR).25                349. The kit of any one of claims 334 to 342, comprising a small moleculeinhibitor of CD274 (PDL1, PD-L1), programmed cell death 1 (PDCD1, PD1, PD-1) or CTLA4.

350. The kit of claim 346, wherein the small molecule inhibitor of CD274 or PDCD1 is selected from the group consisting of GS-4224, GS-4416, INCB086550 and 30  MAX10181.

351. The kit of claim 346, wherein the small molecule inhibitor of CTLA4 comprises BPI-002.2024202988   06 May 2024352.   The kit of any one of claims 284 to 351, comprising one or moreagents that selectively deplete regulatory T (Treg) cells.

353. The kit of claim 352, wherein the one or more agents that selectivelydeplete effector regulatory T (Treg) cells comprise an antibody or antigen-binding fragment 5 thereof that selectively binds to a cell surface receptor selected from the group consisting of C-C motif chemokine receptor 4 (CCR4), C-C motif chemokine receptor 7 (CCR7), C-C motif chemokine receptor 8 (CCR8), C-X-C motif chemokine receptor 4 (CXCR4; CD 184), TNFRSF4 (OX40), TNFRSF18 (GITR, CD357), TNFRSF9 (4-1BB, CD137), cytotoxic T-lymphocyte associated protein 4 (CTLA4, CD 152), programmed cell death 1 (PDCD1, PD-10   1), Sialyl Lewis x (CD 15s), CD27, ectonucleoside triphosphate diphosphohydrolase 1(ENTPD1; CD39), protein tyrosine phosphatase receptor type C (PTPRC; CD45), neural cell adhesion molecule 1 (NCAM1; CD56), selectin L (SELL; CD62L), integrin subunit alpha E (ITGAE; CD 103), interleukin 7 receptor (IL7R; CD 127), CD40 ligand (CD40LG; CD 154), folate receptor alpha (FOLRI), folate receptor beta (FOLR2), leucine rich repeat15 containing 32 (LRRC32; GARP), IKAROS family zinc finger 2 (IKZF2; HELIOS), inducible T cell costimulatory (ICOS; CD278), lymphocyte activating 3 (LAG3; CD223), transforming growth factor beta 1 (TGFB1), hepatitis A virus cellular receptor 2 (HAVCR2; CD366; TIM3), T cell immunoreceptor with Ig and ITIM domains (TIGIT), TNF receptor superfamily member IB (CD 120b; TNFR2), IL-2RA (CD25), and combinations thereof.20                354.  The kit of any one of claims 284 to 353, comprising one or moreadditional therapeutic agents comprising an inhibitor or antagonist of:• mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1) (also called Hematopoietic Progenitor Kinase 1 (HPK1)),• phosphatidylinositol-4,5-bisphosphate 3-kinase, including catalytic25                     subunit alpha (PIK3CA), catalytic subunit beta (PIK3CB), catalyticsubunit gamma (PIK3CG) and catalytic subunit delta (PIK3CD),• diacylglycerol kinase alpha (DGKA, DAGK, DAGK1 or DGK-alpha),• T cell immunoreceptor with Ig and ITIM domains (TIGIT),• X-linked inhibitor of apoptosis (XIAP, BIRC4, IAP-3),30                 • baculoviral IAP repeat containing 2 (BIRC2, cIAPl),• baculoviral IAP repeat containing 3 (BIRC3, cIAP2),• baculoviral IAP repeat containing 5 (BIRC5, survivin), or• cytokine inducible SH2 containing protein (CISH).2024202988   06 May 2024355. The kit of any one of claims 284 to 354, comprising one or more additional therapeutic agents comprising an activator or agonist of:• a toll-like receptor (TLR);• a stimulator of interferon genes (STING) receptor;5                 • inducible T cell costimulator (ICOS, CD278); and / or• a TNF receptor superfamily (TNFRSF) member.

356. The kit of claim 355, wherein the TNF receptor superfamily (TNFRSF) member is selected from the group consisting of: TNFRSF 1 A, TNFRSF IB, TNFRSF4 (OX40), TNFRSF5 (CD40), TNFRSF6 (FAS), TNFRSF7 (CD27), TNFRSF810   (CD30), TNFRSF9 (4-1BB, CD137), TNFRSF10A (CD261, DR4, TRAILRI),TNFRSF10B (CD262, DR5, TRAILR2), TNFRSF10C (CD263, TRAILR3), TNFRSF10D (CD264, TRAILR4), TNFRSF11A (CD265, RANK), TNFRSF 1 IB, TNFRSF 12A (CD266), TNFRSF13B (CD267), TNFRSF13C (CD268), TNFRSF16 (NGFR, CD271), TNFRSF17 (BCMA, CD269), TNFRSF 18 (GITR, CD357), TNFRSF 19, TNFRSF21 (CD358, DR6),15 and TNFRSF25 (DR3).

357. The kit of claim 356, wherein:• the TNFRSF4 (OX40 or CD 134) activator or agonist comprises INCAGN1949, tavolimab (MEDI0562), pogalizumab (MOXR0916 / RG7888), MEDI6469, BMS-986178, PF-04518600,20                  GSK3174998, IBI101, ATOR-1015, ABBV-368 or SL-279252;• the TNFRSF9 (4-IBB or CD 137) activator or agonist comprises urelumab, BMS-663513, utomilumab (PF-05082566), CTX-471, MP-0310, ADG-106, ATOR-1017, AGEN2373 or QL1806; and / or• the TNFRSF 18 (GITR or CD357) activator or agonist comprises25                 GWN323, MEDI1873, MK-1248, MK-4166, TRX518, INCAGN1876,BMS-986156, BMS-986256, AMG-228, ASP1951 (PTZ 522), FPA-154 or OMP-336B11.

358. The kit of any one of claims 356 to 357, comprising a molecule that concurrently binds to TNF receptor superfamily member 4 (TNFRSF4, OX40 or CD 134)30 and TNF receptor superfamily member 18 (TNFRSF 18, GITR or CD357).2024202988   06 May 2024359. The kit of any one of claims 356 to 358, comprising a molecule selected from the group consisting of AGEN 1884 (zalifrelimab), AGEN1181, AGEN 2034 (balstilimab), AGEN1307, AGEN2373, AGEN1223 and GS-1423.

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