Il-2-fc fusion protein for use in treating autoimmune diseases

Abstract

The present invention provides, among other things, a method of treating autoimmune diseases comprising subcutaneously administering to a patient an IL-2 fusion protein comprising an IL-2 variant and an Fc region. The method provides, among other things, particularly effective weight-based and flat dosing of an IL-2 fusion protein for treatment of autoimmune diseases.

Description

Attorney Docket No.: SVI-017WO1METHOD FOR DELIVERING IL-2 FUSION PROTEINCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 746,500, filed January 17, 2025, and U.S. Provisional Application No. 63 / 798,718, filed May 2, 2025, the contents of each of which are hereby incorporated herein by reference in their entireties.BACKGROUND

[0002] Interleukin-2 (IL-2) is a cytokine that regulates the activities of the immune system. It is produced by leukocytes, such as T cells, natural killer (NK) cells, dendritic cells, and macrophages, in response to antigenic or mitogenic stimulation. IL-2 is important for T cell proliferation, B cell stimulation, and other activities associated with immunity and tolerance. It is part of the body’s adaptive immune response and discriminates between foreign and host antigens. IL-2 mediates its effects by binding to IL-2 receptors, which in turn activate downstream signaling events.

[0003] Human IL-2 is an FDA-approved drug for the treatment of diseases such as metastatic renal carcinoma and melanoma. The use of IL-2 in eligible patients is sometimes restricted due to the severe toxicity associated with IL-2 therapy, and only a small subset of eligible patients will actually receive therapy. The toxicities associated with IL-2 therapy can include severe fever, nausea, vomiting, vascular leak and serious hypotension.SUMMARY OF THE INVENTION

[0004] The present invention provides, among other things, a safer and more potent method for treating an autoimmune disease based on IL-2 fusion proteins using dosing regimens described herein. The present invention is, in part, based on a therapeutically effective regimen resulting in (1) selective Tregexpansion with minimal impact on other immune cell populations (e.g., conventional T helper cells, cytotoxic T lymphocytes, and natural killer cells); (2) sustained increase in Tregexpansion; and (3) long-lasting serum concentrations of the IL-2 fusion protein, while keeping adverse events low.Attorney Docket No.: SVI-017WO1

[0005] In one aspect, the present invention provides, among other things, a method of treating an autoimmune disease comprising subcutaneously administering an IL-2 Fc fusion protein to a patient at a dose of 10-24 pg / kg no more frequent than once every two weeks, or an equivalent dosing regimen thereof. In some embodiments, the IL-2 Fc fusion protein comprises an IL-2 variant comprising 95% identity to SEQ ID NO: 1 and amino acid substitutions H16L, V69A, Q74P, and C125S; and an Fc region.

[0006] In some embodiments, the IL-2 Fc fusion protein is administered at a dose of 10 ug / kg. In some embodiments, the IL-2 Fc fusion protein is administered at a dose of 12 pg / kg. In some embodiments, the IL-2 Fc fusion protein is administered at a dose of 14 pg / kg. In some embodiments, the IL-2 Fc fusion protein is administered at a dose of 16 pg / kg. In some embodiments, the IL-2 Fc fusion protein is administered at a dose of 18 pg / kg. In some embodiments, the IL-2 Fc fusion protein is administered at a dose of 20 pg / kg. In some embodiments, the IL-2 Fc fusion protein is administered at a dose of 22 pg / kg. In some embodiments, the IL-2 Fc fusion protein is administered at a dose of or 24 pg / kg. In some embodiments, the IL-2 Fc fusion protein is administered at a dose of or 26 pg / kg. In some embodiments, the IL-2 Fc fusion protein is administered at a dose of or 28 Fg / kg-

[0007] In some embodiments, the IL-2 Fc fusion protein is administered no more frequent than once every two weeks. In some embodiments, the IL-2 Fc fusion protein is administered no more frequent than once every three weeks. In some embodiments, the IL-2 Fc fusion protein is administered no more frequent than once every four weeks. In some embodiments, the IL-2 Fc fusion protein is administered no more frequent than once every five weeks. In some embodiments, the IL-2 Fc fusion protein is administered no more frequent than once every six weeks.

[0008] In some embodiments, the IL-2 Fc fusion protein is administered every week. In some embodiments, the IL-2 Fc fusion protein is administered once every two weeks. In some embodiments, the IL-2 Fc fusion protein is administered once every three weeks. In some embodiments, the IL-2 Fc fusion protein is administered once every four weeks. In some embodiments, the IL-2 Fc fusion protein is administered once every five weeks. In some embodiments, the IL-2 Fc fusion protein is administered once every six weeks. In some embodiments, the IL-2 Fc fusion protein is administered once every eight weeks. In someAttorney Docket No.: SVI-017WO1embodiments, the IL-2 Fc fusion protein is administered once every ten weeks. In some embodiments, the IL-2 Fc fusion protein is administered once every twelve weeks.

[0009] In one aspect, the present invention provides, among other things, a method of treating an autoimmune disease comprising subcutaneously administering an IL-2 Fc fusion protein to a patient at a dose of 12 pg / kg once every four weeks, or an equivalent dosing regimen thereof, and wherein the IL-2 Fc fusion protein comprises an IL-2 variant comprising 95% identity to SEQ ID NO: 1 and amino acid substitutions H16L, V69A, Q74P, and C125S; and an Fc region.

[0010] In some embodiments, the dose is administered for a treatment period of at least 4 weeks. In some embodiments, the dose is administered for a treatment period of at least 6 weeks. In some embodiments, the dose is administered for a treatment period of at least 8 weeks. In some embodiments, the dose is administered for a treatment period of at least 10 weeks. In some embodiments, the dose is administered for a treatment period of at least 12 weeks. In some embodiments, the dose is administered for a treatment period of at least 16 weeks. In some embodiments, the dose is administered for a treatment period of at least 20 weeks. In some embodiments, the dose is administered for a treatment period of at least 24 weeks. In some embodiments, the dose is administered for a treatment period of at least 32 weeks. In some embodiments, the dose is administered for a treatment period of at least 36 weeks.

[0011] In one aspect, the present invention provides, among other things, a method of treating an autoimmune disorder comprising subcutaneously administering an IL-2 Fc fusion protein to a patient at a therapeutically effective dosing regimen wherein the IL-2 Fc fusion protein comprises an IL-2 variant comprising 95% identity to SEQ ID NO: 1 and amino acid substitutions H16L, V69A, Q74P, and C125S; and an Fc region.

[0012] In some embodiments, the therapeutically effective dosing regimen produces a Cmax of between 10 ng / mL and 50 ng / mL. In some embodiments, the therapeutically effective dosing regimen produces a Cmax of at least 10 ng / mL. In some embodiments, the therapeutically effective dosing regimen produces a Cmax of at least 15 ng / mL. In some embodiments, the therapeutically effective dosing regimen produces a Cmax of at least 20 ng / mL. In some embodiments, the therapeutically effective dosing regimen produces a Cmax of at least 25 ng / mL. In some embodiments, the therapeutically effective dosing regimen produces a Cmax of at least 30 ng / mL. In some embodiments, the therapeutically effectiveAttorney Docket No.: SVI-017WO1dosing regimen produces a Cmax of at least 35 ng / mL. In some embodiments, the therapeutically effective dosing regimen produces a Cmax of at least 40 ng / mL. In some embodiments, the therapeutically effective dosing regimen produces a Cmax of at least 45 ng / mL. In some embodiments, the therapeutically effective dosing regimen produces a Cmax of at least 50 ng / mL.

[0013] In some embodiments, the therapeutically effective dosing regimen selectively increases the percentage of regulatory T cells (Tregs) in a population of T cells to at least 10% as compared to a control. In some embodiments, the therapeutically effective dosing regimen selectively increases the percentage of regulatory T cells (Tregs) in a population of T cells to at least 11% as compared to a control. In some embodiments, the therapeutically effective dosing regimen selectively increases the percentage of regulatory T cells (Tregs) in a population of T cells to at least 12% as compared to a control. In some embodiments, the therapeutically effective dosing regimen selectively increases the percentage of regulatory T cells (Tregs) in a population of T cells to at least 13% as compared to a control. In some embodiments, the therapeutically effective dosing regimen selectively increases the percentage of regulatory T cells (Tregs) in a population of T cells to at least 14% as compared to a control. In some embodiments, the therapeutically effective dosing regimen selectively increases the percentage of regulatory T cells (Tregs) in a population of T cells to at least 15% as compared to a control.

[0014] In some embodiments, the control is the patient prior to administration of the IL-2 Fc fusion protein. In some embodiments, the control is historical data. In some embodiments, the control is a comparable recipient without the administration of the IL-2 Fc fusion protein.

[0015] In some embodiments, the therapeutically effective dosing regimen comprises administering the IL-2 Fc fusion protein at a dose of 10 pg / kg. In some embodiments, the therapeutically effective dosing regimen comprises administering the IL-2 Fc fusion protein at a dose of 12 pg / kg. In some embodiments, the therapeutically effective dosing regimen comprises administering the IL-2 Fc fusion protein at a dose of 14 pg / kg. In some embodiments, the therapeutically effective dosing regimen comprises administering the IL-2 Fc fusion protein at a dose of 16 pg / kg. In some embodiments, the therapeutically effective dosing regimen comprises administering the IL-2 Fc fusion protein at a dose of 18 pg / kg. In some embodiments, the therapeutically effective dosing regimen comprises administering theAttorney Docket No.: SVI-017WO1IL-2 Fc fusion protein at a dose of 20 pg / kg. In some embodiments, the therapeutically effective dosing regimen comprises administering the IL-2 Fc fusion protein at a dose of 22 pg / kg. In some embodiments, the therapeutically effective dosing regimen comprises administering the IL-2 Fc fusion protein at a dose of 24 pg / kg.

[0016] In some embodiments, the therapeutically effective dosing regimen comprises administering the IL-2 Fc fusion protein no more frequent than once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises administering the IL-2 Fc fusion protein no more frequent than once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises administering the IL-2 Fc fusion protein no more frequent than once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises administering the IL-2 Fc fusion protein no more frequent than once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises administering the IL-2 Fc fusion protein no more frequent than once every six weeks.

[0017] In some embodiments, the therapeutically effective dosing regimen comprises administering the IL-2 Fc fusion protein once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises administering the IL-2 Fc fusion protein once every three weeks. In some embodiments the therapeutically effective dosing regimen comprises administering the IL-2 Fc fusion protein once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises administering the IL-2 Fc fusion protein once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises administering the IL-2 Fc fusion protein once every six weeks.

[0018] In some embodiments, the therapeutically effective dosing regimen comprises administering the IL-2 Fc fusion protein for a treatment period of at least 4 weeks. In some embodiments, the therapeutically effective dosing regimen comprises administering the IL-2 Fc fusion protein for a treatment period of at least 6 weeks. In some embodiments, the therapeutically effective dosing regimen comprises administering the IL-2 Fc fusion protein for a treatment period of at least 8 weeks. In some embodiments, the therapeutically effective dosing regimen comprises administering the IL-2 Fc fusion protein for a treatment period of at least 10 weeks. In some embodiments, the therapeutically effective dosing regimen comprises administering the IL-2 Fc fusion protein for a treatment period of at least 12 weeks. In some embodiments, the therapeutically effective dosing regimen comprisesAttorney Docket No.: SVI-017WO1administering the IL-2 Fc fusion protein for a treatment period of at least 16 weeks. In some embodiments, the therapeutically effective dosing regimen comprises administering the IL-2 Fc fusion protein for a treatment period of at least 20 weeks. In some embodiments, the therapeutically effective dosing regimen comprises administering the IL-2 Fc fusion protein for a treatment period of at least 24 weeks.

[0019] In one aspect, the present invention provides, among other things, a method of treating an autoimmune disease comprising subcutaneously administering an IL-2 Fc fusion protein to a patient at a flat dose of 100-2000 pg, and wherein the IL-2 Fc fusion protein comprises an IL-2 variant comprising 95% identity to SEQ ID NO: 1 and amino acid substitutions H16L, V69A, Q74P, and C125S; and an Fc region. In some embodiments, the IL-2 Fc fusion protein is administered at a flat dose of 500-1500 pg.

[0020] In some embodiments, the IL-2 Fc fusion protein is administered at a flat dose of 100 pg. In some embodiments, the IL-2 Fc fusion protein is administered at a flat dose of 250 pg. In some embodiments, the IL-2 Fc fusion protein is administered at a flat dose of 300 pg. In some embodiments, the IL-2 Fc fusion protein is administered at a flat dose of 400 pg. In some embodiments, the IL-2 Fc fusion protein is administered at a flat dose of 500 pg. In some embodiments, the IL-2 Fc fusion protein is administered at a flat dose of 600 pg. In some embodiments, the IL-2 Fc fusion protein is administered at a flat dose of 700 pg. In some embodiments, the IL-2 Fc fusion protein is administered at a flat dose of 750 pg. In some embodiments, the IL-2 Fc fusion protein is administered at a flat dose of 800 pg. In some embodiments, the IL-2 Fc fusion protein is administered at a flat dose of 1000 pg. In some embodiments, the IL-2 Fc fusion protein is administered at a flat dose of 1250 pg. In some embodiments, the IL-2 Fc fusion protein is administered at a flat dose of 1500 pg. In some embodiments, the IL-2 Fc fusion protein is administered at a flat dose of 1750 pg. In some embodiments, the IL-2 Fc fusion protein is administered at a flat dose of 2000 pg. In some embodiments, the IL-2 Fc fusion protein is administered at a flat dose of 2500 pg.

[0021] In some embodiments, the IL-2 Fc fusion protein is administered at a flat dose no more frequent than once every two weeks. In some embodiments, the IL-2 Fc fusion protein is administered at a flat dose no more frequent than once every three weeks. In some embodiments, the IL-2 Fc fusion protein is administered at a flat dose no more frequent than once every four weeks. In some embodiments, the IL-2 Fc fusion protein is administered at aAttorney Docket No.: SVI-017WO1flat dose no more frequent than once every five weeks. In some embodiments, the IL-2 Fc fusion protein is administered at a flat dose no more frequent than once every six weeks.

[0022] In some embodiments, the IL-2 Fc fusion protein is administered at a flat dose once every two weeks. In some embodiments, the IL-2 Fc fusion protein is administered at a flat dose once every three weeks. In some embodiments, the IL-2 Fc fusion protein is administered at a flat dose once every four weeks. In some embodiments, the IL-2 Fc fusion protein is administered at a flat dose once every five weeks. In some embodiments, the IL-2 Fc fusion protein is administered at a flat dose once every six weeks.

[0023] In some embodiments, the flat dose is administered as a single dose.

[0024] In some embodiments, the autoimmune disease is systemic lupus erythematosus (SLE). In some embodiments, the autoimmune disease is autoimmune hepatitis (AIH). In some embodiments, the autoimmune disease is immune-mediated focal segmental glomerulosclerosis (FSGS). In some embodiments, the autoimmune disease is alopecia areata (AA).

[0025] In some embodiments, the IL-2 variant comprises an amino acid sequence of SEQ ID NO: 4. In some embodiments, the IL-2 variant further comprises amino acid substitution T3A.

[0026] In some embodiments, the Fc region comprises an Fc region of IgGl. In some embodiments, the Fc region of IgGl comprises amino acid substitution N297G according to EU numbering. In some embodiments, the Fc region comprises an Fc region of human IgGl allotype m3. In some embodiments, the Fc of human IgGl allotype m3 comprises amino acid substitution N297G according to EU numbering.

[0027] In some embodiments, the Fc region comprises an amino acid sequence at least 85% identical to SEQ ID NO: 11. In some embodiments, the Fc region comprises an amino acid sequence at least 90% identical to SEQ ID NO: 11. In some embodiments, the Fc region comprises an amino acid sequence at least 95% identical to SEQ ID NO: 11. In some embodiments, the Fc region comprises an amino acid sequence at least 96% identical to SEQ ID NO: 11. In some embodiments, the Fc region comprises an amino acid sequence at least 97% identical to SEQ ID NO: 11. In some embodiments, the Fc region comprises an amino acid sequence at least 98% identical to SEQ ID NO: 11. In some embodiments, the Fc regionAttorney Docket No.: SVI-017WO1comprises an amino acid sequence at least 99% identical to SEQ ID NO: 11. In some embodiments, the Fc region comprises an amino acid sequence of SEQ ID NO: 11.

[0028] In some embodiments, the Fc region is fused to the C-terminus of the IL-2 variant. In some embodiments, the IL-2 Fc fusion protein further comprises a linker. In some embodiments, the linker comprises an amino acid sequence of SEQ ID NO: 13.

[0029] In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence at least 85% identical to SEQ ID NO: 27. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence at least 90% identical to SEQ ID NO: 27. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence at least 95% identical to SEQ ID NO: 27. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence at least 96% identical to SEQ ID NO: 27. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence at least 97% identical to SEQ ID NO: 27. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence at least 98% identical to SEQ ID NO: 27. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence at least 99% identical to SEQ ID NO: 27. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence of SEQ ID NO: 27.

[0030] In some embodiments, the IL-2 Fc fusion protein forms a dimer. In some embodiments, the dimer is a homodimer. In some embodiments, the dimer is a heterodimer.BRIEF DESCRIPTION OF THE DRAWINGS

[0031] The drawings are for illustration purposes only, and are not meant to be limiting.

[0032] FIG. 1 is an exemplary graph showing the mean percent of regulatory T cells (Tregs) out of the population of CD4+ T cells after administration of an exemplary IL-2 fusion protein at a dose of 1 pg / kg, 4 pg / kg, 12 pg / kg, 24 pg / kg, or 32 pg / kg.

[0033] FIG. 2 is an exemplary graph showing the mean percent of activated Tregs out of the population of CD4+ T cells after administration of an exemplary IL-2 fusion protein at a dose of 1 pg / kg, 4 pg / kg, 12 pg / kg, 24 pg / kg, or 32 pg / kg. Activated Tregs were identified as lacking CD45RA expression and having high FoxP3 expression.Attorney Docket No.: SVI-017WO1

[0034] FIG. 3 is an exemplary graph showing the mean concentration (pg / mL) of soluble CD25 (sCD25) after administration of an exemplary IL-2 fusion protein at a dose of 1 pg / kg, 4 pg / kg, 12 pg / kg, 24 pg / kg, or 32 pg / kg.

[0035] FIG. 4 is an exemplary chart showing the relative abundance of different Treg subsets pre and post administration of an exemplary IL-2 fusion protein at a dose of 1 pg / kg, 4 pg / kg, 12 pg / kg, 24 pg / kg, or 32 pg / kg.

[0036] FIG. 5A is exemplary uniform manifold approximation and projection (UMAP) showing the clustering Tregs induced by administration of an exemplary IL-2 fusion protein. Four clusters were identified: naive Tregs, proliferating Tregs, and two distinct clusters of effector Tregs. FIG. 5B is an exemplary UMAP demonstrating the distinction between effector Treg clusters by expression of Helios (IKZF2) and Galectin-1 (LGALS1).

[0037] FIG. 6 are exemplary cell density UMAP plots showing the Treg subsets before and after dosing with an exemplary IL-2 fusion protein at a dose of 1 pg / kg, 4 pg / kg, 12 pg / kg, 24 pg / kg, or 32 pg / kg.

[0038] FIGs. 7A and 7B are exemplary graphs showing the mean serum concentration (ng / mL), in linear and semi-log scales, respectively, of an exemplary IL-2 fusion protein after administration of the IL-2 fusion protein at a dose of 1 pg / kg, 4 pg / kg, 12 pg / kg, 24 pg / kg, or 32 pg / kg.

[0039] FIG. 8 is an exemplary graph showing the mean percent of regulatory T cells (Tregs) out of the population of CD4+ T cells after Q2W administration of an exemplary IL-2 fusion protein at a dose of 10 pg / kg or 24 pg / kg.

[0040] FIG. 9 is an exemplary graph showing the mean percent of activated Tregs out of the population of CD4+ T cells after Q2W administration of an exemplary IL-2 fusion protein at a dose of 10 pg / kg or 24 pg / kg.

[0041] FIG. 10 is an exemplary graph showing the mean concentration (pg / mL) of soluble CD25 (sCD25) after Q2W administration of an exemplary IL-2 fusion protein at a dose of 10 pg / kg or 24 pg / kg.

[0042] FIGs. HA and 11B are exemplary graphs showing the mean serum concentration (ng / mL), in linear and semi-log scales, respectively, of an exemplary IL-2 fusion protein after the first administration of the IL-2 fusion protein at a dose of 10 pg / kg orAttorney Docket No.: SVI-017WO124 pg / kg on Day 1. FIGs. 11C and 11D are exemplary graphs showing the mean serum concentration (ng / mL), in linear and semi-log scales, respectively, of an exemplary IL-2 fusion protein after the fourth and final administration of the IL-2 fusion protein at a dose of 10 pg / kg or 24 pg / kg on Day 43.DEFINITIONS

[0043] In order for the present disclosure to be more readily understood, certain terms are first defined below. Additional definitions for the following terms and other terms are set forth throughout the specification.

[0044] Any numerical values used in this application are meant to cover any variations within the standard deviation or normal fluctuations appreciated by one of ordinary skill in the relevant art.

[0045] "Alpha-biased IL-2 variant" is used herein to refer to an IL-2 variant that comprises one or more mutations that increase binding to an IL-2 receptor alpha subunit (CD25) or decrease binding to an IL-2 receptor beta subunit (CD 122) or gamma subunit (CD 132) as compared to a wild-type IL-2. In some embodiments, an alpha-biased IL-2 variant has a preferential binding to a trimeric IL-2 receptor over the dimeric IL-2 receptor.

[0046] The term “Fc” refers to a portion of a heavy chain constant region that comprises at least the CH2 and CH3 domains that typically bind to an Fc receptor e.g., an FcyR, namely FcyRI (CD64), FcyRII (CD32), FcyRIII (CD16) or an FcRn, i.e., a neonatal Fc receptor. The Fc variants of the present invention may be optimized for a variety of properties. An Fc variant that is engineered or predicted to display one or more optimized properties is herein referred to as an “optimized Fc variant”. In some embodiments, an optimized Fc variant has reduced or ablated affinity for FcyRI, FcyRIIa, FcyRIIb, FcyRIIIa, FcyRIIIb, and Clq, and retains binding to FcRn.

[0047] As used herein, “increased half-life" or "increase serum half-life" or "extending half-life" means the positive change in the circulating half-life of a modified biologically active molecule (e.g., an IL-2 variant) relative to its non -modified form (or naked form of the peptide). Serum half- life is measured, for example, by taking blood samples at various time points after administration of the biologically active molecule and determining the concentration of that molecule in each sample.Attorney Docket No.: SVI-017WO1

[0048] Treating'. As used herein, the term “treat,” “treatment,” or “treating” refers to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of and / or reduce incidence of one or more symptoms or features of a particular disease, disorder, and / or condition. Treatment may be administered to a subject who does not exhibit signs of a disease and / or exhibits only early signs of the disease for the purpose of decreasing the risk of developing pathology associated with the disease.

[0049] As used herein, “variant” “mutant” and “mutein” refer to biologically active derivatives of the reference molecule that retain desired activity or are engineered for specific activity, such as the alpha-biased IL-2 variants described herein with increased affinity for CD25 and / or decreased affinity for CD122 and / or CD132. In general, the terms “variant” and “mutant” refer to compounds having a native polypeptide sequence and structure with one or more amino acid additions, substitutions (generally conservative in nature) and / or deletions, relative to the native molecule, so long as the modifications do not destroy biological activity, and which are “substantially homologous” to the reference molecule as defined below. In general, the amino acid sequences of such variants will have a high degree of sequence homology to the reference sequence, e.g., amino acid sequence homology of more than 50%, generally more than 60%-70%, even more particularly 80%-85% or more, such as at least 90%-95% or more, when the two sequences are aligned. Often, the variants will include the same number of amino acids but will include substitutions, as explained herein. The term “mutant” further includes polypeptides having one or more amino acid-like molecules including but not limited to compounds comprising only amino and / or imino molecules, polypeptides containing one or more analogs of an amino acid (including, for example, unnatural amino acids, etc.), polypeptides with substituted linkages, as well as other modifications known in the art, both naturally occurring and non-naturally occurring (e.g., synthetic), cyclized, branched molecules and the like.DETAILED DESCRIPTION

[0050] The present invention provides, among other things, a safer and more potent method for treating an autoimmune disease based on IL-2 fusion proteins using dosing regimens described herein. The present invention is, in part, based on a therapeutically effective regimen resulting in (1) selective Tregexpansion with minimal impact on otherAttorney Docket No.: SVI-017WO1immune cell populations (e.g., conventional T helper cells, cytotoxic T lymphocytes, and natural killer cells); (2) sustained increase in Tregexpansion; and (3) long-lasting serum concentrations of the IL-2 fusion protein, while keeping adverse events low.Interleukin-2 (IL-2) Fusion Protein

[0051] The present invention provides, among other things, a method of delivering an IL-2 fusion protein for treating autoimmune diseases. An IL-2 fusion protein described herein comprises an IL-2 variant and a half-life extension domain (e.g., Fc region).IL-2 Variant

[0052] IL-2 is a cytokine that plays a role in the activation, growth, and differentiation of T cells, particularly in T cell stimulation and B cell proliferation and maturation. An IL-2 receptor, with its different affinity forms, mediates the diverse biological functions of IL-2 in the immune system, including T cell activation, proliferation, and regulation of immune responses. The IL-2 receptor consists of one or more subunits selected from: IL-2RP (CD122), IL-2Ry (CD132), and IL-2Ra (CD25). The dimeric IL-2 receptor, comprising CD122 and CD132, is common to cytotoxic T cells and natural killer (NK) cells which participate in the adaptive and innate immune response, respectively. On the other hand, the trimeric IL-2 receptor, further comprising CD25, is associated with regulatory T cells (Tregs) which promote immune tolerance.

[0053] Alpha-biased IL-2 variants are IL-2 variants with mutations that increase binding to IL-2Ra (CD25) and decrease binding to IL-2RP (CD122) and / or IL-2Ry (CD132). Without wishing to be bound to any particular theory, it is thought that alpha-biased IL-2 variants preferentially bind to the trimeric IL-2 receptor, which contains CD25. The preferential binding to the trimeric receptor results in preferential binding to and activation of Tregs, which can induce immune tolerance and reduce transplant rejection. In some embodiments, the IL-2 variant is an alpha-biased IL-2 variant.

[0054] In some embodiments, the IL-2 variant comprises increased affinity to CD25 as compared to wild-type IL-2. In some embodiments, the IL-2 variant comprises increased affinity to CD25 as compared to its affinity to CD122 and / or CD132. In some embodiments, the IL-2 variant comprises decreased affinity to CD122 and / or CD132 as compared to wildtype IL-2. In some embodiments, the IL-2 variant comprises decreased affinity to CD122 and CD 132 as compared to wild-type IL-2. In some embodiments, the IL-2 variant comprisesAttorney Docket No.: SVI-017WO1decreased affinity to CD 122 as compared to wild-type IL-2. In some embodiments, the IL-2 variant comprises decreased affinity to CD 132 as compared to wild-type IL-2. In some embodiments, the IL-2 variant comprises decreased affinity to the CD122 / CD132 heterodimer as compared to wild-type IL-2. In some embodiments, the IL-2 variant preferentially binds to the trimeric IL-2 receptor over the dimeric IL-2 receptor.

[0055] In some embodiments, the IL-2 variant is further engineered to increase protein stability and expression. In some embodiments, the IL-2 variant is further engineered to increase protein stability. In some embodiments, the IL-2 variant is further engineered to increase protein expression.

[0056] In some embodiments, the IL-2 variant comprises a deletion of the alanine at position 1 (e.g., Al).

[0057] In some embodiments, the IL-2 variant comprises an amino acid substitution at the T3 position. In some embodiments, the IL-2 variant alpha-biased comprises an amino acid substitution of T3A, T3R, T3N, T3D, T3C, T3E, T3Q, T3G, T3H, T3I, T3L, T3K, T3M, T3F, T3P, T3W, T3 Y, or T3 V. In some embodiments, the IL-2 alpha-biased variant comprises an amino acid substitution of T3A. In some embodiments, the IL-2 variant comprises an amino acid substitution of T3R. In some embodiments, the IL-2 variant comprises an amino acid substitution of T3N. In some embodiments, the IL-2 variant comprises an amino acid substitution of T3D. In some embodiments, the IL-2 variant comprises an amino acid substitution of T3C. In some embodiments, the IL-2 variant comprises an amino acid substitution of T3E. In some embodiments, the IL-2 variant comprises an amino acid substitution of T3Q. In some embodiments, the IL-2 variant comprises an amino acid substitution of T3G. In some embodiments, the IL-2 variant comprises an amino acid substitution of T3H. In some embodiments, the IL-2 variant comprises an amino acid substitution of T3I. In some embodiments, the IL-2 variant comprises an amino acid substitution of T3L. In some embodiments, the IL-2 variant comprises an amino acid substitution of T3K. In some embodiments, the IL-2 variant comprises an amino acid substitution of T3M. In some embodiments, the IL-2 variant comprises an amino acid substitution of T3F. In some embodiments, the IL-2 variant comprises an amino acid substitution of T3P. In some embodiments, the IL-2 variant comprises an amino acid substitution of T3W. In some embodiments, the IL-2 variantAttorney Docket No.: SVI-017WO1comprises an amino acid substitution of T3Y. In some embodiments, the IL-2 variant comprises an amino acid substitution of T3V.

[0058] In some embodiments, the IL-2 variant comprises an amino acid substitution at the Hl 6 position. In some embodiments, the IL-2 variant comprises an amino acid substitution of H16L, H16N, H16D, H16A, H16G, H16K, H16M, H16R, H16S, H16T, H16V, or H16Y. In some embodiments, the IL-2 variant comprises an amino acid substitution of H16L. In some embodiments, the IL-2 variant comprises an amino acid substitution of H16N. In some embodiments, the IL-2 variant comprises an amino acid substitution of H16D. In some embodiments, the IL-2 variant comprises an amino acid substitution of H16A. In some embodiments, the IL-2 variant comprises an amino acid substitution of H16G. In some embodiments, the IL-2 variant comprises an amino acid substitution of H16K, In some embodiments, the IL-2 variant comprises an amino acid substitution of H16M. In some embodiments, the IL-2 variant comprises an amino acid substitution of H16R. In some embodiments, the IL-2 variant comprises an amino acid substitution of H16S. In some embodiments, the IL-2 variant comprises an amino acid substitution of H16T. In some embodiments, the IL-2 variant comprises an amino acid substitution of H16V. In some embodiments, the IL-2 variant comprises an amino acid substitution of H16Y.

[0059] In some embodiments, the IL-2 variant comprises an amino acid substitution at position V69. In some embodiments, the IL-2 variant comprises an amino acid substitution of V69A. In some embodiments, the IL-2 variant comprises an amino acid substitution of V69L.

[0060] In some embodiments, the IL-2 variant comprises an amino acid substitution at position Q74. In some embodiments, the IL-2 variant comprises an amino acid substitution of Q74P.

[0061] In some embodiments, the IL-2 variant comprises an amino acid substitution at position D84. In some embodiments, the IL-2 variant comprises an amino acid substitution of D84V. In some embodiments, the IL-2 variant comprises an amino acid substitution of D84N. In some embodiments, the IL-2 variant comprises an amino acid substitution of D84A. In some embodiments, the IL-2 variant comprises an amino acid substitution of D84E. In some embodiments, the IL-2 variant comprises an amino acid substitution of D84G. InAttorney Docket No.: SVI-017WO1some embodiments, the IL-2 variant comprises an amino acid substitution of D84I. In some embodiments, the IL-2 variant comprises an amino acid substitution of D84M. In some embodiments, the IL-2 variant comprises an amino acid substitution of D84Q. In some embodiments, the IL-2 variant comprises an amino acid substitution of D84R. In some embodiments, the IL-2 variant comprises an amino acid substitution of D84S. In some embodiments, the IL-2 variant comprises an amino acid substitution of D84T.

[0062] In some embodiments, the IL-2 variant comprises an amino acid substitution at position S87. In some embodiments, the IL-2 variant comprises an amino acid substitution of S87R. In some embodiments, the IL-2 variant comprises an amino acid substitution of S87T.

[0063] In some embodiments, the IL-2 variant comprises an amino acid substitution at position 192. In some embodiments, the IL-2 variant comprises an amino acid substitution of I92S. In some embodiments, the IL-2 variant comprises an amino acid substitution of I92K. In some embodiments, the IL-2 variant comprises an amino acid substitution of I92R. In some embodiments, the IL-2 variant comprises an amino acid substitution of I92L.

[0064] In some embodiments, the IL-2 variant comprises an amino acid substitution at position C125. In some embodiments, the IL-2 variant comprises an amino acid substitution of C125S. In some embodiments, the IL-2 variant comprises an amino acid substitution of C125A. In some embodiments, the IL-2 variant comprises an amino acid substitution of C125V. In some embodiments, the IL-2 variant comprises an amino acid substitution of C125E. In some embodiments, the IL-2 variant comprises an amino acid substitution of C125K. In some embodiments, the IL-2 variant comprises an amino acid substitution of C125H. In some embodiments, the IL-2 variant comprises an amino acid substitution of C125W. In some embodiments, the IL-2 variant comprises an amino acid substitution of C125I.

[0065] In some embodiments, the IL-2 variant comprises an amino acid substitution of H16L, H16N, V69A, Q74P, and / or I92S. In some embodiments, the IL-2 variant comprises an amino acid substitution of H16L. In some embodiments, the IL-2 variant comprises an amino acid substitution of H16N. In some embodiments, the IL-2 variant comprises an amino acid substitution of V69A. In some embodiments, the IL-2 variantAttorney Docket No.: SVI-017WO1comprises an amino acid substitution of Q74P. In some embodiments, the IL-2 variant comprises an amino acid substitution of I92S.

[0066] In some embodiments, the IL-2 variant comprises the amino acid substitutions of H16L, V69A, and Q74P. In some embodiments, the IL-2 variant comprises the amino acid substitutions of H16N, V69A, and Q74P. In some embodiments, the IL-2 variant comprises the amino acid substitutions of V69A, Q74P, and S87R. In some embodiments, the IL-2 variant comprises the amino acid substitutions of V69A, Q74P, and D84V. In some embodiments, the IL-2 variant comprises the amino acid substitutions of V69A, Q74P, and I92S.

[0067] In some embodiments, the IL-2 variant further comprises the amino acid substitution of Cl 25 S.

[0068] In some embodiments, the IL-2 variant further comprises the amino acid substitution of T3A.

[0069] In some embodiments, the IL-2 variant comprises the amino acid substitutions of H16L, V69A, Q74P, and C125S. In some embodiments, the IL-2 variant comprises the amino acid substitutions of H16N, V69A, Q74P, and C125S. In some embodiments, the IL-2 variant comprises the amino acid substitutions of V69A, Q74P, S87R, and C125S. In some embodiments, the IL-2 variant comprises the amino acid substitutions of V69A, Q74P, D84V, and C125S. In some embodiments, the IL-2 variant comprises the amino acid substitutions of V69A, Q74P, I92S, and C125S.

[0070] In some embodiments, the IL-2 variant comprises the amino acid substitutions of T3A, H16L, V69A, and Q74P. In some embodiments, the IL-2 variant comprises the amino acid substitutions of T3A, H16N, V69A, and Q74P. In some embodiments, the IL-2 variant comprises the amino acid substitutions of T3A, V69A, Q74P, and S87R. In some embodiments, the IL-2 variant comprises the amino acid substitutions of T3A, V69A, Q74P, and D84V. In some embodiments, the IL-2 variant comprises the amino acid substitutions of T3A, V69A, Q74P, and I92S.

[0071] In some embodiments, the IL-2 variant comprises the amino acid substitutions of T3A, H16L, V69A, Q74P, and C125S. In some embodiments, the IL-2 variant comprises the amino acid substitutions of T3A, H16N, V69A, Q74P, and C125S. In some embodiments, the IL-2 variant comprises the amino acid substitutions of T3A, V69A, Q74P, S87R, andAttorney Docket No.: SVI-017WO1C125S. In some embodiments, the IL-2 variant comprises the amino acid substitutions of T3A, V69A, Q74P, D84V, and C125S. In some embodiments, the IL-2 variant comprises the amino acid substitutions of T3A, V69A, Q74P, I92S, and C125S.

[0072] In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO: 2. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 2. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 91% identical to SEQ ID NO: 2. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 92% identical to SEQ ID NO: 2. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 93% identical to SEQ ID NO: 2. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 94% identical to SEQ ID NO: 2. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 2. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 96% identical to SEQ ID NO: 2. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 97% identical to SEQ ID NO: 2. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 98% identical to SEQ ID NO: 2. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 2. In some embodiments, the IL-2 variant comprises an amino acid sequence of SEQ ID NO: 2.

[0073] In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO: 3. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 3. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 91% identical to SEQ ID NO: 3. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 92% identical to SEQ ID NO: 3. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 93% identical to SEQ ID NO: 3. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 94% identical to SEQ ID NO: 3. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 3. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 96% identical to SEQ ID NO: 3. In some embodiments, the IL-2Attorney Docket No.: SVI-017WO1variant comprises an amino acid sequence that is at least 97% identical to SEQ ID NO: 3. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 98% identical to SEQ ID NO: 3. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 3. In some embodiments, the IL-2 variant comprises an amino acid sequence of SEQ ID NO: 3.

[0074] In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO: 4. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 4. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 91% identical to SEQ ID NO: 4. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 92% identical to SEQ ID NO: 4. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 93% identical to SEQ ID NO: 4. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 94% identical to SEQ ID NO: 4. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 4. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 96% identical to SEQ ID NO: 4. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 97% identical to SEQ ID NO: 4. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 98% identical to SEQ ID NO: 4. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 4. In some embodiments, the IL-2 variant comprises an amino acid sequence of SEQ ID NO: 4.

[0075] In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO: 5. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 5. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 91% identical to SEQ ID NO: 5. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 92% identical to SEQ ID NO: 5. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 93% identical to SEQ ID NO: 5. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 94% identical to SEQ ID NO: 5. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 95%Attorney Docket No.: SVI-017WO1identical to SEQ ID NO: 5. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 96% identical to SEQ ID NO: 5. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 97% identical to SEQ ID NO: 5. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 98% identical to SEQ ID NO: 5. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 5. In some embodiments, the IL-2 variant comprises an amino acid sequence of SEQ ID NO: 5.

[0076] In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO: 6. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 6. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 91% identical to SEQ ID NO: 6. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 92% identical to SEQ ID NO: 6. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 93% identical to SEQ ID NO: 6. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 94% identical to SEQ ID NO: 6. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 6. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 96% identical to SEQ ID NO: 6. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 97% identical to SEQ ID NO: 6. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 98% identical to SEQ ID NO: 6. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 6. In some embodiments, the IL-2 variant comprises an amino acid sequence of SEQ ID NO: 6.

[0077] In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO: 7. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 7. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 91% identical to SEQ ID NO: 7. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 92% identical to SEQ ID NO: 7. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 93% identical to SEQ ID NO: 7. In some embodiments, the IL-2Attorney Docket No.: SVI-017WO1variant comprises an amino acid sequence that is at least 94% identical to SEQ ID NO: 7. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 7. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 96% identical to SEQ ID NO: 7. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 97% identical to SEQ ID NO: 7. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 98% identical to SEQ ID NO: 7. In some embodiments, the IL-2 variant comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 7. In some embodiments, the IL-2 variant comprises an amino acid sequence of SEQ ID NO: 7.

[0078] In some embodiments, the IL-2 variant comprises the amino acid substitutions of H16L, V69A, and Q74P, and comprises an amino acid sequence at least 90% identical to SEQ ID NO: 1. In some embodiments, the IL-2 variant comprises the amino acid substitutions of H16N, V69A, and Q74P, and comprises an amino acid sequence at least 90% identical to SEQ ID NO: 1. In some embodiments, the IL-2 variant comprises the amino acid substitutions of V69A, Q74P, and D84V, and comprises an amino acid sequence at least 90% identical to SEQ ID NO: 1. In some embodiments, the IL-2 variant comprises the amino acid substitutions of V69A, Q74P, and S87R, and comprises an amino acid sequence at least 90% identical to SEQ ID NO: 1. In some embodiments, the IL-2 variant comprises the amino acid substitutions of V69A, Q74P, and I92S, and comprises an amino acid sequence at least 90% identical to SEQ ID NO: 1.

[0079] In some embodiments, the IL-2 variant comprises the amino acid substitutions of H16L, V69A, and Q74P, and comprises an amino acid sequence at least 95% identical to SEQ ID NO: 1. In some embodiments, the IL-2 variant comprises the amino acid substitutions of H16N, V69A, and Q74P, and comprises an amino acid sequence at least 95% identical to SEQ ID NO: 1. In some embodiments, the IL-2 variant comprises the amino acid substitutions of V69A, Q74P, and D84V, and comprises an amino acid sequence at least 95% identical to SEQ ID NO: 1. In some embodiments, the IL-2 variant comprises the amino acid substitutions of V69A, Q74P, and S87R, and comprises an amino acid sequence at least 95% identical to SEQ ID NO: 1. In some embodiments, the IL-2 variant comprises the amino acid substitutions of V69A, Q74P, and I92S, and comprises an amino acid sequence at least 95% identical to SEQ ID NO: 1.Attorney Docket No.: SVI-017WO1

[0080] In some embodiments, the IL-2 variant comprises the amino acid substitutions of H16L, V69A, and Q74P, and comprises an amino acid sequence at least 90% identical to SEQ ID NO: 2. In some embodiments, the IL-2 variant comprises the amino acid substitutions of H16N, V69A, and Q74P, and comprises an amino acid sequence at least 90% identical to SEQ ID NO: 2. In some embodiments, the IL-2 variant comprises the amino acid substitutions of V69A, Q74P, and D84V, and comprises an amino acid sequence at least 90% identical to SEQ ID NO: 2. In some embodiments, the IL-2 variant comprises the amino acid substitutions of V69A, Q74P, and S87R, and comprises an amino acid sequence at least 90% identical to SEQ ID NO: 2. In some embodiments, the IL-2 variant comprises the amino acid substitutions of V69A, Q74P, and I92S, and comprises an amino acid sequence at least 90% identical to SEQ ID NO: 2.

[0081] In some embodiments, the IL-2 variant comprises the amino acid substitutions of H16L, V69A, and Q74P, and comprises an amino acid sequence at least 95% identical to SEQ ID NO: 2. In some embodiments, the IL-2 variant comprises the amino acid substitutions of H16N, V69A, and Q74P, and comprises an amino acid sequence at least 95% identical to SEQ ID NO: 2. In some embodiments, the IL-2 variant comprises the amino acid substitutions of V69A, Q74P, and D84V, and comprises an amino acid sequence at least 95% identical to SEQ ID NO: 2. In some embodiments, the IL-2 variant comprises the amino acid substitutions of V69A, Q74P, and S87R, and comprises an amino acid sequence at least 95% identical to SEQ ID NO: 2. In some embodiments, the IL-2 variant comprises the amino acid substitutions of V69A, Q74P, and I92S, and comprises an amino acid sequence at least 95% identical to SEQ ID NO: 2.

[0082] In some embodiments, the IL-2 variant comprises the amino acid substitutions of H16L, V69A, and Q74P, and comprises an amino acid sequence at least 90% identical to SEQ ID NO: 3. In some embodiments, the IL-2 variant comprises the amino acid substitutions of H16N, V69A, and Q74P, and comprises an amino acid sequence at least 90% identical to SEQ ID NO: 3. In some embodiments, the IL-2 variant comprises the amino acid substitutions of V69A, Q74P, and D84V, and comprises an amino acid sequence at least 90% identical to SEQ ID NO: 3. In some embodiments, the IL-2 variant comprises the amino acid substitutions of V69A, Q74P, and S87R, and comprises an amino acid sequence at least 90% identical to SEQ ID NO: 3. In some embodiments, the IL-2 variant comprises the amino acidAttorney Docket No.: SVI-017WO1substitutions of V69A, Q74P, and I92S, and comprises an amino acid sequence at least 90% identical to SEQ ID NO: 3.

[0083] In some embodiments, the IL-2 variant comprises the amino acid substitutions of H16L, V69A, and Q74P, and comprises an amino acid sequence at least 95% identical to SEQ ID NO: 3. In some embodiments, the IL-2 variant comprises the amino acid substitutions of H16N, V69A, and Q74P, and comprises an amino acid sequence at least 95% identical to SEQ ID NO: 3. In some embodiments, the IL-2 variant comprises the amino acid substitutions of V69A, Q74P, and D84V, and comprises an amino acid sequence at least 95% identical to SEQ ID NO: 3. In some embodiments, the IL-2 variant comprises the amino acid substitutions of V69A, Q74P, and S87R, and comprises an amino acid sequence at least 95% identical to SEQ ID NO: 3. In some embodiments, the IL-2 variant comprises the amino acid substitutions of V69A, Q74P, and I92S, and comprises an amino acid sequence at least 95% identical to SEQ ID NO: 3.

[0084] In some embodiments, the IL-2 variant comprises the amino acid substitutions of H16L, V69A, and Q74P, and comprises an amino acid sequence at least 90% identical to SEQ ID NO: 4. In some embodiments, the IL-2 variant comprises the amino acid substitutions of H16N, V69A, and Q74P, and comprises an amino acid sequence at least 90% identical to SEQ ID NO: 4. In some embodiments, the IL-2 variant comprises the amino acid substitutions of V69A, Q74P, and D84V, and comprises an amino acid sequence at least 90% identical to SEQ ID NO: 4. In some embodiments, the IL-2 variant comprises the amino acid substitutions of V69A, Q74P, and S87R, and comprises an amino acid sequence at least 90% identical to SEQ ID NO: 4. In some embodiments, the IL-2 variant comprises the amino acid substitutions of V69A, Q74P, and I92S, and comprises an amino acid sequence at least 90% identical to SEQ ID NO: 4.

[0085] In some embodiments, the IL-2 variant comprises the amino acid substitutions of H16L, V69A, and Q74P, and comprises an amino acid sequence at least 95% identical to SEQ ID NO: 4. In some embodiments, the IL-2 variant comprises the amino acid substitutions of H16N, V69A, and Q74P, and comprises an amino acid sequence at least 95% identical to SEQ ID NO: 4. In some embodiments, the IL-2 variant comprises the amino acid substitutions of V69A, Q74P, and D84V, and comprises an amino acid sequence at least 95% identical to SEQ ID NO: 4. In some embodiments, the IL-2 variant comprises the amino acid substitutions of V69A, Q74P, and S87R, and comprises an amino acid sequence at least 95%Attorney Docket No.: SVI-017WO1identical to SEQ ID NO: 4. In some embodiments, the IL-2 variant comprises the amino acid substitutions of V69A, Q74P, and I92S, and comprises an amino acid sequence at least 95% identical to SEQ ID NO: 4.

[0086] In some embodiments, the IL-2 variant comprises the amino acid substitutions of H16L, V69A, and Q74P, and comprises an amino acid sequence at least 90% identical to SEQ ID NO: 5. In some embodiments, the IL-2 variant comprises the amino acid substitutions of H16N, V69A, and Q74P, and comprises an amino acid sequence at least 90% identical to SEQ ID NO: 5. In some embodiments, the IL-2 variant comprises the amino acid substitutions of V69A, Q74P, and D84V, and comprises an amino acid sequence at least 90% identical to SEQ ID NO: 5. In some embodiments, the IL-2 variant comprises the amino acid substitutions of V69A, Q74P, and S87R, and comprises an amino acid sequence at least 90% identical to SEQ ID NO: 5. In some embodiments, the IL-2 variant comprises the amino acid substitutions of V69A, Q74P, and I92S, and comprises an amino acid sequence at least 90% identical to SEQ ID NO: 5.

[0087] In some embodiments, the IL-2 variant comprises the amino acid substitutions of H16L, V69A, and Q74P, and comprises an amino acid sequence at least 95% identical to SEQ ID NO: 5. In some embodiments, the IL-2 variant comprises the amino acid substitutions of H16N, V69A, and Q74P, and comprises an amino acid sequence at least 95% identical to SEQ ID NO: 5. In some embodiments, the IL-2 variant comprises the amino acid substitutions of V69A, Q74P, and D84V, and comprises an amino acid sequence at least 95% identical to SEQ ID NO: 5. In some embodiments, the IL-2 variant comprises the amino acid substitutions of V69A, Q74P, and S87R, and comprises an amino acid sequence at least 95% identical to SEQ ID NO: 5. In some embodiments, the IL-2 variant comprises the amino acid substitutions of V69A, Q74P, and I92S, and comprises an amino acid sequence at least 95% identical to SEQ ID NO: 5.

[0088] In some embodiments, the IL-2 variant comprises the amino acid substitutions of H16L, V69A, and Q74P, and comprises an amino acid sequence at least 90% identical to SEQ ID NO: 6. In some embodiments, the IL-2 variant comprises the amino acid substitutions of H16N, V69A, and Q74P, and comprises an amino acid sequence at least 90% identical to SEQ ID NO: 6. In some embodiments, the IL-2 variant comprises the amino acid substitutions of V69A, Q74P, and D84V, and comprises an amino acid sequence at least 90% identical to SEQ ID NO: 6. In some embodiments, the IL-2 variant comprises the amino acidAttorney Docket No.: SVI-017WO1substitutions of V69A, Q74P, and S87R, and comprises an amino acid sequence at least 90% identical to SEQ ID NO: 6. In some embodiments, the IL-2 variant comprises the amino acid substitutions of V69A, Q74P, and I92S, and comprises an amino acid sequence at least 90% identical to SEQ ID NO: 6.

[0089] In some embodiments, the IL-2 variant comprises the amino acid substitutions of H16L, V69A, and Q74P, and comprises an amino acid sequence at least 95% identical to SEQ ID NO: 6. In some embodiments, the IL-2 variant comprises the amino acid substitutions of H16N, V69A, and Q74P, and comprises an amino acid sequence at least 95% identical to SEQ ID NO: 6. In some embodiments, the IL-2 variant comprises the amino acid substitutions of V69A, Q74P, and D84V, and comprises an amino acid sequence at least 95% identical to SEQ ID NO: 6. In some embodiments, the IL-2 variant comprises the amino acid substitutions of V69A, Q74P, and S87R, and comprises an amino acid sequence at least 95% identical to SEQ ID NO: 6. In some embodiments, the IL-2 variant comprises the amino acid substitutions of V69A, Q74P, and I92S, and comprises an amino acid sequence at least 95% identical to SEQ ID NO: 6.

[0090] In some embodiments, the IL-2 variant comprises the amino acid substitutions of H16L, V69A, and Q74P, and comprises an amino acid sequence at least 90% identical to SEQ ID NO: 7. In some embodiments, the IL-2 variant comprises the amino acid substitutions of H16N, V69A, and Q74P, and comprises an amino acid sequence at least 90% identical to SEQ ID NO: 7. In some embodiments, the IL-2 variant comprises the amino acid substitutions of V69A, Q74P, and D84V, and comprises an amino acid sequence at least 90% identical to SEQ ID NO: 7. In some embodiments, the IL-2 variant comprises the amino acid substitutions of V69A, Q74P, and S87R, and comprises an amino acid sequence at least 90% identical to SEQ ID NO: 7. In some embodiments, the IL-2 variant comprises the amino acid substitutions of V69A, Q74P, and I92S, and comprises an amino acid sequence at least 90% identical to SEQ ID NO: 7.

[0091] In some embodiments, the IL-2 variant comprises the amino acid substitutions of H16L, V69A, and Q74P, and comprises an amino acid sequence at least 95% identical to SEQ ID NO: 7. In some embodiments, the IL-2 variant comprises the amino acid substitutions of H16N, V69A, and Q74P, and comprises an amino acid sequence at least 95% identical to SEQ ID NO: 7. In some embodiments, the IL-2 variant comprises the amino acid substitutions of V69A, Q74P, and D84V, and comprises an amino acid sequence at least 95%Attorney Docket No.: SVI-017WO1identical to SEQ ID NO: 7. In some embodiments, the IL-2 variant comprises the amino acid substitutions of V69A, Q74P, and S87R, and comprises an amino acid sequence at least 95% identical to SEQ ID NO: 7. In some embodiments, the IL-2 variant comprises the amino acid substitutions of V69A, Q74P, and I92S, and comprises an amino acid sequence at least 95% identical to SEQ ID NO: 7.Table 1. Amino Acid Sequences of Exemplary IL-2 Variants.

[0092] In some embodiments, an IL-2 variant comprises amino acid substitutions of V69A and Q74P relative to SEQ ID NO: 1. In some embodiments, an IL-2 variant comprises amino acid substitutions of H16L, V69A and Q74P relative to SEQ ID NO: 1. In some embodiments, an IL-2 variant comprises amino acid substitutions of H16N, V69A and Q74P relative to SEQ ID NO: 1. In some embodiments, an IL-2 variant comprises amino acid substitutions of V69A, Q74P and I92S relative to SEQ ID NO: 1. In some embodiments, an IL-2 variant comprises amino acid substitutions of T3A, V69A and Q74P relative to SEQ ID NO: 1. In some embodiments, an IL-2 variant comprises amino acid substitutions of V69A, Q74P and C125S relative to SEQ ID NO: 1. In some embodiments, an IL-2 variant comprises amino acid substitutions of H16L, V69A, Q74P and C125S relative to SEQ ID NO: 1. In some embodiments, an IL-2 variant comprises amino acid substitutions of H16N, V69A, Q74P and C125S relative to SEQ ID NO: 1. In some embodiments, an IL-2 variantAttorney Docket No.: SVI-017WO1comprises amino acid substitutions of V69A, Q74P, I92S and C125S relative to SEQ ID NO: 1. In some embodiments, an IL-2 variant comprises amino acid substitutions of T3A, V69A Q74P and C125S relative to SEQ ID NO: 1.

[0093] In some embodiments, an IL-2 variant comprises amino acid substitutions of V69A and Q74P relative to SEQ ID NO: 2. In some embodiments, an IL-2 variant comprises amino acid substitutions of H16L, V69A and Q74P relative to SEQ ID NO: 2. In some embodiments, an IL-2 variant comprises amino acid substitutions of H16N, V69A and Q74P relative to SEQ ID NO: 2. In some embodiments, an IL-2 variant comprises amino acid substitutions of V69A, Q74P and I92S relative to SEQ ID NO: 2. In some embodiments, an IL-2 variant comprises amino acid substitutions of T3A, V69A and Q74P relative to SEQ ID NO: 2.

[0094] The IL-2 variants of the present invention may further comprise any mutation well known in the art to have increased binding affinity to CD25 and / or decreased binding affinity for CD122 and / or CD132 as compared to a wild-type IL-2. In some embodiments, the IL-2 variant comprises one or more mutations or combinations disclosed in U.S. Published Patent Application Nos. US20190300592A1, US20240043491A1, US20220213162A1, US20240059751A1, US20110274650A1, US20050142106A1, or US20140343252A1, each of which is incorporated herein by reference. In some embodiments, the IL-2 variant comprises one or more mutations or combinations disclosed in International Application No. WO2016164937A2, which is incorporated herein by reference.

[0095] In some embodiments, the IL-2 variant comprises an amino acid substitution at the QI 1 position. In some embodiments, the IL-2 variant comprises an amino acid substitution of QI IE. In some embodiments, the IL-2 variant comprises an amino acid substitution of QI 1R.

[0096] In some embodiments, the IL-2 variant comprises an amino acid substitution at the L12 position. In some embodiments, the IL-2 variant comprises an amino acid substitution of L12G, L12K, L12Q, L12S, or L12D. In some embodiments, the IL-2 variant comprises an amino acid substitution of L12G. In some embodiments, the IL-2 variant comprises an amino acid substitution of L12K. In some embodiments, the IL-2 variant comprises an amino acid substitution of L12Q. In some embodiments, the IL-2 variantAttorney Docket No.: SVI-017WO1comprises an amino acid substitution of L12S. In some embodiments, the IL-2 variant comprises an amino acid substitution of L12D.

[0097] In some embodiments, the IL-2 variant comprises an amino acid substitution at the Q13 position. In some embodiments, the IL-2 variant comprises an amino acid substitution of Q13G.

[0098] In some embodiments, the IL-2 variant comprises an amino acid substitution at the El 5 position. In some embodiments, the IL-2 variant comprises an amino acid substitution of E15A, E15G, or E15S. In some embodiments, the IL-2 variant comprises an amino acid substitution of El 5 A. In some embodiments, the IL-2 variant comprises an amino acid substitution of E15G. In some embodiments, the IL-2 variant comprises an amino acid sub stituti on of E 15 S .

[0099] In some embodiments, the IL-2 variant comprises an amino acid substitution at position LI 9. In some embodiments, the IL-2 variant comprises an amino acid substitution of L19H, L19Y, L19N, L19R, L19Q, L19D, L19P, L19S, L19A, L19E, L19G, L19T, or L19V. In some embodiments, the IL-2 variant comprises an amino acid substitution of L19H. In some embodiments, the IL-2 variant comprises an amino acid substitution of L19Y. In some embodiments, the IL-2 variant comprises an amino acid substitution of L19N. In some embodiments, the IL-2 variant comprises an amino acid substitution of L19R. In some embodiments, the IL-2 variant comprises an amino acid substitution of L19Q. In some embodiments, the IL-2 variant comprises an amino acid substitution of L19D. In some embodiments, the IL-2 variant comprises an amino acid substitution of L19P. In some embodiments, the IL-2 variant comprises an amino acid substitution of L19S. In some embodiments, the IL-2 variant comprises an amino acid substitution of L19A. In some embodiments, the IL-2 variant comprises an amino acid substitution of L19E. In some embodiments, the IL-2 variant comprises an amino acid substitution of L19G. In some embodiments, the IL-2 variant comprises an amino acid substitution of L19T. In some embodiments, the IL-2 variant comprises an amino acid substitution of L 19V.

[0100] In some embodiments, the IL-2 variant comprises an amino acid substitution at position D20. In some embodiments, the IL-2 variant comprises an amino acid substitution of D20T, D20E, D20N, D20Q, D20S, D20Y, D20I, D20A, D20F, D20G, or D20W. In some embodiments, the IL-2 variant comprises an amino acid substitution of D20T. In someAttorney Docket No.: SVI-017WO1embodiments, the IL-2 variant comprises an amino acid substitution of D20E. In some embodiments, the IL-2 variant comprises an amino acid substitution of D20N. In some embodiments, the IL-2 variant comprises an amino acid substitution of D20Q. In some embodiments, the IL-2 variant comprises an amino acid substitution of D20S. In some embodiments, the IL-2 variant comprises an amino acid substitution of D20Y. In some embodiments, the IL-2 variant comprises an amino acid substitution of D20I. In some embodiments, the IL-2 variant comprises an amino acid substitution of D20A. In some embodiments, the IL-2 variant comprises an amino acid substitution of D20F. In some embodiments, the IL-2 variant comprises an amino acid substitution of D20G. In some embodiments, the IL-2 variant comprises an amino acid substitution of D20W.

[0101] In some embodiments, the IL-2 variant comprises an amino acid substitution at position L21. In some embodiments, the IL-2 variant comprises an amino acid substitution of L21S, L21N, or L21R. In some embodiments, the IL-2 variant comprises an amino acid substitution of L21S. In some embodiments, the IL-2 variant comprises an amino acid substitution of L21N. In some embodiments, the IL-2 variant comprises an amino acid sub stituti on of L21 R.

[0102] In some embodiments, the IL-2 variant comprises an amino acid substitution at position Q22. In some embodiments, the IL-2 variant comprises an amino acid substitution of Q22N, Q22H, Q22K, Q22Y, or Q22I. In some embodiments, the IL-2 variant comprises an amino acid substitution of Q22N. In some embodiments, the IL-2 variant comprises an amino acid substitution of Q22H. In some embodiments, the IL-2 variant comprises an amino acid substitution of Q22K. In some embodiments, the IL-2 variant comprises an amino acid substitution of Q22Y. In some embodiments, the IL-2 variant comprises an amino acid substitution of Q22I.

[0103] In some embodiments, the IL-2 variant comprises an amino acid substitution at position M23. In some embodiments, the IL-2 variant comprises an amino acid substitution ofM23R.

[0104] In some embodiments, the IL-2 variant comprises an amino acid substitution at position 124. In some embodiments, the IL-2 variant comprises an amino acid substitution ofI24L.Attorney Docket No.: SVI-017WO1

[0105] In some embodiments, the IL-2 variant comprises an amino acid substitution at position 128. In some embodiments, the IL-2 variant comprises an amino acid substitution of I28T. In some embodiments, the IL-2 variant comprises an amino acid substitution of I28F.

[0106] In some embodiments, the IL-2 variant comprises an amino acid substitution at position P34. In some embodiments, the IL-2 variant comprises an amino acid substitution of P34T. In some embodiments, the IL-2 variant comprises an amino acid substitution of P34R.

[0107] In some embodiments, the IL-2 variant comprises an amino acid substitution at position R38. In some embodiments, the IL-2 variant comprises an amino acid substitution ofR38I.

[0108] In some embodiments, the IL-2 variant comprises an amino acid substitution at position T41. In some embodiments, the IL-2 variant comprises an amino acid substitution of T41K. In some embodiments, the IL-2 variant comprises an amino acid substitution of T41Q.

[0109] In some embodiments, the IL-2 variant comprises an amino acid substitution at position M46. In some embodiments, the IL-2 variant comprises an amino acid substitution ofM46L.

[0110] In some embodiments, the IL-2 variant comprises an amino acid substitution at position K48. In some embodiments, the IL-2 variant comprises an amino acid substitution ofK48E.[oni] In some embodiments, the IL-2 variant comprises an amino acid substitution at position K49. In some embodiments, the IL-2 variant comprises an amino acid substitution ofK49R.

[0112] In some embodiments, the IL-2 variant comprises an amino acid substitution at position E61. In some embodiments, the IL-2 variant comprises an amino acid substitution ofE61D.

[0113] In some embodiments, the IL-2 variant comprises an amino acid substitution at position K64. In some embodiments, the IL-2 variant comprises an amino acid substitution ofK64R.Attorney Docket No.: SVI-017WO1

[0114] In some embodiments, the IL-2 variant comprises an amino acid substitution at position E68. In some embodiments, the IL-2 variant comprises an amino acid substitution of E68D. In some embodiments, the IL-2 variant comprises an amino acid substitution of E68S.

[0115] In some embodiments, the IL-2 variant comprises an amino acid substitution at position N71. In some embodiments, the IL-2 variant comprises an amino acid substitution ofN71T.

[0116] In some embodiments, the IL-2 variant comprises an amino acid substitution at position H79. In some embodiments, the IL-2 variant comprises an amino acid substitution ofH79R.

[0117] In some embodiments, the IL-2 variant comprises an amino acid substitution at position R81. In some embodiments, the IL-2 variant comprises an amino acid substitution of R81A. In some embodiments, the IL-2 variant comprises an amino acid substitution of R81G. In some embodiments, the IL-2 variant comprises an amino acid substitution of R81S. In some embodiments, the IL-2 variant comprises an amino acid substitution of R81T.

[0118] In some embodiments, the IL-2 variant comprises an amino acid substitution at position N88. In some embodiments, the IL-2 variant comprises an amino acid substitution of N88S. In some embodiments, the IL-2 variant comprises an amino acid substitution of N88L. In some embodiments, the IL-2 variant comprises an amino acid substitution of N88D. In some embodiments, the IL-2 variant comprises an amino acid substitution of N88A. In some embodiments, the IL-2 variant comprises an amino acid substitution of N88E. In some embodiments, the IL-2 variant comprises an amino acid substitution of N88F. In some embodiments, the IL-2 variant comprises an amino acid substitution of N88G. In some embodiments, the IL-2 variant comprises an amino acid substitution of N88M. In some embodiments, the IL-2 variant comprises an amino acid substitution of N88R. In some embodiments, the IL-2 variant comprises an amino acid substitution of N88V. In some embodiments, the IL-2 variant comprises an amino acid substitution of N88W. In some embodiments, the IL-2 variant comprises an amino acid substitution of N88I. In some embodiments, the IL-2 variant comprises an amino acid substitution of N88Q. In some embodiments, the IL-2 variant comprises an amino acid substitution of N88M. In some embodiments, the IL-2 variant comprises an amino acid substitution of N88T.Attorney Docket No.: SVI-017WO1

[0119] In some embodiments, the IL-2 variant comprises an amino acid substitution at position N90. In some embodiments, the IL-2 variant comprises an amino acid substitution ofN90H.

[0120] In some embodiments, the IL-2 variant comprises an amino acid substitution at position V91. In some embodiments, the IL-2 variant comprises an amino acid substitution of V91K. In some embodiments, the IL-2 variant comprises an amino acid substitution of V91D. In some embodiments, the IL-2 variant comprises an amino acid substitution of V91E. In some embodiments, the IL-2 variant comprises an amino acid substitution of V91G. In some embodiments, the IL-2 variant comprises an amino acid substitution of V91S. In some embodiments, the IL-2 variant comprises an amino acid substitution of V91L.

[0121] In some embodiments, the IL-2 variant comprises an amino acid substitution at position E95. In some embodiments, the IL-2 variant comprises an amino acid substitution of E95G. In some embodiments, the IL-2 variant comprises an amino acid substitution of E95Q.

[0122] In some embodiments, the IL-2 variant comprises an amino acid substitution at position T101. In some embodiments, the IL-2 variant comprises an amino acid substitution of T101R. In some embodiments, the IL-2 variant comprises an amino acid substitution of T101A.

[0123] In some embodiments, the IL-2 variant comprises an amino acid substitution at position Fl 03. In some embodiments, the IL-2 variant comprises an amino acid substitution of F103S.

[0124] In some embodiments, the IL-2 variant comprises an amino acid substitution at position DI 09. In some embodiments, the IL-2 variant comprises an amino acid substitution of D109N.

[0125] In some embodiments, the IL-2 variant comprises an amino acid substitution at position II 14. In some embodiments, the IL-2 variant comprises an amino acid substitution of II 14V.

[0126] In some embodiments, the IL-2 variant comprises an amino acid substitution at position LI 18. In some embodiments, the IL-2 variant comprises an amino acid substitution of LI 181.Attorney Docket No.: SVI-017WO1

[0127] In some embodiments, the IL-2 variant comprises an amino acid substitution at position N119. In some embodiments, the IL-2 variant comprises an amino acid substitution of N119D.

[0128] In some embodiments, the IL-2 variant comprises an amino acid substitution at position R120. In some embodiments, the IL-2 variant comprises an amino acid substitution of R120G. In some embodiments, the IL-2 variant comprises an amino acid substitution of R120D.

[0129] In some embodiments, the IL-2 variant comprises an amino acid substitution at position T123. In some embodiments, the IL-2 variant comprises an amino acid substitution of T123S. In some embodiments, the IL-2 variant comprises an amino acid substitution of T123A.

[0130] In some embodiments, the IL-2 variant comprises an amino acid substitution at position Q126. In some embodiments, the IL-2 variant comprises an amino acid substitution of Q126R. In some embodiments, the IL-2 variant comprises an amino acid substitution of Q126T. In some embodiments, the IL-2 variant comprises an amino acid substitution of Q126K. In some embodiments, the IL-2 variant comprises an amino acid substitution of Q126E. In some embodiments, the IL-2 variant comprises an amino acid substitution of Q126L. In some embodiments, the IL-2 variant comprises an amino acid substitution of Q126N. In some embodiments, the IL-2 variant comprises an amino acid substitution of Q126D. In some embodiments, the IL-2 variant comprises an amino acid substitution of Q126M. In some embodiments, the IL-2 variant comprises an amino acid substitution of Q126H. In some embodiments, the IL-2 variant comprises an amino acid substitution of Q126Y.

[0131] In some embodiments, the IL-2 variant comprises an amino acid substitution at position 1128. In some embodiments, the IL-2 variant comprises an amino acid substitution ofI128T.

[0132] In some embodiments, the IL-2 variant comprises an amino acid substitution at position S130. In some embodiments, the IL-2 variant comprises an amino acid substitution of S130T.

[0133] In some embodiments, the IL-2 variant comprises an amino acid substitution at position T133. In some embodiments, the IL-2 variant comprises an amino acidAttorney Docket No.: SVI-017WO1substitution of T133S. In some embodiments, the IL-2 variant comprises an amino acid substitution of T133N.Half-Life Extension Domain

[0134] In some embodiments, the IL-2 fusion protein comprises an IL-2 variant described herein and a half-life extension domain. In some embodiments, the half-life extension domain comprises an Fc region, an albumin binding domain, a human serum albumin, one or more lipids, one or more polyethylene glycols (PEGs), or any other half-life extending polypeptide or polymer known in the art.

[0135] In some embodiments, the half-life extension domain comprises a serum protein binding moiety. In some embodiments, the half-life extension domain comprises human serum albumin. In some embodiments, the half-life extension domain comprises one or more lipids. In some embodiments, the half-life extension domain comprises one or more half-life extending polymers. In some embodiments, the half-life extension domain comprises one or more PEGs. In some embodiments, the half-life extension domain comprises a halflife extending polypeptide.

[0136] In some embodiments, the IL-2 fusion protein comprises an IL-2 variant described herein and an Fc region. Fusion proteins comprising an IL-2 variant and an Fc region are also described as IL-2 Fc fusion proteins herein. In some embodiments, the IL-2 Fc fusion protein forms a dimer. In some embodiments, the IL-2 Fc fusion protein forms a heterodimer. In some embodiments, the IL-2 Fc fusion protein forms a homodimer.Fc region

[0137] In some embodiments, the Fc region comprises an Fc region of IgGl. In some embodiments, the Fc region comprises an Fc region of IgG2. In some embodiments, the Fc region comprises an Fc region of IgG3. In some embodiments, the Fc region comprises an Fc region of IgG4.

[0138] In some embodiments, an Fc region is a modified Fc region comprising one or more mutations. In some embodiments, the Fc region is engineered to reduce effector function. In some embodiments, the Fc region is engineered to further increase half-life.

[0139] In some embodiments, the Fc region comprises one or more (e.g., 2, 3, 4, 5, 6, or 7) mutations in residues chosen from T256, H285, N286, T307, Q311, N315, or A378. InAttorney Docket No.: SVI-017WO1some embodiments, the Fc region comprises one or more (e.g., 2, 3, 4, 5, 6, or 7) mutations chosen from T256D, H285N, N286D, T307Q, Q311V, N315D, or A378V.

[0140] In some embodiments, the Fc region comprises a half-life enhancing mutation, a mutation that is capable of disrupting an Fc effector function, or both. In some embodiments, the Fc region comprises one or more mutations or combinations of mutations described herein, e.g., chosen from M252W, V308F / N434Y, R255Y, P257L / N434Y, V308F, P257N / M252Y, G385N, P257N / V308Y, N434Y, M252Y / S254T / T256E (“YTE”), M428L / N434S (“LS”), or any combination thereof. Alternatively, or additionally, in some embodiments, the Fc region comprises (a) one or more (e.g., 2, 3, 4, 5, or all) combinations of mutations chosen from: T256D / Q311V / A378V, H285N / T307Q / N315D, H285D / T307Q / A378V, T307Q / Q311V / A378V, T256D / N286D / T307R / Q311V / A378V, or T256D / T307R / Q31 IV; (b) a mutation or a combination of mutations capable of disrupting an Fc effector function, e.g., N297G, L234A / L235A (also known as “LALA” mutation), L234A / L235A / P329G (also known as “LALAPG” mutation), or (c) both (a) and (b).

[0141] In some embodiments, the Fc region comprises mutationsT256D / Q311 V / A378V and a mutation or a combination of mutations capable of disrupting an Fc effector function, e.g., N297G. In some embodiments, the Fc region comprises mutations H285N / T307Q / N315D and a mutation or a combination of mutations capable of disrupting an Fc effector function, e.g., N297G. In some embodiments, the Fc region comprises mutations H285D / T307Q / A378V and a mutation or a combination of mutations capable of disrupting an Fc effector function, e.g., N297G. In some embodiments, the Fc region comprises mutations T307Q / Q311 V / A378V and a mutation or a combination of mutations capable of disrupting an Fc effector function, e.g., N297G. In some embodiments, the Fc region comprises mutations T256D / N286D / T307R / Q311 V / A378V and a mutation or a combination of mutations capable of disrupting an Fc effector function, e.g., N297G. In some embodiments, the Fc region comprises mutations T256D / T307R / Q311V and a mutation or a combination of mutations capable of disrupting an Fc effector function, e.g., N297G.

[0142] In some embodiments, the Fc region comprises mutationsT256D / Q311 V / A378V and a mutation or a combination of mutations capable of disrupting an Fc effector function, e.g., L234A / L235A. In some embodiments, the Fc region comprises mutations H285N / T307Q / N315D and a mutation or a combination of mutations capable of disrupting an Fc effector function, e.g., L234A / L235A. In some embodiments, the Fc regionAttorney Docket No.: SVI-017WO1comprises mutations H285D / T307Q / A378V and a mutation or a combination of mutations capable of disrupting an Fc effector function, e.g., L234A / L235A. In some embodiments, the Fc region comprises mutations T307Q / Q311 V / A378V and a mutation or a combination of mutations capable of disrupting an Fc effector function, e.g., L234A / L235A. In some embodiments, the Fc region comprises mutations T256D / N286D / T307R / Q311V / A378V and a mutation or a combination of mutations capable of disrupting an Fc effector function, e.g., L234A / L235A. In some embodiments, the Fc region comprises mutations T256D / T307R / Q31 IV and a mutation or a combination of mutations capable of disrupting an Fc effector function, e.g., L234A / L235A.

[0143] In some embodiments, the Fc region comprises mutationsT256D / Q311 V / A378V and a mutation or a combination of mutations capable of disrupting an Fc effector function, e.g., L234A / L235A / P329G. In some embodiments, the Fc region comprises mutations H285N / T307Q / N315D and a mutation or a combination of mutations capable of disrupting an Fc effector function, e.g, L234A / L235A / P329G. In some embodiments, the Fc region comprises mutations H285D / T307Q / A378V and a mutation or a combination of mutations capable of disrupting an Fc effector function, e.g, L234A / L235A / P329G. In some embodiments, the Fc region comprises mutations T307Q / Q311 V / A378V and a mutation or a combination of mutations capable of disrupting an Fc effector function, e.g., L234A / L235A / P329G. In some embodiments, the Fc region comprises mutations T256D / N286D / T307R / Q311 V / A378V and a mutation or a combination of mutations capable of disrupting an Fc effector function, e.g., L234A / L235A / P329G. In some embodiments, the Fc region comprises mutations T256D / T307R / Q31 IV and a mutation or a combination of mutations capable of disrupting an Fc effector function, e.g., L234A / L235A / P329G.

[0144] In some embodiments, the Fc region comprises the N297G mutation. In some embodiments the Fc region comprises the L234A / L235A mutations. In some embodiments, the Fc region comprises the L234A / L235A / P329G mutations.

[0145] In some embodiments, the Fc region comprises the Fc region of human IgGl, e.g., human IgGl m3 allotype. In some embodiments, the Fc region comprises the mutation N297G. In some embodiments, the Fc region comprises the Fc region of human IgGl allotype m3, human IgGl allotype m3 comprising the mutation N297G and / or other mutations of the Fc region of human IgGl allotype m3, or a fragment thereof.Attorney Docket No.: SVI-017WO1

[0146] In some embodiments, the Fc region comprises an amino acid sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99% identical to an amino acid sequence selected from Table 2.

[0147] In some embodiments, the Fc region comprises an amino acid sequence at least 85% identical to SEQ ID NO: 8. In some embodiments, the Fc region comprises an amino acid sequence at least 90% identical to SEQ ID NO: 8. In some embodiments, the Fc region comprises an amino acid sequence at least 92% identical to SEQ ID NO: 8. In some embodiments, the Fc region comprises an amino acid sequence at least 93% identical to SEQ ID NO: 8. In some embodiments, the Fc region comprises an amino acid sequence at least 95% identical to SEQ ID NO: 8. In some embodiments, the Fc region comprises an amino acid sequence at least 98% identical to SEQ ID NO: 8. In some embodiments, the Fc region comprises an amino acid sequence at least 99% identical to SEQ ID NO: 8. In some embodiments, the Fc region comprises an amino acid sequence identical to SEQ ID NO: 8.

[0148] In some embodiments, the Fc region comprises an amino acid sequence at least 85% identical to SEQ ID NO: 9. In some embodiments, the Fc region comprises an amino acid sequence at least 90% identical to SEQ ID NO: 9. In some embodiments, the Fc region comprises an amino acid sequence at least 92% identical to SEQ ID NO: 9. In some embodiments, the Fc region comprises an amino acid sequence at least 93% identical to SEQ ID NO: 9. In some embodiments, the Fc region comprises an amino acid sequence at least 95% identical to SEQ ID NO: 9. In some embodiments, the Fc region comprises an amino acid sequence at least 98% identical to SEQ ID NO: 9. In some embodiments, the Fc region comprises an amino acid sequence at least 99% identical to SEQ ID NO: 9. In some embodiments, the Fc region comprises an amino acid sequence identical to SEQ ID NO: 9.

[0149] In some embodiments, the Fc region comprises an amino acid sequence at least 85% identical to SEQ ID NO: 10. In some embodiments, the Fc region comprises an amino acid sequence at least 90% identical to SEQ ID NO: 10. In some embodiments, the Fc region comprises an amino acid sequence at least 92% identical to SEQ ID NO: 10. In some embodiments, the Fc region comprises an amino acid sequence at least 93% identical to SEQ ID NO: 10. In some embodiments, the Fc region comprises an amino acid sequence at least 95% identical to SEQ ID NO: 10. In some embodiments, the Fc region comprises an amino acid sequence at least 98% identical to SEQ ID NO: 10. In some embodiments, the Fc regionAttorney Docket No.: SVI-017WO1comprises an amino acid sequence at least 99% identical to SEQ ID NO: 10. In some embodiments, the Fc region comprises an amino acid sequence identical to SEQ ID NO: 10.

[0150] In some embodiments, the Fc region comprises an amino acid sequence at least 85% identical to SEQ ID NO: 11. In some embodiments, the Fc region comprises an amino acid sequence at least 90% identical to SEQ ID NO: 11. In some embodiments, the Fc region comprises an amino acid sequence at least 92% identical to SEQ ID NO: 11. In some embodiments, the Fc region comprises an amino acid sequence at least 93% identical to SEQ ID NO: 11. In some embodiments, the Fc region comprises an amino acid sequence at least 95% identical to SEQ ID NO: 11. In some embodiments, the Fc region comprises an amino acid sequence at least 98% identical to SEQ ID NO: 11. In some embodiments, the Fc region comprises an amino acid sequence at least 99% identical to SEQ ID NO: 11. In some embodiments, the Fc region comprises an amino acid sequence identical to SEQ ID NO: 11.Table 2. Sequences of Exemplary Fc regions.Attorney Docket No.: SVI-017WO1

[0151] Any of the mutations in the Fc region that extend half-life described herein can be used in combination with any Fc mutation capable of enhancing or disrupting an Fc effector function. Other exemplary Fc mutations are described, e.g., in International Application Publication No. WO2018 / 052556, U.S. Application Publication No.US2018 / 0037634, and Booth et al. MAbs. 2018; 10(7): 1098-1110, the contents of which are incorporated by reference in their entirety.Linkers

[0152] In some embodiments, the IL-2 variant is fused to the half-life extension domain via a linker. In some embodiments, the IL-2 variant is fused to the half-life extension domain via a linker such that the fusion protein comprises, from the N-terminus to the C- terminus, the IL-2 variant - linker - half-life extension domain. In some embodiments, the fusion protein comprises, from the N-terminus to the C-terminus, the half-life extension domain - linker - IL-2 variant.

[0153] In some embodiments, the IL-2 variant is fused to the Fc region via a linker. In some embodiments, the IL-2 variant is fused to the Fc region via a linker such that the fusion protein comprises, from the N-terminus to the C-terminus, the IL-2 variant - linker - Fc region. In some embodiments, the fusion protein comprises, from the N-terminus to the C- terminus, the Fc region - linker - IL-2 variant.

[0154] In some embodiments, the linker is a polypeptide linker. In some embodiments, the linker is a flexible linker. In some embodiments, the linker is a rigid linker. In some embodiments, the linker is a cleavable linker. In some embodiments, the linker comprises an immunoglobulin hinge region or portion thereof.

[0155] In some embodiments, the linker is a Gly-Ser linker. In some embodiments, the linker comprises (G4S)n, wherein n is 1, 2, 3, 4, 5, 6, or more. In some embodiments, the linker comprises (648)1 (SEQ ID NO: 12). In some embodiments, the linker comprises (648)2. In some embodiments, the linker comprises (648)3. In some embodiments, the linker comprises (648)4. In some embodiments, the linker comprises (648)5. In some embodiments, the linker comprises (648)6.Attorney Docket No.: SVI-017WO1

[0156] In some embodiments, the linker comprises a non-GS linker. In some embodiments, the linker comprises (GGGSA)n, wherein n is 1, 2, 3, 4, 5, or more. In some embodiments, the linker comprises (GGGSA)i (SEQ ID NO: 14). In some embodiments, the linker comprises (GGGSA)2. In some embodiments, the linker comprises (GGGSA)3. In some embodiments, the linker comprises (GGGSA)4. In some embodiments, the linker comprises (GGGSA)5. In some embodiments, the linker comprises (GGGSA)e.

[0157] In some embodiments, the linker comprises a rigid linker. In some embodiments, the linker comprises a proline-rich linker. In some embodiments, the linker comprises an a-helical rigid linker. In some embodiments, the linker comprises A(EAAAK)nA, wherein n is 1, 2, 3, 4, 5, 6, or more. In some embodiments, the linker comprises A(EAAAK)iA (SEQ ID NO: 15). In some embodiments, the linker comprises A(EAAAK)iA. In some embodiments, the linker comprises A(EAAAK)2A. In some embodiments, the linker comprises A(EAAAK)3A. In some embodiments, the linker comprises A(EAAAK)4A. In some embodiments, the linker comprises A(EAAAK)sA. In some embodiments, the linker comprises A(EAAAK)eA.

[0158] In some embodiments, the linker comprises a sequence selected from Table 3.In some embodiments, the linker comprises an amino acid sequence of SEQ ID NO: 12. In some embodiments, the linker comprises an amino acid sequence of SEQ ID NO: 13. In some embodiments, the linker comprises an amino acid sequence of SEQ ID NO: 14. In some embodiments, the linker comprises an amino acid sequence of SEQ ID NO: 15. In some embodiments, the linker comprises an amino acid sequence of SEQ ID NO: 16. In some embodiments, the linker comprises an amino acid sequence of SEQ ID NO: 17. In some embodiments, the linker comprises an amino acid sequence of SEQ ID NO: 18. In some embodiments, the linker comprises an amino acid sequence of SEQ ID NO: 19. In some embodiments, the linker comprises an amino acid sequence of SEQ ID NO: 20. In some embodiments, the linker comprises an amino acid sequence of SEQ ID NO: 21. In some embodiments, the linker comprises an amino acid sequence of SEQ ID NO: 22.Table 3. Sequences of Exemplary Linkers.Attorney Docket No.: SVI-017WO1Exemplary IL-2 Fc Fusion Proteins Comprising IL-2 Variants

[0159] In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence at least 80% identical to any one of the sequences in Table 4. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence at least 85% identical to any one of the sequences in Table 4. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence at least 87% identical to any one of the sequences in Table 4. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence at least 90% identical to any one of the sequences in Table 4. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence at least 92% identical to any one of the sequences in Table 4. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence at least 93% identical to any one of the sequences in Table 4. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence at least 95% identical to any one of the sequences in Table 4. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence at least 97% identical to any one of the sequences in Table 4. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence at least 98% identical to any one of the sequences in Table 4. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence at least 99% identical to any one of the sequences in Table 4. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence identical to any one of the sequences in Table 4.

[0160] In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 80%, at least 90%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO: 23. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 80% identical to SEQ ID NO: 23. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 83% identical to SEQ ID NO: 23. In some embodiments, the IL-2 Fc fusion protein comprises an amino acidAttorney Docket No.: SVI-017WO1sequence that is at least 85% identical to SEQ ID NO: 23. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 87% identical to SEQ ID NO: 23. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 23. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 91% identical to SEQ ID NO: 23. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 92% identical to SEQ ID NO: 23. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 93% identical to SEQ ID NO: 23. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 94% identical to SEQ ID NO: 23. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 23. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 96% identical to SEQ ID NO: 23. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 97% identical to SEQ ID NO: 23. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 98% identical to SEQ ID NO: 23. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 23. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is identical to SEQ ID NO: 23.

[0161] In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 80%, at least 90%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO: 24. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 80% identical to SEQ ID NO: 24. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 83% identical to SEQ ID NO: 24. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 85% identical to SEQ ID NO: 24. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 87% identical to SEQ ID NO: 24. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 24. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 91% identical to SEQ ID NO: 24. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 92% identical to SEQ ID NO: 24. In some embodiments, the IL-2 Fc fusion proteinAttorney Docket No.: SVI-017WO1comprises an amino acid sequence that is at least 93% identical to SEQ ID NO: 24. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 94% identical to SEQ ID NO: 24. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 24. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 96% identical to SEQ ID NO: 24. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 97% identical to SEQ ID NO: 24. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 98% identical to SEQ ID NO: 24. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 24. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is identical to SEQ ID NO: 24.

[0162] In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 80%, at least 90%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO: 25. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 80% identical to SEQ ID NO: 25. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 83% identical to SEQ ID NO: 25. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 85% identical to SEQ ID NO: 25. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 87% identical to SEQ ID NO: 25. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 25. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 91% identical to SEQ ID NO: 25. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 92% identical to SEQ ID NO: 25. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 93% identical to SEQ ID NO: 25. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 94% identical to SEQ ID NO: 25. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 25. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 96% identical to SEQ ID NO: 25. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 97% identical to SEQ ID NO: 25. In someAttorney Docket No.: SVI-017WO1embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 98% identical to SEQ ID NO: 25. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 25. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is identical to SEQ ID NO: 25.

[0163] In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 80%, at least 90%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO: 26. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 80% identical to SEQ ID NO: 26. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 83% identical to SEQ ID NO: 26. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 85% identical to SEQ ID NO: 26. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 87% identical to SEQ ID NO: 26. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 26. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 91% identical to SEQ ID NO: 26. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 92% identical to SEQ ID NO: 26. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 93% identical to SEQ ID NO: 26. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 94% identical to SEQ ID NO: 26. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 26. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 96% identical to SEQ ID NO: 26. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 97% identical to SEQ ID NO: 26. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 98% identical to SEQ ID NO: 26. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 26. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is identical to SEQ ID NO: 26.

[0164] In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 80%, at least 90%, at least 95%, at least 98%, or at least 99%Attorney Docket No.: SVI-017WO1identical to SEQ ID NO: 27. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 80% identical to SEQ ID NO: 27. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 83% identical to SEQ ID NO: 27. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 85% identical to SEQ ID NO: 27. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 87% identical to SEQ ID NO: 27. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 27. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 91% identical to SEQ ID NO: 27. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 92% identical to SEQ ID NO: 27. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 93% identical to SEQ ID NO: 27. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 94% identical to SEQ ID NO: 27. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 27. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 96% identical to SEQ ID NO: 27. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 97% identical to SEQ ID NO: 27. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 98% identical to SEQ ID NO: 27. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 27. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is identical to SEQ ID NO: 27.

[0165] In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 80%, at least 90%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO: 28. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 80% identical to SEQ ID NO: 28. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 83% identical to SEQ ID NO: 28. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 85% identical to SEQ ID NO: 28. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 87% identical to SEQ ID NO: 28. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence thatAttorney Docket No.: SVI-017WO1is at least 90% identical to SEQ ID NO: 28. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 91% identical to SEQ ID NO: 28. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 92% identical to SEQ ID NO: 28. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 93% identical to SEQ ID NO: 28. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 94% identical to SEQ ID NO: 28. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 28. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 96% identical to SEQ ID NO: 28. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 97% identical to SEQ ID NO: 28. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 98% identical to SEQ ID NO: 28. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 28. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is identical to SEQ ID NO: 28.

[0166] In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 80%, at least 90%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO: 29. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 80% identical to SEQ ID NO: 29. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 83% identical to SEQ ID NO: 29. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 85% identical to SEQ ID NO: 29. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 87% identical to SEQ ID NO: 29. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 29. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 91% identical to SEQ ID NO: 29. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 92% identical to SEQ ID NO: 29. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 93% identical to SEQ ID NO: 29. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 94% identical to SEQ ID NO: 29. In some embodiments, the IL-2 Fc fusion proteinAttorney Docket No.: SVI-017WO1comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 29. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 96% identical to SEQ ID NO: 29. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 97% identical to SEQ ID NO: 29. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 98% identical to SEQ ID NO: 29. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 29. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is identical to SEQ ID NO: 29.

[0167] In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 80%, at least 90%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO: 30. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 80% identical to SEQ ID NO: 30. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 83% identical to SEQ ID NO: 30. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 85% identical to SEQ ID NO: 30. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 87% identical to SEQ ID NO: 30. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 30. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 91% identical to SEQ ID NO: 30. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 92% identical to SEQ ID NO: 30. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 93% identical to SEQ ID NO: 30. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 94% identical to SEQ ID NO: 30. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 30. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 96% identical to SEQ ID NO: 30. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 97% identical to SEQ ID NO: 30. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 98% identical to SEQ ID NO: 30. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 30. In someAttorney Docket No.: SVI-017WO1embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is identical to SEQ ID NO: 30.

[0168] In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 80%, at least 90%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO: 31. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 80% identical to SEQ ID NO: 31. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 83% identical to SEQ ID NO: 31. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 85% identical to SEQ ID NO: 31. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 87% identical to SEQ ID NO: 31. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 31. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 91% identical to SEQ ID NO: 31. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 92% identical to SEQ ID NO: 31. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 93% identical to SEQ ID NO: 31. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 94% identical to SEQ ID NO: 31. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 31. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 96% identical to SEQ ID NO: 31. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 97% identical to SEQ ID NO: 31. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 98% identical to SEQ ID NO: 31. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 31. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is identical to SEQ ID NO: 31.

[0169] In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 80%, at least 90%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO: 32. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 80% identical to SEQ ID NO: 32. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 83% identical toAttorney Docket No.: SVI-017WO1SEQ ID NO: 32. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 85% identical to SEQ ID NO: 32. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 87% identical to SEQ ID NO: 32. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 32. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 91% identical to SEQ ID NO: 32. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 92% identical to SEQ ID NO: 32. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 93% identical to SEQ ID NO: 32. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 94% identical to SEQ ID NO: 32. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 32. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 96% identical to SEQ ID NO: 32. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 97% identical to SEQ ID NO: 32. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 98% identical to SEQ ID NO: 32. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 32. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is identical to SEQ ID NO: 32.

[0170] In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 80%, at least 90%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO: 33. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 80% identical to SEQ ID NO: 33. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 83% identical to SEQ ID NO: 33. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 85% identical to SEQ ID NO: 33. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 87% identical to SEQ ID NO: 33. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 33. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 91% identical to SEQ ID NO: 33. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at leastAttorney Docket No.: SVI-017WO192% identical to SEQ ID NO: 33. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 93% identical to SEQ ID NO: 33. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 94% identical to SEQ ID NO: 33. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 33. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 96% identical to SEQ ID NO: 33. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 97% identical to SEQ ID NO: 33. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 98% identical to SEQ ID NO: 33. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 33. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is identical to SEQ ID NO: 33.

[0171] In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 80%, at least 90%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO: 34. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 80% identical to SEQ ID NO: 34. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 83% identical to SEQ ID NO: 34. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 85% identical to SEQ ID NO: 34. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 87% identical to SEQ ID NO: 34. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 34. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 91% identical to SEQ ID NO: 34. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 92% identical to SEQ ID NO: 34. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 93% identical to SEQ ID NO: 34. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 94% identical to SEQ ID NO: 34. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 34. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 96% identical to SEQ ID NO: 34. In some embodiments, the IL-2 Fc fusion proteinAttorney Docket No.: SVI-017WO1comprises an amino acid sequence that is at least 97% identical to SEQ ID NO: 34. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 98% identical to SEQ ID NO: 34. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 34. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is identical to SEQ ID NO: 34.

[0172] In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 80%, at least 90%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO: 35. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 80% identical to SEQ ID NO: 35. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 83% identical to SEQ ID NO: 35. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 85% identical to SEQ ID NO: 35. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 87% identical to SEQ ID NO: 35. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 35. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 91% identical to SEQ ID NO: 35. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 92% identical to SEQ ID NO: 35. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 93% identical to SEQ ID NO: 35. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 94% identical to SEQ ID NO: 35. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 35. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 96% identical to SEQ ID NO: 35. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 97% identical to SEQ ID NO: 35. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 98% identical to SEQ ID NO: 35. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 35. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is identical to SEQ ID NO: 35.Attorney Docket No.: SVI-017WO1

[0173] In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 80%, at least 90%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO: 36. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 80% identical to SEQ ID NO: 36. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 83% identical to SEQ ID NO: 36. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 85% identical to SEQ ID NO: 36. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 87% identical to SEQ ID NO: 36. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 36. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 91% identical to SEQ ID NO: 36. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 92% identical to SEQ ID NO: 36. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 93% identical to SEQ ID NO: 36. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 94% identical to SEQ ID NO: 36. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 36. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 96% identical to SEQ ID NO: 36. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 97% identical to SEQ ID NO: 36. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 98% identical to SEQ ID NO: 36. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 36. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is identical to SEQ ID NO: 36.

[0174] In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 80%, at least 90%, at least 95%, at least 98%, or at least 99% identical to SEQ ID NO: 37. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 80% identical to SEQ ID NO: 37. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 83% identical to SEQ ID NO: 37. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 85% identical to SEQ ID NO: 37. In some embodiments, the IL-2 FcAttorney Docket No.: SVI-017WO1fusion protein comprises an amino acid sequence that is at least 87% identical to SEQ ID NO: 37. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 37. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 91% identical to SEQ ID NO: 37. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 92% identical to SEQ ID NO: 37. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 93% identical to SEQ ID NO: 37. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 94% identical to SEQ ID NO: 37. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 37. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 96% identical to SEQ ID NO: 37. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 97% identical to SEQ ID NO: 37. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 98% identical to SEQ ID NO: 37. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 37. In some embodiments, the IL-2 Fc fusion protein comprises an amino acid sequence that is identical to SEQ ID NO: 37.

[0175] In some embodiments, the IL-2 variant comprises the amino acid substitutions of H16L, V69A, and Q74P, and the IL-2 Fc fusion protein comprises an amino acid sequence at least 95% identical to SEQ ID NO: 26. In some embodiments, the IL-2 variant comprises the amino acid substitutions of H16N, V69A, and Q74P, and the IL-2 Fc fusion protein comprises an amino acid sequence at least 95% identical to SEQ ID NO: 26. In some embodiments, the IL-2 variant comprises the amino acid substitutions of V69A, Q74P, and D84V, and the IL-2 Fc fusion protein comprises an amino acid sequence at least 95% identical to SEQ ID NO: 26. In some embodiments, the IL-2 variant comprises the amino acid substitutions of V69A, Q74P, and S87R, and the IL-2 Fc fusion protein comprises an amino acid sequence at least 95% identical to SEQ ID NO: 26. In some embodiments, the IL-2 variant comprises the amino acid substitutions of V69A, Q74P, and I92S, and the IL-2 Fc fusion protein comprises an amino acid sequence at least 95% identical to SEQ ID NO: 26.Attorney Docket No.: SVI-017WO1Table 4. Amino Acid Sequences of Exemplary IL-2 Fc Fusion Proteins.Attorney Docket No.: SVI-017WO1Attorney Docket No.: SVI-017WO1Autoimmune Diseases

[0176] In one aspect, the present invention provides, among other things, a method of treating an autoimmune disease comprising administering subcutaneously a therapeutically effective dosing regimen of an IL-2 Fc fusion protein.

[0177] In some embodiments, the autoimmune disease is Addison’s disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, anti-GBM / anti- TBM nephritis, antiphospholipid syndrome (APS), autoimmune hepatitis, autoimmune inner ear disease (AIED), axonal & neuronal neuropathy (AMAN), Behcet’s disease, Bullous pemphigoid, Castleman disease (CD), Celiac disease, Chagas disease, chronic inflammatory demyelinating polyneuropathy (CIDP), chronic recurrent multifocal osteomyelitis (CRMO), Churg-Strauss, Cicatricial pemphigoid / benign mucosal pemphigoid, Cogan’s syndrome, Cold agglutinin disease, Congenital heart block, Coxsackie myocarditis, CREST syndrome,Attorney Docket No.: SVI-017WO1Crohn’s disease, dermatitis herpetiformis, dermatomyositis, Devic’s disease (neuromyelitis optica), Discoid lupus, Dressier’s syndrome, endometriosis, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, Evans syndrome, fibromyalgia, fibrosing alveolitis, focal segmented glomerulosclerosis (FSGS) (e.g., immune-mediated FSGS (IM-FSGS)), giant cell arteritis (temporal arteritis), giant cell myocarditis, Glomerulonephritis, Goodpasture’s syndrome, Granulomatosis with Polyangiitis, Graft-versus-host disease (GvHD), Graves’ disease, Guillain-Barre syndrome, Hashimoto’s thyroiditis, hemolytic anemia, Henoch-Schonlein purpura (HSP), herpes gestationis or pemphigoid gestationis (PG), hypogammalglobulinemia, IgA nephropathy, IgG4-related sclerosing disease, inclusion body myositis (IBM), interstitial cystitis (IC), juvenile arthritis, juvenile diabetes (Type 1 diabetes), juvenile myositis (JM), Kawasaki disease, Lambert-Eaton syndrome, leukocytoclastic vasculitis, Lichen planus, Lichen sclerosus, Ligneous conjunctivitis, linear IgA disease (LAD), lupus (e.g., systemic lupus erythematosus (SLE) or lupus nephritis), Lyme disease chronic, Membranous neuropathy, Meniere’s disease, microscopic polyangiitis (MPA), mixed connective tissue disease (MCTD), Mooren’s ulcer, Mucha-Habermann disease, multiple sclerosis (MS), Myasthenia gravis, Myositis, Narcolepsy, nephrotic syndrome, Neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis, palindromic rheumatism (PR), PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus), paraneoplastic cerebellar degeneration (PCD), Paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome, Pars planitis (peripheral uveitis), Parsonnage-Tumer syndrome, Pemphigus, peripheral neuropathy, Perivenous encephalomyelitis, pernicious anemia (PA), POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes), polyarteritis nodosa, polymyalgia rheumatica, polymyositis, postmyocardial infarction syndrome, postpericardiotomy syndrome, primary biliary cirrhosis, primary sclerosing cholangitis, progesterone dermatitis, psoriasis, psoriatic arthritis, pure red cell aplasia (PRC A), pyoderma gangrenosum, Raynaud’s phenomenon, Reactive Arthritis, Reflex sympathetic dystrophy, Reiter’s syndrome, relapsing polychondritis, restless legs syndrome (RLS), retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis (RA), sarcoidosis, Schmidt syndrome, scleritis, scleroderma, Sjogren’s syndrome, sperm & testicular autoimmunity, Stiff person syndrome (SPS), subacute bacterial endocarditis (SBE), Susac’s syndrome, sympathetic ophthalmia (SO), Takayasu’s arteritis, temporal arteritis / Giant cell arteritis, thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome (THS), transverseAttorney Docket No.: SVI-017WO1myelitis, type 1 diabetes, ulcerative colitis (UC), undifferentiated connective tissue disease (UCTD), uveitis, vasculitis, vitiligo, or Wegener’s granulomatosis (Granulomatosis with Polyangiitis (GPA)).

[0178] In some embodiments, the autoimmune disease is lupus nephritis. In some embodiments, the autoimmune disease is autoimmune hepatitis. In some embodiments, the autoimmune disease is nephrotic syndrome. In some embodiments, the autoimmune disease is psoriasis. In some embodiments, the autoimmune disease is systemic lupus erythematous (SLE). In some embodiments, the autoimmune disease is focal segmented glomerulosclerosis (FSGS). In some embodiments, the autoimmune disease is immune-mediated FSGS (IM-FSGS). In some embodiments, the autoimmune disease is alopecia areata (AA).

[0179] In some embodiments, the autoimmune disease is an acute disease. In some embodiments, the autoimmune disease is a chronic disease.Systemic Lupus Erythematosus (SLE)

[0180] SLE is a systemic autoimmune vasculitic disease typically characterized by immune complexes containing autoantibodies (anti-nuclear antibodies (ANA), anti dsDNA) to self-nuclear antigens and failure of self-tolerance. SLE can affect multiple organ systems, and consequently has a range of clinical manifestations, including cutaneous, neurologic, musculoskeletal, cardiac, and kidney manifestations. Up to 50% of patients with SLE develop lupus nephritis, which comprises a spectrum of inflammatory kidney manifestations. Control of auto-reactive T cells is important to immune tolerance and reduced IL 2 and Treg can play a role in the pathogenesis of SLE and lupus nephritis. Without wishing to be bound by theory, it is believed that in some embodiments preferential Treg expansion with minimal NK cell expansion can provide clinical benefits in SLE and lupus nephritis, with reduced risk of adverse effects.

[0181] Exemplary symptoms of SLE include severe fatigue, joint pain, joint swelling, headaches, a rash on the cheeks and nose, which is called a “butterfly rash”, hair loss, anemia, blood-clotting problems, fingers turning white or blue and tingling when cold, which is known as Raynaud’s phenomenon. Other exemplary symptoms may depend on the part of the body the disease is attacking, such as the digestive tract, the heart, or the skin.

[0182] Diagnosis of SLE can be based on antinuclear antibody (ANA), complete blood count (CBC), chest X-ray, serum creatinine, and urinalysis.Attorney Docket No.: SVI-017WO1Lupus Nephritis

[0183] Lupus nephritis is an autoimmune disease that is a form of glomerulonephritis that can constitute the most severe organ manifestation of systemic lupus erythematosus (SLE). Lupus nephritis leads to autoantibodies in the kidney, e.g., antibodies to nucleic acid containing particles (anti-nuclear antibodies (ANA)), which causes inflammation, e.g., inflammation in the nephrons, and impairs kidney function, e.g., waste removal and filtration. It can result in permanent scarring and damage to the kidneys and possibly end-stage renal disease (ESRD). Lupus nephritis often develops in a subject within five years of developing lupus. In some embodiments, lupus, e.g., SLE and / or lupus nephritis, can result from a combination of factors, e.g., genetic, environmental, immunoregulatory, hormonal, and / or epigenetic factors.

[0184] Imbalance of T cells due to IL-2 deprivation can amplify murine lupus and IL-2 can restore Treg:Tcon balance and impede disease progression. Adoptive transfer of ex vivo expanded regulatory T cells can suppress disease in lupus-prone mice. Lower number of Tregs are typically associated with patients with active SLE and Tregs can decline during flare and increase during remission.

[0185] Exemplary symptoms of lupus nephritis include, but are not limited to, blood in the urine (hematuria), proteinuria, foamy urine (e.g., foamy urine due to excess protein in the urine), increased urination, edema, Reynaud syndrome, joint pain, pericarditis and effusion, arthritis, pleural effusion, high blood pressure, swelling in hands, ankles, and feet, excess levels of creatine in the blood, muscle pain, weight gain, fever of unknown etiology, neurological complications, and a red rash that is typically localized to the face (e.g., across the nose and face).

[0186] Diagnosis of lupus nephritis can be based on urinalysis and the measurement of blood, cell casts (e.g., cell fragments often found in the blood and / or the tubules of the kidneys), and protein levels in the urine. Diagnosis can also be based on a blood test to estimate kidney function, e.g., a creatine blood test with or without a blood urea nitrogen (BUN) test. Additionally, to test kidney function, the person's estimated glomerular filtration rate (eGFR) can be measured from a blood sample. A kidney biopsy can also be performed, which can be used to stage lupus nephritis. In some embodiments, lupus nephritis is classified as one of six stages under the International Society of Nephrol ogy / Renal Pathology SocietyAttorney Docket No.: SVI-017WO1(ISN / RPS) classification system, which include, minimal mesangial lupus nephritis (Class I), mesangial proliferative lupus nephritis (Class II), focal lupus nephritis (<50% of all glomeruli) (Class III), diffuse segmental or global lupus nephritis (>50% of all glomeruli) (Class IV), membranous lupus nephritis (Class V), or advanced sclerosing lupus nephritis (>90% of all glomeruli) (Class VI).Autoimmune Hepatitis (AIH)

[0187] Autoimmune hepatitis is an autoimmune disease that affects the liver, resulting in progressive and chronic inflammation as well as liver damage. It can result in permanent scarring and cirrhosis of the liver and / or liver failure. In some embodiments, autoimmune hepatitis can be characterized by a T cell-mediated immune response against liver autoantigens that results from a loss of regulatory immune control and tolerance. In some embodiments, autoimmune hepatitis can result from a from a combination of factors, e.g., genetic, environmental, dietary, and immunoregulatory factors. In some embodiments, autoimmune hepatitis can result from an unknown etiology.

[0188] There are three subtypes: AIH type 1 is characterized by the presence of ANA and / or anti-smooth muscle antibody (SMA) autoantibodies. AIH type 2 is characterized by anti-LKM 1 autoantibodies, and a lower frequency of anti-LKM 3 autoantibodies (with or without ANA or SMA autoantibodies). AIH type 3 is characterized by autoantibodies against SLA / LP (with or without ANA or SMA autoantibodies). AIH Type 1 occurs predominantly in adults while Type 2 is generally observed in a younger, pediatric population. AIH most commonly presents with acute hepatitis, which may progress to cirrhosis and end-stage liver disease. AIH may also be associated with other autoimmune diseases such as thyroiditis, inflammatory bowel disease, type 1 diabetes mellitus, and Addison’s disease.

[0189] Hepatic inflammation typically depends on the balance between T effector cells and Tregs. Biopsy is required for diagnosis and modulation of treatment and interface hepatitis is often the hallmark finding in biopsy. AIH patients can have lower IL-2 levels and Tregs respond well to IL-2 supplement. Without wishing to be bound by theory, it is believed that In some embodiments, T cells (both Tregs and T effector cells) play a role in the development and persistence of AIH. For example, impaired Treg function and the ratio of Tregs to T effector cells in inflamed liver tissue may serve as potential drivers of disease. Without wising to be bound by theory, it is believed that in some embodiments, preferentialAttorney Docket No.: SVI-017WO1Treg expansion with minimal NK cell expansion can provide clinical benefits in AIH, with reduced risk of adverse effects associated with chronic immunosuppressive maintenance therapy.

[0190] Exemplary symptoms of autoimmune hepatitis include, but are not limited to, joint pain, lethargy, nausea, poor appetite, pain over the liver in the upper abdomenjaundice of the eyes and skin, dark colored urine, rash, psoriasis, vitiligo, acne, fatigue, spider angiomas, hepatomegaly, rectal bleeding or vomiting, unexplained weight loss, pruritis, edema of lower legs, ankles, or feet, and bloating from a buildup of fluid in the abdomen. In some embodiments, autoimmune hepatitis results in increased levels of the serum transaminase, IgG levels, autoantibodies, liver interface hepatitis, and / or liver enzymes, alanine transaminase (ALT) and an aspartate transaminase (AST). In some embodiments, autoimmune hepatitis results in decreased levels of IL-2.

[0191] Diagnosis of autoimmune hepatitis can be based on a laboratory test and / or liver function test, e.g., a blood test, a liver biopsy, an ultrasound, a Doppler ultrasonography, a CT and / or an MRI and cholangiography (x-rays of the bile ducts). In some embodiments, the blood test include one or more of a coagulation test (e.g., to measure clotting factors), a complete blood count (CBC), an electrolyte panel, a serum bilirubin test, a serum albumin test, a serum alkaline phosphatase test, a serum aminotransferases (transaminases) test, a prothrombin time (PTT) test, an alanine transaminase (ALT) test, an aspartate transaminase (AST) test, gamma-glutamyl transpeptidase test, a lactic dehydrogenase test, a 5 -nucleotidase test, an alpha-fetoprotein test, and a mitochondrial antibodies test. In some embodiments, diagnosis of autoimmune hepatitis includes a measure of autoimmune antibodies, e.g., antinuclear antibodies (ANA) and anti-smooth muscle antibodies (SMA).

[0192] In some embodiments, diagnosis of autoimmune hepatitis comprises quantifying a Revised Diagnostic Criteria (RDC) score. In some embodiments, quantification of an RDC score comprises one or more of the following criteria: gender (e.g., being a female); ratio of alkaline phosphatase levels to aspartate aminotransferase or alanine aminotransferase levels; y-globulin or IgG levels; ANA, SNA and anti-liver kidney microsomal type I (anti-LKMl) antibody titers, anti -mitochondrial antibody positivity, viral serological markers, use of drugs with hepatoxic potential, alcohol use, HLADR3 or HLADR4 genotypes, concurrent immunological diseases (e.g., thyroiditis and / or colitis), and / or histological features (e.g., presence or absence of interface hepatitis, plasma cells,Attorney Docket No.: SVI-017WO1rosettes, and / or biliary changes). In some embodiments, an aggregate RDC score of >15 points is classified as autoimmune hepatitis. In some embodiments, an aggregate RDC score of 10-15 is classified as probable autoimmune hepatitis.

[0193] In some embodiments, diagnosis of autoimmune hepatitis comprises quantifying a Simplified Diagnostic Criteria (SDC) score. In some embodiments, an SDC aggregate score of >7 is classified as autoimmune hepatitis. In some embodiments, an SDC aggregate score of >6 is classified as probable autoimmune hepatitis. In some embodiments, quantification of an SDC score comprises one or more of the following criteria: presence of autoantibodies (e.g., ANA, SNA and / or anti-LKMl antibodies), immunoglobulin levels (e.g., levels of y-globulin or IgG), viral hepatitis, and / or histological features compatible with autoimmune hepatitis.

[0194] In some embodiments, autoimmune hepatitis can be classified as Type I autoimmune hepatitis. Type I autoimmune hepatitis can occur at an any age. In some embodiments, Type I autoimmune hepatitis can often be associated with other autoimmune diseases, e.g., thyroiditis, inflammatory bowel disease, type I diabetes, Addison’s disease. In some embodiments, autoimmune hepatitis can be classified as Type II autoimmune hepatitis. Type II autoimmune hepatitis can be more common in children and younger adults. In some embodiments, Type II autoimmune hepatitis may be associated with other autoimmune diseases, thyroiditis, inflammatory bowel disease, type I diabetes, Addison’s disease.Nephrotic Syndrome

[0195] Nephrotic syndrome is a collection of symptoms that indicate kidney damage, which include but are not limited to, albuminuria (increased protein in the urine), hyperlipidemia (higher than normal fat and cholesterol levels in the blood), edema (e.g., usually in the legs, feet, ankles and less often in the hands or face), and / or hypoalbuminemia (low levels of albumin in the blood). In some embodiments, nephrotic syndrome results from damage to the glomeruli of the kidneys, which impairs kidney function, e.g., waste removal and filtration. In some embodiments, in nephrotic syndrome, the damaged glomeruli allow at least about 3 grams or more of protein to leak into the urine, as measured over a 24-hour period. In some embodiments, nephrotic syndrome can lead to other health problems, e.g., anemia, heart disease, high blood pressure, fluid buildup, blood clots, infections,Attorney Docket No.: SVI-017WO1malnutrition, stroke, heart attack, acute kidney injury, chronic kidney disease, kidney failure, and / or end-stage renal disease (ESRD).

[0196] In some embodiments, nephrotic syndrome results from systemic T-cell dysregulation, e.g., a reduction of CD4+ T helper cells and increased prevalence of CD8+ cytotoxic T cells; imbalance between Th2 and Thl cells with increased production of IL-13, and / or reduced frequency and / or function of T regulatory cells.

[0197] In some embodiments, nephrotic syndrome is the result of other diseases that affect the kidneys, e.g., focal segmental glomerulosclerosis (FSGS), minimal change disease (MCD), IgA nephropathy, lupus nephritis, and membranous nephropathy. In some embodiments, nephrotic syndrome is the result of systemic diseases that affect the whole body including but not limited to the kidneys, e.g., diabetes, amyloidosis, and / or lupus (e.g., systemic lupus erythematosus (SLE) and / or lupus nephritis). In some embodiments, idiopathic neuropathy results from MCD or Primary FSGS. In some embodiments, focal segmental glomerulosclerosis (FSGS) is the most common etiology of idiopathic nephrotic syndrome in adults. In some embodiments, minimal change disease (MCD) is the most common etiology of idiopathic nephrotic syndrome in children. In some embodiments, MCD results in decreased levels of T regulatory cells, T regulatory cell-related cytokines (e.g., TGF-pi and IL-10), and T regulatory cell-related transcription factors (e.g., FOXP3). In some embodiments, increasing the number of T regulatory cells can induce remission of FSGS.

[0198] Exemplary symptoms of nephrotic syndrome include, but are not limited to, edema, foamy urine (e.g., foamy urine due to excess protein in the urine), weigh gain (e.g., weight gain due to excessive fluid retention), fatigue, and loss of appetite.

[0199] Diagnosis of nephrotic syndrome can be based on urinalysis and the measurement of blood, cell casts (e.g., cell fragments often found in the blood and / or the tubules of the kidneys), albumin and / or creatine levels in the urine, and protein levels in the urine. Diagnosis can also be based on a blood test to estimate kidney function, e.g., a creatine blood test with or without a blood urea nitrogen (BUN) test. Additionally, to test kidney function, the person's estimated glomerular filtration rate (eGFR) can be measured from a blood sample. A kidney biopsy can also be performed.Attorney Docket No.: SVI-017WO1Immune-Mediated Focal Segmental Glomerulosclerosis (IM-FSGS)

[0200] FSGS is a histopathologic lesion describing segmental glomerular scarring in distinct, focal areas of the kidney, typically resulting from a spectrum of underlying etiologies. Immune-mediated FSGS (IM FSGS) is a sub-population of FSGS that arises in the absence of known causes such as human immunodeficiency virus or specific nephrotoxic agents, and is generally characterized by incomplete response to immunosuppression. FSGS patients with persistent dependence on immunosuppressive therapy have an increased risk of progression to end stage kidney disease, as well as a higher probability of experiencing recurrence of FSGS after transplantation (often within the first-year post-transplant), despite aggressive standard of care pre- & peri transplant therapy with plasmapheresis. In contrast, non-IM FSGS (e.g., resulting from genetic mutations in critical glomerular structural proteins) is typically resistant to immunosuppression, and does not typically recur after transplantation.

[0201] Immunosuppression-resistant FSGS typically results from monogenic mutations that cause structural defects in the glomerular filtration barrier. Many such mutations are known (over 80 have been identified, e.g., NPHS1, NPHS2, ACTN4, TRPC6, CD2AP, PLCE1), while some familial FSGS cohorts likely harbor as yet undiscovered mutations.

[0202] In contrast, immunosuppression-responsive FSGS likely represents the subpopulation of IM FSGS patients. This group is further defined by the response to initial courses of steroid therapy and other second line immunosuppression (e.g., calcineurin inhibitors, cyclophosphamide, rituximab, and mycophenolate mofetil). IM-FSGS patients with steroid-sensitive nephrotic syndrome (SSNS) remain in remission after completing a course and taper of steroid therapy, while patients with the steroid-dependent or frequently relapsing nephrotic syndrome (SDNS / FRNS) form of IM FSGS require chronic steroid therapy to repeatedly achieve or maintain remission. FRNS often progresses to secondary steroid-resistant nephrotic syndrome (SRNS) that may respond to second line immunosuppression.

[0203] While the terms “FSGS” and “minimal change disease” (MCD) are typically associated with SRNS and SSNS, respectively, there are numerous contradictory instances. More likely, a histologic diagnosis of MCD reflects an earlier stage of the disease, prior toAttorney Docket No.: SVI-017WO1more extensive focal involvement of the kidney, and may be the result of statistical sampling given the limitations of kidney biopsies (Schachter, Pediatr Nephrol 21, 953 - 957, 2006; Maas et al., Nat Rev Nephrol (12):768-776, 2016). Therefore, SSNS / SDNS / FRNS patients with biopsy findings showing either MCD or FSGS are included in the definition of IM-FSGS, and henceforth the term “IM-FSGS” will implicitly include immune-mediated MCD.

[0204] Tregs play a key role in the pathogenesis of IM-FSGS. Without wishing to be bound by theory, it is believed that in some embodiments Treg expansion can provide significant clinical benefits in IM-FSGS (both native kidney and post-transplant), allowing for higher rates of remission with reduced or no steroid therapy.

[0205] Exemplary symptoms of FSGS include swelling in body parts like legs, ankles and around eyes (edema), weight gain due to extra fluid building in the body, foamy urine caused by high protein levels in the urine (proteinuria), high fat levels in the blood (high cholesterol), and low levels of protein in the blood. FSGS can cause nephrotic syndrome.

[0206] Diagnosis of FSGS can be based on urine test, blood test, glomerular filtration rate (GFR), and kidney biopsy.Alopecia Areata (AA)

[0207] Alopecia Areata (AA) is an autoimmune disease typically resulting in inflammation induced hair loss. The most common patterns include patchy alopecia areata (small round or patchy bald lesion, usually on the scalp), alopecia totalis (total loss of scalp hair only), and alopecia universalis (total loss of all body hair). Alopecia areata affects approximately 4.5 million people in the United States, with most under the age of 30 years, and can impart significant emotional distress in this mostly young adult population. Systemic therapy with immunosuppressive therapy is the primary standard of care for more extensive AA, although topical therapy may also be co-administered. JAK inhibitors are the key investigational agents in clinical trials of AA, however chronic use may be limited by safety concerns such as leukopenia, elevated liver enzymes, and thromboembolic events. Without wishing to be bound by theory, it is believed that in some embodiments, preferential Treg expansion can provide clinical benefits in AA, with reduced risk of the adverse effects that may accompany JAK inhibitor therapy.

[0208] Exemplary symptoms of AA include hair loss. Diagnosis of AA can be based on extent of hair loss, scalp biopsy, and blood tests.Attorney Docket No.: SVI-017WO1Dosing RegimenDose

[0209] In one aspect, the present invention provides, among other things, a method of treating an autoimmune disease comprising administering a therapeutically effective dosing regimen of an IL-2 fusion protein. In some embodiments, then IL-2 fusion protein is administered subcutaneously.

[0210] In one aspect, the present invention provides, among other things, a method of treating an autoimmune disease comprising administering subcutaneously a therapeutically effective dosing regimen of an IL-2 fusion protein.

[0211] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a weight-based dose. In some embodiments, a therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a flat dose.

[0212] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 10 pg / kg to 24 pg / kg. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 10 pg / kg to 12 pg / kg. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 12 pg / kg to 24 pg / kg. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 11 pg / kg to 15 pg / kg. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 10 pg / kg to 14 pg / kg. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 11 pg / kg to 14 pg / kg. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 11 pg / kg to 13 pg / kg.

[0213] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 10 pg / kg. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein 11 pg / kg. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 12 pg / kg. In some embodiments, the therapeutically effective dosing regimenAttorney Docket No.: SVI-017WO1comprises subcutaneously administering the IL-2 fusion protein at a dose of 13 pg / kg. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 14 pg / kg. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 15 pg / kg. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 16 pg / kg. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 18 pg / kg. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 20 pg / kg. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 22 pg / kg. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 24 pg / kg.

[0214] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 100 pg to 2000 pg. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 500 pg to 1500 pg. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 250 pg to 1750 pg. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 500 pg to 2000 pg. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 100 pg to 1500 pg. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 500 pg to 1000 pg. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 1000 pg to 1500 pg.

[0215] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 100 pg. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 250 pg. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 500 pg. In some embodiments, the therapeutically effective dosingAttorney Docket No.: SVI-017WO1regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 750 pg. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 1000 pg. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 1250 pg. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 1500 pg. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 1750 pg. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 2000 pg.Administration Interval

[0216] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein no more frequent than once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein no more frequent than once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein no more frequent than once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein no more frequent than once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein no more frequent than once every six weeks.

[0217] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein once every six weeks.Attorney Docket No.: SVI-017WO1

[0218] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 10 pg / kg to 24 pg / kg no more frequent than once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 10 pg / kg to 24 pg / kg no more frequent than once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 10 pg / kg to 24 pg / kg no more frequent than once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 10 pg / kg to 24 pg / kg no more frequent than once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 10 pg / kg to 24 pg / kg no more frequent than once every six weeks.

[0219] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 10 pg / kg to 24 pg / kg once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 10 pg / kg to 24 pg / kg once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 10 pg / kg to 24 pg / kg once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 10 pg / kg to 24 pg / kg once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 10 pg / kg to 24 pg / kg once every six weeks.

[0220] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 10 pg / kg to 12 pg / kg no more frequent than once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 10 pg / kg to 12 pg / kg no more frequent than once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 10 pg / kg to 12 pg / kg no more frequent than once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 10 pg / kg to 12 pg / kg no more frequent than once every five weeks. In some embodiments, theAttorney Docket No.: SVI-017WO1therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 10 pg / kg to 12 pg / kg no more frequent than once every six weeks.

[0221] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 10 pg / kg to 12 pg / kg once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 10 pg / kg to 12 pg / kg once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 10 pg / kg to 12 pg / kg once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 10 pg / kg to 12 pg / kg once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 10 pg / kg to 12 pg / kg once every six weeks.

[0222] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 12 pg / kg to 24 pg / kg no more frequent than once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 12 pg / kg to 24 pg / kg no more frequent than once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 12 pg / kg to 24 pg / kg no more frequent than once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 12 pg / kg to 24 pg / kg no more frequent than once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 12 pg / kg to 24 pg / kg no more frequent than once every six weeks.

[0223] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 12 pg / kg to 24 pg / kg once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 12 pg / kg to 24 pg / kg once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 12 pg / kg to 24 pg / kg once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose ofAttorney Docket No.: SVI-017WO112 pg / kg to 24 pg / kg once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 12 pg / kg to 24 pg / kg once every six weeks.

[0224] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 11 pg / kg to 15 pg / kg no more frequent than once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 11 pg / kg to 15 pg / kg no more frequent than once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 11 pg / kg to 15 pg / kg no more frequent than once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 11 pg / kg to 15 pg / kg no more frequent than once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 11 pg / kg to 15 pg / kg no more frequent than once every six weeks.

[0225] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 11 pg / kg to 15 pg / kg once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 11 pg / kg to 15 pg / kg once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 11 pg / kg to 15 pg / kg once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 11 pg / kg to 15 pg / kg once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 11 pg / kg to 15 pg / kg once every six weeks.

[0226] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 10 pg / kg to 14 pg / kg no more frequent than once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 10 pg / kg to 14 pg / kg no more frequent than once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 10 pg / kg to 14 pg / kg no more frequent thanAttorney Docket No.: SVI-017WO1once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 10 pg / kg to 14 pg / kg no more frequent than once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 10 pg / kg to 14 pg / kg no more frequent than once every six weeks.

[0227] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 10 pg / kg to 14 pg / kg once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 10 pg / kg to 14 pg / kg once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 10 pg / kg to 14 pg / kg once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 10 pg / kg to 14 pg / kg once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 10 pg / kg to 14 pg / kg once every six weeks.

[0228] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 11 pg / kg to 14 pg / kg no more frequent than once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 11 pg / kg to 14 pg / kg no more frequent than once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 11 pg / kg to 14 pg / kg no more frequent than once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 11 pg / kg to 14 pg / kg no more frequent than once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 11 pg / kg to 14 pg / kg no more frequent than once every six weeks.

[0229] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 11 pg / kg to 14 pg / kg once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 11 pg / kg to 14 pg / kg once every three weeks. In some embodiments, the therapeutically effective dosingAttorney Docket No.: SVI-017WO1regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 11 pg / kg to 14 pg / kg once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 11 pg / kg to 14 pg / kg once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 11 pg / kg to 14 pg / kg once every six weeks.

[0230] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 11 pg / kg to 13 pg / kg no more frequent than once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 11 pg / kg to 13 pg / kg no more frequent than once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 11 pg / kg to 13 pg / kg no more frequent than once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 11 pg / kg to 13 pg / kg no more frequent than once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 11 pg / kg to 13 pg / kg no more frequent than once every six weeks.

[0231] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 11 pg / kg to 13 pg / kg once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 11 pg / kg to 13 pg / kg once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 11 pg / kg to 13 pg / kg once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 11 pg / kg to 13 pg / kg once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 11 pg / kg to 13 pg / kg once every six weeks.

[0232] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 10 pg / kg no more frequent than once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 10Attorney Docket No.: SVI-017WO1pg / kg no more frequent than once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 10 pg / kg no more frequent than once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 10 pg / kg no more frequent than once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 10 pg / kg no more frequent than once every six weeks.

[0233] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 10 pg / kg once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 10 pg / kg once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 10 pg / kg once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 10 pg / kg once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 10 pg / kg once every six weeks.

[0234] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 11 pg / kg no more frequent than once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 11 pg / kg no more frequent than once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 11 pg / kg no more frequent than once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 11 pg / kg no more frequent than once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 11 pg / kg no more frequent than once every six weeks.

[0235] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 11 pg / kg once every twoAttorney Docket No.: SVI-017WO1weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 11 pg / kg once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 11 pg / kg once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 11 pg / kg once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 11 pg / kg once every six weeks.

[0236] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 12 pg / kg no more frequent than once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 12 pg / kg no more frequent than once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 12 pg / kg no more frequent than once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 12 pg / kg no more frequent than once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 12 pg / kg no more frequent than once every six weeks.

[0237] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 12 pg / kg once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 12 pg / kg once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 12 pg / kg once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 12 pg / kg once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 12 pg / kg once every six weeks.Attorney Docket No.: SVI-017WO1

[0238] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 13 pg / kg no more frequent than once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 13 pg / kg no more frequent than once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 13 pg / kg no more frequent than once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 13 pg / kg no more frequent than once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 13 pg / kg no more frequent than once every six weeks.

[0239] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 13 pg / kg once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 13 pg / kg once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 13 pg / kg once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 13 pg / kg once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 13 pg / kg once every six weeks.

[0240] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 14 pg / kg no more frequent than once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 14 pg / kg no more frequent than once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 14 pg / kg no more frequent than once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 14 pg / kg no more frequent than once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprisesAttorney Docket No.: SVI-017WO1subcutaneously administering the IL-2 fusion protein at a dose of 14 pg / kg no more frequent than once every six weeks.

[0241] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 14 pg / kg once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 14 pg / kg once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 14 pg / kg once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 14 pg / kg once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 14 pg / kg once every six weeks.

[0242] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 15 pg / kg no more frequent than once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 15 pg / kg no more frequent than once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 15 pg / kg no more frequent than once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 15 pg / kg no more frequent than once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 15 pg / kg no more frequent than once every six weeks.

[0243] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 15 pg / kg once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 15 pg / kg once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 15 pg / kg once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 15 pg / kg once every fiveAttorney Docket No.: SVI-017WO1weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 15 pg / kg once every six weeks.

[0244] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 16 pg / kg no more frequent than once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 16 pg / kg no more frequent than once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 16 pg / kg no more frequent than once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 16 pg / kg no more frequent than once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 16 pg / kg no more frequent than once every six weeks.

[0245] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 16 pg / kg once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 16 pg / kg once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 16 pg / kg once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 16 pg / kg once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 16 pg / kg once every six weeks.

[0246] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 18 pg / kg no more frequent than once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 18 pg / kg no more frequent than once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 18 pg / kg no more frequent than once every four weeks. In someAttorney Docket No.: SVI-017WO1embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 18 pg / kg no more frequent than once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 18 pg / kg no more frequent than once every six weeks.

[0247] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 18 pg / kg once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 18 pg / kg once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 18 pg / kg once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 18 pg / kg once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 18 pg / kg once every six weeks.

[0248] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 20 pg / kg no more frequent than once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 20 pg / kg no more frequent than once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 20 pg / kg no more frequent than once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 20 pg / kg no more frequent than once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 20 pg / kg no more frequent than once every six weeks.

[0249] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 20 pg / kg once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 20 pg / kg once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprisesAttorney Docket No.: SVI-017WO1subcutaneously administering the IL-2 fusion protein at a dose of 20 pg / kg once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 20 pg / kg once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 20 pg / kg once every six weeks.

[0250] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 22 pg / kg no more frequent than once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 22 pg / kg no more frequent than once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 22 pg / kg no more frequent than once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 22 pg / kg no more frequent than once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 22 pg / kg no more frequent than once every six weeks.

[0251] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 22 pg / kg once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 22 pg / kg once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 22 pg / kg once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 22 pg / kg once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 22 pg / kg once every six weeks.

[0252] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 24 pg / kg no more frequent than once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 24Attorney Docket No.: SVI-017WO1pg / kg no more frequent than once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 24 pg / kg no more frequent than once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 24 pg / kg no more frequent than once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 24 pg / kg no more frequent than once every six weeks.

[0253] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 24 pg / kg once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 24 pg / kg once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 24 pg / kg once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 24 pg / kg once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 24 pg / kg once every six weeks.

[0254] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 100 pg to 2000 pg no more frequent than once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 100 pg to 2000 pg no more frequent than once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 100 pg to 2000 pg no more frequent than once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 100 pg to 2000 pg no more frequent than once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 100 pg to 2000 pg no more frequent than once every six weeks.

[0255] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 100 pg to 2000 pg onceAttorney Docket No.: SVI-017WO1every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 100 pg to 2000 pg once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 100 pg to 2000 pg once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 100 pg to 2000 pg once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 100 pg to 2000 pg once every six weeks.

[0256] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 500 pg to 1500 pg no more frequent than once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 500 pg to 1500 pg no more frequent than once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 500 pg to 1500 pg no more frequent than once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 500 pg to 1500 pg no more frequent than once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 500 pg to 1500 pg no more frequent than once every six weeks.

[0257] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 500 pg to 1500 pg once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 500 pg to 1500 pg once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 500 pg to 1500 pg once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 500 pg to 1500 pg once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 500 pg to 1500 pg once every six weeks.Attorney Docket No.: SVI-017WO1

[0258] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 250 pg to 1750 pg no more frequent than once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 250 pg to 1750 pg no more frequent than once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 250 pg to 1750 pg no more frequent than once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 250 pg to 1750 pg no more frequent than once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 250 pg to 1750 pg no more frequent than once every six weeks.

[0259] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 250 pg to 1750 pg once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 250 pg to 1750 pg once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 250 pg to 1750 pg once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 250 pg to 1750 pg once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 250 pg to 1750 pg once every six weeks.

[0260] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 500 pg to 2000 pg no more frequent than once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 500 pg to 2000 pg no more frequent than once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 500 pg to 2000 pg no more frequent than once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 500 pg to 2000 pg no more frequent than once every five weeks. In some embodiments, the therapeutically effectiveAttorney Docket No.: SVI-017WO1dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 500 pg to 2000 pg no more frequent than once every six weeks.

[0261] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 500 pg to 2000 pg once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 500 pg to 2000 pg once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 500 pg to 2000 pg once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 500 pg to 2000 pg once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 500 pg to 2000 pg once every six weeks.

[0262] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 100 pg to 1500 pg no more frequent than once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 100 pg to 1500 pg no more frequent than once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 100 pg to 1500 pg no more frequent than once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 100 pg to 1500 pg no more frequent than once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 100 pg to 1500 pg no more frequent than once every six weeks.

[0263] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 100 pg to 1500 pg once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 100 pg to 1500 pg once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 100 pg to 1500 pg once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 100 pgAttorney Docket No.: SVI-017WO1to 1500 pg once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 100 pg to 1500 pg once every six weeks.

[0264] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 500 pg to 1000 pg no more frequent than once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 500 pg to 1000 pg no more frequent than once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 500 pg to 1000 pg no more frequent than once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 500 pg to 1000 pg no more frequent than once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 500 pg to 1000 pg no more frequent than once every six weeks.

[0265] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 500 pg to 1000 pg once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 500 pg to 1000 pg once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 500 pg to 1000 pg once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 500 pg to 1000 pg once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 500 pg to 1000 pg once every six weeks.

[0266] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 1000 pg to 1500 pg no more frequent than once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 1000 pg to 1500 pg no more frequent than once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 1000 pg to 1500 pg no more frequent thanAttorney Docket No.: SVI-017WO1once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 1000 pg to 1500 pg no more frequent than once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 1000 pg to 1500 pg no more frequent than once every six weeks.

[0267] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 1000 pg to 1500 pg once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 1000 pg to 1500 pg once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 1000 pg to 1500 pg once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 1000 pg to 1500 pg once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 1000 pg to 1500 pg once every six weeks.

[0268] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 100 pg no more frequent than once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 100 pg no more frequent than once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 100 pg no more frequent than once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 100 pg no more frequent than once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 100 pg no more frequent than once every six weeks.

[0269] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 100 pg once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 100 pg once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprisesAttorney Docket No.: SVI-017WO1subcutaneously administering the IL-2 fusion protein at a dose of 100 pg once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 100 pg once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 100 pg once every six weeks.

[0270] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 250 pg no more frequent than once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 250 pg no more frequent than once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 250 pg no more frequent than once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 250 pg no more frequent than once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 250 pg no more frequent than once every six weeks.

[0271] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 250 pg once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 250 pg once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 250 pg once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 250 pg once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 250 pg once every six weeks.

[0272] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 500 pg no more frequent than once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 500 pgAttorney Docket No.: SVI-017WO1no more frequent than once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 500 pg no more frequent than once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 500 pg no more frequent than once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 500 pg no more frequent than once every six weeks.

[0273] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 500 pg once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 500 pg once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 500 pg once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 500 pg once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 500 pg once every six weeks.

[0274] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 750 pg no more frequent than once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 750 pg no more frequent than once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 750 pg no more frequent than once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 750 pg no more frequent than once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 750 pg no more frequent than once every six weeks.

[0275] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 750 pg once every twoAttorney Docket No.: SVI-017WO1weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 750 pg once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 750 pg once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 750 pg once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 750 pg once every six weeks.

[0276] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 1000 pg no more frequent than once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 1000 pg no more frequent than once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 1000 pg no more frequent than once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 1000 pg no more frequent than once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 1000 pg no more frequent than once every six weeks.

[0277] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 1000 pg once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 1000 pg once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 1000 pg once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 1000 pg once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 1000 pg once every six weeks.Attorney Docket No.: SVI-017WO1

[0278] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 1250 pg no more frequent than once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 1250 pg no more frequent than once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 1250 pg no more frequent than once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 1250 pg no more frequent than once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 1250 pg no more frequent than once every six weeks.

[0279] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 1250 pg once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 1250 pg once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 1250 pg once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 1250 pg once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 1250 pg once every six weeks.

[0280] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 1500 pg no more frequent than once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 1500 pg no more frequent than once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 1500 pg no more frequent than once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 1500 pg no more frequent than once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneouslyAttorney Docket No.: SVI-017WO1administering the IL-2 fusion protein at a dose of 1500 pg no more frequent than once every six weeks.

[0281] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 1500 pg once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 1500 pg once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 1500 pg once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 1500 pg once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 1500 pg once every six weeks.

[0282] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 1750 pg no more frequent than once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 1750 pg no more frequent than once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 1750 pg no more frequent than once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 1750 pg no more frequent than once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 1750 pg no more frequent than once every six weeks.

[0283] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 1750 pg once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 1750 pg once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 1750 pg once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 1750 pg once every fiveAttorney Docket No.: SVI-017WO1weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 1750 pg once every six weeks.

[0284] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 2000 pg no more frequent than once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 2000 pg no more frequent than once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 2000 pg no more frequent than once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 2000 pg no more frequent than once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 2000 pg no more frequent than once every six weeks.

[0285] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 2000 pg once every two weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 2000 pg once every three weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 2000 pg once every four weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 2000 pg once every five weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein at a dose of 2000 pg once every six weeks.

[0286] In some embodiments, an equivalent dosing regimen comprises administering an IL-2 fusion protein at a therapeutically effective dosing regimen to reduce one or more symptoms associated with autoimmune diseases. For example, an equivalent dosing regimen of 12 pg / kg every four weeks is 6 pg / kg every two weeks, 24 pg / kg every eight weeks, or 36 pg / kg every 12 weeks.Attorney Docket No.: SVI-017WO1Treatment Period

[0287] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein for a treatment period of at least 10 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein for a treatment period of at least 12 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein for a treatment period of at least 14 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein for a treatment period of at least 16 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein for a treatment period of at least 18 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein for a treatment period of at least 20 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein for a treatment period of at least 22 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein for a treatment period of at least 24 weeks.

[0288] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein no more frequent than once every two weeks for a treatment period of at least 10 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein no more frequent than once every two weeks for a treatment period of at least 12 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein no more frequent than once every two weeks for a treatment period of at least 14 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein no more frequent than once every two weeks for a treatment period of at least 16 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein no more frequent than once every two weeks for a treatment period of at least 18 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein no moreAttorney Docket No.: SVI-017WO1frequent than once every two weeks for a treatment period of at least 20 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein no more frequent than once every two weeks for a treatment period of at least 22 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein no more frequent than once every two weeks for a treatment period of at least 24 weeks.

[0289] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein once every two weeks for a treatment period of at least 10 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein once every two weeks for a treatment period of at least 12 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein once every two weeks for a treatment period of at least 14 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein once every two weeks for a treatment period of at least 16 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein once every two weeks for a treatment period of at least 18 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein once every two weeks for a treatment period of at least 20 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein once every two weeks for a treatment period of at least 22 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein once every two weeks for a treatment period of at least 24 weeks.

[0290] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein no more frequent than once every three weeks for a treatment period of at least 10 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein no more frequent than once every three weeks for a treatment period of at least 12 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein no more frequent than once every three weeks for a treatment period of at least 14 weeks. In some embodiments, the therapeutically effectiveAttorney Docket No.: SVI-017WO1dosing regimen comprises subcutaneously administering the IL-2 fusion protein no more frequent than once every three weeks for a treatment period of at least 16 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein no more frequent than once every three weeks for a treatment period of at least 18 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein no more frequent than once every three weeks for a treatment period of at least 20 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein no more frequent than once every three weeks for a treatment period of at least 22 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein no more frequent than once every three weeks for a treatment period of at least 24 weeks.

[0291] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein once every three weeks for a treatment period of at least 10 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein once every three weeks for a treatment period of at least 12 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein once every three weeks for a treatment period of at least 14 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein once every three weeks for a treatment period of at least 16 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein once every three weeks for a treatment period of at least 18 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein once every three weeks for a treatment period of at least 20 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein once every three weeks for a treatment period of at least 22 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein once every three weeks for a treatment period of at least 24 weeks.

[0292] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein no more frequent than once every fourAttorney Docket No.: SVI-017WO1weeks for a treatment period of at least 10 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein no more frequent than once every four weeks for a treatment period of at least 12 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein no more frequent than once every four weeks for a treatment period of at least 14 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein no more frequent than once every four weeks for a treatment period of at least 16 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein no more frequent than once every four weeks for a treatment period of at least 18 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein no more frequent than once every four weeks for a treatment period of at least 20 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein no more frequent than once every four weeks for a treatment period of at least 22 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein no more frequent than once every four weeks for a treatment period of at least 24 weeks.

[0293] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein once every four weeks for a treatment period of at least 10 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein once every four weeks for a treatment period of at least 12 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein once every four weeks for a treatment period of at least 14 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein once every four weeks for a treatment period of at least 16 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein once every four weeks for a treatment period of at least 18 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein once every four weeks for a treatment period of at least 20 weeks. In some embodiments, the therapeutically effective dosingAttorney Docket No.: SVI-017WO1regimen comprises subcutaneously administering the IL-2 fusion protein once every four weeks for a treatment period of at least 22 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein once every four weeks for a treatment period of at least 24 weeks.

[0294] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein no more frequent than once every five weeks for a treatment period of at least 10 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein no more frequent than once every five weeks for a treatment period of at least 12 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein no more frequent than once every five weeks for a treatment period of at least 14 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein no more frequent than once every five weeks for a treatment period of at least 16 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein no more frequent than once every five weeks for a treatment period of at least 18 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein no more frequent than once every five weeks for a treatment period of at least 20 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein no more frequent than once every five weeks for a treatment period of at least 22 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein no more frequent than once every five weeks for a treatment period of at least 24 weeks.

[0295] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein once every five weeks for a treatment period of at least 10 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein once every five weeks for a treatment period of at least 12 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein once every five weeks for a treatment period of at least 14 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2Attorney Docket No.: SVI-017WO1fusion protein once every five weeks for a treatment period of at least 16 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein once every five weeks for a treatment period of at least 18 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein once every five weeks for a treatment period of at least 20 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein once every five weeks for a treatment period of at least 22 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein once every five weeks for a treatment period of at least 24 weeks.

[0296] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein no more frequent than once every six weeks for a treatment period of at least 10 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein no more frequent than once every six weeks for a treatment period of at least 12 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein no more frequent than once every six weeks for a treatment period of at least 14 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein no more frequent than once every six weeks for a treatment period of at least 16 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein no more frequent than once every six weeks for a treatment period of at least 18 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein no more frequent than once every six weeks for a treatment period of at least 20 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein no more frequent than once every six weeks for a treatment period of at least 22 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein no more frequent than once every six weeks for a treatment period of at least 24 weeks.

[0297] In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein once every six weeks for a treatmentAttorney Docket No.: SVI-017WO1period of at least 10 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein once every six weeks for a treatment period of at least 12 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein once every six weeks for a treatment period of at least 14 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein once every six weeks for a treatment period of at least 16 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein once every six weeks for a treatment period of at least 18 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein once every six weeks for a treatment period of at least 20 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein once every six weeks for a treatment period of at least 22 weeks. In some embodiments, the therapeutically effective dosing regimen comprises subcutaneously administering the IL-2 fusion protein once every six weeks for a treatment period of at least 24 weeks.

[0298] In some embodiments, a method of treating an autoimmune disease comprises subcutaneously administering an IL-2 Fc fusion protein to a patient at a dose of 10 pg / kg every four weeks, wherein the IL-2 Fc fusion protein comprises an IL-2 variant comprising 95% identity to SEQ ID NO: 1 and amino acid substitutions H16L, V69A, Q74P, and C125S; and an Fc region.

[0299] In some embodiments, a method of treating an autoimmune disease comprises subcutaneously administering an IL-2 Fc fusion protein to a patient at a dose of 12 pg / kg every four weeks, wherein the IL-2 Fc fusion protein comprises an IL-2 variant comprising 95% identity to SEQ ID NO: 1 and amino acid substitutions H16L, V69A, Q74P, and C125S; and an Fc region.

[0300] In some embodiments, a method of treating an autoimmune disease comprises subcutaneously administering an IL-2 Fc fusion protein to a patient at a dose of 16 pg / kg every four weeks, wherein the IL-2 Fc fusion protein comprises an IL-2 variant comprising 95% identity to SEQ ID NO: 1 and amino acid substitutions H16L, V69A, Q74P, and C125S; and an Fc region.Attorney Docket No.: SVI-017WO1

[0301] In some embodiments, a method of treating an autoimmune disease comprises subcutaneously administering an IL-2 Fc fusion protein to a patient at a dose of 20 pg / kg every four weeks, wherein the IL-2 Fc fusion protein comprises an IL-2 variant comprising 95% identity to SEQ ID NO: 1 and amino acid substitutions H16L, V69A, Q74P, and C125S; and an Fc region.

[0302] In some embodiments, a method of treating an autoimmune disease comprises subcutaneously administering an IL-2 Fc fusion protein to a patient at a dose of 24 pg / kg every four weeks, wherein the IL-2 Fc fusion protein comprises an IL-2 variant comprising 95% identity to SEQ ID NO: 1 and amino acid substitutions H16L, V69A, Q74P, and C125S; and an Fc region.

[0303] In some embodiments, a method of treating an autoimmune disease comprises subcutaneously administering an IL-2 Fc fusion protein to a patient at a dose of 12 pg / kg every four weeks, wherein the IL-2 Fc fusion protein comprises an IL-2 variant of SEQ ID NO: 1 and an Fc region.

[0304] In some embodiments, a method of treating an autoimmune disease comprises subcutaneously administering an IL-2 Fc fusion protein to a patient at a dose of 12 pg / kg every four weeks, wherein the IL-2 Fc fusion protein comprises an IL-2 variant of SEQ ID NO: 2 and an Fc region.

[0305] In some embodiments, a method of treating an autoimmune disease comprises subcutaneously administering an IL-2 Fc fusion protein to a patient at a dose of 12 pg / kg every four weeks, wherein the IL-2 Fc fusion protein comprises an IL-2 variant of SEQ ID NO: 3 and an Fc region.

[0306] In some embodiments, a method of treating an autoimmune disease comprises subcutaneously administering an IL-2 Fc fusion protein to a patient at a dose of 12 pg / kg every four weeks, wherein the IL-2 Fc fusion protein comprises an IL-2 variant of SEQ ID NO: 4 and an Fc region.

[0307] In some embodiments, a method of treating an autoimmune disease comprises subcutaneously administering an IL-2 Fc fusion protein to a patient at a dose of 12 pg / kg every four weeks, wherein the IL-2 Fc fusion protein comprises an IL-2 variant of SEQ ID NO: 5 and an Fc region.Attorney Docket No.: SVI-017WO1

[0308] In some embodiments, a method of treating an autoimmune disease comprises subcutaneously administering an IL-2 Fc fusion protein to a patient at a dose of 12 pg / kg every four weeks, wherein the IL-2 Fc fusion protein comprises an IL-2 variant of SEQ ID NO: 6 and an Fc region.

[0309] In some embodiments, a method of treating an autoimmune disease comprises subcutaneously administering an IL-2 Fc fusion protein to a patient at a dose of 12 pg / kg every four weeks, wherein the IL-2 Fc fusion protein comprises an IL-2 variant of SEQ ID NO: 7 and an Fc region.

[0310] In some embodiments, a method of treating an autoimmune disease comprises subcutaneously administering an IL-2 Fc fusion protein to a patient at a dose of 12 pg / kg every four weeks, wherein the IL-2 Fc fusion protein comprises SEQ ID NO: 23.

[0311] In some embodiments, a method of treating an autoimmune disease comprises subcutaneously administering an IL-2 Fc fusion protein to a patient at a dose of 12 pg / kg every four weeks, wherein the IL-2 Fc fusion protein comprises SEQ ID NO: 24.

[0312] In some embodiments, a method of treating an autoimmune disease comprises subcutaneously administering an IL-2 Fc fusion protein to a patient at a dose of 12 pg / kg every four weeks, wherein the IL-2 Fc fusion protein comprises SEQ ID NO: 25.

[0313] In some embodiments, a method of treating an autoimmune disease comprises subcutaneously administering an IL-2 Fc fusion protein to a patient at a dose of 12 pg / kg every four weeks, wherein the IL-2 Fc fusion protein comprises SEQ ID NO: 26.

[0314] In some embodiments, a method of treating an autoimmune disease comprises subcutaneously administering an IL-2 Fc fusion protein to a patient at a dose of 12 pg / kg every four weeks, wherein the IL-2 Fc fusion protein comprises SEQ ID NO: 27.

[0315] In some embodiments, a method of treating an autoimmune disease comprises subcutaneously administering an IL-2 Fc fusion protein to a patient at a dose of 12 pg / kg every four weeks, wherein the IL-2 Fc fusion protein comprises SEQ ID NO: 28.

[0316] In some embodiments, a method of treating an autoimmune disease comprises subcutaneously administering an IL-2 Fc fusion protein to a patient at a dose of 12 pg / kg every four weeks, wherein the IL-2 Fc fusion protein comprises SEQ ID NO: 29.Attorney Docket No.: SVI-017WO1

[0317] In some embodiments, a method of treating an autoimmune disease comprises subcutaneously administering an IL-2 Fc fusion protein to a patient at a dose of 12 pg / kg every four weeks, wherein the IL-2 Fc fusion protein comprises SEQ ID NO: 30.

[0318] In some embodiments, a method of treating an autoimmune disease comprises subcutaneously administering an IL-2 Fc fusion protein to a patient at a dose of 12 pg / kg every four weeks, wherein the IL-2 Fc fusion protein comprises SEQ ID NO: 31.

[0319] In some embodiments, a method of treating an autoimmune disease comprises subcutaneously administering an IL-2 Fc fusion protein to a patient at a dose of 12 pg / kg every four weeks, wherein the IL-2 Fc fusion protein comprises SEQ ID NO: 32.

[0320] In some embodiments, a method of treating an autoimmune disease comprises subcutaneously administering an IL-2 Fc fusion protein to a patient at a dose of 12 pg / kg every four weeks, wherein the IL-2 Fc fusion protein comprises SEQ ID NO: 33.

[0321] In some embodiments, a method of treating an autoimmune disease comprises subcutaneously administering an IL-2 Fc fusion protein to a patient at a dose of 12 pg / kg every four weeks, wherein the IL-2 Fc fusion protein comprises SEQ ID NO: 34.

[0322] In some embodiments, a method of treating an autoimmune disease comprises subcutaneously administering an IL-2 Fc fusion protein to a patient at a dose of 12 pg / kg every four weeks, wherein the IL-2 Fc fusion protein comprises SEQ ID NO: 35.

[0323] In some embodiments, a method of treating an autoimmune disease comprises subcutaneously administering an IL-2 Fc fusion protein to a patient at a dose of 12 pg / kg every four weeks, wherein the IL-2 Fc fusion protein comprises SEQ ID NO: 36.

[0324] In some embodiments, a method of treating an autoimmune disease comprises subcutaneously administering an IL-2 Fc fusion protein to a patient at a dose of 12 pg / kg every four weeks, wherein the IL-2 Fc fusion protein comprises SEQ ID NO: 37.Therapeutic Efficacy

[0325] In some embodiments, the present invention provides, among other things, methods of selectively increasing regulatory T cells in a patient. In some embodiments, administration of the therapeutically effective dosing regimen selectively increases regulatory T cells in a patient.Attorney Docket No.: SVI-017WO1

[0326] Without wishing to be bound to any theory, it is contemplated herein that IL-2 therapy can induce two different subsets of effector regulatory T cells: (1) a Helios111subset showing higher expression of the gene IZKF2 (Helios), which has been associated with stability of Treg function and (2) a Galectin-l111subset showing (a) lower or no expression of key genes associated with retaining the function and phenotype of Tregs and (b) elevated expression of genes associated with apoptosis. The Helios111subset is associated with greater stability in a patient and is referred to interchangeably herein as “Helios111subset”, “subset of stable” effector regulatory T cells, and effector regulatory T cells with “inferred greater stability”. The Galectin-l111subset is associated with reduced stability in a patient and is referred to interchangeably herein as “Galectin-l111subset”, “subset of unstable” effector regulatory T cells, and effector regulatory T cells with “inferred lower stability”.

[0327] In some embodiments, the present invention provides, among other things, a method of expanding a subset of stable effector regulatory T cells in a patient. In some embodiments, administration of the therapeutically effective dosing regimen induces expansion of the subset of stable effector regulatory T cells in a patient. In some embodiments, the subset of stable effector regulatory T cells is associated with higher Helios (IKZF2) gene expression. In some embodiments, the subset of stable effector regulatory T cells is associated with higher TET2 gene expression, a gene involved in the epigenetic regulation of regulatory T cells. In some embodiments, the subset of stable effector regulatory T cells is associated with higher BCL2 gene expression, which mediates anti-apoptotic activity. In some embodiments, the subset of stable effector regulatory T cells is associated with higher composite gene expression of transcription factors and regulators that support maintenance ofFOXP3 expression.

[0328] In some embodiments, administration of the therapeutically effective dosing regimen induces more expansion of the subset of stable effector regulatory T cells as compared to a subset of unstable effector regulatory T cells in a patient. In some embodiments, the subset of unstable effector regulatory T cells is more prone to apoptosis. In some embodiments, the subset of unstable effector regulatory T cells is associated with higher Galectin-l (LGALS1) gene expression. In some embodiments, the subset of unstable effector regulatory T cells is associated with higher expression of the BAX gene, which is associated with pro-apoptosis.Attorney Docket No.: SVI-017WO1

[0329] In some embodiments, administration of the IL-2 fusion protein at a dose of 4 pg / kg induces expansion of the subset of stable effector regulatory T cells. In some embodiments, administration of the IL-2 fusion protein at a dose of 4 pg / kg induces more expansion of the subset of stable effector regulatory T cells as compared to the subset of unstable effector regulatory T cells. In some embodiments, administration of the IL-2 fusion protein at a dose of 12 pg / kg induces expansion of the subset of stable effector regulatory T cells. In some embodiments, administration of the IL-2 fusion protein at a dose of 12 pg / kg induces more expansion of the subset of stable effector regulatory T cells as compared to the subset of unstable effector regulatory T cells.

[0330] In some embodiments, the present invention provides, among other things, methods of selectively increasing the percentage of regulatory T cells in a population of T cells in a patient. In some embodiments, administration of the therapeutically effective dosing regimen selectively increases the percentage of regulatory T cells in a population of T cells in a patient.

[0331] In some embodiments, the therapeutically effective dosing regimen selectively increases the percentage of regulatory T cells in a population of T cells to at least 10% as compared to a control. In some embodiments, the therapeutically effective dosing regimen selectively increases the percentage of regulatory T cells in a population of T cells to at least 11% as compared to a control. In some embodiments, the therapeutically effective dosing regimen selectively increases the percentage of regulatory T cells in a population of T cells to at least 12% as compared to a control. In some embodiments, the therapeutically effective dosing regimen selectively increases the percentage of regulatory T cells in a population of T cells to at least 13% as compared to a control. In some embodiments, the therapeutically effective dosing regimen selectively increases the percentage of regulatory T cells in a population of T cells to at least 14% as compared to a control. In some embodiments, the therapeutically effective dosing regimen selectively increases the percentage of regulatory T cells in a population of T cells to at least 15% as compared to a control.

[0332] In some embodiments, administration of the therapeutically effective dosing regimen increases the percentage of activated regulatory T cells in a population of T cells as compared to a control. In some embodiments, administration of the therapeutically effective dosing regimen increases the absolute number of absolute regulatory T cells as compared to a control.Attorney Docket No.: SVI-017WO1

[0333] In some embodiments, administration of the therapeutically effective dosing regimen increases the percentage of activated regulatory T cells in a population of T cells for at least 2 days, at least 3 days, at least 4 days, at least 6 days, at least 9 days, at least 12 days, at least 15 days, at least 18 days, or at least 21 days as compared to a control. In some embodiments, administration of the therapeutically effective dosing regimen increases the percentage of activated regulatory T cells in a population of T cells for at least 2 days as compared to a control. In some embodiments, administration of the therapeutically effective dosing regimen increases the percentage of activated regulatory T cells in a population of T cells for at least 3 days as compared to a control. In some embodiments, administration of the therapeutically effective dosing regimen increases the percentage of activated regulatory T cells in a population of T cells for at least 4 days as compared to a control. In some embodiments, administration of the therapeutically effective dosing regimen increases the percentage of activated regulatory T cells in a population of T cells for at least 6 days as compared to a control.

[0334] In some embodiments, administration of the therapeutically effective dosing regimen increases the percentage of activated regulatory T cells in a population of T cells for at least 9 days as compared to a control. In some embodiments, administration of the therapeutically effective dosing regimen increases the percentage of activated regulatory T cells in a population of T cells for at least 12 days as compared to a control. In some embodiments, administration of the therapeutically effective dosing regimen increases the percentage of activated regulatory T cells in a population of T cells for at least 15 days as compared to a control. In some embodiments, administration of the therapeutically effective dosing regimen increases the percentage of activated regulatory T cells in a population of T cells for at least 18 days as compared to a control. In some embodiments, administration of the therapeutically effective dosing regimen increases the percentage of activated regulatory T cells in a population of T cells for at least 21 days as compared to a control.

[0335] In some embodiments, administration of the therapeutically effective dosing regimen increases levels of soluble CD25 as compared to a control. In some embodiments, administration of the therapeutically effective dosing regimen increases levels of soluble CD25 for at least 2 days, at least 3 days, at least 4 days, at least 6 days, at least 9 days, at least 12 days, at least 15 days, at least 18 days, or at least 21 days as compared to a control. In some embodiments, administration of the therapeutically effective dosing regimen increasesAttorney Docket No.: SVI-017WO1levels of soluble CD25 for at least 2 days as compared to a control. In some embodiments, administration of the therapeutically effective dosing regimen increases levels of soluble CD25 for at least 3 days as compared to a control. In some embodiments, administration of the therapeutically effective dosing regimen increases levels of soluble CD25 for at least 4 days as compared to a control. In some embodiments, administration of the therapeutically effective dosing regimen increases levels of soluble CD25 for at least 6 days as compared to a control.

[0336] In some embodiments, administration of the therapeutically effective dosing regimen increases levels of soluble CD25 for at least 9 days as compared to a control. In some embodiments, administration of the therapeutically effective dosing regimen increases levels of soluble CD25 for at least 12 days as compared to a control. In some embodiments, administration of the therapeutically effective dosing regimen increases levels of soluble CD25 for at least 15 days as compared to a control. In some embodiments, administration of the therapeutically effective dosing regimen increases levels of soluble CD25 for at least 18 days as compared to a control. In some embodiments, administration of the therapeutically effective dosing regimen increases levels of soluble CD25 for at least 21 days as compared to a control.

[0337] In some embodiments, the therapeutically effective dosing regimen prevents worsening of an autoimmune disease as compared to a control. In some embodiments, the therapeutically effective dosing regimen prevents relapse of an autoimmune disease as compared to a control. In some embodiments, the therapeutically effective dosing regimen improves one or more clinical measures of disease state as compared to a control. In some embodiments, a clinical measure of disease state is an assessment well-known and established in the field to measure disease activity, severity, and / or progression in a patient with an autoimmune disease.

[0338] Exemplary clinical measures of disease state for SLE include, but are not limited to, the Safety of Estrogens in Lupus Erythematosus: National Assessment Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI), the Easy British Isles Lupus Assessment Group (Easy-BILAG), urine protein / creatine ratio (uPCR) in first morning voided specimens, the urine albumin / creatine ratio (uACR) in first morning voided specimens, the estimated glomerular filtration rate (eGFR), anti-ds-DNA antibody titers, C3 levels, C4 levels, and CH50 levels. Exemplary clinical measures of disease state for AAAttorney Docket No.: SVI-017WO1include, but are not limited to, the Severity of Alopecia Tool (SALT), the Clinician Reported Outcomes for eyelashes and eyebrows (ClinRO), and the percentage of scalp affected based on photographs. Exemplary clinical measures of disease state for FSGS include, but are not limited to, uPCR from 24-hour urine collection, serum albumin level, relapse, eGFR, and anti-nephrin antibodies.

[0339] In some embodiments, the control is the patient prior to administration of the IL-2 fusion protein. In some embodiments, the control is historical data. In some embodiments, the control is a comparable recipient without the administration of the IL-2 fusion protein.

[0340] In some embodiments, the therapeutically effective dosing regimen produces a maximum drug concentration (Cmax) in serum of at least 10 ng / mL. In some embodiments, the therapeutically effective dosing regimen produces a Cmax of at least 11 ng / mL. In some embodiments, the therapeutically effective dosing regimen produces a Cmax of at least 12 ng / mL. In some embodiments, the therapeutically effective dosing regimen produces a Cmax of at least 13 ng / mL. In some embodiments, the therapeutically effective dosing regimen produces a Cmax of at least 14 ng / mL. In some embodiments, the therapeutically effective dosing regimen produces a Cmax of at least 15 ng / mL.

[0341] In some embodiments, the therapeutically effective dosing regimen produces a Cmax of at least 16 ng / mL. In some embodiments, the therapeutically effective dosing regimen produces a Cmax of at least 17 ng / mL. In some embodiments, the therapeutically effective dosing regimen produces a Cmax of at least 18 ng / mL. In some embodiments, the therapeutically effective dosing regimen produces a Cmax of at least 19 ng / mL. In some embodiments, the therapeutically effective dosing regimen produces a Cmax of at least 20 ng / mL.

[0342] In some embodiments, the therapeutically effective dosing regimen produces a Cmax of at least 21 ng / mL. In some embodiments, the therapeutically effective dosing regimen produces a Cmax of at least 22 ng / mL. In some embodiments, the therapeutically effective dosing regimen produces a Cmax of at least 23 ng / mL. In some embodiments, the therapeutically effective dosing regimen produces a Cmax of at least 24 ng / mL. In some embodiments, the therapeutically effective dosing regimen produces a Cmax of at least 25 ng / mL.Attorney Docket No.: SVI-017WO1

[0343] In some embodiments, the therapeutically effective dosing regimen produces a Cmax of at least 26 ng / mL. In some embodiments, the therapeutically effective dosing regimen produces a Cmax of at least 27 ng / mL. In some embodiments, the therapeutically effective dosing regimen produces a Cmax of at least 28 ng / mL. In some embodiments, the therapeutically effective dosing regimen produces a Cmax of at least 29 ng / mL. In some embodiments, the therapeutically effective dosing regimen produces a Cmax of at least 30 ng / mL.

[0344] In some embodiments, the therapeutically effective dosing regimen produces a Cmax of 10 ng / mL to 50 ng / mL. In some embodiments, the therapeutically effective dosing regimen produces a Cmax of 10 ng / mL to 40 ng / mL. In some embodiments, the therapeutically effective dosing regimen produces a Cmax of 10 ng / mL to 30 ng / mL. In some embodiments, the therapeutically effective dosing regimen produces a Cmax of 10 ng / mL to 20 ng / mL.

[0345] In some embodiments, the therapeutically effective dosing regimen produces a Cmax of 11 ng / mL to 40 ng / mL. In some embodiments, the therapeutically effective dosing regimen produces a Cmax of 11 ng / mL to 35 ng / mL. In some embodiments, the therapeutically effective dosing regimen produces a Cmax of 11 ng / mL to 30 ng / mL. In some embodiments, the therapeutically effective dosing regimen produces a Cmax of 14 ng / mL to 40 ng / mL. In some embodiments, the therapeutically effective dosing regimen produces a Cmax of 14 ng / mL to 35 ng / mL. In some embodiments, the therapeutically effective dosing regimen produces a Cmax of 14 ng / mL to 30 ng / mL.EXAMPLES

[0346] Various aspects of the invention are described in further detail in the following Examples. The following examples describe some of the exemplary modes of making and practicing the present invention. However, it should be understood that these examples are for illustrative purposes only and are not meant to limit the scope of the invention.Example 1: Single Ascending Dose (SAD) study of IL-2 Fc fusion protein in healthy participants

[0347] This Example describes a phase 1, randomized, double-blind, placebo controlled, single ascending dose (SAD) study to evaluate the safety, tolerability, pharmacodynamics, and pharmacokinetics of an IL-2 Fc fusion protein in healthy participants. 5 Cohorts of 8 participants were examined. In each cohort, patients wereAttorney Docket No.: SVI-017WO1randomly assigned to receive an exemplary IL-2 Fc fusion protein or a placebo (6 IL-2 Fc fusion protein, 2 placebo). Subjects were subcutaneously administered a single dose of an exemplary IL-2 Fc fusion protein comprising an IL-2 variant with the amino acid substitutions of H16L / V69A / Q74P / C125S, at the concentrations shown in Table A.Table A: Dosages for SAD studySafety

[0348] Injection site reaction (ISR) and asymptomatic eosinophilia were identified as the most common treatment-emergent adverse events (TEAEs). Both ISRs and eosinophil elevation are well recognized on-target effects of IL-2 therapy. There were no participants with TEAEs leading to discontinuation of the trial across the dose range of 1, 4, 12, 24, and 32 pg / kg.Pharmacodynamic Analysis

[0349] The treatment resulted in selective Treg expansion with minimal impact on other immune cell populations (e.g., conventional T helper cells, cytotoxic T lymphocytes, and natural killer cells). All treatment cohorts showed a less than 2-fold maximum mean fold change from baseline response for percent NK, CTL, and T helper cells, with the placebo group showing 1.342-, 1.000-, and 1.027-fold maximum increases, respectively. In contrast, the maximum mean fold change from baseline response for %Treg was between 3.121- to 4.307-fold for 12 and 24 pg / kg, 5.189-fold for 32 pg / kg, and between 1.519- to 1.543-fold at 1 and 4 pg / kg, with placebo showing no-to-minimal increases (1.126-fold).

[0350] Mean %Treg / CD4+ values for each cohort are shown in FIG. 1. The peak %Treg / CD4+was similar at the 12, 24, and 32 pg / kg dose levels, ranging from ~11 to 13%, as compared to the 1 to 4 pg / kg dose levels with a mean peak %Treg / CD4+of ~5 to 6%. The mean baseline %Treg / CD4+was ~3 to 4%.Attorney Docket No.: SVI-017WO1

[0351] Exploratory analyses were performed to examine the Treg subsets that were expanded by administration of the exemplary IL-2 Fc fusion protein. Activated Tregs, as noted by a lack of CD45RA expression and a high FoxP3 expression, increased in individuals dosed with 4 pg / kg to 32 pg / kg as shown in FIG. 2. At doses from 12 to 32 pg / kg, the mean percent and absolute number of activated Treg remained elevated above baseline until approximately Days 15 to 22. Resting Tregs, as defined by expression of CD45RA, also showed mean peak increases in percent and absolute cell count after dosing. There were no observed modulations of percent or absolute cell counts of CD4+ T conventional cells (CD4+ Tcon), B cells, monocytes, or total T cells, beyond a transient decline in some cell populations immediately post dosing. These further bolster the selective nature of the exemplary IL-2 Fc fusion protein to act on Tregs.

[0352] Whole blood samples were assessed for cytokine and chemokine levels.Trends were only clearly observed in the mean values for IL-5 and soluble CD25 (sCD25). Increases in IL-5 have been observed with other IL-2 products and was an anticipated biological effect. However, sCD25 levels saw a dose-proportional increase as shown in FIG.3. This is significant as sCD25 is shed by activated Tregs, and increased levels of sCD25 are often indicative of an increased presence of Tregs.Single Cell Analysis

[0353] Further characterization of the Treg subsets was performed using single cell transcriptomics and started with identifying the relative abundance (as compared to all T and NK cells) of three core Treg subsets: effector (activated) Tregs, naive (resting) Tregs, and proliferating Tregs, as shown in FIG. 4. Consistent with previous analysis, the majority of expanded Tregs across all doses were identified as effector Tregs, which are associated with immunosuppressive activity. However, upon mapping the Tregs according to gene markers such as CD25, FOXP3, and CTLA4, the inventors of the instant application identified two distinct effector cell subsets, as shown by FIG. 5A.

[0354] Based on gene expression, signature genes, or markers, for the two distinct effector cell subsets were determined as shown in FIG. 5B. The first subset of effector Tregs (Helios111) had higher expression of Helios (IKZF2), a transcription factor associated with Treg stability. Additional genes associated with Treg stability were enriched within the Helios111subset, such as, for example, TET2, which has been shown to be a key regulator ofAttorney Docket No.: SVI-017WO1Treg stability, and BCL2, which encodes an anti-apoptotic protein. Helios111Tregs also demonstrated a higher composite expression score based on 39 genes representing key transcription factors and regulators of F0XP3 expression, further underscoring this subset’s properties of maintaining a strong Treg phenotype. The second subset of effector Tregs (Galectin-l111) had higher expression of Galectin-1 (LGALS1), a gene associated with apoptosis of T cells, and was also enriched with BAX expression, which encodes a pro-apoptotic protein. Galectin-l111effector Tregs were also found to be more susceptible to conversion into cytotoxic and pro-inflammatory exTregs.

[0355] Cell density UMAP plots were generated to assess the distribution of the Treg subsets across the different doses. As shown in FIG. 6, the lower doses (e.g., 4 and 12 pg / kg) showed preferential expansion Helios111Tregs, and the higher doses (e.g., 24 and 32 pg / kg) showed a large shift towards the Galectin-l111subset.Pharmacokinetic Analysis

[0356] A summary of pharmacokinetic data including serum concentrations over nominal time points is presented by dose in Table B. Following administration of a single dose of IL-2 Fc fusion protein at doses from 1 to 32 pg / kg (Cohorts 1 to 5), serum concentrations of IL-2 Fc fusion protein increased with an increase in dose. The majority (more than 50% of the samples at each nominal time point) were below the limit of quantification (BLQ) for Cohort 1 (1 pg / kg) after a single dose of IL-2 Fc fusion protein. All but 1 participant administered a single dose of 4 pg / kg IL-2 Fc fusion protein had measurable serum concentrations of IL-2 Fc fusion protein up to 48 hours post-dose (Day 3). Following single doses of 12 to 32 pg / kg IL-2 Fc fusion protein, serum concentrations were quantifiable up to 72 hours post-dose (Day 4) for all participants in their respective cohorts. Quantifiable IL-2 Fc fusion protein serum concentrations were detected up to 120 hours (Day 6) for 2 out of 6 participants in the 12 pg / kg cohort, 3 out of 6 participants in the 24 pg / kg dose cohort, and 2 out of 6 participants in the 32 pg / kg cohort. The serum concentrations of the exemplary IL-2 Fc fusion proteins for each dose cohort are also shown in FIGs. 7A and 7B.Attorney Docket No.: SVI-017WO1Table B: Summary of selected serum pharmacokinetic parameters following a single dose of an exemplary IL-2 Fc fusion protein.AUC(o-inf) = area under the concentration-time curve from time zero to infinity; AUCiast= area under the concentration-time curve from time zero to the last observable concentration; BLQ = below the limit of quantification; CL / F = apparent total clearance; Cmax= maximum (peak) drug concentration in serum;CV = coefficient of variation; GM = geometric mean; NC = not calculated; PK = pharmacokinetic;R2= coefficient of determination; Tiast = time of the last measurable observed concentration; tmax= time of maximum (peak) drug concentration in serum; Vz / F = apparent volume of distribution.

[0357] The inter-individual variability in PK parameters in Cohorts 3 to 5 (12 to 32 pg / kg) was moderate to high following single ascending doses, with AUCiastand Cmax percent of variation of geometric mean (CV%) ranging from 29.9% to 109.0% and 37.9% to 97.8%, respectively. Cmax increased with increasing dose, ranging from geometric means of 0.9010 ng / mL at the 1 pg / kg dose to 31.80 ng / mL at the 32 pg / kg dose, with a median time to (tmax) of approximately 24 hours for each dose cohort, with the exception of the 1 pg / kg and 32 pg / kg doses which had a tmax of 15 and 36.05 hours, respectively. Median Tiast in Cohorts 2 to 5 (4 to 32 pg / kg) ranged from 48 to 96 hours. Mean Cmax increased in a greater than dose-proportional manner from 4 pg / kg to 12 pg / kg, and mean Cmax increased in a generally dose-proportional manner from 12 pg / kg to 32 pg / kg doses.

[0358] The geometric mean AUCiastincreased with increasing dose, ranging from 26.50 h*ng / mL at the 1 pg / kg dose to 1540.0 h*ng / mL at the 32 pg / kg dose. The AUC(o-inf)Attorney Docket No.: SVI-017WO1could not be calculated for all participants due to the limited number of serum samples collected in the terminal phase that were above the lower limit of quantification (LLOQ), especially at the lower doses (1 to 4 pg / kg); however, the geometric mean AUC(o-inf) ranged from 1180.0 h*ng / mL at the 12 pg / kg dose to 1600.0 h*ng / mL at the highest dose evaluated of 32 pg / kg. Similar to Cmax, AUCiastincreased in a greater than dose-proportional manner from 4 pg / kg to 12 pg / kg and was generally dose-proportional from 12 pg / kg to 32 pg / kg doses.

[0359] There was no dose-dependent effect observed on the estimated half-life, with geometric means ranging from 11.6 hours to 14.7 hours across the range of 12 to 32 pg / kg doses.Example 2: Multiple Ascending Dose (MAD) study of IL-2 Fc fusion protein in participants with autoimmune disease

[0360] This Example describes a randomized, double-blind, placebo controlled, multiple ascending dose (MAD) study that evaluated the safety, tolerability, pharmacodynamics, and pharmacokinetics of an IL-2 Fc fusion protein in participants with an autoimmune disease. The exemplary autoimmune diseases that were included the MAD example are systemic lupus erythematosus (SLE), autoimmune hepatitis (AIH), immune-mediated focal segmental glomerulosclerosis (FSGS), and alopecia areata (AA).

[0361] SLE, AIH, FSGS, and AA share an underlying mechanism of diminished Treg responses contributing to disease pathogenesis. These diseases are typically characterized by overactivation of the immune system causing destruction of otherwise healthy tissues. These diseases present with a dampened Treg response or population size, and clinical improvements may be mediated through amplification of Treg. These cells are a subpopulation of cluster of differentiation (CD4+) T helper cells that moderate immune responses by releasing anti-inflammatory cytokines and suppressing the activation of CD4+and CD8+effector T cells (Teff). Without wishing to be bound by theory, it is believed that the IL-2 Fc fusion protein used in this study causes robust expansion of Treg with minimal to no expansion of Teff at physiological relevant doses.

[0362] A total of 21 participants were enrolled in MAD study, and this part of the trial consisted of Cohort 1 (10 pg / kg) and Cohort 2 (24 pg / kg). Within Cohort 1 (10 pg / kg), 4Attomey Docket No.: SVI-017WO1participants with SLE, 3 participants with FSGS, and 6 participants with AA were enrolled. Within Cohort 2 (24 pg / kg), 4 participants with SLE and 4 participants with AA were enrolled. An exemplary IL-2 Fc fusion protein comprising an IL-2 variant with the amino acid substitutions of H16L / V69A / Q74P / C125S, or a placebo, was administered Q2W for 4 doses.

[0363] The treatment resulted in selective Treg expansion with minimal impact on other immune cell populations (e.g., conventional T helper cells, cytotoxic T lymphocytes, and natural killer cells) in patients with autoimmune diseases. Both cohorts showed a less than 2-fold maximum mean fold change from baseline response for percent NK, CTL, and T helper cells. The maximum observed mean fold change from baseline response for %Treg / CD4+ was 7.157-fold for 10 pg / kg and 4.105-fold for 24 pg / kg. The selective increase in Treg expansion was also observed in absolute cell counts for each immune cell type.

[0364] As shown in FIG. 8, peak % Treg / CD4+levels were observed approximately 8 days post-dose in both cohorts, with maximum observed levels of ~11-18%. Treg / CD4+levels in both cohorts typically did not return to baseline prior to the subsequent doses 14 days later. Treg levels returned to baseline at approximately 29 days after the fourth and final dose.

[0365] The percent of activated Tregs also increased for both cohorts as shown in FIG. 9. Mean fold change from baseline for percent and absolute cell counts of activated Treg peaked between 12.45- to 23.76-fold for Cohort 1 and Cohort 2. There was also an increase observed in resting Tregs. There were no observed modulations of percent or absolute cell counts of CD4+ T conventional cells (CD4+ Tcon), B cells, monocytes, or total T cells, beyond a transient decline in some cell populations immediately post dosing.Notably, there was no robust expansion of activated CTL after repeated doses of the exemplary IL-2 Fc fusion protein at 10 pg / kg (fold increase < 2). This is significant as CTL is known to normally respond to and become activated by IL-2.

[0366] Whole blood samples were assessed for cytokine and chemokine levels.Trends were only clearly observed in the mean values for IL-5 and soluble CD25 (sCD25), with some instances of IL- 10, an anti-inflammatory cytokine secreted by Tregs that helps suppress immune responses and maintain immune homeostasis. There was a dose-Attorney Docket No.: SVI-017WO1proportional increase in sCD25 levels for both cohorts, as shown in FIG. 10, that did not return to baseline prior to the next dose. Notably, the sCD25 peak post-dose follows a similar trend to the peak in Treg after administration of the exemplary IL-2 Fc fusion protein. There was no significant increase in mean levels of pro-inflammatory cytokines in the study.

[0367] Summaries of selected serum PK parameters are presented by study day and dose in Table C. The serum concentrations of the exemplary IL-2 Fc fusion protein after the first dose and the fourth dose are also shown in FIGs. 11A-B and FIG. 11C-D, respectively.Table C: Summary of Selected Serum Pharmacokinetic ParametersAR = accumulation ratio; AUCinf = area under the concentration-time curve from time zero to infinity;AUCiast = area under the concentration-time curve from time zero to the last observable concentration; AUC(o-tau) = area under the concentration-time curve over the dosing interval at steady-state;BLQ = below the limit of quantification; CL / F = apparent total clearance; CLss / F = apparent total clearance at steady state; Cmax= maximum (peak) drug concentration in serum; CV = coefficient of variation; GM = geometric mean; NA = not applicable; NC = not calculated; PK = pharmacokinetic;Q2W = every 2 weeks; R2= coefficient of determination; SD = standard deviation; Tiast = time of the last measurable observed concentration; tmax= time of maximum (peak) drug concentration in serum;Vss / F = apparent volume of distribution at steady state; Vz / F = apparent volume of distribution.Attorney Docket No.: SVI-017WO1Individual AUC(o-tau), AUCinf, CL / F, CLss / F, Vz / F, Vss / F, ti / 2, R2adjusted were not included in the summary statistics if they did not have a calculated lambda z value.Cmax and AUG accumulation ratios are calculated as Day 43 / Day 1.aFor Day 1, CL / F is reported and for Day 43, CLss / F is reported.bFor Day 1, Vz / F is reported and for Day 43, Vss / F is reported.Arithmetic mean.

[0368] The variability in the PK exposure parameters was moderate across dosing cohorts in Part B, with geometric CV% ranging from 40.8% to 69.4% for Cmax and 38.8% to 70.5% for AUCiast across study Days 1 and 43 and across indications.

[0369] Geometric mean Cmax on Day 1 was 11.00 ng / mL for 10 pg / kg and19.90 ng / mL for 24 pg / kg across all indications. Median tmax was approximately 24 hours for each dose cohort across all indications after a single dose on Day 1. Geometric mean AUC(o-336) was 721.0 hr*ng / mL for 10 pg / kg and 803.0 hr*ng / mL for 24 pg / kg after a single dose on Day 1 across all indications.

[0370] Following Q2W dosing of IL-2 Fc fusion protein, the geometric mean Cmax on Day 43 was 10.70 ng / mL for 10 pg / kg and 32.50 ng / mL for 24 pg / kg, respectively, with a median tmax of 24 hours for both cohorts. The time to reach Cmax was similar between both dosing cohorts and on Day 1 and Day 43. Geometric mean AUCiastalso increased with dose from 463.0 hr*ng / mL at the 10 pg / kg dose to 1160.0 hr*ng / mL at the 24 pg / kg dose on Day 43 after every 2-week dosing.

[0371] Due to the limited number of PK samples that were above the LLOQ between 24 and 72 hours, the terminal phase of the PK profile was not able to be captured well and therefore lambda z-based parameters (half-life, AUCtau, CL / F, Vz / F) could not be estimated for multiple participants in this study. For participants where the terminal elimination of IL-2 Fc fusion protein was captured, the half-life ranged from 10.60 to 15.50 hours and did not appear to be dose dependent.

[0372] Negligible accumulation of IL-2 Fc fusion protein was observed on Day 43 in either cohort. The accumulation mean ratios were 1.310 and 1.940, at 10 and 24 pg / kgrespectively. The AUC(o-tau) accumulation ratio was 0.7340 for the 24 pg / kg cohort (AUC(o-tau) and could not be calculated in Cohort 1 and therefore no accumulation ratio for AUC could be estimated.Attorney Docket No.: SVI-017WO1

[0373] Although the number of participants stratified by indication (AA, FSGS, SLE) are low in this study, there does not appear to be differences in IL-2 Fc fusion protein exposure metrics among the 3 different indications after a single or multiple doses up to 24 Fg / kg-Example 3: An open-label, single-arm trial to assess pharmacodynamics, pharmacokinetics, and immunogenicity of IL-2 Fc fusion protein in participants with autoimmune diseasesStudy Overview

[0374] This IL-2 Fc fusion protein trial will be performed as an open-label, singlearm trial to further assess the pharmacodynamics, pharmacokinetics, and immunogenicity of an exemplary IL-2 Fc fusion protein comprising an IL-2 variant with the amino acid substitutions of H16L / V69A / Q74P / C125S, given as a subcutaneous (SC) dose of 12 pg / kg every 4 weeks (Q4W) for a total of 6 doses in participants with autoimmune disease(s). The autoimmune diseases that will be included are systemic lupus erythematosus (SLE, which may include lupus nephritis), alopecia areata (AA), and, optionally, immune-mediated focal segmental glomerulosclerosis (IM-FSGS).Objectives and Endpoints

[0375] The objectives and endpoints of example 3 are summarized below in Table D.Table D: Objectives and EndpointsAttorney Docket No.: SVI-017WO1A = alopecia areata; ADA = anti-drug antibody; BILAG = British Isles Lupus Assessment Group;CKD-EPI = Chronic Kidney Disease Epidemiology Collaboration; CD = cluster of differentiation;ClinRO = Clinician Reported Outcomes for eyelashes and eyebrows; ds-DNA = double-stranded deoxyribonucleic acid; eGFR = estimated glomerular filtration rate; FOXP3 = Forkhead boxprotein P3; FSGS = focal segmental glomerulosclerosis; ISR = injection site reaction;PD = pharmacodynamic; PK = pharmacokinetic; SALT = Severity of Alopecia Tool;SELENA = Safety of Estrogens in Lupus Erythematosus: National Assessment; SLE = Systemiclupus erythematosus; SLEDAI = Systemic Lupus Erythematosus Disease Activity Index;TEAE = treatment-emergent adverse event; Treg = regulatory T cell(s); uACR = urinealbumin / creatinine ratio; uPCR = urine protein / creatinine ratio.a Relapse is defined as an increase in proteinuria to > 3500 mg / g (> 350 mg / mmol) and serum albumin < 2.5 g / dL (25 g / L).b Estimated glomerular filtration rate will be calculated using the CKD-EPI formula (2021).Attorney Docket No.: SVI-017WO1Participants

[0376] At least 15 and up to approximately 30 participants with an autoimmune disease will be enrolled, with varying amounts according to the specific autoimmune disease being tested (10-15 for SLE, 5-10 for AA, and up to 5 for IM-FSGS). Male and female adult participants with an autoimmune disease ages 18-75 years with a body mass index between 17 and 35 kg / m2 will be considered. A list of conditions for meeting inclusion or exclusion criteria are listed below:Inclusion Criteria1. Estimated glomerular filtration rate (eGFR) >30 mL / min / 1.73 m2 (calculated using the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] formula

[2021] ), at the screening visit.Additional inclusion criteria for participants with SLE only2. Participant has a confirmed diagnosis of SLE according to European League Against Rheumatism / American College of Rheumatology SLE classification criteria > 24 weeks prior to signing the ICF.Additional inclusion criteria for participants with AA only3. Current scalp involvement between 25% and 95%, inclusive (Severity of Alopecia Tool [SALT] score between 25 and 95, inclusive), at screening.4. Current episode of A A is of duration > 24 weeks (without evidence of spontaneous terminal hair regrowth at the time of screening and first treatment, z.e., no more than 10% regrowth), but < 5 years from onset of current episode of severe scalp hair loss.Additional inclusion criteria for participants with FSGS only5. Prior biopsy (no time limit) showing histologic minimal change disease (MCD), FSGS, or MCD / FSGS spectrum.6. History of at least one prior episode of nephrotic syndrome, defined as 24- hour urine protein > 3.5 g / day and serum albumin < 3.5 g / dL.7. History of steroid responsive nephrotic syndrome, including participants who achieved complete remission, partial remission, had a course of steroid dependent nephrotic syndrome or relapsing nephrotic syndrome (all defined as per the managing physician at the time of the episode).Attorney Docket No.: SVI-017WO1Exclusion Criteria1. Receipt of high-dose corticosteroid therapy within 4 weeks prior to screening as either (a) intravenous (IV) pulse corticosteroid therapy or (b) daily oral corticosteroid therapy of > 1 milligrams per kilogram (mg / kg) or up to 40 milligrams per day (mg / day) prednisone (or equivalent).2. Receipt of blood products within 6 months prior to screening.3. Previous exposure to the exemplary IL-2 Fc fusion protein or any other drug targeting interleukins (IL)-2 or the IL-2 receptor or T regulatory cells.4. History of or current diagnosis of catastrophic or severe anti-phospholipid syndrome (APS) within 1 year prior to signing ICF. SLE participants with APS adequately controlled by anticoagulant are eligible. SLE participants who are found to be triple positive for anti-phospholipid antibodies at screening (without clinical APS) will be excluded unless they are on stable anti -thrombotic therapy.5. Known primary immunodeficiency disorder.Additional exclusion criteria for participants with SLE only6. Participant has a history of Class V lupus nephritis.7. Receipt of anifrolumab, tumor necrosis factor-alpha monoclonal antibodies ([TNF]-a mAb), immunoglobulins (IV / SC) plasmapheresis, or any other immunosuppressants (calcineurin inhibitors, Janus kinase [JAK] inhibitors or other kinase inhibitors), other than hydroxychloroquine, mycophenolic acid (MPA) / mycophenolate mofetil (MMF) and corticosteroids, within 6 months prior to screening.Additional exclusion criteria for participants with AA only8. Participant has concomitant hair loss of another form, including but not limited to traction alopecia, central centrifugal cicatricial alopecia, lichen planopilaris, frontal fibrosing alopecia, or androgenetic alopecia.9. Participant has received (1) Within 12 weeks prior to Day 1 : Systemic therapies (oral or injection), such as corticosteroids, JAK inhibitors, methotrexate, calcineurin inhibitors, oral minoxidil, low-dose IL-2 and topical immunotherapies such as psoralen plus UVA (PUVA), diphenylcyclopropenone (DPCP), dinitrochlorobenzene (DNCB), intralesional steroids or (2) Within 4 weeks prior toAttorney Docket No.: SVI-017WO1Day 1 : Other topical therapies, such as topical minoxidil, clobetasol etc. These therapies will also not be allowed during this trial.Additional exclusion criteria for participants with FSGS only10. Steroid resistant nephrotic syndrome defined as absence of history of at least 1 episode of complete or partial remission following at least 12 weeks of full dose corticosteroid therapy.11. Receipt of anifrolumab, TNF-a mAb, immunoglobulins (IV / SC) plasmapheresis, or any other immunosuppressants (JAK inhibitors or other kinase inhibitors).Study Design

[0377] This study will be conducted as an open-label, single-arm study. Participants will be screened up to 28 days before dosing. Following the Screening Period and verification of inclusion / exclusion criteria, the Intervention Period will occur. On Day 1 of the Intervention Period, participants will be administered IL-2 Fc fusion protein subcutaneously at a concentration of 12 pg / kg at the trial site. Treatment will be administered at a frequency of once every 4 weeks (Q4W) with 6 doses total throughout the Intervention Period (21 weeks). All participants will then have a Follow-up Period of up to 6 months from study completion (week 21).

[0378] Preliminary safety data has been made available regarding the SAD and MAD studies in Example 1 and Example 2, respectively. This study will ultimately assess the effects of IL-2 Fc treatment in a variety of immune-mediated diseases. The % Treg / CD4+benchmark is expected to be an accurate assessment across all diseases.

[0379] In relation to Example 2, a dosing of Q4W frequency has been selected to compare potential patterns of eosinophilia counts to the effects observed in a Q2W treatment frequency.Attorney Docket No.: SVI-017WO1AssessmentsSLE

[0380] The Safety of Estrogens in Lupus Erythematosus: National Assessment Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) is a well-established, validated instrument to assess disease activity in patients with SLE. The SELENA-SLEDAI incorporates the signs and symptoms of disease activity in 9 organ systems with 24 descriptors. The 9 organ systems include the central nervous, vascular, renal, musculoskeletal, serosal, dermal, immunologic, constitutional and hematologic systems. The 24 descriptors include various manifestations of the disease, such as seizure, headache, arthritis, new rash, mucosal ulcers, and laboratory findings. Each descriptor has a specific definition and is rated as present or absent over the 10 days before and including the day of evaluation. All of the descriptors are weighted to yield a composite score ranging from 0 to 105, with higher scores indicating more severe disease.Lupus

[0381] The Easy British Isles Lupus Assessment Group (BILAG) will be performed.Urinalysis

[0382] The ratio of urine protein: creatinine and albumin: creatinine will be assessed.Estimated Glomerular Filtration Rate

[0383] Estimated glomerular filtration rate will be determined, using the CKD-EPI formula (2021), from the blood samples collected for clinical chemistry.Blood

[0384] Blood samples for anti-double-stranded deoxyribonucleic acid (ds-DNA) antibodies, anti-nuclear antibodies, and markers of complement activity will be collected. Blood samples for circulating anti-nephrin antibodies will be collected.Severity of Alopecia Tool

[0385] The SALT will be performed for participants with AA.The SALT score is a physician administered scale measuring the amount of scalp without any terminal hair assessed by the investigator. Possible scores range from 0 (no scalp hairAttorney Docket No.: SVI-017WO1loss) to 100 (complete scalp hair loss). A negative change in the SALT score over time represents hair regrowth by adding the percentage hair loss in the various areas (i.e., top, back, each side) of the scalp.Clinician Reported Outcomes for Eyelashes and Eyebrows

[0386] An assessment of eyebrows and eyelashes will be performed using Clinician Reported Outcomes for eyelashes and eyebrows (ClinRO) for participants with AA.Example 4: A Phase 1 trial to evaluate safety and characterize Treatment Emergent Adverse Events in using a flat dose in healthy participants

[0387] In this study, fixed-doses are used to understand the safety and tolerability, PD, and PK of an exemplary IL-2 Fc fusion protein comprising an IL-2 variant with the amino acid substitutions of H16L / V69A / Q74P / C125S, by administering subcutaneously to healthy participants.

[0388] The current trial will assess fixed single doses of IL-2 Fc fusion protein.Monitoring for potential TEAEs is incorporated into the design of this trial through safety assessments of physical examinations, vital sign measurements, electrocardiograms (ECGs), clinical laboratory assessments (hematology, serum chemistry, coagulation, urinalysis), and adverse event solicitation. Furthermore, trial assessments will include serial D-dimer monitoring to detect potential thrombosis. Brief physical examinations will include evaluations of the skin, so that the skin is frequently observed and any risk is identified early. Assessments of the injection site will also be performed after each dose, and ISR mitigation measures are in place for any dermal reactions. Overall objectives and endpoints for the flat dose study are presented in Table E.Table E: Objectives and Endpoints for the flat dose studySecondary: Secondary:• To determine the PD effect of IL-2 Fc • Change from baseline in immune cell types, including the fusion protein. following:• Absolute number of T reg and frequency %T reg / CD4+cells.• Absolute number and frequency (%) of T helper cells,Attorney Docket No.: SVI-017WO1Study Design

[0389] Approximately 24 participants (3 cohorts of 8 with 6 receiving treatment and 2 receiving placebo) will be enrolled and randomly assigned to study intervention in a random, double-blind format. Participants in each cohort will receive either a single SC dose of IL-2 Fc fusion protein or placebo on Day 1. The proposed doses are 500, 1000, and 1500 pg in Cohorts 1, 2, and 3, respectively. When 100% of participants have completed > 9 days in a cohort, a review of the safety data will be performed to approve escalation to the next cohort. Assessment of safety and tolerability will be determined by evaluation of clinical signs, clinical laboratory tests, and TEAEs, and dose escalation will be conditional based on the characteristics, toxicity grade (as defined in the United States Food and Drug Administration Guidance for Industry “Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Trials”) and / or number of TEAEs or serious TEAEsAttorney Docket No.: SVI-017WO1observed. If the dose is found to be reasonably safe and tolerable, the decision will be made to proceed to the next cohort. It may be decided to increase, decrease, or dose at the same level for each subsequent cohort; however, the maximum dose will not exceed 1500 pg.

[0390] The total duration of the clinical trial for each participant will be up to approximately 57 days, including the following:• A screening visit up to 28 days before dosing (Days -28 to -2)• An in-clinic stay of approximately 3 to 4 days, with admission to the trial center ...

Claims

Attorney Docket No.: SVI-017WO1CLAIMS1. A method of treating an autoimmune disease comprising subcutaneously administering an IL-2 Fc fusion protein to a patient at a dose of 10-24 pg / kg no more frequent than once every two weeks, or an equivalent dosing regimen thereof, and wherein the IL-2 Fc fusion protein comprises:a) an IL-2 variant comprising 95% identity to SEQ ID NO: 1 and amino acid substitutions H16L, V69A, Q74P, and C125S; andb) an Fc region.

2. The method of claim 1, wherein the IL-2 Fc fusion protein is administered at a dose of 10 pg / kg, 12 pg / kg, 14 pg / kg, 16 pg / kg, 18, pg / kg, 20 pg / kg, 22 pg / kg, or 24 pg / kg.

3. The method of claim 1 or claim 2, wherein the IL-2 Fc fusion protein is administered at a dose of 12 pg / kg.

4. The method of any one of the preceding claims, wherein the IL-2 Fc fusion protein is administered no more frequent than once every two weeks, no more frequent than once every three weeks, no more frequent than once every four weeks, no more frequent than once every five weeks, or no more frequent than once every six weeks.

5. The method of any one of the preceding claims, wherein the IL-2 Fc fusion protein is administered once every two weeks, once every three weeks, once every four weeks, once every five weeks, or once every six weeks.

6. The method of claim 5, wherein the IL-2 Fc fusion protein is administered once every four weeks.

7. A method of treating an autoimmune disease comprising subcutaneously administering an IL-2 Fc fusion protein to a patient at a dose of 12 pg / kg once every four weeks, or an equivalent dosing regimen thereof, andwherein the IL-2 Fc fusion protein comprises:a) an IL-2 variant comprising 95% identity to SEQ ID NO: 1 and amino acid substitutions H16L, V69A, Q74P, and C125S; andAttorney Docket No.: SVI-017WO1b) an Fc region.

8. The method of any one of the preceding claims, wherein the dose is administered for a treatment period of at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, or at least 24 weeks.

9. A method of treating an autoimmune disorder comprising subcutaneously administering an IL-2 Fc fusion protein to a patient at a therapeutically effective dosing regimenwherein the IL-2 Fc fusion protein comprisesa) an IL-2 variant comprising 95% identity to SEQ ID NO: 1 and amino acid substitutions H16L, V69A, Q74P, and C125S; andb) an Fc region.

10. The method of claim 9, wherein the therapeutically effective dosing regimen produces a Cmax of at least 10 ng / mL.

11. The method of claim 10, wherein the therapeutically effective dosing regimen produces Cmax of between 10 ng / mL and 50 ng / mL.

12. The method of any one of claims 9-11, wherein the therapeutically effective dosing regimen selectively increases the percentage of regulatory T cells (Tregs) in a population of T cells to at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, or at least 15% as compared to a control.

13. The method of claim 12, wherein the control is the patient prior to administration of the IL-2 Fc fusion protein.

14. The method of claim 12, wherein the control is historical data.

15. The method of claim 12, wherein the control is a comparable recipient without the administration of the IL-2 Fc fusion protein.Attorney Docket No.: SVI-017WO116. The method of any one of claims 9-15, wherein the therapeutically effective dosing regimen comprises administering the IL-2 Fc fusion protein at a dose of 10-24 pg / kg.

17. The method of claim 16, wherein the IL-2 Fc fusion protein is administered at a dose of 10 pg / kg, 12 pg / kg, 14 pg / kg, 16 pg / kg, 18, pg / kg, 20 pg / kg, 22 pg / kg, or 24 Fg / kg-18. The method of claim 16 or claim 17, wherein the IL-2 Fc fusion protein is administered at a dose of 12 pg / kg.

19. The method of any one of claims 9-18, wherein the therapeutically effective dosing regimen comprises administering the IL-2 Fc fusion protein no more frequent than once every two weeks, no more frequent than once every three weeks, no more frequent than once every four weeks, no more frequent than once every five weeks, or no more frequent than once every six weeks.

20. The method of any one of claims 9-19, wherein the IL-2 Fc fusion protein is administered once every two weeks, once every three weeks, once every four weeks, once every five weeks, or once every six weeks.

21. The method of any one of claims 9-20, wherein the IL-2 Fc fusion protein is administered once every four weeks.

22. The method of any one of claims 9-21, wherein the therapeutically effective dosing regimen comprises administering the IL-2 Fc fusion protein for a treatment period of at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, or at least 24 weeks.

23. A method of treating an autoimmune disease comprising subcutaneously administering an IL-2 Fc fusion protein to a patient at a flat dose of 100-2000 pg, and wherein the IL-2 Fc fusion protein comprisesa) an IL-2 variant comprising 95% identity to SEQ ID NO: 1 and amino acid substitutions H16L, V69A, Q74P, and C125S; andAttorney Docket No.: SVI-017WO1b) an Fc region.

24. The method of claim 23, wherein the IL-2 Fc fusion protein is administered at a flat dose of 500-1500 pg.

25. The method of claim 23 or claim 24, wherein the IL-2 Fc fusion protein is administered at a flat dose of 100 pg, 250 pg, 500 pg, 750 pg, 1000 pg, 1250 pg, 1500 pg, 1750 pg, or 2000 pg.

26. The method of any one of claims 23-25, wherein the IL-2 Fc fusion protein is administered at a flat dose of 500 pg.

27. The method of any one of claims 23-25, wherein IL-2 Fc fusion protein is administered at a flat dose of 1000 pg.

28. The method of any one of claims 23-25, wherein the IL-2 Fc fusion protein is administered at a flat dose of 1500 pg.

29. The method of any one of claims 23-28, wherein the IL-2 Fc fusion protein is administered no more frequent than once every two weeks, no more frequent than once every three weeks, no more frequent than once every four weeks, no more frequent than once every five weeks, or no more frequent than once every six weeks.

30. The method of any one of claims 23-29, wherein the IL-2 Fc fusion protein is administered once every two weeks, once every three weeks, once every four weeks, once every five weeks, or once every six weeks.

31. The method of any one of claims 23-28, wherein the flat dose is administered as a single dose.

32. The method of any one of the preceding claims, wherein the autoimmune disease is systemic lupus erythematosus (SLE), autoimmune hepatitis (AH4), immune-mediated focal segmental glomerulosclerosis (FSGS), or alopecia areata (AA).Attorney Docket No.: SVI-017WO133. The method of any one of the preceding claims, wherein the IL-2 variant comprises an amino acid sequence of SEQ ID NO: 4.

34. The method of any one of the preceding claims, wherein the IL-2 variant further comprises amino acid substitution T3 A.

35. The method of any one of the preceding claims, wherein the Fc region comprises an Fc region of IgGl.

36. The method of claim 35, wherein the Fc region of IgGl comprises amino acid substitution N297G according to EU numbering.

37. The method of any one of the preceding claims, wherein the Fc region comprises an Fc region of human IgGl allotype m3.

38. The method of any one of the preceding claims, wherein the Fc region comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical to SEQ ID NO: 11.

39. The method of any one of the preceding claims, wherein the Fc region comprises an amino acid sequence of SEQ ID NO: 11.

40. The method of any one of the preceding claims, wherein the Fc region is fused to the C-terminus of the IL-2 variant.

41. The method of any one of the preceding claims, wherein the IL-2 Fc fusion protein further comprises a linker.

42. The method of claim 41, wherein the linker comprises an amino acid sequence of SEQ ID NO: 13.Attorney Docket No.: SVI-017WO143. The method of any one of the preceding claims, wherein the IL-2 Fc fusion protein comprises an amino acid sequence at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical to SEQ ID NO: 27.

44. The method of claim 43, wherein the IL-2 Fc fusion protein comprises an amino acid sequence of SEQ ID NO: 27.

45. The method of any one of the preceding claims, wherein the IL-2 Fc fusion protein forms a dimer.

46. The method of claim 45, wherein the dimer is a homodimer.

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