Dosage regimen for selective Treg stimulator RUR20kD-IL-2 and related compositions

Abstract

The present disclosure provides selective Treg stimulatory compositions, including RUR20kD-IL-2 and related compositions, as well as respegaldesleukin and formulations, for treating autoimmune diseases, including, for example, atopic dermatitis, and dosing regimens for methods of using these compositions.

Description

[Technical Field]

[0001] This application relates to formulations and dosing regimens of long-acting interleukin-2 receptor (IL-2R) agonist, selective regulatory T cell (Treg) stimulator compositions that increase the number and / or activation of regulatory T cells, and methods of using these compositions in the treatment of autoimmune and inflammatory diseases and / or other conditions that respond to Treg stimulation therapy. In particular, this application relates to the formulation and dosing regimens of long-acting interleukin-2 receptor (IL-2R) agonist, selective Treg stimulator compositions RUR for the treatment of autoimmune and inflammatory diseases. 20kD -Relates to formulations and administration regimens for IL-2 and related compositions such as respegardesleukin. [Background technology]

[0002] Recent efforts to develop therapeutics for autoimmune diseases have focused on inhibiting specific immune pathways potentially involved in disease pathogenesis. An alternative therapeutic concept has emerged that targets the selective upregulation of T regulatory cell mechanisms. A constant imbalance of functional Tregs relative to conventional T cells (Tcons) is common to many autoimmune diseases (Abbas AK, et al., Revisiting IL-2: biology and therapeutic prospects. Sci Immunol. 2018;3(25); Sharabi A, et al., Regulatory T cells in the treatment of disease. Nat Rev Drug Discov. 2018 Oct 12). IL-2 is a pleiotropic cytokine that influences the development of both Tcons and Tregs by associating with dimeric IL-2Rβγ or trimeric IL-2Rαβγ receptors on lymphocytes and inducing downstream signaling cascades. Increased expression of IL-2 is essential for the generation of productive Tcon responses in response to infection or during cancer treatment. High levels of IL-2 stimulate the proliferation, differentiation, and function of T effector cells (Teff) and natural killer (NK) cells, and therefore it has been used in high doses to promote antitumor responses. High doses of IL-2 are administered to certain cancer patients to promote the expansion and, therefore, activation of cytotoxic lymphocytes with antitumor activity. For approved cancer indications, the recommended treatment regimen for IL-2 (aldesleukin) is 600,000 international units / kg (0.037 mg / kg) administered intravenously every 8 hours for up to 14 doses (Proleukin® package insert, 2015). Recombinant IL-2 (aldesleukin) is an IL-2 analog with biological activity similar to endogenous human IL-2. Its elimination half-life is approximately 85 minutes, necessitating its administration every 8 hours during cancer treatment (Proleukin® package insert, 2015).However, high-dose IL-2 therapy can cause serious adverse events (AEs), such as hypotension, vascular leak syndrome, pulmonary edema, increased risk of disseminated infection, cytokine release syndrome, inflammatory diseases, cardiac toxicity (cardiac rhythm disturbances and angina pectoris or myocardial infarction), severe anemia / thrombocytopenia, and other toxicities (Proleukin package insert, 2015). In addition, high-dose IL-2 therapy may reduce the normal suppressive activity of Treg cells against effector T cells, disrupting immune homeostasis. However, at resting physiological levels, IL-2 is also required for the development of Tregs and their survival in the peripheral circulation. Due to differences in the biology of the IL-2 receptor, Tregs are stimulated at much lower concentrations of IL-2 than Tregs, which constitutes a therapeutic window in which low-dose IL-2 agonists can be used locally to selectively enhance Treg responses in autoimmune patients. Given these differential effects, low-dose recombinant human IL-2 (rhIL-2) therapy is being evaluated for its ability to selectively induce Tregs and thereby treat autoimmune diseases. Several clinical studies have demonstrated that low-dose IL-2 attenuates Treg deficiency and enhances the survival of these cells. Open-label and randomized, double-blind, placebo-controlled trials in patients with SLE have provided evidence that IL-2 treatment can improve disease activity indicators (see, for example, He et al., "Efficacy and safety of low-dose IL-2 in the treatment of systemic lupus erythematosus: a randomized, double-blind, placebo-controlled trial." Ann Rheum Dis. 2019). In addition to SLE, a small study of 46 patients with various autoimmune diseases suggested that IL-2 may be beneficial in the treatment of ulcerative colitis, psoriasis, and ankylosing spondylitis (Rosenzwajg et al., "Immunological and clinical effects of low-dose interleukin 2 across 11 autoimmune diseases in a single, open clinical trial." Ann Rheum Dis. 2019;78(2):209-217). Despite early promising results, the utility of low-dose rhIL-2 treatments such as unmodified aldesleukin is limited by a narrow therapeutic window for Treg selectivity and a short half-life requiring frequent administration. There remains a high unmet need for effective and safe therapeutic options to replace existing Treg stimulation approaches. [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Abbas AK,el.,Revisiting IL-2:biology and therapeutic prospects.Sci Immunol.2018;3(25) [Non-patent document 2] Sharabi A,et al.,Regulatory T cells in the treatment of disease.Nat Rev Drug Discov.2018 Oct 12 [Non-patent document 3] He et al.,Efficacy and safety of low dose IL 2 in the treatment of systemic lupus erythematosus:a randomized,double blind,placebo controlled trial.Ann Rheum Dis.2019 [Non-patent document 4] Rosenzwajg al.,Immunological and clinical effects of low dose interleukin 2 across 11 autoimmune diseases in a single, open clinical trial.Ann Rheum Dis.2019;78(2):209-217 Summary of the Invention [Problem to be solved by the invention]

[0004] Selective Treg stimulating composition, particularly RUR 20kDIL-2 and related compositions are described in WO 2019 / 226,538, including certain polyethylene glycol (PEG)-conjugated recombinant human interleukin-2 (rhIL-2) conjugate compositions, which exhibit enhanced RUR compared to native IL-2 and / or other pro-effector PEGylated IL-2 compositions. 20kD -IL-2 and related compositions, in contrast, have the superior ability to effectively and selectively promote the expansion and activation of regulatory T cells (Tregs) over conventional T cells (Tcons), potentially providing a therapeutic alternative for autoimmune diseases. RUR with therapeutic benefits for clinical use in autoimmune diseases 20kD Improved methods of formulation, administration and treatment regimens are needed to enable therapeutic use of IL-2 and related compositions. [Means for solving the problem]

[0005] In some aspects, the present disclosure provides a selective Treg stimulator (RUR) for the treatment of autoimmune diseases, including atopic dermatitis, systemic lupus erythematosus (SLE), allergies, GVHD, Crohn's disease, ulcerative colitis, rheumatoid arthritis, type 1 diabetes, multiple sclerosis, and other inflammatory and / or immune-mediated diseases. 20kD Therapeutically advantageous formulations, dosages, and administration regimens for IL-2 and related compositions, particularly respegaldesleukin, are provided, including a variety of fixed unit doses and administration regimens for the treatment of autoimmune diseases, particularly induction and maintenance dosing, that maximize patient compliance, convenience, and tolerability while minimizing the risk of T effector stimulation, thereby enhancing management of the autoimmune disease state, thereby achieving effective disease treatment.

[0006] The selective Treg stimulating agent compositions described herein are useful in the formulations, doses and administration regimens of the present disclosure. 20kDRespegaldesleukin, an IL-2-selective Treg stimulatory composition, is being studied in a Phase 1b trial (NCT04081350) in patients with moderate to severe atopic dermatitis. This Phase 1b trial was a double-blind, randomized, placebo-controlled, multiple-dose study of respegaldesleukin, evaluating its safety, tolerability, and pharmacokinetics in approximately 40 adults with moderate to severe atopic dermatitis. Patients were treated with subcutaneous administration of respegaldesleukin once every two weeks at two different doses for 12 weeks. To continue in the study, patients were required to be EASI-50 (EASI = Eczema Area and Severity Index) responders at Week 19.

[0007] Interim data analysis from this study showed that respegaldesleukin treatment resulted in a dose-dependent reduction in Eczema Area and Severity Index (EASI) scores, with a maximum reduction of approximately 70% in EASI scores at week 12 at the 24 μg / kg dose (administered Q2W according to patient weight). Figure 3 shows interim analysis results from this Phase 1b study, showing the mean percent change in EASI scores from baseline over time, providing evidence that the 24 μg / kg dose resulted in a more robust effect on EASI score changes than patients in the placebo group. These observations in some patients provide proof-of-concept evidence for respegaldesleukin treatment for moderate-to-severe atopic dermatitis. Remarkably, treatment with 24 μg / kg Q2W for 12 weeks in this study resulted in sustained disease control in a subset of patients up to 6 months after the last dose (see Figure 3). Therefore, the sustained disease control provided by this treatment may offer a superior therapeutic option for atopic dermatitis than current standard treatments.

[0008] On the other hand, it has also been commonly observed that administration of respegaldesleukin can cause clinically undesirable injection site reactions (ISRs) in patients. These reactions are characterized by localized erythema, pain, swelling, and induration with a moderate peak size. Onset occurs 1-5 days after administration, has a dose-related duration (approximately 7-27 days), and may resolve without treatment. Patients seeking treatment for inflammatory skin diseases and / or other autoimmune diseases would benefit from measures that effectively treat the disease while minimizing the frequency and / or severity of associated ISRs. Furthermore, for example, taking higher doses more frequently and for longer periods of time increases the risk of pro-effector stimulation (e.g., excessive stimulation of NK cells, eosinophils, and T effector cells), which may interfere with the desired selective Treg stimulation effect. Therefore, the discovery of an advantageous fixed unit dose and administration schedule represents an important step forward in the clinical management of autoimmune diseases with respegaldesleukin. Optionally, administration of respegaldesleukin may be accompanied by simultaneous or sequential administration of a topical corticosteroid, a tacrolimus inhibitor, an oral or topical antihistamine, or a topical JAK inhibitor to reduce undesirable injection site reactions (ISRs). Preferably, ISRs are prevented or reduced by administration of a topical antihistamine. Topical antihistamines useful for reducing ISRs include, but are not limited to, doxepin, diphenhydramine, and diphenhydramine / zinc acetate.

[0009] Embodiments of the disclosed respegaldesleukin formulations and dosing regimens provide a means of maximizing patient treatment compliance, convenience, and effective disease management through less frequent and / or modulated administration, including selected doses that provide advantageous approaches to treating autoimmune diseases, such as specific induction and maintenance doses and dosing regimens. Thus, the formulations and dosing regimens described herein offer improved clinical tolerability, and they are designed to increase compliance and promote improved clinical disease management in patients with atopic dermatitis, SLE, and / or other autoimmune diseases described herein.

[0010] Formulations, unit doses and administration regimens for the treatment of autoimmune diseases Unit dose: In some aspects, embodiments of the present disclosure provide a selective Treg stimulatory agent RUR containing about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose for use in treating an autoimmune disease. 20kD In some aspects, embodiments of the present disclosure provide a unit dose of about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg of the selective Treg stimulator RUR per dose for use in treating autoimmune diseases. 20kD Preferred unit doses of IL-2 and related compositions are provided. Preferably, the present disclosure provides unit doses of respegaldesleukin of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose for use in treating autoimmune diseases. Preferably, the present disclosure provides unit doses of respegaldesleukin of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, and about 1800 μg per dose for use in treating autoimmune diseases. Most preferably, the present disclosure provides unit doses of respegaldesleukin that are about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose for use in treating autoimmune diseases. These unit doses of respegaldesleukin and / or the selective Treg stimulator RUR 20kD Uses of IL-2 and related compositions described herein are described in further detail below. For a description of the respegaldesleukin compositions of Formulas A-F, see, e.g., about pages 68 and / or 84 below and elsewhere herein.

[0011] In one embodiment, the disclosure provides a selective Treg stimulatory agent RUR at a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose. 20kD The present invention provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject IL-2 and related compositions, wherein the composition comprises a composition of Formulas A-F. For a description of the compositions of Formulas A-F, see about page 84 below and the present specification. Preferably, the composition is a composition of Formula A. Preferably, the composition is a composition of Formula F. Preferably, the composition is a composition of Formula F.

[0012] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of the selective Treg stimulator RUR20kD-IL-2 and related compositions, wherein the composition comprises a composition of Formula A through Formula F. Preferably, the composition is a composition of Formula A. Preferably, the composition is a composition of Formula B, including, for example, certain exemplary preparations of respegaldesleukin described herein.

[0013] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of respegaldesleukin.

[0014] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg of respegaldesleukin per dose.

[0015] In one embodiment, the present disclosure provides a method of treating a human subject with an autoimmune disease, comprising administering to the human subject a dose of respegaldesleukin of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose, wherein the administration is performed once every two weeks or once every four weeks. Preferably, the administration is performed once every two weeks. Preferably, the administration is performed once every four weeks.

[0016] In one embodiment, the present disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject respegaldesleukin at a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, or about 1800 μg per dose, wherein the administration is performed once every two weeks or once every four weeks. Preferably, the administration is performed once every two weeks. Preferably, the administration is performed once every four weeks.

[0017] In one embodiment, the present disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject respegaldesleukin at a dose of about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose, wherein the administration is performed once every two weeks or once every four weeks. Preferably, the administration is performed once every two weeks. Preferably, the administration is performed once every four weeks.

[0018] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of a composition of Formula A, wherein the composition contains about 5% or more moles of IgG on a molar basis. The composition comprises a mono-PEGylated IL-2 conjugate of the formula (I), about 28 mol % to about 60 mol % of a di-PEGylated IL-2 conjugate, about 24 mol % to about 65 mol % of a tri-PEGylated IL-2 conjugate, and about 12 mol % or less of a higher-order PEGylated IL-2 conjugate, wherein each branched polyethylene glycol moiety has a nominal average molecular weight of about 20,000 daltons; the administration is performed once every two weeks or once every four weeks. Preferably, the administration is performed once every two weeks. Preferably, the administration is performed once every four weeks.

[0019] In one embodiment, the present disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of a composition of Formula A, wherein the composition comprises, on a molar basis, about 5 mol% or less of a mono-PEGylated IL-2 conjugate, about 28 mol% to about 60 mol% of a di-PEGylated IL-2 conjugate, about 24 mol% to about 65 mol% of a tri-PEGylated IL-2 conjugate, and about 12 mol% or less of a higher-PEGylated IL-2 conjugate, wherein each branched polyethylene glycol moiety has a nominal average molecular weight of about 20,000 daltons; and the administration is performed once every two weeks or once every four weeks. Preferably, the administration is performed once every two weeks. Preferably, the administration is performed once every four weeks.

[0020] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of a composition of Formula B, wherein the composition is from about 2.5 to about 300 μg on a molar basis. The composition comprises 4.5 mol % mono-PEGylated IL-2 conjugates, about 35 to about 50 mol % di-PEGylated IL-2 conjugates, about 38 to about 46 mol % tri-PEGylated IL-2 conjugates, and about 3 to about 10 mol % higher-order PEGylated IL-2 conjugates, wherein each branched polyethylene glycol moiety has a nominal average molecular weight of about 20,000 daltons; the administration is performed once every two weeks or once every four weeks. Preferably, the administration is performed once every two weeks. Preferably, the administration is performed once every four weeks.

[0021] In one embodiment, the present disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, or about 1800 μg per dose of a composition of Formula B, the composition comprising, on a molar basis, about 2.5 to about 4.5 mol % mono-PEGylated IL-2 conjugate, about 35 to about 50 mol % di-PEGylated IL-2 conjugate, about 38 to about 46 mol % tri-PEGylated IL-2 conjugate, and about 3 to about 10 mol % higher-PEGylated IL-2 conjugate, wherein each branched polyethylene glycol moiety has a nominal average molecular weight of about 20,000 daltons; the administration is performed biweekly or 4 weeks. Preferably, the administration is performed biweekly. Preferably, the administration is carried out once every four weeks.

[0022] In one embodiment, the present disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of a composition of Formula B, the composition comprising, on a molar basis, about 2.5 to about 4.5 mol % mono-PEGylated IL-2 conjugate, about 35 to about 50 mol % di-PEGylated IL-2 conjugate, about 38 to about 46 mol % tri-PEGylated IL-2 conjugate, and about 3 to about 10 mol % higher-PEGylated IL-2 conjugate, wherein each branched polyethylene glycol moiety has a nominal average molecular weight of about 20,000 daltons; the administration is performed biweekly or 4 weeks. Preferably, the administration is performed biweekly. Preferably, the administration is carried out once every four weeks.

[0023] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of a composition of Formula C, wherein the composition is about 2.8 to 3600 μg on a molar basis. The composition comprises about 3.8 mol % mono-PEGylated IL-2 conjugates, about 44 to about 48 mol % di-PEGylated IL-2 conjugates, about 41 to about 44 mol % tri-PEGylated IL-2 conjugates, and about 7 to about 9 mol % higher-PEGylated IL-2 conjugates, wherein each branched polyethylene glycol moiety has a nominal average molecular weight of about 20,000 daltons; the administration is performed once every two weeks or once every four weeks. Preferably, the administration is performed once every two weeks. Preferably, the administration is performed once every four weeks.

[0024] In one embodiment, the present disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of a composition of Formula C, the composition comprising, on a molar basis, about 2.8 to about 3.8 mol % mono-PEGylated IL-2 conjugate, about 44 to about 48 mol % di-PEGylated IL-2 conjugate, about 41 to about 44 mol % tri-PEGylated IL-2 conjugate, and about 7 to about 9 mol % higher-PEGylated IL-2 conjugate, wherein each branched polyethylene glycol moiety has a nominal average molecular weight of about 20,000 daltons; the administration is performed biweekly or 4 weeks. Preferably, the administration is performed biweekly. Preferably, the administration is carried out once every four weeks.

[0025] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of a composition of Formula D, wherein the composition comprises, on a molar basis, about 2.8 to about 3.8 mole % mono-PEGylated IL-2 conjugate and about 44 to about 48 mole % % di-PEGylated IL-2 conjugate, about 41 to about 44 mol % tri-PEGylated IL-2 conjugate, and about 7 to about 9 mol % higher order PEGylated IL-2 conjugate, wherein the composition comprises a mixture of mono-PEGylated IL-2 conjugates having a PEG moiety attached at one of lysines K7, or K8, or K31, or K75, and each branched polyethylene glycol moiety has a nominal average molecular weight of about 20,000 daltons; the administration is performed once every two weeks or once every four weeks. Preferably, the administration is performed once every two weeks. Preferably, the administration is performed once every four weeks.

[0026] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of a composition of Formula D, wherein the composition comprises, on a molar basis, about 2.8 to about 3.8 mole % mono-PEGylated IL-2 conjugate, about 44 to about 48 mole % di-PEGylated IL-2 conjugate, and about 41 to about 4 The composition comprises 4 mole % tri-PEGylated IL-2 conjugate and about 7 to about 9 mole % higher order PEGylated IL-2 conjugate, the composition comprising a mixture of mono-PEGylated IL-2 conjugates having a PEG moiety attached at one of lysines K7, K8, K31, or K75, each branched polyethylene glycol moiety having a nominal average molecular weight of about 20,000 daltons; the administration is performed once every two weeks or once every four weeks. Preferably, the administration is performed once every two weeks. Preferably, the administration is performed once every four weeks.

[0027] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of a composition of Formula E, wherein the composition comprises about 2.8 to about 3.8 mole % on a molar basis of a mono-PEGylated IL-2 conjugate. and about 44 to about 48 mol % of a di-PEGylated IL-2 conjugate, about 41 to about 44 mol % of a tri-PEGylated IL-2 conjugate, and about 7 to about 9 mol % of a higher-order PEGylated IL-2 conjugate, wherein the composition comprises a mono-PEGylated IL-2 conjugate having a PEG moiety attached at lysine K7, and each branched polyethylene glycol moiety has a nominal average molecular weight of about 20,000 daltons; the administration is performed once every two weeks or once every four weeks. Preferably, the administration is performed once every two weeks. Preferably, the administration is performed once every four weeks.

[0028] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of a composition of Formula E, the composition comprising, on a molar basis, about 2.8 to about 3.8 mole % of a mono-PEGylated IL-2 conjugate, about 44 to about 48 mole % of a di-PEGylated IL-2 conjugate, about 41 to about 44 mole % of a tri-PEGylated IL-2 conjugate, and about 7 to about 9 mole % of a higher-PEGylated IL-2 conjugate, wherein the composition comprises a mono-PEGylated IL-2 conjugate having a PEG moiety attached at lysine K7, and wherein each branched polyethylene glycol moiety has a nominal average molecular weight of about 20,000 daltons; and the administration is performed once every two weeks or once every four weeks. Preferably, the administration is performed once every two weeks. Preferably, the administration is performed once every four weeks.

[0029] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of a composition of Formula F, wherein the composition comprises about 2-4 mole% on a molar basis. The composition comprises the following: a mono-PEGylated IL-2 conjugate, about 35 mol % to about 55 mol % di-PEGylated IL-2 conjugate, about 35 mol % to about 55 mol % tri-PEGylated IL-2 conjugate, and about 12 mol % or less higher-PEGylated IL-2 conjugate, wherein each branched polyethylene glycol moiety has a nominal average molecular weight of about 20,000 daltons; and the administration is performed once every two weeks or once every four weeks. Preferably, the administration is performed once every two weeks. Preferably, the administration is performed once every four weeks.

[0030] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of a composition of Formula F, wherein the composition comprises about 2-4 mole% on a molar basis. The composition comprises the following: a mono-PEGylated IL-2 conjugate, about 35 mol % to about 55 mol % di-PEGylated IL-2 conjugate, about 35 mol % to about 55 mol % tri-PEGylated IL-2 conjugate, and about 12 mol % or less higher-PEGylated IL-2 conjugate, wherein each branched polyethylene glycol moiety has a nominal average molecular weight of about 20,000 daltons; and the administration is performed once every two weeks or once every four weeks. Preferably, the administration is performed once every two weeks. Preferably, the administration is performed once every four weeks.

[0031] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of respegaldesleukin, wherein said administration occurs once every two weeks.

[0032] In one embodiment, the present disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg of respegaldesleukin per dose, wherein the administration is performed once every two weeks.

[0033] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of respegaldesleukin, wherein said administration occurs once every four weeks.

[0034] In one embodiment, the present disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg of respegaldesleukin per dose, wherein the administration is performed once every four weeks.

[0035] For each of the foregoing embodiments, the present disclosure further provides embodiments in which the autoimmune disease is selected from systemic lupus erythematosus (SLE), ulcerative colitis, Crohn's disease, rheumatoid arthritis, atopic dermatitis, systemic sclerosis, ankylosing spondylitis, graft-versus-host disease, and polymyositis; type 1 diabetes, Addison's disease, Hashimoto's thyroiditis, Graves' disease, Sjogren's syndrome, vitiligo, pernicious anemia, glomerulonephritis, lupus nephritis, myasthenia gravis, Goodpasture's syndrome, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, peanut allergy, pulmonary fibrosis, celiac disease, alopecia areata, psoriasis, hidradenitis suppurativa, or asthma.

[0036] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of respegaldesleukin, wherein said administration occurs once every two weeks; and the autoimmune disease is systemic lupus erythematosus. (SLE), ulcerative colitis, Crohn's disease, rheumatoid arthritis, atopic dermatitis, systemic sclerosis, ankylosing spondylitis, graft-versus-host disease and polymyositis; type 1 diabetes, Addison's disease, Hashimoto's thyroiditis, Graves' disease, Sjogren's syndrome, vitiligo, pernicious anemia, glomerulonephritis, lupus nephritis, myasthenia gravis, Goodpasture's syndrome, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, peanut allergy, pulmonary fibrosis, celiac disease, alopecia areata, psoriasis, hidradenitis suppurativa or asthma.

[0037] In one embodiment, the present disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of respegaldesleukin, wherein said administration occurs once every two weeks; the autoimmune disease is selected from the group consisting of systemic lupus erythematosus (SLE), ulcerative colitis, Crohn's disease, rheumatoid arthritis, Selected from atopic dermatitis, systemic sclerosis, ankylosing spondylitis, graft-versus-host disease and polymyositis; type 1 diabetes, Addison's disease, Hashimoto's thyroiditis, Graves' disease, Sjogren's syndrome, vitiligo, pernicious anemia, glomerulonephritis, lupus nephritis, myasthenia gravis, Goodpasture's syndrome, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, peanut allergy, pulmonary fibrosis, celiac disease, alopecia areata, psoriasis, hidradenitis suppurativa or asthma.

[0038] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of respegaldesleukin, wherein said administration occurs once every four weeks; and the autoimmune disease is systemic lupus erythematosus. (SLE), ulcerative colitis, Crohn's disease, rheumatoid arthritis, atopic dermatitis, systemic sclerosis, ankylosing spondylitis, graft-versus-host disease and polymyositis; type 1 diabetes, Addison's disease, Hashimoto's thyroiditis, Graves' disease, Sjogren's syndrome, vitiligo, pernicious anemia, glomerulonephritis, lupus nephritis, myasthenia gravis, Goodpasture's syndrome, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, peanut allergy, pulmonary fibrosis, celiac disease, alopecia areata, psoriasis, hidradenitis suppurativa or asthma.

[0039] In one embodiment, the present disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg of respegaldesleukin per dose, wherein said administration occurs once every four weeks; the autoimmune disease is selected from the group consisting of systemic lupus erythematosus (SLE), ulcerative colitis, Crohn's disease, rheumatoid arthritis, Selected from atopic dermatitis, systemic sclerosis, ankylosing spondylitis, graft-versus-host disease and polymyositis; type 1 diabetes, Addison's disease, Hashimoto's thyroiditis, Graves' disease, Sjogren's syndrome, vitiligo, pernicious anemia, glomerulonephritis, lupus nephritis, myasthenia gravis, Goodpasture's syndrome, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, peanut allergy, pulmonary fibrosis, celiac disease, alopecia areata, psoriasis, hidradenitis suppurativa or asthma.

[0040] In yet another aspect of each of the foregoing embodiments, preferably, the autoimmune disease is atopic dermatitis. In each of the embodiments in which the autoimmune disease is atopic dermatitis, a further preferred patient is a bio-experienced patient as defined herein. In another aspect of each of the foregoing embodiments, preferably, the autoimmune disease is systemic lupus erythematosus (SLE). In yet another aspect of each of the foregoing embodiments, preferably, the autoimmune disease is ulcerative colitis. In yet another aspect of each of the foregoing embodiments, preferably, the autoimmune disease is type 1 diabetes. In yet another aspect of each of the foregoing embodiments, preferably, the autoimmune disease is peanut allergy.

[0041] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of respegaldesleukin, wherein the administration is performed once every two weeks; and the autoimmune disease is atopic dermatitis.

[0042] In one embodiment, the present disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of respegaldesleukin, wherein the administration is performed once every two weeks; and the autoimmune disease is atopic dermatitis.

[0043] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of respegaldesleukin, wherein the administration is performed once every four weeks; and the autoimmune disease is atopic dermatitis.

[0044] In one embodiment, the present disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg of respegaldesleukin per dose, wherein the administration is performed once every four weeks; and the autoimmune disease is atopic dermatitis.

[0045] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of respegaldesleukin, wherein the administration is performed once every two weeks; and the autoimmune disease is systemic lupus erythematosus (SLE).

[0046] In one embodiment, the present disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of respegaldesleukin, wherein the administration is performed once every two weeks; and the autoimmune disease is systemic lupus erythematosus (SLE).

[0047] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of respegaldesleukin, wherein the administration is performed once every four weeks; and the autoimmune disease is systemic lupus erythematosus (SLE).

[0048] In one embodiment, the present disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of respegaldesleukin, wherein the administration is performed once every four weeks; and the autoimmune disease is systemic lupus erythematosus (SLE).

[0049] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of respegaldesleukin, wherein the administration occurs once every two weeks; and the autoimmune disease is ulcerative colitis.

[0050] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg of respegaldesleukin per dose, wherein the administration is performed once every two weeks; and the autoimmune disease is ulcerative colitis.

[0051] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of respegaldesleukin, wherein the administration occurs once every four weeks; and the autoimmune disease is ulcerative colitis.

[0052] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg of respegaldesleukin per dose, wherein the administration is performed once every four weeks; and the autoimmune disease is ulcerative colitis.

[0053] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of respegaldesleukin, wherein the administration occurs once every two weeks; and the autoimmune disease is type 1 diabetes.

[0054] In one embodiment, the present disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg of respegaldesleukin per dose, wherein the administration is performed once every two weeks; and the autoimmune disease is type 1 diabetes.

[0055] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of respegaldesleukin, wherein the administration occurs once every four weeks; and the autoimmune disease is type 1 diabetes.

[0056] In one embodiment, the present disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg of respegaldesleukin per dose, wherein the administration is performed once every four weeks; and the autoimmune disease is type 1 diabetes.

[0057] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of respegaldesleukin, wherein the administration occurs once every two weeks; and the autoimmune disease is peanut allergy.

[0058] In one embodiment, the present disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of respegaldesleukin, wherein the administration is performed once every two weeks; and the autoimmune disease is peanut allergy.

[0059] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of respegaldesleukin, wherein said administration occurs once every four weeks; and the autoimmune disease is peanut allergy.

[0060] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg of respegaldesleukin per dose, wherein the administration is performed once every four weeks; and the autoimmune disease is peanut allergy.

[0061] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of respegaldesleukin, wherein said dose further comprises a formulation of 5 mM sodium acetate, 25 mM sodium chloride, 7.5% (w / v) sucrose, pH 5.0; said administration The autoimmune disease is selected from systemic lupus erythematosus (SLE), ulcerative colitis, Crohn's disease, rheumatoid arthritis, atopic dermatitis, systemic sclerosis, ankylosing spondylitis, graft-versus-host disease, and polymyositis; type 1 diabetes, Addison's disease, Hashimoto's thyroiditis, Graves' disease, Sjogren's syndrome, vitiligo, pernicious anemia, glomerulonephritis, lupus nephritis, myasthenia gravis, Goodpasture's syndrome, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, peanut allergy, pulmonary fibrosis, celiac disease, alopecia areata, psoriasis, hidradenitis suppurativa, or asthma.

[0062] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of respegaldesleukin, wherein said dose further comprises a formulation of 5 mM sodium acetate, 25 mM sodium chloride, 7.5% (w / v) sucrose, pH 5.0; said administration is performed once every two weeks; and said autoimmune disease is systemic erythropoietin. Therapeutic conditions include but are not limited to: rheumatoid arthritis (SLE), ulcerative colitis, Crohn's disease, rheumatoid arthritis, atopic dermatitis, systemic sclerosis, ankylosing spondylitis, graft-versus-host disease, and polymyositis; type 1 diabetes, Addison's disease, Hashimoto's thyroiditis, Graves' disease, Sjogren's syndrome, vitiligo, pernicious anemia, glomerulonephritis, lupus nephritis, myasthenia gravis, Goodpasture's syndrome, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, peanut allergy, pulmonary fibrosis, celiac disease, alopecia areata, psoriasis, hidradenitis suppurativa, and asthma.

[0063] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of respegaldesleukin, wherein said dose further comprises a formulation of 5 mM sodium acetate, 25 mM sodium chloride, 7.5% (w / v) sucrose, pH 5.0; said administration The autoimmune disease is selected from systemic lupus erythematosus (SLE), ulcerative colitis, Crohn's disease, rheumatoid arthritis, atopic dermatitis, systemic sclerosis, ankylosing spondylitis, graft-versus-host disease, and polymyositis; type 1 diabetes, Addison's disease, Hashimoto's thyroiditis, Graves' disease, Sjogren's syndrome, vitiligo, pernicious anemia, glomerulonephritis, lupus nephritis, myasthenia gravis, Goodpasture's syndrome, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, peanut allergy, pulmonary fibrosis, celiac disease, alopecia areata, psoriasis, hidradenitis suppurativa, or asthma.

[0064] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of respegaldesleukin, wherein said dose further comprises a formulation of 5 mM sodium acetate, 25 mM sodium chloride, 7.5% (w / v) sucrose, pH 5.0; said administration is performed once every four weeks; and said autoimmune disease is systemic erythropoietin. Therapeutic conditions include but are not limited to: rheumatoid arthritis (SLE), ulcerative colitis, Crohn's disease, rheumatoid arthritis, atopic dermatitis, systemic sclerosis, ankylosing spondylitis, graft-versus-host disease, and polymyositis; type 1 diabetes, Addison's disease, Hashimoto's thyroiditis, Graves' disease, Sjogren's syndrome, vitiligo, pernicious anemia, glomerulonephritis, lupus nephritis, myasthenia gravis, Goodpasture's syndrome, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, peanut allergy, pulmonary fibrosis, celiac disease, alopecia areata, psoriasis, hidradenitis suppurativa, and asthma.

[0065] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of a composition of Formula A, wherein the composition contains, on a molar basis, about 5 mole % or less of a mono-PEGylated IL-2 conjugate and about 28 mole % to about 60 mol % di-PEGylated IL-2 conjugates, about 24 mol % to about 65 mol % tri-PEGylated IL-2 conjugates, and about 12 mol % or less higher order PEGylated IL-2 conjugates, wherein each branched polyethylene glycol moiety has a nominal average molecular weight of about 20,000 daltons; the dosage further comprises a formulation of 5 mM sodium acetate, 25 mM sodium chloride, 7.5% (w / v) sucrose, pH 5.0; and the administration is performed once every two weeks or once every four weeks.

[0066] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of a composition of Formula A, wherein the composition contains, on a molar basis, about 5 mole % or less of a mono-PEGylated IL-2 conjugate, about 28 mole % to about 60 mole % of a di-PEGylated IL-2 conjugate, and about The dosage comprises 24 mol % to about 65 mol % tri-PEGylated IL-2 conjugate and about 12 mol % or less higher-order PEGylated IL-2 conjugate, wherein each branched polyethylene glycol moiety has a nominal average molecular weight of about 20,000 daltons; the dosage further comprises a formulation of 5 mM sodium acetate, 25 mM sodium chloride, 7.5% (w / v) sucrose, pH 5.0; and the administration is performed once every two weeks or once every four weeks.

[0067] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of a composition of Formula B, wherein the composition comprises about 2.5 to about 4.5 moles of a mono-PEGylated IL-2 conjugate and about 35 moles of a mono-PEGylated IL-2 conjugate per molar basis. and about 50 mol % to about 50 mol % di-PEGylated IL-2 conjugate, about 38 to about 46 mol % tri-PEGylated IL-2 conjugate, and about 3 to about 10 mol % higher order PEGylated IL-2 conjugate, wherein each branched polyethylene glycol moiety has a nominal average molecular weight of about 20,000 daltons; the dose further comprises a formulation of 5 mM sodium acetate, 25 mM sodium chloride, 7.5% (w / v) sucrose, pH 5.0; and the administration is performed once every two weeks or once every four weeks.

[0068] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of a composition of Formula B, wherein the composition comprises, on a molar basis, about 2.5 to about 4.5 mole % of a mono-PEGylated IL-2 conjugate and about 35 to about 50 mole % of a di-PEGylated IL-2 conjugate. , about 38 to about 46 mol % tri-PEGylated IL-2 conjugate and about 3 to about 10 mol % higher order PEGylated IL-2 conjugate, wherein each branched polyethylene glycol moiety has a nominal average molecular weight of about 20,000 daltons; the dosage further comprises a formulation of 5 mM sodium acetate, 25 mM sodium chloride, 7.5% (w / v) sucrose, pH 5.0; and the administration is performed once every two weeks or once every four weeks.

[0069] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of a composition of Formula C, wherein the composition comprises about 2.8 to about 3.8 mole % on a molar basis of a mono-PEGylated IL-2 conjugate and about 4 The formulation comprises 4 to about 48 mol % di-PEGylated IL-2 conjugate, about 41 to about 44 mol % tri-PEGylated IL-2 conjugate, and about 7 to about 9 mol % higher order PEGylated IL-2 conjugate, wherein each branched polyethylene glycol moiety has a nominal average molecular weight of about 20,000 daltons; the dosage further comprises a formulation of 5 mM sodium acetate, 25 mM sodium chloride, 7.5% (w / v) sucrose, pH 5.0; and the administration is performed once every two weeks or once every four weeks.

[0070] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of a composition of Formula C, wherein the composition comprises, on a molar basis, about 2.8 to about 3.8 mole % mono-PEGylated IL-2 conjugate and about 44 to about 48 mole % di-PEGylated IL-2 conjugate. and about 41 to about 44 mol % tri-PEGylated IL-2 conjugate and about 7 to about 9 mol % higher order PEGylated IL-2 conjugate, wherein each branched polyethylene glycol moiety has a nominal average molecular weight of about 20,000 daltons; the dose further comprises a formulation of 5 mM sodium acetate, 25 mM sodium chloride, 7.5% (w / v) sucrose, pH 5.0; and the administration is performed once every two weeks or once every four weeks.

[0071] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of a composition of Formula D, comprising, on a molar basis, about 2.8 to about 3.8 mole % mono-PEGylated IL-2 conjugate, about 44 to about 48 mole % di-PEGylated IL-2 conjugate, and about 41 to about 44 mole % and about 7 to about 9 mole % of a higher order PEGylated IL-2 conjugate, the composition comprising a mixture of mono-PEGylated IL-2 conjugates having a PEG moiety attached at one of lysines K7, or K8, or K31, or K75, each branched polyethylene glycol moiety having a nominal average molecular weight of about 20,000 daltons; the dose further comprises a formulation of 5 mM sodium acetate, 25 mM sodium chloride, 7.5% (w / v) sucrose, pH 5.0; the administration is performed once every two weeks or once every four weeks.

[0072] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of a composition of Formula D, wherein the composition comprises, on a molar basis, about 2.8 to about 3.8 mole % mono-PEGylated IL-2 conjugate, about 44 to about 48 mole % di-PEGylated IL-2 conjugate, about 41 to about 44 mole % tri-PEGylated IL-2 conjugate, and about 7 to about 9 mole % IL-2 conjugate. and mol % of a higher order PEGylated IL-2 conjugate, wherein the composition comprises a mixture of mono-PEGylated IL-2 conjugates having a PEG moiety attached at one of lysines K7, or K8, or K31, or K75, wherein each branched polyethylene glycol moiety has a nominal average molecular weight of about 20,000 daltons; the dose further comprises a formulation of 5 mM sodium acetate, 25 mM sodium chloride, 7.5% (w / v) sucrose, pH 5.0; and the administration is performed once every two weeks or once every four weeks.

[0073] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of a composition of Formula E, wherein the composition comprises, on a molar basis, about 2.8 to about 3.8 mole % mono-PEGylated IL-2 conjugate and about 44 to about 48 mole % di-PEGylated IL-2 conjugate. and about 41 to about 44 mole % of a tri-PEGylated IL-2 conjugate and about 7 to about 9 mole % of a higher order PEGylated IL-2 conjugate, the composition comprising a mono-PEGylated IL-2 conjugate having a PEG moiety attached at lysine K7, each branched polyethylene glycol moiety having a nominal average molecular weight of about 20,000 daltons; the dose further comprises a formulation of 5 mM sodium acetate, 25 mM sodium chloride, 7.5% (w / v) sucrose, pH 5.0; the administration is performed once every two weeks or once every four weeks.

[0074] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of a composition of Formula E, wherein the composition contains, on a molar basis, about 2.8 to about 3.8 mole % mono-PEGylated IL-2 conjugate, about 44 to about 48 mole % di-PEGylated IL-2 conjugate, and about 41 to about 44 mole % tri-PEGylated IL-2 conjugate. and about 7 to about 9 mole % of a higher-order PEGylated IL-2 conjugate, the composition comprising a mono-PEGylated IL-2 conjugate having a PEG moiety attached at lysine K7, each branched polyethylene glycol moiety having a nominal average molecular weight of about 20,000 daltons; the dosage further comprises a formulation of 5 mM sodium acetate, 25 mM sodium chloride, 7.5% (w / v) sucrose, pH 5.0; and the administration is performed once every two weeks or once every four weeks.

[0075] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of a composition of Formula F, wherein the composition contains, on a molar basis, about 2-4 mole % or less of a mono-PEGylated IL-2 conjugate and about 35 mole % to 5 mole % of a mono-PEGylated IL-2 conjugate. The formulation comprises about 55 mol% di-PEGylated IL-2 conjugates, about 35 mol% to about 55 mol% tri-PEGylated IL-2 conjugates, and about 12 mol% or less higher-order PEGylated IL-2 conjugates, each branched polyethylene glycol moiety having a nominal average molecular weight of about 20,000 daltons; the dosage further comprises a formulation of 5 mM sodium acetate, 25 mM sodium chloride, 7.5% (w / v) sucrose, pH 5.0; and the administration is performed once every two weeks or once every four weeks. Preferably, the administration is performed once every two weeks.

[0076] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of a composition of Formula F, the composition comprising, on a molar basis, about 2-4 mole % or less of a mono-PEGylated IL-2 conjugate, about 35 mole % to about 55 mole % of a di-PEGylated IL-2 conjugate, The formulation comprises about 35 mol % to about 55 mol % tri-PEGylated IL-2 conjugate and about 12 mol % or less higher-order PEGylated IL-2 conjugate, each branched polyethylene glycol moiety having a nominal average molecular weight of about 20,000 daltons; the dosage further comprises a formulation of 5 mM sodium acetate, 25 mM sodium chloride, 7.5% (w / v) sucrose, pH 5.0; and the administration is performed once every two weeks or once every four weeks. Preferably, the administration is performed once every two weeks.

[0077] In yet another aspect of each of the foregoing embodiments, preferably, the respegaldesleukin dose further comprises a formulation of 5 mM sodium acetate, 25 mM sodium chloride, 7.5% (w / v) sucrose, pH 5.0. In yet another aspect of each of the foregoing embodiments, preferably, the respegaldesleukin concentration of the 1800 μg dose is selected from 0.9, 1.8, or 3.6 mg / mL protein equivalent, depending on the autoinjector or prefilled syringe used. In yet another aspect of each of the foregoing embodiments, preferably, the delivery device is selected from 0.5 mL, 1.0 mL, or 2.0 mL autoinjectors or prefilled syringes equivalent to the same dose. In yet another aspect of each of the foregoing embodiments, preferably, the respegaldesleukin dose of the 3000 μg dose has a concentration of 1.5, 3.0, or 6.0 mg / mL (depending on the autoinjector or prefilled syringe). In yet another aspect of each of the foregoing embodiments, preferably the 3300 μg dose of respegaldesleukin has a concentration of 1.5, 3.0, or 6.0 mg / mL (depending on the autoinjector or prefilled syringe). In yet another aspect of each of the foregoing embodiments, preferably the 3600 μg dose of respegaldesleukin has a concentration of 1.5, 3.0, or 6.0 mg / mL (depending on the autoinjector or prefilled syringe).

[0078] The present disclosure provides a pharmaceutical formulation comprising a selective Treg stimulating agent RUR20kD-IL-2 and related compositions at a concentration of about 4.0 mg / mL to about 5.0 mg / mL, sodium acetate at a concentration of about 5 mM, sodium chloride at a concentration of about 25 mM, sucrose at a concentration of about 7.5% (w / v), and a pH of about 5.0. Preferably, the selective Treg stimulating agent RUR20kD-IL-2 and related compositions comprises, on a molar basis, about 5 mole percent or less of mono-PEGylated IL-2 conjugates, about 28 mole percent to about 60 mole percent of di-PEGylated IL-2 conjugates, about 24 mole percent to about 65 mole percent of tri-PEGylated IL-2 conjugates, and about 12 mole percent or less of higher-order PEGylated IL-2 conjugates, wherein each branched polyethylene glycol moiety has a nominal average molecular weight of about 20,000 daltons. Preferably, the selective Treg stimulator RUR20kD-IL-2 and related compositions comprise, on a molar basis, from about 2 mole percent to about 4 mole percent mono-PEGylated IL-2 conjugates, from about 35 mole percent to about 55 mole percent di-PEGylated IL-2 conjugates, from about 35 mole percent to about 55 mole percent tri-PEGylated IL-2 conjugates, and up to about 12 mole percent higher-PEGylated IL-2 conjugates, wherein each branched polyethylene glycol moiety has a nominal average molecular weight of about 20,000 daltons. Preferably, the selective Treg stimulating agent RUR20kD-IL-2 and related compositions comprise, on a molar basis, about 2.5 mole percent to about 4.5 mole percent mono-PEGylated IL-2 conjugates, about 35 mole percent to about 50 mole percent di-PEGylated IL-2 conjugates, about 38 mole percent to about 46 mole percent tri-PEGylated IL-2 conjugates, and about 3 mole percent to 10 mole percent higher-PEGylated IL-2 conjugates, wherein each branched polyethylene glycol moiety has a nominal average molecular weight of about 20,000 daltons.Preferably, the selective Treg stimulating agent RUR20kD-IL-2 and related compositions comprise, on a molar basis, about 2.8 mole percent to about 3.8 mole percent mono-PEGylated IL-2 conjugates, about 44 mole percent to about 48 mole percent di-PEGylated IL-2 conjugates, about 41 mole percent to about 44 mole percent tri-PEGylated IL-2 conjugates, and about 7 mole percent to about 9 mole percent higher-PEGylated IL-2 conjugates, wherein each branched polyethylene glycol moiety has a nominal average molecular weight of about 20,000 daltons.

[0079] In one embodiment, a method for treating an autoimmune disease is provided, comprising administering to a human in need thereof an effective dose of one of the pharmaceutical compositions described herein. Preferably, the autoimmune disease is selected from systemic lupus erythematosus (SLE), ulcerative colitis, Crohn's disease, rheumatoid arthritis, atopic dermatitis, systemic sclerosis, ankylosing spondylitis, graft-versus-host disease, and polymyositis; type 1 diabetes, Addison's disease, Hashimoto's thyroiditis, Graves' disease, Sjögren's syndrome, vitiligo, pernicious anemia, glomerulonephritis, lupus nephritis, myasthenia gravis, Goodpasture's syndrome, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, peanut allergy, pulmonary fibrosis, celiac disease, alopecia areata, psoriasis, hidradenitis suppurativa, and asthma. In one embodiment, a method for treating SLE is provided, comprising administering to a human in need thereof an effective dose of one of the pharmaceutical compositions described herein. In one embodiment, there is provided a method for treating atopic dermatitis, comprising administering to a human in need thereof an effective dose of one of the aforementioned compositions. In one embodiment, there is provided a method for treating type 1 diabetes, comprising administering to a human in need thereof an effective dose of one of the aforementioned compositions.

[0080] In one embodiment, there is provided one of the pharmaceutical compositions described herein for use as a medicament.

[0081] The pharmaceutical compositions of the present invention are typically administered by injection, including, for example, subcutaneous, intravenous, and intramuscular injections, and infusion injections. Exemplary compositions for administration to patients include, for example, subcutaneous formulations as described herein, which contain the dosages described herein. The pharmaceutical compositions of the present invention are in the form of a liquid solution. The pharmaceutical compositions of the present disclosure are typically administered subcutaneously. The pharmaceutical compositions are typically administered using a prefilled, disposable pen, a reusable pen, or an automatic pen injector. The pharmaceutical composition can be administered using a disposable syringe equipped with an attached needle of appropriate gauge and length. In one embodiment, the device is an automatic injection device. According to another aspect of the present invention, an article of manufacture is provided comprising one of the above pharmaceutical compositions. In certain embodiments, the article of manufacture is a single-use vial. In certain embodiments, the article of manufacture is a pre-filled syringe, such as a 0.5 ml autoinjector, or a 1 ml autoinjector, or a 2 ml autoinjector, as known to those of skill in the art (see, e.g., Lange J, Richard P, Bradley N. Usability of a new disposable autoinjector platform device: results of a formative study conducted with a broad user population. Med Devices (Auckl). 2015;8:255-264 and / or BD Physioject™ Disposable Autoinjector 1 mL, BD Medical - Pharmaceutical Systems). In certain embodiments, the article of manufacture is an autoinjector device ("autoinjector").

[0082] In yet another aspect of each of the above embodiments including a 300 μg dose, preferably the dose of respegaldesleukin is about 300 μg. In yet another aspect of each of the above embodiments including a 450 μg dose, preferably the dose of respegaldesleukin is about 450 μg. In yet another aspect of each of the above embodiments including a 600 μg dose, preferably the dose of respegaldesleukin is about 600 μg. In yet another aspect of each of the above embodiments including a 900 μg dose, preferably the dose of respegaldesleukin is about 900 μg. In yet another aspect of each of the above embodiments including a 1200 μg dose, preferably the dose of respegaldesleukin is about 1200 μg. In yet another aspect of each of the above embodiments including a 1500 μg dose, preferably the dose of respegaldesleukin is about 1500 μg. In yet another aspect of each of the above embodiments including a 1800 μg dose, preferably the dose of respegaldesleukin is about 1800 μg. In yet another aspect of each of the above embodiments including a 2100 μg dose, preferably the dose of respegaldesleukin is about 2100 μg. In yet another aspect of each of the above embodiments including a 2400 μg dose, preferably the dose of respegaldesleukin is about 2400 μg. In yet another aspect of each of the above embodiments including a 2700 μg dose, preferably the dose of respegaldesleukin is about 2700 μg. In yet another aspect of each of the above embodiments including a 3000 μg dose, preferably the dose of respegaldesleukin is about 3000 μg. In yet another aspect of each of the above embodiments including a 3300 μg dose, preferably the dose of respegaldesleukin is about 3300 μg. In yet another aspect of each of the above embodiments including a 3600 μg dose, preferably the dose of respegaldesleukin is about 3600 μg.

[0083] The above embodiments provide specific dosages for use in autoimmune diseases and conditions, maximizing the Treg stimulatory effect while minimizing the extent to which T effector cell responses and pro-inflammatory responses are elicited, thereby providing an advantageous means for treating these diseases.

[0084] For the foregoing embodiments, the patient is administered the prescribed dose for the period of time necessary to treat the autoimmune disease being treated, as determined by one of skill in the art according to art-known methods described herein.

[0085] As used herein, "method of treatment" is equally applicable to the use of a composition to treat a disease or disorder described herein and / or the composition for use and / or use in the manufacture of a medicament to treat a disease or disorder described herein.

[0086] Induction phase followed by maintenance phase: In some aspects, embodiments of the present disclosure provide a selective Treg stimulator, RUR. 20kD Dosage regimens for the administration of IL-2 and related compositions, such as respegaldesleukin, are provided, in which the compositions are administered in an induction phase followed by a maintenance phase. Unit doses of respegaldesleukin, as described above, can be used to induce a selective Treg stimulatory response over a period of several weeks, e.g., 12-24 weeks, followed by a maintenance phase, in which the dose is reduced and / or the frequency of administration is decreased according to the embodiments described below. Such regimens provide an advantageous means of treating the autoimmune conditions described herein in that they can reduce the frequency or intensity of ISRs and / or reduce the risk of eliciting T effector and pro-effector responses. Particular embodiments of the dosage regimens disclosed herein are summarized in the table below.

[0087] [Table 6]

[0088] In some embodiments of the induction phase, respegaldesleukin is administered to the patient for a period of 12 to 24 weeks (e.g., about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, about 20 weeks, about 21 weeks, about 22 weeks, about 23 weeks, about 24 weeks).

[0089] In some embodiments of the maintenance phase, respegaldesleukin is administered to the patient for a period of 4 to 52 weeks (e.g., about 4 weeks, about 6 weeks, about 8 weeks, about 10 weeks, about 12 weeks, about 14 weeks, about 16 weeks, about 18 weeks, about 20 weeks, about 22 weeks, about 24 weeks, about 26 weeks, about 28 weeks, about 30 weeks, about 32 weeks, about 34 weeks, about 36 weeks, about 38 weeks, about 40 weeks, about 42 weeks, about 44 weeks, about 46 weeks, about 48 weeks, about 50 weeks, about 52 weeks).

[0090] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering respegaldesleukin to the human subject at a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose during an induction phase, the method comprising administering respegaldesleukin to the human subject once every week, every two weeks, every three weeks, every four weeks, or every six months. the respegaldesleukin is administered for a total of 12 weeks, a total of 16 weeks, a total of 20 weeks, or a total of 24 weeks of administration during the induction phase; followed by administration of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3500 μg per dose. a maintenance phase comprising administering a 600 μg dose of respegaldesleukin to a human subject, said administration occurring once every 2 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 12 weeks, once every 24 weeks, once every 36 weeks, once every 48 weeks, or once every 52 weeks; said respegaldesleukin being administered for a total of 4 to 52 weeks or for a total of 1 to 5 years of administration; and wherein the autoimmune disease is systemic lupus erythematosus (SLE), ulcerative colitis, or rheumatoid arthritis. ulcerative colitis, Crohn's disease, rheumatoid arthritis, atopic dermatitis, systemic sclerosis, ankylosing spondylitis, graft-versus-host disease and polymyositis; type 1 diabetes, Addison's disease, Hashimoto's thyroiditis, Graves' disease, Sjogren's syndrome, vitiligo, pernicious anemia, glomerulonephritis, lupus nephritis, myasthenia gravis, Goodpasture's syndrome, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, peanut allergy, pulmonary fibrosis, celiac disease, alopecia areata, psoriasis, hidradenitis suppurativa or asthma.

[0091] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering respegaldesleukin to the human subject at a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose during an induction phase, the method comprising administering respegaldesleukin to the human subject once every two weeks, once every three weeks, once every four weeks, or once every five weeks. the respegaldesleukin is administered for a total of 12 weeks, a total of 16 weeks, a total of 20 weeks, or a total of 24 weeks of administration during the induction phase; followed by administration of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about a maintenance phase comprising administering a 3600 μg dose of respegaldesleukin to a human subject, said administration occurring once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 12 weeks, once every 24 weeks, once every 36 weeks, once every 48 weeks, or once every 52 weeks; said respegaldesleukin being administered for a total of 4 to 52 weeks or for a total of 1 to 5 years of administration; and wherein the autoimmune disease is systemic lupus erythematosus (SLE), ulcerative colitis, or rheumatoid arthritis. enteritis, Crohn's disease, rheumatoid arthritis, atopic dermatitis, systemic sclerosis, ankylosing spondylitis, graft-versus-host disease and polymyositis; type 1 diabetes, Addison's disease, Hashimoto's thyroiditis, Graves' disease, Sjogren's syndrome, vitiligo, pernicious anemia, glomerulonephritis, lupus nephritis, myasthenia gravis, Goodpasture's syndrome, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, peanut allergy, pulmonary fibrosis, celiac disease, alopecia areata, psoriasis, hidradenitis suppurativa or asthma.

[0092] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject respegaldesleukin at a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg per dose during an induction phase, the induction phase being administered once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, or once every 8 weeks; the respegaldesleukin is administered for a total of 12 weeks during the induction phase. and administering to the human subject a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of respegaldesleukin. a maintenance phase, in which the administration is performed once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 12 weeks, once every 24 weeks, once every 36 weeks, once every 48 weeks, or once every 52 weeks; wherein the respegaldesleukin is administered for a total of 4 weeks to 52 weeks or for a total of 1 to 5 years; and the autoimmune disease is systemic lupus erythematosus (SLE), ulcerative colitis, Crohn's disease, rheumatoid arthritis, atrioventricular vasculitis, urticaria ... dermatitis, systemic sclerosis, ankylosing spondylitis, graft-versus-host disease and polymyositis; type 1 diabetes, Addison's disease, Hashimoto's thyroiditis, Graves' disease, Sjogren's syndrome, vitiligo, pernicious anemia, glomerulonephritis, lupus nephritis, myasthenia gravis, Goodpasture's syndrome, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, peanut allergy, pulmonary fibrosis, celiac disease, alopecia areata, psoriasis, hidradenitis suppurativa or asthma.

[0093] Preferably, the dose of respegaldesleukin during the induction phase comprises 300 μg. Preferably, the dose of respegaldesleukin during the induction phase comprises 450 μg. Preferably, the dose of respegaldesleukin during the induction phase comprises 600 μg. Preferably, the dose of respegaldesleukin during the induction phase comprises 900 μg. Preferably, the dose of respegaldesleukin during the induction phase comprises 1200 μg. Preferably, the dose of respegaldesleukin during the induction phase comprises 1500 μg. Preferably, the dose of respegaldesleukin during the induction phase comprises 1800 μg. Preferably, the dose of respegaldesleukin during the induction phase comprises 2100 μg. Preferably, the dose of respegaldesleukin during the induction phase comprises 2400 μg. Preferably, the dose of respegaldesleukin during the induction phase comprises 2700 μg. Preferably, the dose of respegaldesleukin during the induction phase comprises 3000 μg. Preferably, the dose of respegaldesleukin during the induction phase comprises 3300 μg. Preferably, the dose of respegaldesleukin during the induction phase comprises 3600 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 300 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 450 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 600 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 900 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 1200 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 1500 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 1800 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 2100 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 2400 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 2700 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 3000 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 3300 μg.Preferably, the dose of respegaldesleukin in the maintenance phase comprises 3600 μg. Preferably, the induction dose is administered once every two weeks. Preferably, the induction dose is administered once every four weeks. Preferably, the maintenance dose is administered once every four weeks. Preferably, the maintenance dose is administered once every eight weeks. Preferably, the maintenance dose is administered once every 12 weeks. Preferably, the maintenance dose is administered once every 24 weeks. Preferably, the maintenance dose is administered once every 36 weeks. Preferably, the maintenance dose is administered once every 48 weeks. Preferably, the maintenance dose is administered once every 52 weeks.

[0094] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject respegaldesleukin at a dose of about 1200 μg per dose during an induction phase, the induction phase being carried out once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, or once every 8 weeks; the respegaldesleukin is administered for a total of 12 weeks, a total of 16 weeks, a total of 20 weeks, or wherein the administration is for a total of 24 weeks of administration; followed by a maintenance phase comprising administering to the human subject a dose of respegaldesleukin at about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose, The administration is performed once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 12 weeks, once every 24 weeks, once every 36 weeks, once every 48 weeks, or once every 52 weeks; the administration includes a maintenance phase in which the respegaldesleukin is administered for a total of 4 to 52 weeks or for a total of 1 to 5 years; and the autoimmune disease is systemic lupus erythematosus (SLE), ulcerative colitis, Crohn's disease, rheumatoid arthritis, atopic dermatitis, or the like. The maintenance phase is preferably selected from the group consisting of inflammatory bowel disease, systemic sclerosis, ankylosing spondylitis, graft-versus-host disease, and polymyositis; type 1 diabetes, Addison's disease, Hashimoto's thyroiditis, Graves' disease, Sjögren's syndrome, vitiligo, pernicious anemia, glomerulonephritis, lupus nephritis, myasthenia gravis, Goodpasture's syndrome, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, peanut allergy, pulmonary fibrosis, celiac disease, alopecia areata, psoriasis, hidradenitis suppurativa, and asthma. Preferably, the maintenance phase dose of respegaldesleukin comprises 300 μg. Preferably, the maintenance phase dose of respegaldesleukin comprises 450 μg. Preferably, the maintenance phase dose of respegaldesleukin comprises 600 μg. Preferably, the maintenance phase dose of respegaldesleukin comprises 900 μg. Preferably, the dose of respegaldesleukin in the maintenance phase comprises 1200 μg. Preferably, the dose of respegaldesleukin in the maintenance phase comprises 1500 μg. Preferably, the dose of respegaldesleukin in the maintenance phase comprises 1800 μg.Preferably, the dose of respegaldesleukin during the maintenance phase comprises 2100 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 2400 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 2700 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 3000 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 3300 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 3600 μg. Preferably, the induction dose is administered once every two weeks. Preferably, the induction dose is administered once every four weeks. Preferably, the maintenance dose is administered once every four weeks. Preferably, the maintenance dose is administered once every eight weeks. Preferably, the maintenance dose is administered once every 12 weeks. Preferably, the maintenance dose is administered once every 24 weeks. Preferably, the maintenance dose is administered once every 36 weeks. Preferably, the maintenance dose is administered once every 48 weeks. Preferably, the maintenance dose is administered once every 52 weeks.

[0095] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject respegaldesleukin at a dose of about 1500 μg per dose during an induction phase, the induction phase being carried out once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, or once every 8 weeks; the respegaldesleukin is administered for a total of 12 weeks, a total of 16 weeks, a total of 20 weeks, or wherein the administration is for a total of 24 weeks of administration; followed by a maintenance phase comprising administering to the human subject a dose of respegaldesleukin at about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose, The administration is performed once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 12 weeks, once every 24 weeks, once every 36 weeks, once every 48 weeks, or once every 52 weeks; the administration includes a maintenance phase in which the respegaldesleukin is administered for a total of 4 to 52 weeks or for a total of 1 to 5 years; and the autoimmune disease is systemic lupus erythematosus (SLE), ulcerative colitis, Crohn's disease, rheumatoid arthritis, atopic dermatitis, or the like. The maintenance phase is preferably selected from the group consisting of inflammatory bowel disease, systemic sclerosis, ankylosing spondylitis, graft-versus-host disease, and polymyositis; type 1 diabetes, Addison's disease, Hashimoto's thyroiditis, Graves' disease, Sjögren's syndrome, vitiligo, pernicious anemia, glomerulonephritis, lupus nephritis, myasthenia gravis, Goodpasture's syndrome, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, peanut allergy, pulmonary fibrosis, celiac disease, alopecia areata, psoriasis, hidradenitis suppurativa, and asthma. Preferably, the maintenance phase dose of respegaldesleukin comprises 300 μg. Preferably, the maintenance phase dose of respegaldesleukin comprises 450 μg. Preferably, the maintenance phase dose of respegaldesleukin comprises 600 μg. Preferably, the maintenance phase dose of respegaldesleukin comprises 900 μg. Preferably, the dose of respegaldesleukin in the maintenance phase comprises 1200 μg. Preferably, the dose of respegaldesleukin in the maintenance phase comprises 1500 μg. Preferably, the dose of respegaldesleukin in the maintenance phase comprises 1800 μg.Preferably, the dose of respegaldesleukin during the maintenance phase comprises 2100 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 2400 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 2700 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 3000 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 3300 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 3600 μg. Preferably, the induction dose is administered once every two weeks. Preferably, the induction dose is administered once every four weeks. Preferably, the maintenance dose is administered once every four weeks. Preferably, the maintenance dose is administered once every eight weeks. Preferably, the maintenance dose is administered once every 12 weeks. Preferably, the maintenance dose is administered once every 24 weeks. Preferably, the maintenance dose is administered once every 36 weeks. Preferably, the maintenance dose is administered once every 48 weeks. Preferably, the maintenance dose is administered once every 52 weeks.

[0096] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject respegaldesleukin at a dose of about 1800 μg per dose during an induction phase, the induction phase being carried out once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, or once every 8 weeks; the respegaldesleukin is administered for a total of 12 weeks, a total of 16 weeks, a total of 20 weeks, or wherein the administration is for a total of 24 weeks of administration; followed by a maintenance phase comprising administering to the human subject a dose of respegaldesleukin at about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose, The administration is performed once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 12 weeks, once every 24 weeks, once every 36 weeks, once every 48 weeks, or once every 52 weeks; the administration includes a maintenance phase in which the respegaldesleukin is administered for a total of 4 to 52 weeks or for a total of 1 to 5 years; and the autoimmune disease is systemic lupus erythematosus (SLE), ulcerative colitis, Crohn's disease, rheumatoid arthritis, atopic dermatitis, or the like. The maintenance phase is preferably selected from the group consisting of inflammatory bowel disease, systemic sclerosis, ankylosing spondylitis, graft-versus-host disease, and polymyositis; type 1 diabetes, Addison's disease, Hashimoto's thyroiditis, Graves' disease, Sjögren's syndrome, vitiligo, pernicious anemia, glomerulonephritis, lupus nephritis, myasthenia gravis, Goodpasture's syndrome, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, peanut allergy, pulmonary fibrosis, celiac disease, alopecia areata, psoriasis, hidradenitis suppurativa, and asthma. Preferably, the maintenance phase dose of respegaldesleukin comprises 300 μg. Preferably, the maintenance phase dose of respegaldesleukin comprises 450 μg. Preferably, the maintenance phase dose of respegaldesleukin comprises 600 μg. Preferably, the maintenance phase dose of respegaldesleukin comprises 900 μg. Preferably, the dose of respegaldesleukin in the maintenance phase comprises 1200 μg. Preferably, the dose of respegaldesleukin in the maintenance phase comprises 1500 μg. Preferably, the dose of respegaldesleukin in the maintenance phase comprises 1800 μg.Preferably, the dose of respegaldesleukin during the maintenance phase comprises 2100 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 2400 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 2700 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 3000 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 3300 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 3600 μg. Preferably, the induction dose is administered once every two weeks. Preferably, the induction dose is administered once every four weeks. Preferably, the maintenance dose is administered once every four weeks. Preferably, the maintenance dose is administered once every eight weeks. Preferably, the maintenance dose is administered once every 12 weeks. Preferably, the maintenance dose is administered once every 24 weeks. Preferably, the maintenance dose is administered once every 36 weeks. Preferably, the maintenance dose is administered once every 48 weeks. Preferably, the maintenance dose is administered once every 52 weeks.

[0097] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject respegaldesleukin at a dose of about 2100 μg per dose during an induction phase, the induction phase being carried out once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, or once every 8 weeks; the respegaldesleukin is administered for a total of 12 weeks, a total of 16 weeks, a total of 20 weeks, or wherein the administration is for a total of 24 weeks of administration; followed by a maintenance phase comprising administering to the human subject a dose of respegaldesleukin at about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose, The administration is performed once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 12 weeks, once every 24 weeks, once every 36 weeks, once every 48 weeks, or once every 52 weeks; the administration includes an induction period in which the respegaldesleukin is administered for a total of 4 to 52 weeks or for a total of 1 to 5 years; and the autoimmune disease is systemic lupus erythematosus (SLE), ulcerative colitis, Crohn's disease, rheumatoid arthritis, atopic dermatitis, or the like. The maintenance phase is preferably selected from the group consisting of inflammatory bowel disease, systemic sclerosis, ankylosing spondylitis, graft-versus-host disease, and polymyositis; type 1 diabetes, Addison's disease, Hashimoto's thyroiditis, Graves' disease, Sjögren's syndrome, vitiligo, pernicious anemia, glomerulonephritis, lupus nephritis, myasthenia gravis, Goodpasture's syndrome, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, peanut allergy, pulmonary fibrosis, celiac disease, alopecia areata, psoriasis, hidradenitis suppurativa, and asthma. Preferably, the maintenance phase dose of respegaldesleukin comprises 300 μg. Preferably, the maintenance phase dose of respegaldesleukin comprises 450 μg. Preferably, the maintenance phase dose of respegaldesleukin comprises 600 μg. Preferably, the maintenance phase dose of respegaldesleukin comprises 900 μg. Preferably, the dose of respegaldesleukin in the maintenance phase comprises 1200 μg. Preferably, the dose of respegaldesleukin in the maintenance phase comprises 1500 μg. Preferably, the dose of respegaldesleukin in the maintenance phase comprises 1800 μg.Preferably, the dose of respegaldesleukin during the maintenance phase comprises 2100 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 2400 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 2700 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 3000 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 3300 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 3600 μg. Preferably, the induction dose is administered once every two weeks. Preferably, the induction dose is administered once every four weeks. Preferably, the maintenance dose is administered once every four weeks. Preferably, the maintenance dose is administered once every eight weeks. Preferably, the maintenance dose is administered once every 12 weeks. Preferably, the maintenance dose is administered once every 24 weeks. Preferably, the maintenance dose is administered once every 36 weeks. Preferably, the maintenance dose is administered once every 48 weeks. Preferably, the maintenance dose is administered once every 52 weeks.

[0098] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject respegaldesleukin at a dose of about 2400 μg per dose during an induction phase, the induction phase being carried out once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, or once every 8 weeks; the respegaldesleukin is administered for a total of 12 weeks, a total of 16 weeks, a total of 20 weeks, or wherein the administration is for a total of 24 weeks of administration; followed by a maintenance phase comprising administering to the human subject a dose of respegaldesleukin at about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose, The administration is performed once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 12 weeks, once every 24 weeks, once every 36 weeks, once every 48 weeks, or once every 52 weeks; the administration includes a maintenance phase in which the respegaldesleukin is administered for a total of 4 to 52 weeks or for a total of 1 to 5 years; and the autoimmune disease is systemic lupus erythematosus (SLE), ulcerative colitis, Crohn's disease, rheumatoid arthritis, atopic dermatitis, or the like. The maintenance phase is preferably selected from the group consisting of inflammatory bowel disease, systemic sclerosis, ankylosing spondylitis, graft-versus-host disease, and polymyositis; type 1 diabetes, Addison's disease, Hashimoto's thyroiditis, Graves' disease, Sjögren's syndrome, vitiligo, pernicious anemia, glomerulonephritis, lupus nephritis, myasthenia gravis, Goodpasture's syndrome, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, peanut allergy, pulmonary fibrosis, celiac disease, alopecia areata, psoriasis, hidradenitis suppurativa, and asthma. Preferably, the maintenance phase dose of respegaldesleukin comprises 300 μg. Preferably, the maintenance phase dose of respegaldesleukin comprises 450 μg. Preferably, the maintenance phase dose of respegaldesleukin comprises 600 μg. Preferably, the maintenance phase dose of respegaldesleukin comprises 900 μg. Preferably, the dose of respegaldesleukin in the maintenance phase comprises 1200 μg. Preferably, the dose of respegaldesleukin in the maintenance phase comprises 1500 μg. Preferably, the dose of respegaldesleukin in the maintenance phase comprises 1800 μg.Preferably, the dose of respegaldesleukin during the maintenance phase comprises 2100 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 2400 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 2700 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 3000 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 3300 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 3600 μg. Preferably, the induction dose is administered once every two weeks. Preferably, the induction dose is administered once every four weeks. Preferably, the maintenance dose is administered once every four weeks. Preferably, the maintenance dose is administered once every eight weeks. Preferably, the maintenance dose is administered once every 12 weeks. Preferably, the maintenance dose is administered once every 24 weeks. Preferably, the maintenance dose is administered once every 36 weeks. Preferably, the maintenance dose is administered once every 48 weeks. Preferably, the maintenance dose is administered once every 52 weeks.

[0099] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject respegaldesleukin at a dose of about 2700 μg per dose during an induction phase, the induction phase being carried out once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 6 weeks, or once every 8 weeks; the respegaldesleukin is administered for a total of 12 weeks, a total of 16 weeks, a total of 20 weeks, or wherein the administration is for a total of 24 weeks of administration; followed by a maintenance phase comprising administering to the human subject a dose of respegaldesleukin at about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose, The administration is performed once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 12 weeks, once every 24 weeks, once every 36 weeks, once every 48 weeks, or once every 52 weeks; the administration includes a maintenance phase in which the respegaldesleukin is administered for a total of 4 to 52 weeks or for a total of 1 to 5 years; and the autoimmune disease is systemic lupus erythematosus (SLE), ulcerative colitis, Crohn's disease, rheumatoid arthritis, atopic dermatitis, or the like. The maintenance phase is preferably selected from the group consisting of inflammatory bowel disease, systemic sclerosis, ankylosing spondylitis, graft-versus-host disease, and polymyositis; type 1 diabetes, Addison's disease, Hashimoto's thyroiditis, Graves' disease, Sjögren's syndrome, vitiligo, pernicious anemia, glomerulonephritis, lupus nephritis, myasthenia gravis, Goodpasture's syndrome, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, peanut allergy, pulmonary fibrosis, celiac disease, alopecia areata, psoriasis, hidradenitis suppurativa, and asthma. Preferably, the maintenance phase dose of respegaldesleukin comprises 300 μg. Preferably, the maintenance phase dose of respegaldesleukin comprises 450 μg. Preferably, the maintenance phase dose of respegaldesleukin comprises 600 μg. Preferably, the maintenance phase dose of respegaldesleukin comprises 900 μg. Preferably, the dose of respegaldesleukin in the maintenance phase comprises 1200 μg. Preferably, the dose of respegaldesleukin in the maintenance phase comprises 1500 μg. Preferably, the dose of respegaldesleukin in the maintenance phase comprises 1800 μg.Preferably, the dose of respegaldesleukin during the maintenance phase comprises 2100 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 2400 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 2700 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 3000 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 3300 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 3600 μg. Preferably, the induction dose is administered once every two weeks. Preferably, the induction dose is administered once every four weeks. Preferably, the maintenance dose is administered once every four weeks. Preferably, the maintenance dose is administered once every eight weeks. Preferably, the maintenance dose is administered once every 12 weeks. Preferably, the maintenance dose is administered once every 24 weeks. Preferably, the maintenance dose is administered once every 36 weeks. Preferably, the maintenance dose is administered once every 48 weeks. Preferably, the maintenance dose is administered once every 52 weeks.

[0100] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject respegaldesleukin at a dose of about 3000 μg, about 3300 μg, or about 3600 μg per dose during an induction phase, the induction phase being administered once every two weeks, once every three weeks, once every four weeks, once every six weeks, or once every eight weeks; the respegaldesleukin is administered for a total of 12 weeks for a total of 12 weeks during the induction phase. 6 weeks, a total of 20 weeks, or a total of 24 weeks of administration; followed by a maintenance dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of respegaldesleukin to the human subject. a maintenance phase in which the respegaldesleukin is administered for a total of 4 to 52 weeks or for a total of 1 to 5 years; and the autoimmune disease is systemic lupus erythematosus (SLE), ulcerative colitis, Crohn's disease, rheumatoid arthritis, atopic dermatitis, or the like. The maintenance phase is preferably selected from the group consisting of: inflammatory dermatitis, systemic sclerosis, ankylosing spondylitis, graft-versus-host disease, and polymyositis; type 1 diabetes, Addison's disease, Hashimoto's thyroiditis, Graves' disease, Sjögren's syndrome, vitiligo, pernicious anemia, glomerulonephritis, lupus nephritis, myasthenia gravis, Goodpasture's syndrome, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, peanut allergy, pulmonary fibrosis, celiac disease, alopecia areata, psoriasis, hidradenitis suppurativa, and asthma. Preferably, the maintenance phase dose of respegaldesleukin comprises 300 μg. Preferably, the maintenance phase dose of respegaldesleukin comprises 450 μg. Preferably, the maintenance phase dose of respegaldesleukin comprises 600 μg. Preferably, the maintenance phase dose of respegaldesleukin comprises 900 μg. Preferably, the dose of respegaldesleukin in the maintenance phase comprises 1200 μg. Preferably, the dose of respegaldesleukin in the maintenance phase comprises 1500 μg.Preferably, the dose of respegaldesleukin during the maintenance phase comprises 1800 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 2100 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 2400 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 2700 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 3000 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 3300 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 3600 μg. Preferably, the induction dose is administered once every two weeks. Preferably, the induction dose is administered once every four weeks. Preferably, the maintenance dose is administered once every four weeks. Preferably, the maintenance dose is administered once every eight weeks. Preferably, the maintenance dose is administered once every 12 weeks. Preferably, the maintenance dose is administered once every 24 weeks. Preferably, the maintenance dose is administered once every 36 weeks. Preferably, the maintenance dose is administered once every 48 weeks. Preferably, the maintenance dose is administered once every 52 weeks.

[0101] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of respegaldesleukin during an induction phase, which is administered once every two weeks, once every three weeks, once every four weeks, once every six weeks, or once every eight weeks; a run-in phase administered for a total of 12 weeks, a total of 16 weeks, a total of 20 weeks, or a total of 24 weeks of administration; followed by administering respegaldesleukin to a human subject at a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose; the maintenance phase includes administering respegaldesleukin to a patient once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 12 weeks, once every 24 weeks, once every 36 weeks, once every 48 weeks, or once every 52 weeks; ... The maintenance phase is preferably selected from the group consisting of rheumatoid arthritis, atopic dermatitis, systemic sclerosis, ankylosing spondylitis, graft-versus-host disease, and polymyositis; type 1 diabetes, Addison's disease, Hashimoto's thyroiditis, Graves' disease, Sjögren's syndrome, vitiligo, pernicious anemia, glomerulonephritis, lupus nephritis, myasthenia gravis, Goodpasture's syndrome, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, peanut allergy, pulmonary fibrosis, celiac disease, alopecia areata, psoriasis, hidradenitis suppurativa, and asthma. Preferably, the maintenance phase dose of respegaldesleukin is 300 μg. Preferably, the maintenance phase dose of respegaldesleukin is 450 μg. Preferably, the maintenance phase dose of respegaldesleukin is 600 μg. Preferably, the maintenance phase dose of respegaldesleukin is 900 μg. Preferably, the dose of respegaldesleukin in the maintenance phase comprises 1200 μg. Preferably, the dose of respegaldesleukin in the maintenance phase comprises 1500 μg.Preferably, the dose of respegaldesleukin during the maintenance phase comprises 1800 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 2100 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 2400 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 2700 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 3000 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 3300 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 3600 μg. Preferably, the induction dose is administered once every two weeks. Preferably, the induction dose is administered once every four weeks. Preferably, the maintenance dose is administered once every four weeks. Preferably, the maintenance dose is administered once every eight weeks. Preferably, the maintenance dose is administered once every 12 weeks. Preferably, the maintenance dose is administered once every 24 weeks. Preferably, the maintenance dose is administered once every 36 weeks. Preferably, the maintenance dose is administered once every 48 weeks. Preferably, the maintenance dose is administered once every 52 weeks.

[0102] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject an induction phase of about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of respegaldesleukin, wherein the induction phase is administered for a total of 12 weeks, a total of 16 weeks, a total of 20 weeks, or a total of 24 weeks of administration; followed by a maintenance phase comprising administering to the human subject a dose of about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of respegaldesleukin, wherein the administration is administered for a total of 12 weeks, a total of 16 weeks, a total of 20 weeks, or a total of 24 weeks of administration. the administration is performed once every 6 weeks, once every 8 weeks, once every 12 weeks, once every 24 weeks, once every 36 weeks, once every 48 weeks, or once every 52 weeks; the administration includes a maintenance phase in which the respegaldesleukin is administered for a total of 4 weeks to 52 weeks or for a total of 1 to 5 years; the autoimmune disease is systemic lupus erythematosus (SLE), ulcerative colitis, Crohn's disease, rheumatoid arthritis, atopic dermatitis, allergic rheumatoid arthritis, ... The disease is selected from systemic sclerosis, ankylosing spondylitis, graft-versus-host disease, and polymyositis; type 1 diabetes, Addison's disease, Hashimoto's thyroiditis, Graves' disease, Sjögren's syndrome, vitiligo, pernicious anemia, glomerulonephritis, lupus nephritis, myasthenia gravis, Goodpasture's syndrome, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, peanut allergy, pulmonary fibrosis, celiac disease, alopecia areata, psoriasis, hidradenitis suppurativa, and asthma. Preferably, the dose of respegaldesleukin in the maintenance phase comprises 2100 μg. Preferably, the dose of respegaldesleukin in the maintenance phase comprises 2400 μg. Preferably, the dose of respegaldesleukin in the maintenance phase comprises 2700 μg. Preferably, the dose of respegaldesleukin in the maintenance phase comprises 3000 μg. Preferably, the dose of respegaldesleukin in the maintenance phase comprises 3300 μg. Preferably, the dose of respegaldesleukin in the maintenance phase comprises 3600 μg. Preferably, the induction dose is administered once every two weeks. Preferably, the induction dose is administered once every four weeks.Preferably, the maintenance dose is administered once every 4 weeks. Preferably, the maintenance dose is administered once every 8 weeks. Preferably, the maintenance dose is administered once every 12 weeks. Preferably, the maintenance dose is administered once every 24 weeks. Preferably, the maintenance dose is administered once every 36 weeks. Preferably, the maintenance dose is administered once every 48 weeks. Preferably, the maintenance dose is administered once every 52 weeks.

[0103] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject respegaldesleukin at a dose of about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose during an induction phase, the administration being performed once every two weeks, once every three weeks, once every four weeks, once every six weeks, or once every eight weeks; and administering galdesleukin during said induction phase for a total of 12 weeks, a total of 16 weeks, a total of 20 weeks, or a total of 24 weeks of administration; followed by a maintenance phase comprising administering galdesleukin at a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, or about 1800 μg per dose to the human subject, said administration being for 4 weeks. The administration is performed once a week, once every 6 weeks, once every 8 weeks, once every 12 weeks, once every 24 weeks, once every 36 weeks, once every 48 weeks, or once every 52 weeks; the administration includes a maintenance phase in which the respegaldesleukin is administered for a total of 4 weeks to 52 weeks or for a total of 1 to 5 years; and the autoimmune disease is selected from the group consisting of systemic lupus erythematosus (SLE), ulcerative colitis, Crohn's disease, rheumatoid arthritis, atopic dermatitis, The maintenance phase is preferably selected from systemic sclerosis, ankylosing spondylitis, graft-versus-host disease, and polymyositis; type 1 diabetes, Addison's disease, Hashimoto's thyroiditis, Graves' disease, Sjögren's syndrome, vitiligo, pernicious anemia, glomerulonephritis, lupus nephritis, myasthenia gravis, Goodpasture's syndrome, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, peanut allergy, pulmonary fibrosis, celiac disease, alopecia areata, psoriasis, hidradenitis suppurativa, and asthma. Preferably, the maintenance phase dose of respegaldesleukin is 300 μg. Preferably, the maintenance phase dose of respegaldesleukin is 450 μg. Preferably, the maintenance phase dose of respegaldesleukin is 600 μg. Preferably, the maintenance phase dose of respegaldesleukin is 900 μg. Preferably, the dose of respegaldesleukin in the maintenance phase comprises 1200 μg. Preferably, the dose of respegaldesleukin in the maintenance phase comprises 1500 μg. Preferably, the dose of respegaldesleukin in the maintenance phase comprises 1800 μg.Preferably, the induction dose is administered once every two weeks. Preferably, the induction dose is administered once every four weeks. Preferably, the maintenance dose is administered once every four weeks. Preferably, the maintenance dose is administered once every eight weeks. Preferably, the maintenance dose is administered once every 12 weeks. Preferably, the maintenance dose is administered once every 24 weeks. Preferably, the maintenance dose is administered once every 36 weeks. Preferably, the maintenance dose is administered once every 48 weeks. Preferably, the maintenance dose is administered once every 52 weeks.

[0104] In one embodiment, the disclosure provides a method of treating a human subject having an autoimmune disease, comprising administering to the human subject a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of respegaldesleukin during an induction phase, the method comprising administering to the human subject once every two weeks the respegaldesleukin is administered for a total of 12 weeks, a total of 16 weeks, a total of 20 weeks, or a total of 24 weeks of administration during the run-in phase; followed by administering respegaldesleukin at a dose of about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose to the human subject. the maintenance phase includes administering respegaldesleukin to a patient once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 12 weeks, once every 24 weeks, once every 36 weeks, once every 48 weeks, or once every 52 weeks; ... The maintenance phase is preferably selected from the group consisting of rheumatoid arthritis, atopic dermatitis, systemic sclerosis, ankylosing spondylitis, graft-versus-host disease, and polymyositis; type 1 diabetes, Addison's disease, Hashimoto's thyroiditis, Graves' disease, Sjögren's syndrome, vitiligo, pernicious anemia, glomerulonephritis, lupus nephritis, myasthenia gravis, Goodpasture's syndrome, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, peanut allergy, pulmonary fibrosis, celiac disease, alopecia areata, psoriasis, hidradenitis suppurativa, and asthma. Preferably, the maintenance phase dose of respegaldesleukin is 2400 μg. Preferably, the maintenance phase dose of respegaldesleukin is 2700 μg. Preferably, the maintenance phase dose of respegaldesleukin is 3000 μg. Preferably, the maintenance phase dose of respegaldesleukin is 3300 μg. Preferably, the dose of respegaldesleukin in the maintenance phase comprises 3600 μg. Preferably, the induction dose is administered once every two weeks.Preferably, the induction dose is administered once every 4 weeks. Preferably, the maintenance dose is administered once every 4 weeks. Preferably, the maintenance dose is administered once every 8 weeks. Preferably, the maintenance dose is administered once every 12 weeks. Preferably, the maintenance dose is administered once every 24 weeks. Preferably, the maintenance dose is administered once every 36 weeks. Preferably, the maintenance dose is administered once every 48 weeks. Preferably, the maintenance dose is administered once every 52 weeks.

[0105] For each of the above embodiments, the present disclosure further provides embodiments in which the autoimmune disease is selected from systemic lupus erythematosus (SLE), ulcerative colitis, Crohn's disease, rheumatoid arthritis, atopic dermatitis, systemic sclerosis, ankylosing spondylitis, graft-versus-host disease, and polymyositis; type 1 diabetes, Addison's disease, Hashimoto's thyroiditis, Graves' disease, Sjogren's syndrome, vitiligo, pernicious anemia, glomerulonephritis, lupus nephritis, myasthenia gravis, Goodpasture's syndrome, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, peanut allergy, pulmonary fibrosis, celiac disease, alopecia areata, psoriasis, hidradenitis suppurativa, or asthma.

[0106] In one embodiment, the disclosure provides a method of treating moderate to severe atopic dermatitis in a patient in need thereof, comprising administering respegaldesleukin to a human subject at a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose during an induction phase, wherein the respegaldesleukin is administered for a total of 12 weeks, a total of 16 weeks, a total of 20 weeks, or a total of 24 weeks of administration during the induction phase; determining whether the patient is a responder to respegaldesleukin; and if the patient is a responder, proceeding to a maintenance phase comprising administering to the human subject a dose of respegaldesleukin of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose, wherein the administration occurs once every 2 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 12 weeks, once every 24 weeks, once every 36 weeks, once every 48 weeks, or once every 52 weeks; and wherein the respegaldesleukin is administered for a total of 4 to 52 weeks or for a total of 1 to 5 years of administration. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 300 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 450 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 600 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 900 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 1200 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 1500 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 1800 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 2100 μg.Preferably, the dose of respegaldesleukin during the maintenance phase comprises 2400 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 2700 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 3000 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 3300 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 3600 μg. Preferably, the induction dose is administered once every two weeks. Preferably, the induction dose is administered once every four weeks. Preferably, the maintenance dose is administered once every four weeks. Preferably, the maintenance dose is administered once every eight weeks. Preferably, the maintenance dose is administered once every 12 weeks. Preferably, the maintenance dose is administered once every 24 weeks. Preferably, the maintenance dose is administered once every 36 weeks. Preferably, the maintenance dose is administered once every 48 weeks. Preferably, the maintenance dose is administered once every 52 weeks.

[0107] In one embodiment, the disclosure provides a method of reducing sleep deprivation in a patient with moderate to severe atopic dermatitis in a patient in need thereof, comprising administering respegaldesleukin to a human subject at a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose during a lead-in period, wherein the respegaldesleukin is administered once every week, once every two weeks, once every three weeks, once every four weeks, once every six weeks, or once every eight weeks during the lead-in period; and wherein after the lead-in period, the patient determining whether the patient is a responder to respegaldesleukin; and if the patient is a responder, administering respegaldesleukin at a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose; and advancing to a maintenance phase comprising administering respegaldesleukin to a human subject, said administration occurring once every 2 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 12 weeks, once every 24 weeks, once every 36 weeks, once every 48 weeks, or once every 52 weeks; said respegaldesleukin being administered for a total of 4 to 52 weeks or for a total of 1 to 5 years. Preferably, the dose of respegaldesleukin in the induction phase comprises 300 μg. Preferably, the dose of respegaldesleukin in the induction phase comprises 450 μg. Preferably, the dose of respegaldesleukin in the induction phase comprises 600 μg. Preferably, the dose of respegaldesleukin in the induction phase comprises 900 μg. Preferably, the dose of respegaldesleukin in the induction phase comprises 1200 μg. Preferably, the dose of respegaldesleukin in the induction phase comprises 1500 μg. Preferably, the dose of respegaldesleukin in the induction phase comprises 1800 μg. Preferably, the dose of respegaldesleukin in the induction phase comprises 2100 μg.Preferably, the dose of respegaldesleukin during the induction phase comprises 2400 μg. Preferably, the dose of respegaldesleukin during the induction phase comprises 2700 μg. Preferably, the dose of respegaldesleukin during the induction phase comprises 3000 μg. Preferably, the dose of respegaldesleukin during the induction phase comprises 3300 μg. Preferably, the dose of respegaldesleukin during the induction phase comprises 3600 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 300 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 450 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 600 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 900 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 1200 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 1500 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 1800 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 2100 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 2400 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 2700 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 3000 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 3300 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 3600 μg. Preferably, the induction dose is administered once every two weeks. Preferably, the induction dose is administered once every four weeks. Preferably, the maintenance dose is administered once every four weeks. Preferably, the maintenance dose is administered once every 8 weeks. Preferably, the maintenance dose is administered once every 12 weeks. Preferably, the maintenance dose is administered once every 24 weeks. Preferably, the maintenance dose is administered once every 36 weeks. Preferably, the maintenance dose is administered once every 48 weeks. Preferably, the maintenance dose is administered once every 52 weeks.

[0108] In one embodiment, the disclosure provides a method of treating moderate to severe atopic dermatitis in a patient in need thereof, wherein the patient continues to experience moderate to severe disease after treatment with a topical corticosteroid, a topical calcineurin inhibitor or crisaborole, or a topical JAK inhibitor, systemic steroid, cyclosporine, biologic therapy (i.e., targeting the IL-4 / 13 pathway), an oral JAK inhibitor, and / or a topical PDE4 inhibitor; or wherein JAK inhibitors and / or topical PDE4 inhibitors, systemic steroids, cyclosporine, biologic therapy (i.e., targeting the IL-4 / 13 pathway), and oral JAK inhibitors are medically inadvisable for the patient, and the method comprises administering respegaldesleukin to a human subject at a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose during an induction phase; once every week, once every two weeks, once every three weeks, once every four weeks, once every six weeks, or once every eight weeks; wherein the respegaldesleukin is administered for a total of 12 weeks, a total of 16 weeks, a total of 20 weeks, or a total of 24 weeks of administration during the lead-in period; followed by administration of respegaldesleukin at a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose. a maintenance phase comprising administering respegaldesleukin to a human subject, said administration occurring once every 2 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 12 weeks, once every 24 weeks, once every 36 weeks, once every 48 weeks, or once every 52 weeks; an induction phase wherein said respegaldesleukin is administered for a total of 4 to 52 weeks or for a total of 1 to 5 years; said autoimmune disease being systemic lupus erythematosus (SLE), ulcerative colitis, Crohn's disease, rheumatoid arthritis, atopic dermatitis, systemic sclerosis, ankylosing spondylitis, graft-versus-host disease, and polymyositis;The disease is selected from type 1 diabetes, Addison's disease, Hashimoto's thyroiditis, Graves' disease, Sjogren's syndrome, vitiligo, pernicious anemia, glomerulonephritis, lupus nephritis, myasthenia gravis, Goodpasture's syndrome, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, peanut allergy, pulmonary fibrosis, celiac disease, alopecia areata, psoriasis, hidradenitis suppurativa, and asthma. Preferably, the dose of respegaldesleukin in the maintenance phase comprises 300 μg. Preferably, the dose of respegaldesleukin in the maintenance phase comprises 450 μg. Preferably, the dose of respegaldesleukin in the maintenance phase comprises 600 μg. Preferably, the dose of respegaldesleukin in the maintenance phase comprises 900 μg. Preferably, the dose of respegaldesleukin in the maintenance phase comprises 1200 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 1500 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 1800 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 2100 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 2400 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 2700 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 3000 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 3300 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 3600 μg. Preferably, the induction dose is administered once every two weeks. Preferably, the induction dose is administered once every four weeks. Preferably, the maintenance dose is administered once every four weeks. Preferably, the maintenance dose is administered once every 8 weeks. Preferably, the maintenance dose is administered once every 12 weeks. Preferably, the maintenance dose is administered once every 24 weeks. Preferably, the maintenance dose is administered once every 36 weeks. Preferably, the maintenance dose is administered once every 48 weeks. Preferably, the maintenance dose is administered once every 52 weeks.

[0109] In other embodiments, the present disclosure provides a method of treating an autoimmune disease identified herein in a patient in need thereof, wherein the patient continues to experience clinical disease symptoms after treatment with an existing standard of care or the patient is intolerant to an existing standard of care, the method comprising administering an induction phase of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg or about 3600 μg per dose. administering to a human subject a dose of respegaldesleukin at about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, or about 300 μg per dose, wherein the respegaldesleukin is administered once every week, once every two weeks, once every three weeks, once every four weeks, once every six weeks, or once every eight weeks; wherein the respegaldesleukin is administered for a total of 12 weeks, a total of 16 weeks, a total of 20 weeks, or a total of 24 weeks of administration during the induction phase; followed by administration of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, or about 300 μg per dose; a maintenance phase comprising administering to a human subject respegaldesleukin at a dose of about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg, wherein said administration occurs once every 2 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 12 weeks, once every 24 weeks, once every 36 weeks, once every 48 weeks, or once every 52 weeks; an induction phase wherein said respegaldesleukin is administered for a total of 4 to 52 weeks of administration or for a total of 1 to 5 years of administration; is selected from systemic lupus erythematosus (SLE), ulcerative colitis, Crohn's disease, rheumatoid arthritis, atopic dermatitis, systemic sclerosis, ankylosing spondylitis, graft-versus-host disease, and polymyositis; type 1 diabetes, Addison's disease, Hashimoto's thyroiditis, Graves' disease, Sjogren's syndrome, vitiligo, pernicious anemia, glomerulonephritis, lupus nephritis, myasthenia gravis, Goodpasture's syndrome, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, peanut allergy, pulmonary fibrosis, celiac disease, alopecia areata, psoriasis, hidradenitis suppurativa, and asthma. Preferably, the dose of respegaldesleukin in the maintenance phase comprises 300 μg. Preferably, the dose of respegaldesleukin in the maintenance phase comprises 450 μg.Preferably, the dose of respegaldesleukin during the maintenance phase comprises 600 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 900 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 1200 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 1500 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 1800 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 2100 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 2400 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 2700 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 3000 μg. Preferably, the dose of respegaldesleukin in the maintenance phase comprises 3300 μg. Preferably, the dose of respegaldesleukin in the maintenance phase comprises 3600 μg. Preferably, the induction dose is administered once every two weeks. Preferably, the induction dose is administered once every four weeks. Preferably, the maintenance dose is administered once every four weeks. Preferably, the maintenance dose is administered once every eight weeks. Preferably, the maintenance dose is administered once every 12 weeks. Preferably, the maintenance dose is administered once every 24 weeks. Preferably, the maintenance dose is administered once every 36 weeks. Preferably, the maintenance dose is administered once every 48 weeks. Preferably, the maintenance dose is administered once every 52 weeks.

[0110] A preferred embodiment of the present disclosure includes a method for treating moderate to severe atopic dermatitis comprising a respegaldesleukin dosing regimen. Determining whether a patient with moderate to severe atopic dermatitis is a responder to respegaldesleukin can be assessed by evaluating the patient's skin clearance, skin improvement, and / or improvement in itch, sleep, or quality of life. For example, skin clearance can be measured by the Investigator's Global Assessment (IGA) or Eczema Area and Severity Index (EASI) score. Itch, sleep deprivation, and quality of life can be measured by the Pruritus Numeric Rating Scale (NRS), sleep deprivation score, and DLQI (Dermatology Life Quality Index) or CDLQI (Pediatric Dermatology Life Quality Index) scale, respectively. In some embodiments, a patient is a responder if the patient's EASI score, determined after the run-in period, is reduced by 75% or more compared to the patient's EASI score at baseline. In some embodiments, a patient is a responder if the patient's IGA score after the run-in period is 0 or 1. In some embodiments, if the patient's IGA score after the run-in period is 0 or 1 and the patient's IGA score determined after the run-in period is reduced by 2 or more points compared to the patient's IGA score at baseline, the patient is a responder. In some embodiments, if the atopic dermatitis patient is a responder, respegaldesleukin is administered at about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose once every 4 weeks during the maintenance period. In some embodiments, respegaldesleukin is administered to the patient subcutaneously.

[0111] In some embodiments, the patient has moderate to severe atopic dermatitis for at least one year at baseline. Moderate to severe atopic dermatitis can be determined by criteria known in the art, such as the American Academy of Dermatology consensus criteria for chronic atopic dermatitis. In some embodiments, the patient has an EASI score of 16 or greater, an IGA score of 3 or greater, and more than 10% of their body surface area (BSA) is affected by atopic dermatitis at baseline. In some embodiments, the patient has an inadequate response to topical corticosteroids, topical calcineurin inhibitors, or crisaborole; or topical corticosteroids, topical calcineurin inhibitors, or crisaborole are medically inadvisable for the patient.

[0112] In each of the embodiments described herein for the treatment of atopic dermatitis, atopic dermatitis patients treated with respegaldesleukin are either 1) previously untreated with a biologic containing an antibody against IL-4 / IL-13 and / or IL-31, such as, but not limited to, dupilumab, lebrikizumab, or tralokinumab, or 2) previously treated with such a biologic. As used herein, the term "biologic-experienced atopic dermatitis patient" refers to a patient who has previously been treated with one or more antibody therapeutics targeting IL-4 / IL-13 and / or IL-31. Treatment with these agents is well known to those skilled in the art (see, e.g., Vikram N. Sahni, et al., (2022), The evolving atopic dermatitis management landscape, Expert Opinion on Pharmacotherapy, 23:4, 517-526). In each of the embodiments described herein for the treatment of atopic dermatitis, patients treated with respegaldesleukin are either 1) naive to treatment with a PDE4 inhibitor or a Janus kinase (JAK) inhibitor, such as, but not limited to, abrocitinib, baricitinib, or upadacitinib, or 2) patients who have previously been treated with such a treatment. As used herein, the term "JAK inhibitor-experienced atopic dermatitis patient" refers to a patient who has previously been treated with one or more JAK inhibitors. In one embodiment, patients treated for moderate to severe atopic dermatitis are patients who have not previously been treated with a biologic agent for atopic dermatitis. In one embodiment, patients treated for moderate to severe atopic dermatitis are biologic-experienced patients, which, as used herein, refers to patients who have previously been treated with a biologic agent for atopic dermatitis.As used herein, a biologic-experienced atopic dermatitis patient is one who has previously received one or more courses of treatment with an antibody, including, for example, dupilumab, tralokinumab, lebrikizumab, nemolizumab, eburusakimab, or sendakimab. In one embodiment, a patient treated for moderate to severe atopic dermatitis is JAK-experienced, which as used herein means a patient who has previously received one or more treatments with a JAK inhibitor for atopic dermatitis, such as, for example, baricitinib, upadacinib, or abrocitinib.

[0113] Because patients who have been treated with these biological or small molecule therapies may or may not have any significant efficacy, or may find that the efficacy of these agents diminishes over time to the extent that alternative and / or more effective treatments are needed, respegaldesleukin is believed to provide efficacy for these patients due to its distinct mechanism of action, which results in the stimulation of Treg cells. Methods for assessing the unmet needs of patients with atopic dermatitis are well known to those skilled in the art and are described herein. Patients in need of respegaldesleukin treatment as described herein may be identified as patients who continue to have mild, moderate, or severe atopic dermatitis after receiving treatment with other biological or small molecule therapies for atopic dermatitis. According to embodiments provided herein, atopic dermatitis patients require treatment with respegaldesleukin if previous atopic dermatitis treatments have not provided adequate relief of disease symptoms as described herein or have provided only low or insufficient relief. The embodiments described herein for treating atopic dermatitis with respegaldesleukin dosing regimens and formulations may offer various advantages, such as increased efficacy responses and / or improved safety profiles with respect to the risk of adverse effects. The embodiments provided herein provide a means for treating biologic-experienced atopic dermatitis patients with induction and maintenance regimens, and each embodiment for treating atopic dermatitis is understood to represent the treatment of either biologic-naive or biologic-experienced patients, or both. The atopic dermatitis patient studies described herein can be modified to include biologic-experienced atopic dermatitis patients, e.g., with a study population consisting of, for example, 75% biologic-experienced atopic dermatitis patients (e.g., dupilumab-experienced patients) and 25% biologic-naive atopic dermatitis patients. The number and ratio of the aforementioned groups can be varied based on the desired study design.

[0114] The embodiments provided herein provide a means for treating JAK inhibitor-experienced atopic dermatitis patients with induction and maintenance dosing regimens, and each embodiment for the treatment of atopic dermatitis is understood to represent the treatment of either biologic-naive or JAK inhibitor-experienced atopic dermatitis patients, or both. The atopic dermatitis patient studies described herein can be modified to include JAK inhibitor-experienced atopic dermatitis patients, e.g., study subjects comprised of, for example, 75% JAK inhibitor-experienced atopic dermatitis patients (e.g., abrocitinib or upadacitinib) and 25% JAK-naive atopic dermatitis patients. The number and ratio of the aforementioned groups can be varied based on the desired study design.

[0115] In some embodiments, the methods described herein further comprise determining one or more of the following characteristics of the patient at baseline and during and after the run-in period: EASI score; IGA score; percentage of BSA affected by atopic dermatitis; pruritus NRS score; SCORAD (Severity Assessment of Atopic Dermatitis) score; sleep deprivation score; POEM (Patient Thoughts on Eczema Measure) total score; DLQI (Dermatology Life Quality Index) or CDLQI (Paediatric Dermatology Life Quality Index) score; EQ-5D (European Quality of Life Scale); ACQ-5 (Asthma Control Questionnaire-5); PROMIS (Patient Reported Outcomes Measurement Information System) anxiety and depression symptoms.

[0116] In some embodiments, the methods described herein further include determining one or more of the following characteristics of the patient during and after the maintenance period: EASI score; IGA score; percentage of BSA affected by atopic dermatitis; pruritus NRS score; SCORAD score; sleep deprivation score; POEM total score; DLQI or CDLQI score; EQ-5D; ACQ-5; PROMIS anxiety and depression symptoms.

[0117] In another aspect, provided herein are methods of reducing sleep deprivation in a patient with moderate to severe atopic dermatitis, such methods comprising administering respegaldesleukin to a human subject at a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose during an induction phase, wherein the respegaldesleukin is administered once every week, once every two weeks, once every three weeks, once every four weeks, once every six weeks, or once every eight weeks for a total of 12 weeks, a total of 16 weeks, a total of 20 weeks, or a total of 24 weeks during the induction phase. followed by a maintenance phase comprising administering to a human subject a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of respegaldesleukin, wherein said administration occurs once every 2 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 12 weeks, once every 24 weeks, once every 36 weeks, once every 48 weeks, or once every 52 weeks; wherein said respegaldesleukin is administered for a total of 4 to 52 weeks of administration or for a total of 1 to 5 years of administration.

[0118] In some embodiments, sleep deprivation is determined by the patient's sleep deprivation score. In some embodiments, the patient's sleep deprivation score after treatment with respegaldesleukin is reduced by 2 or more points compared to the patient's sleep score at baseline.

[0119] Further provided herein are methods for reducing sleep deprivation in a patient with moderate to severe atopic dermatitis, such methods comprising administering respegaldesleukin to a human subject at a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose during an induction period, wherein the respegaldesleukin is administered for a total of 12 weeks, a total of 16 weeks, a total of 20 weeks, or a total of 24 weeks of administration during the induction period; and determining whether the patient is a responder to respegaldesleukin; and if the patient is a responder, administering respegaldesleukin to the human subject at a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose once every 2 weeks, 4 weeks, 6 weeks, 8 weeks, 12 weeks, 24 weeks, 36 weeks, 48 ​​weeks, or 52 weeks; wherein the respegaldesleukin is administered for a total of 4 to 52 weeks or for a total of 1 to 5 years. In some embodiments, sleep deprivation is determined by the patient's sleep deprivation score. In some embodiments, the patient's sleep deprivation score after treatment with respegaldesleukin is reduced by 2 or more points compared to the patient's sleep score at baseline.

[0120] Embodiments of the uses and formulations and dosing regimens of respegaldesleukin provided herein for increasing the survival and efficacy of autologous Treg therapy: Treg therapy has shown promise in early clinical trials for the treatment of graft-versus-host disease, transplant rejection, and autoimmune diseases; however, isolating sufficiently pure Tregs and expanding them to clinical doses has been a challenge (K.N. MacDonald, et al., Methods to manufacture regulatory T cells for cell therapy Clinical and Experimental Immunology, 197:52-63). Various production protocols have been tested in clinical trials and are well known to those skilled in the art, as summarized by MacDonald et al. Methods used to produce Tregs for administration to patients undergoing treatment for graft-versus-host disease, transplant rejection, and / or autoimmune diseases are well known to those skilled in the art, including the selection of cell sources for Treg therapy and protocols for cell isolation and expansion (see, e.g., K.N. MacDonald, et al., Methods to manufacture regulatory T cells for cell therapy Clinical and Experimental Immunology, 197:52-63). Furthermore, methods for treating inflammatory diseases and conditions by the preparation and / or administration of Treg / Th2 hybrid cells from autologous Tregs and / or dedifferentiated T cells (from the diseased subject) are also described in the art, for example in WO2021231797 A1.

[0121] Despite advances in short-term graft survival, long-term graft survival remains a major challenge, given the increased mortality and morbidity associated with chronic rejection and the toxicity of immunosuppressants. Novel and safe approaches are also needed to extend graft survival in transplant recipients (see AH Mansourabadi et al., Cell therapy in transplantation: A comprehensive review of the current applications of cell therapy in transplant patients with focus on Tregs, CAR Tregs, and mesenchymal stem cells, (2021), International Immunopharmacology 97:107669). Suppressing immune responses through the number and / or activity of polyclonal Tregs and / or antigen-specific Tregs (e.g., those engineered with chimeric antigen receptors (CAR Tregs)) is yet another concept of the present disclosure, in which respegaldesleukin is used to promote the survival, proliferation, and / or activity of these cells in recipients for organ transplant applications. The use of respegaldesleukin administered according to the induction and maintenance regimens described herein is believed to induce or promote tolerance and suppress undesirable immune and / or inflammatory responses by resulting in increased survival, proliferation, and / or Treg activity of cellular Treg therapy transplanted into patients with graft-versus-host disease, transplant rejection, and / or autoimmune disease. The clinical trials and results described herein provide evidence of Treg stimulation and proliferation and alleviation of autoimmune and / or inflammatory symptoms, and support the use of respegaldesleukin therapy as a means of promoting prolonged survival and / or proliferation of autologous Treg cell therapy and / or treating graft-versus-host disease and / or transplant rejection.

[0122] In embodiments of the present disclosure, respegaldesleukin and formulations and compositions thereof described herein are used as a method of cellular Treg therapy, as an adjunct to or in combination with various ex vivo Treg preparations for transplantation or administration to patients with graft-versus-host disease, transplant rejection, and / or autoimmune disease. In other embodiments, respegaldesleukin and formulations and compositions thereof described herein are used to stimulate endogenous Tregs in the recipient for the treatment of graft-versus-host disease and / or transplant rejection.

[0123] In one embodiment, the present disclosure provides the use of respegaldesleukin for the treatment of a patient receiving autologous Treg cell therapy for the purposes of treating graft-versus-host disease, transplant rejection, and autoimmune diseases, wherein the respegaldesleukin treatment promotes the prolongation of survival and / or expansion of the autologous Treg cell therapy received by the patient.

[0124] In one embodiment, the present disclosure provides a method of separate, simultaneous, or sequential combination therapy involving administration of cellular Tregs to a patient in need thereof, such as a graft-versus-host disease, transplant recipient, and / or patient with an autoimmune disease, comprising administering a single dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 240 μg, or about 300 μg per dose in an induction phase. administering to a human subject a dose of respegaldesleukin at about 0 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg once every week, once every two weeks, once every three weeks, once every four weeks, once every six weeks, or once every eight weeks; wherein the respegaldesleukin is administered for a total of 12 weeks, a total of 16 weeks, a total of 20 weeks, or a total of 24 weeks of administration during the lead-in period. administering a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose; and proceeding to a maintenance phase comprising administering to the human subject a dose of respegaldesleukin of 300 μg or more, said administration occurring once every 2 weeks, 4 weeks, 6 weeks, 8 weeks, 12 weeks, 24 weeks, 36 weeks, 48 ​​weeks, or 52 weeks; said respegaldesleukin being administered for a total of 4 to 52 weeks or for a total of 1 to 5 years. Preferably, the dose of respegaldesleukin in the induction phase comprises 300 μg. Preferably, the dose of respegaldesleukin in the induction phase comprises 450 μg. Preferably, the dose of respegaldesleukin in the induction phase comprises 600 μg. Preferably, the dose of respegaldesleukin in the induction phase comprises 900 μg. Preferably, the dose of respegaldesleukin in the induction phase comprises 1200 μg. Preferably, the dose of respegaldesleukin in the induction phase comprises 1500 μg. Preferably, the dose of respegaldesleukin in the induction phase comprises 1800 μg.Preferably, the dose of respegaldesleukin during the induction phase comprises 2100 μg. Preferably, the dose of respegaldesleukin during the induction phase comprises 2400 μg. Preferably, the dose of respegaldesleukin during the induction phase comprises 2700 μg. Preferably, the dose of respegaldesleukin during the induction phase comprises 3000 μg. Preferably, the dose of respegaldesleukin during the induction phase comprises 3300 μg. Preferably, the dose of respegaldesleukin during the induction phase comprises 3600 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 300 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 450 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 600 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 900 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 1200 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 1500 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 1800 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 2100 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 2400 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 2700 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 3000 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 3300 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 3600 μg. Preferably, the induction dose is administered once every two weeks. Preferably, the induction dose is administered once every 4 weeks. Preferably, the maintenance dose is administered once every 4 weeks. Preferably, the maintenance dose is administered once every 8 weeks. Preferably, the maintenance dose is administered once every 12 weeks. Preferably, the maintenance dose is administered once every 24 weeks. Preferably, the maintenance dose is administered once every 36 weeks. Preferably, the maintenance dose is administered once every 48 weeks. Preferably, the maintenance dose is administered once every 52 weeks. Preferably, the patient has or is at risk of graft-versus-host disease.Preferably, the patient is a transplant recipient. Preferably, the patient has an autoimmune disease.

[0125] In one embodiment, the disclosure provides a method of treating a patient having or at risk of graft-versus-host disease in a patient in need thereof, comprising administering respegaldesleukin to a human subject at a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose during an induction phase, wherein the respegaldesleukin is administered for a total of 12 weeks, a total of 16 weeks, a total of 20 weeks, or a total of 24 weeks of administration during the induction phase; and determining whether the patient is a responder to respegaldesleukin; and if the patient is a responder, administering respegaldesleukin at a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose; and advancing to a maintenance phase comprising administering respegaldesleukin to a human subject, said administration occurring once every 2 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 12 weeks, once every 24 weeks, once every 36 weeks, once every 48 weeks, or once every 52 weeks; said respegaldesleukin being administered for a total of 4 to 52 weeks or for a total of 1 to 5 years. Preferably, the dose of respegaldesleukin in the induction phase comprises 300 μg. Preferably, the dose of respegaldesleukin in the induction phase comprises 450 μg. Preferably, the dose of respegaldesleukin in the induction phase comprises 600 μg. Preferably, the dose of respegaldesleukin in the induction phase comprises 900 μg. Preferably, the dose of respegaldesleukin in the induction phase comprises 1200 μg. Preferably, the dose of respegaldesleukin in the induction phase comprises 1500 μg. Preferably, the dose of respegaldesleukin in the induction phase comprises 1800 μg. Preferably, the dose of respegaldesleukin in the induction phase comprises 2100 μg.Preferably, the dose of respegaldesleukin during the induction phase comprises 2400 μg. Preferably, the dose of respegaldesleukin during the induction phase comprises 2700 μg. Preferably, the dose of respegaldesleukin during the induction phase comprises 3000 μg. Preferably, the dose of respegaldesleukin during the induction phase comprises 3300 μg. Preferably, the dose of respegaldesleukin during the induction phase comprises 3600 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 300 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 450 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 600 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 900 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 1200 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 1500 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 1800 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 2100 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 2400 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 2700 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 3000 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 3300 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 3600 μg. Preferably, the induction dose is administered once every two weeks. Preferably, the induction dose is administered once every four weeks. Preferably, the maintenance dose is administered once every four weeks. Preferably, the maintenance dose is administered once every 8 weeks. Preferably, the maintenance dose is administered once every 12 weeks. Preferably, the maintenance dose is administered once every 24 weeks. Preferably, the maintenance dose is administered once every 36 weeks. Preferably, the maintenance dose is administered once every 48 weeks. Preferably, the maintenance dose is administered once every 52 weeks. Preferably, the patient has or is at risk of graft-versus-host disease. Preferably, the patient is a transplant recipient. Preferably, the patient has an autoimmune disease.

[0126] In one embodiment, the present disclosure provides the use of respegaldesleukin for the treatment of a patient undergoing a transplant, such as a hematopoietic stem cell transplant, where respegaldesleukin treatment stimulates the proliferation and / or activity of transplant recipient Tregs to induce tolerance (see Copsel SN, et al (2022), Recipient Tregs: Can They Be Exploited for Successful Hematopoietic Stem Cell Transplant Outcomes?, Front. Immunol. 13:932527). Tregs comprise a non-redundant regulatory compartment that maintains self-tolerance, which has been found to be useful in the treatment of autoimmune diseases and transplants, including allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although treatment of patients with low-dose IL-2 administration several months after HSCT has shown promise, manipulation of Tregs in recipients early after transplant has been challenging, likely in part as an indirect result of damage to the microenvironment necessary to support Treg proliferation, which is poorly understood (see Copsel SN, et al.). Means for manipulating recipient Tregs in vivo before and after HSCT are needed, and embodiments of the present invention provide the use of respegaldesleukin to induce tolerance and improve HSCT outcomes by promoting Treg survival, proliferation, and / or activity. Administration of respegaldesleukin can be used to stimulate endogenous recipient Tregs or autologous Tregs co-administered to the recipient. Methods for preparing and using Tregs (optionally including natural killer (NK) cells) capable of suppressing immune responses to donor alloantigens or autoantigens to promote allograft acceptance and treat autoimmune diseases in transplant recipients are described in WO2020123825 A1. Treg or mixed populations of Treg and NK cells are derived from a subject's blood cells and can reduce or replace the use of broad acting immunosuppressive drugs.Methods for treating or preventing GvHD in transplant patients by administering autologous Treg cells to the patient are well known to those skilled in the art and are described, for example, in WO2020095284 A1.

[0127] Chimeric antigen receptor regulatory T cells (CAR-Tregs) generally exhibit limited persistence after administration to patients. Methods for preparing and using CAR-Tregs are described, for example, in International Publication No. WO 2019241549 A1. In one embodiment, the present disclosure provides the use of respegaldesleukin for the treatment of a patient undergoing chimeric antigen receptor regulatory T cell therapy, wherein respegaldesleukin treatment promotes the prolongation of survival and / or proliferation of the chimeric antigen receptor regulatory T cell therapy received by the patient.

[0128] The present disclosure provides a method of administration, individual, simultaneous or sequential combination therapy with cellular Tregs, NK cells or chimeric antigen receptor regulatory T cells (CAR-Tregs), or mixtures thereof, to patients with graft-versus-host disease, transplant recipients and / or autoimmune diseases in a patient in need thereof, comprising administering a single dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, or about 2000 μg per dose during an induction phase. Administering respegaldesleukin at a dose of about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg to a human subject, wherein the respegaldesleukin is administered once every week, once every two weeks, once every three weeks, once every four weeks, once every six weeks, or once every eight weeks for a total of 12 weeks, a total of 16 weeks, a total of 20 weeks, or a total of 24 weeks during the induction phase. administering a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose; and advancing to a maintenance phase comprising administering a 600 μg dose of respegaldesleukin to the human subject, said administration occurring once every 2 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 12 weeks, once every 24 weeks, once every 36 weeks, once every 48 weeks, or once every 52 weeks; said respegaldesleukin being administered for a total of 4 to 52 weeks or for a total of 1 to 5 years. Preferably, the dose of respegaldesleukin in the induction phase comprises 300 μg. Preferably, the dose of respegaldesleukin in the induction phase comprises 450 μg. Preferably, the dose of respegaldesleukin in the induction phase comprises 600 μg. Preferably, the dose of respegaldesleukin in the induction phase comprises 900 μg. Preferably, the dose of respegaldesleukin in the induction phase comprises 1200 μg. Preferably, the dose of respegaldesleukin in the induction phase comprises 1500 μg.Preferably, the dose of respegaldesleukin during the induction phase comprises 1800 μg. Preferably, the dose of respegaldesleukin during the induction phase comprises 2100 μg. Preferably, the dose of respegaldesleukin during the induction phase comprises 2400 μg. Preferably, the dose of respegaldesleukin during the induction phase comprises 2700 μg. Preferably, the dose of respegaldesleukin during the induction phase comprises 3000 μg. Preferably, the dose of respegaldesleukin during the induction phase comprises 3300 μg. Preferably, the dose of respegaldesleukin during the induction phase comprises 3600 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 300 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 450 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 600 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 900 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 1200 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 1500 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 1800 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 2100 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 2400 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 2700 μg. Preferably, the dose of respegaldesleukin during the maintenance phase comprises 3000 μg. Preferably, the dose of respegaldesleukin in the maintenance phase comprises 3300 μg. Preferably, the dose of respegaldesleukin in the maintenance phase comprises 3600 μg. Preferably, the induction dose is administered once every two weeks. Preferably, the induction dose is administered once every four weeks. Preferably, the maintenance dose is administered once every four weeks. Preferably, the maintenance dose is administered once every eight weeks. Preferably, the maintenance dose is administered once every 12 weeks. Preferably, the maintenance dose is administered once every 24 weeks. Preferably, the maintenance dose is administered once every 36 weeks. Preferably, the maintenance dose is administered once every 48 weeks. Preferably, the maintenance dose is administered once every 52 weeks.Preferably, the patient has or is at risk of graft-versus-host disease. Preferably, the patient is a transplant recipient. Preferably, the patient has an autoimmune disease. Preferably, the cell therapy comprises Treg cells and NK cells. Preferably, the cell therapy comprises chimeric antigen receptor regulatory T cells (CAR-Treg).

[0129] In each of the induction and maintenance embodiments described above, preferably the respegaldesleukin composition administered is replaced with a composition defined by one of the compositions of formulae A-F below.

[0130] Composition of Formula A: This composition comprises, on a molar basis, about 5 mole percent or less of mono-PEGylated IL-2 conjugates, about 28 mole percent to about 60 mole percent of di-PEGylated IL-2 conjugates, about 24 mole percent to about 65 mole percent of tri-PEGylated IL-2 conjugates, and about 12 mole percent or less of higher-PEGylated IL-2 conjugates, wherein each branched polyethylene glycol moiety has a nominal average molecular weight of about 20,000 daltons.

[0131] Composition of Formula A: The composition comprises, on a molar basis, about 5 mole percent or less of mono-PEGylated IL-2 conjugates, about 28 mole percent to about 60 mole percent of di-PEGylated IL-2 conjugates, about 24 mole percent to about 65 mole percent of tri-PEGylated IL-2 conjugates, and about 12 mole percent or less of higher-PEGylated IL-2 conjugates, wherein each branched polyethylene glycol moiety has a nominal average molecular weight of about 20,000 daltons, and the composition further comprises a formulation of 5 mM sodium acetate, 25 mM sodium chloride, and 7.5% (w / v) sucrose at pH 5.0.

[0132] Composition of Formula B: This composition comprises, on a molar basis, about 2.5 mole percent to about 4.5 mole percent of a mono-PEGylated IL-2 conjugate, about 35 mole percent to about 50 mole percent of a di-PEGylated IL-2 conjugate, about 38 mole percent to about 46 mole percent of a tri-PEGylated IL-2 conjugate, and about 3 mole percent to about 10 mole percent of a higher order PEGylated IL-2 conjugate, wherein each branched polyethylene glycol moiety has a nominal average molecular weight of about 20,000 daltons.

[0133] Composition of Formula B: This composition comprises, on a molar basis, about 2.5 mole percent to about 4.5 mole percent of a mono-PEGylated IL-2 conjugate, about 35 mole percent to about 50 mole percent of a di-PEGylated IL-2 conjugate, about 38 mole percent to about 46 mole percent of a tri-PEGylated IL-2 conjugate, and about 3 mole percent to about 10 mole percent of a higher-PEGylated IL-2 conjugate, wherein each branched polyethylene glycol moiety has a nominal average molecular weight of about 20,000 daltons, and the composition further comprises a formulation of 5 mM sodium acetate, 25 mM sodium chloride, and 7.5% (w / v) sucrose at pH 5.0.

[0134] Composition of Formula C: This composition comprises, on a molar basis, about 2.8 mole percent to about 3.8 mole percent mono-PEGylated IL-2 conjugate, about 44 mole percent to about 48 mole percent di-PEGylated IL-2 conjugate, about 41 mole percent to about 44 mole percent tri-PEGylated IL-2 conjugate, and about 7 mole percent to about 9 mole percent higher order PEGylated IL-2 conjugate, wherein each branched polyethylene glycol moiety has a nominal average molecular weight of about 20,000 daltons.

[0135] Composition of Formula C: This composition comprises, on a molar basis, about 2.8 mole percent to about 3.8 mole percent of a mono-PEGylated IL-2 conjugate, about 44 mole percent to about 48 mole percent of a di-PEGylated IL-2 conjugate, about 41 mole percent to about 44 mole percent of a tri-PEGylated IL-2 conjugate, and about 7 mole percent to about 9 mole percent of a higher-PEGylated IL-2 conjugate, wherein the nominal average molecular weight of each branched polyethylene glycol moiety is about 20,000 daltons; the composition further comprises a formulation of 5 mM sodium acetate, 25 mM sodium chloride, and 7.5% (w / v) sucrose at pH 5.0.

[0136] Composition of Formula D: This composition comprises, on a molar basis, about 2.8 mole percent to about 3.8 mole percent of a mono-PEGylated IL-2 conjugate, about 44 mole percent to about 48 mole percent of a di-PEGylated IL-2 conjugate, about 41 mole percent to about 44 mole percent of a tri-PEGylated IL-2 conjugate, and about 7 mole percent to about 9 mole percent of a higher order PEGylated IL-2 conjugate, wherein the composition comprises a mixture of mono-PEGylated IL-2 conjugates having a PEG moiety attached at one of lysines K7, or K8, or K31, or K75, and wherein each branched polyethylene glycol moiety has a nominal average molecular weight of about 20,000 daltons.

[0137] Composition of Formula D: This composition comprises, on a molar basis, about 2.8 mole percent to about 3.8 mole percent of mono-PEGylated IL-2 conjugates, about 44 mole percent to about 48 mole percent of di-PEGylated IL-2 conjugates, about 41 mole percent to about 44 mole percent of tri-PEGylated IL-2 conjugates, and about 7 mole percent to about 9 mole percent of higher order PEGylated IL-2 conjugates, said composition comprising a mixture of mono-PEGylated IL-2 conjugates having a PEG moiety attached at one of lysines K7, or K8, or K31, or K75, wherein each branched polyethylene glycol moiety has a nominal average molecular weight of about 20,000 daltons; the composition further comprises a formulation of 5 mM sodium acetate, 25 mM sodium chloride, 7.5% (w / v) sucrose at pH 5.0.

[0138] Composition of Formula E: This composition comprises, on a molar basis, about 2.8 mole percent to about 3.8 mole percent of a mono-PEGylated IL-2 conjugate, about 44 mole percent to about 48 mole percent of a di-PEGylated IL-2 conjugate, about 41 mole percent to about 44 mole percent of a tri-PEGylated IL-2 conjugate, and about 7 mole percent to about 9 mole percent of a higher order PEGylated IL-2 conjugate, said composition comprising a mono-PEGylated IL-2 conjugate having a PEG moiety attached at lysine K7, and wherein each branched polyethylene glycol moiety has a nominal average molecular weight of about 20,000 daltons.

[0139] Composition of Formula E: The composition comprises, on a molar basis, about 2.8 mole percent to about 3.8 mole percent of a mono-PEGylated IL-2 conjugate, about 44 mole percent to about 48 mole percent of a di-PEGylated IL-2 conjugate, about 41 mole percent to about 44 mole percent of a tri-PEGylated IL-2 conjugate, and about 7 mole percent to about 9 mole percent of a higher order PEGylated IL-2 conjugate, the composition comprising a mono-PEGylated IL-2 conjugate having a PEG moiety attached at lysine K7, wherein each branched polyethylene glycol moiety has a nominal average molecular weight of about 20,000 daltons; the composition further comprises a formulation of 5 mM sodium acetate, 25 mM sodium chloride, and 7.5% (w / v) sucrose at pH 5.0.

[0140] Composition of Formula F: This composition comprises, on a molar basis, about 2 mole percent to 4 mole percent mono-PEGylated IL-2 conjugates, about 35 mole percent to about 55 mole percent di-PEGylated IL-2 conjugates, about 35 mole percent to about 55 mole percent tri-PEGylated IL-2 conjugates, and up to about 12 mole percent higher order PEGylated IL-2 conjugates, wherein each branched polyethylene glycol moiety has a nominal average molecular weight of about 20,000 daltons.

[0141] Composition of Formula F: The composition comprises, on a molar basis, about 2 mole percent to 4 mole percent of mono-PEGylated IL-2 conjugates, about 35 mole percent to about 55 mole percent of di-PEGylated IL-2 conjugates, about 35 mole percent to about 55 mole percent of tri-PEGylated IL-2 conjugates, and up to about 12 mole percent of higher-PEGylated IL-2 conjugates, wherein each branched polyethylene glycol moiety has a nominal average molecular weight of about 20,000 daltons; the composition further comprises a formulation of 5 mM sodium acetate, 25 mM sodium chloride, 7.5% (w / v) sucrose at pH 5.0.

[0142] In some embodiments, the methods described herein further comprise determining one or more of the following characteristics of the patient: EASI score; IGA score; percentage of BSA affected by atopic dermatitis; pruritus NRS score; SCORAD (Severity Rating Scale for Atopic Dermatitis) score; sleep deprivation score; POEM total score; DLQ or CDLQI score; ACQ-5; PROMIS positive and depressive symptoms.

[0143] Before, during, and after treatment with respegaldesleukin, patients can be assessed for one or more characteristics of the Atopic Dermatitis Severity Scale (ADDSM), which assesses specific signs, symptoms, characteristics, or parameters associated with atopic dermatitis and which can be assessed quantitatively or qualitatively. Exemplary ADDSM measures include, but are not limited to, the Eczema Area and Severity Index (EASI), Investigator's Global Assessment (IGA), Body Surface Area (BSA), Scora Atopic Dermatitis Severity Assessment Scale (SCORAD), Numerical Rating Scale for Pruritus (NRS), Sleep Deprivation Scale, Skin Pain NRS score, Patient Oriented Eczema Measurement (POEM) total score, Dermatology Life Quality Index (DLQI) or Paediatric Dermatology Life Quality Index (CDLQI), DLQI-Related (DLQI-R) score, Patient Reported Outcomes Measurement Information System (PROMIS), anxiety and depressive symptoms, EQ-5D (European Quality of Life-5 Scale), ACQ-5 (Asthma Control Questionnaire-5), World Health Organization-5 Well-Being Index (WHO-5) score, Long-Term Control Index of Atopic Eczema (RECAP) score, and Treatment Satisfaction with Medication Questionnaire-9 item (TSQM-9) score. ADDSM can be measured at baseline and at one or more time points after administration of respegaldesleukin. The difference between the ADDSM value at a particular time point after initiation of treatment and the baseline ADDSM value is used to determine whether there has been an improvement (e.g., reduction) in ADDSM.

[0144] In some embodiments, the methods described herein further comprise determining one or more of the following characteristics of the patient at baseline, during the run-in period, and after the run-in period: EASI score; IGA score; percentage of BSA affected by atopic dermatitis; itch NRS score; SCORAD score; sleep deprivation score; POEM total score; DLQI or CDLQI score; EQ-5D; ACQ-5; PROMIS anxiety and depression symptoms.

[0145] In some embodiments, the patient's EASI score is determined after the induction period. In some embodiments, the patient's EASI score determined after the induction period is reduced by 50% or more compared to the patient's EASI score at baseline, meaning the patient has achieved "EASI-50." In some embodiments, the patient's EASI score determined after the induction period is reduced by 75% or more compared to the patient's EASI score at baseline, meaning the patient has achieved "EASI-75." In some embodiments, the patient's EASI score determined after the induction period is reduced by 90% or more compared to the patient's EASI score at baseline, meaning the patient has achieved "EASI-90." If the patient achieves EASI-75 after the induction period, the patient is considered a responder to respegaldesleukin.

[0146] In some embodiments, the patient's IGA score is determined after the lead-in period. A patient is considered a responder to respegaldesleukin if the patient's IGA score after the lead-in period is 0 or 1. In some embodiments, a patient is considered a responder to respegaldesleukin if the patient's IGA score after the lead-in period is 0 or 1 and the patient's IGA score after the lead-in period is reduced by 2 or more points compared to the patient's IGA score determined at baseline.

[0147] In some embodiments, after completion of the induction period, the patient enters a maintenance period, as described. During the maintenance period, the patient is further treated with respegaldesleukin. The dosing regimen during the maintenance period can be selected based on the patient's ADDSM assessment and response to respegaldesleukin after the induction period, e.g., the patient's IGA or EASI score after the induction period, and / or the patient's own characteristics, e.g., weight, age.

[0148] In some embodiments, the methods described herein further comprise assessing one or more of the following characteristics of the patient during and after the maintenance period: EASI score; IGA score; percentage of BSA affected by atopic dermatitis; itch NRS score; SCORAD score; sleep deprivation score; POEM total score; DLQI or CDLQI score; EQ-5D; ACQ-5; PROMIS anxiety and depression symptoms. Similarly, the patient's EASI score during and after the maintenance period can be evaluated to determine whether the patient has reached EASI-50, EASI-75, or EASI-90. The patient's IGA score during and after the maintenance period can be evaluated to determine whether the patient's IGA score is 0 or 1 and whether the patient's IGA score has decreased by 2 or more points.

[0149] The "Investigator's Global Assessment" or "IGA" is a rating scale used worldwide to assess the severity of AD in patients (Simpson E, et al. 2020;83(3):839-846). It is based on a 5-point scale ranging from 0 (clear) to 4 (severe), with the score selected using descriptors that best describe the overall appearance of the lesion at a given time point (see Table 2). Not all features of the morphological description need to be present. The IGA can be performed before conducting the EASI and BSA assessments.

[0150] [Table 2-1]

[0151] The "Eczema Area and Severity Index" (EASI) is a scale used in clinical practice to assess the severity and extent of AD (Hanifin et al., Exp Dermatol. 2001;10:11-18). The EASI is a composite index using a score ranging from 0 to 72, with higher scores indicating more severe and / or widespread disease. The severity of erythema, induration / papules, scaling, and lichenification is assessed by a clinician or other medical professional on a scale of 0 (absent) to 3 (severe) for each of four body regions: head and neck, trunk, upper limbs, and lower limbs. In addition, the extent of AD involvement in each of the four body regions can be assessed as a percentage of the body surface area of ​​the head, trunk, upper limbs, and lower limbs and converted to a score ranging from 0 to 6. A total score (0 to 72) is assigned based on the sum of the total scores for each of the four body regions.

[0152] Body surface area (BSA) assessment estimates the extent of disease or skin lesions associated with AD and is expressed as a percentage of total body surface area. BSA is determined by a clinician or other medical professional using the palm of the patient's hand, with an approximate 1% BSA rule.

[0153] The "Severity Assessment of Atopic Dermatitis" or "SCORAD" is a validated clinical tool for assessing the extent and intensity of AD, developed by the European Task Force on Atopic Dermatitis (Consensus report of the European Task Force on Atopic Dermatitis. Dermatology. 1993;186(1):23-31). The assessment has three components: (i) the extent of AD, assessed as a percentage of a defined body surface area and reported as the sum of the total area, with a score ranging from 0 to 100 (assigned as an "A" in the overall SCORAD calculation); (ii) the severity of six AD symptoms: redness, swelling, oozing / crusting, excoriation, thickened / lichenified skin, and dryness. Each item is graded as follows: none (0), mild (1), moderate (2), or severe (3) (for a maximum total score of 18, assigned as "B" in the overall SCORAD calculation); (iii) subjective assessment of itch and insomnia is recorded for each symptom using a visual analog scale (VAS), where 0 is no itch (or insomnia) and 10 is the worst imaginable itch (or insomnia), with a maximum score of 20 (assigned as "C" in the overall SCORAD calculation). The formula for the SCORAD index is A / 5+7B / 2+C. The maximum score for the SCORAD index is 103.

[0154] The Pruritus Numerical Rating Scale (NRS) is an 11-point scale used by patients (and, if applicable, parents / caregivers, as appropriate) to rate the severity of their worst itch over the past 24 hours, with 0 indicating "no itch" and 10 indicating "worst itch imaginable" (Phan NQ et al. Acta Derm Venereol 2012;92:502-507). Ratings are recorded daily by patients using an electronic diary. The baseline itch NRS is determined based on the average daily itch NRS scores for the 7 days immediately preceding baseline. This calculation requires daily scores for a minimum of 4 of the 7 days immediately preceding baseline.

[0155] The Sleep Deprivation Scale assesses a patient's sleep deprivation due to pruritus on a 5-point Likert scale (scores range from 0 (not at all), 1 (a little), 2 (moderate), 3 (a lot), and 4 (no sleep at all). Assessments are recorded daily by the patient using an electronic diary. Sleep deprivation can also be monitored by actigraphy, which is well known to those skilled in the art.

[0156] The Cutaneous Pain NRS is an 11-point scale completed by patients (and parents / caregivers, if applicable) to assess the severity of their worst skin pain (e.g., discomfort or pain) over the past 24 hours, with 0 being "no pain" and 10 being "the worst pain imaginable" (Newton L, et al. J Patient Rep Outcomes. 2019 Jul 16;3:42). Ratings are recorded daily until week 16 and weekly thereafter by patients using an electronic diary. The baseline Cutaneous Pain NRS is determined based on the average daily Cutaneous Pain NRS scores for the 7 days immediately preceding baseline. This calculation requires daily scores for a minimum of 4 of the 7 days immediately preceding baseline.

[0157] The Patient Oriented Eczema Measure (POEM) is a seven-item validated questionnaire completed by patients (and parents / caregivers, if applicable) to assess disease symptoms over the past week (Centre of Evidence Based Dermatology. POEM - Patient Oriented Eczema Measure. Available at: https: / / www.nottingham.ac.uk / research / groups / cebd / resources / poem.aspx). Patients are asked to answer seven questions regarding dry, itchy, swelling, cracked skin, poor sleep, bleeding, and weeping. All seven responses have equal weighting, and the total score can range from 0 to 28 (responses are scored as follows: 0 days = 0, 1-2 days = 1, 3-4 days = 2, 5-6 days = 3, and every day = 4). High scores indicate poor quality of life. POEM responses are captured weekly using an electronic diary.

[0158] The Dermatology Life Quality Index (DLQI) is a validated 10-item questionnaire completed by patients or caregivers to assess the impact of skin diseases on patients' quality of life (Finlay, A. Y. and Khan, G. K. 1994. Clinical and Experimental Dermatology 1993 Sep 23;19:210-216). The 10 questions cover the following topics over the past week: symptoms, embarrassment, shopping and home care, clothing, social and leisure activities, sports, work or study, close relationships, sex life, and medical treatment. Each question is scored from 0 to 3 ("not at all," "a little," "some," "very much"), with a total score ranging from 0 to 30. High scores indicate poor quality of life.

[0159] For adolescents under 16 years of age, the Pediatric DLQI (CDLQI) is used, which is based on a set of 10 questions that is different from the DLQI (Lewis-Jones MS, Finlay AY. British Journal of Dermatology, 1995;132:942-949).

[0160] The DLQI-Related (DLQI-R) is a recently developed scoring system that adjusts the total score of the DLQI questionnaire according to the number of irrelevant responses (NRR) provided by the patient (Rencz F, et al. 2020;182(5):1167-1175).

[0161] The Patient-Reported Outcomes Measurement Information System (PROMIS) is a set of person-centered scales that assess and monitor the physical, mental, and social health of adults and children. The PROMIS® scales used in this study include the Anxiety and Depression Short Form, which assesses patient symptoms over the past week. Patients 17 years of age and younger will complete the pediatric version for the duration of the study.

[0162] The PROMIS Anxiety Short Form v1.0-Anxiety 8a is a participant-completed questionnaire that assesses the following in adults: self-reported fear (fear, panic); distressing anxiety (worry, fear); hyperarousal (tension, nervousness, restlessness) and arousal-related physical symptoms (pounding heart, dizziness) (PROMIS Anxiety 2019, published March 1, 2019; accessed March 8, 2021; available at https: / / www.healthmeasures.net / images / PROMIS / manuals / PROMIS_Anxiety_Scoring_Manual.pdf). Each question has five response options and is scored from 1 to 5. The total score ranges from 8 to 40, with higher scores indicating higher levels of anxiety. Adult self-report assesses anxiety "over the past seven days."

[0163] The PROMIS Depression Short Form v1.0-Depression 8a is a participant-completed questionnaire that assesses the following in adults: self-reported negative mood (sadness, guilt); self-image (self-criticism, feelings of worthlessness); social cognition (loneliness, feelings of interpersonal alienation); and declines in positive affect and engagement (loss of interest, meaning, and purpose) (PROMIS Depression 2019, published February 28, 2019, accessed March 8, 2021, available at https: / / www.healthmeasures.net / images / PROMIS / manuals / PROMIS_Depression_Scoring_Manual.pdf). Physical symptoms (e.g., changes in appetite or sleep patterns) are not included. This helps eliminate the potentially confounding effects of these items when assessing participants with comorbid physical illnesses. Each question has five response options and is scored from 1 to 5. The total score ranges from 8 to 40, with higher scores indicating higher levels of depression. Adult self-report measures depression over the past seven days.

[0164] The EQ-5D (European Quality of Life-Five Dimensions) includes five dimensions: mobility, managing personal care, usual activities, pain / discomfort, and anxiety / depression. The EQ VAS records patients' self-rated health status on a vertical visual analogue scale. Scores based on these five dimensions can be presented as a health profile or converted into a single summary index number (utility) that reflects priority compared with other health profiles. The EQ-5D is completed by patients at the trial clinic.

[0165] The European Quality of Life-5 Dimensions-5 Levels (EuroQol-5D-5L or EQ-5D-5L) is a participant-administered, five-question, one visual analogue scale (VAS) standardized measure of health status in adults, providing a brief, comprehensive measure of health for clinical and economic evaluation. The EQ-5D-5L consists of two components: a health description system and an assessment of the respondent's current health status using a 0-100 mm VAS (20 cm). The description system includes five dimensions: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. Each dimension has five levels: no disability, mild disability, moderate disability, severe disability, and extreme disability. Respondents are asked to indicate their health status by checking (or crossing) the box associated with the most appropriate description for each of the five dimensions. Note that the numbers 1 to 5 do not have an arithmetic property and should not be used as an ordinal score. The EQ-5D-5L health status determined by the EQ-5D-5L descriptor system can be converted into a single summary index by applying a formula that essentially assigns a value (also called a weight) to each level of each dimension. The VAS records the respondent's self-rated health status on a vertical VAS with endpoints labeled "best imaginable health state" and "worst imaginable health state." This information can be used as a quantitative measure of health outcomes (Herdman et al., Qual Life Res. 2011;20(10):1727-1736; EuroQol Group, EQ-5D-5L User Guide. Version 2.1. April 2015. Accessed January 14, 2021. Available at https: / / euroqol.org / wp-content / uploads / 2016 / 09 / EQ-5D-5L_UserGuide_2015.pdf). The self-rated health status captured by the EQ-5D-5L relates to the participant's situation at the time of completion; no attempt is made to recall health status in previous days or weeks (EuroQol Group 2015).

[0166] The ACQ-5 is an asthma control questionnaire. In this trial, patients who report comorbid asthma prior to enrollment will complete the Asthma Control Questionnaire (ACQ-5) in addition to other patient-reported outcomes. The ACQ-5 has been proven to reliably measure asthma control and distinguish patients with well-controlled asthma (score ≤ 0.75) from those with poor asthma control (score ≥ 1.5). The ACQ-5 consists of five questions scored on a 7-point Likert scale with a 1-week recall period. The total ACQ-5 score is the average score across all questions, with lower scores indicating better asthma control. The ACQ-5 will be completed by patients at the study clinic.

[0167] As used herein, "inadequate response" refers to the failure to achieve good disease control of atopic dermatitis (e.g., failure to achieve IGA≦2 or EASI 75) with a therapeutic agent for the duration recommended in the product's prescribing information, or the occurrence of atopic dermatitis flare-up during treatment.

[0168] As used herein, the term "intolerance" or "intolerance" means unacceptable toxicity (e.g., elevated creatinine, elevated liver function tests, uncontrolled hypertension, paresthesia, headache, nausea, hirsutism) or the requirement for a drug at a dose or for a duration greater than that specified in the prescribing information.

[0169] As used herein, the term "topical corticosteroid" or "TCS" includes Group I, Group II, Group III, and Group IV topical corticosteroids. According to the World Health Organization's Anatomical Therapeutic Chemical (ATC) classification, corticosteroids are classified into weak (Group I), moderately potent (Group II), potent (Group III), and very potent (Group IV) based on their activity relative to hydrocortisone. Group IV TCS (very potent) are up to 600 times more potent than hydrocortisone and include clobetasol and halcinonide. Group III TCS (potent) are 50 to 100 times more potent than hydrocortisone and include, but are not limited to, betamethasone valerate, betamethasone dipropionate, diflucortolo valerate, hydrocortisone-17-butyrate, mometasone furoate, and methylprednisolone aceponate. Class II TCS (moderately strong) are 2 to 25 times more potent than hydrocortisone and include, but are not limited to, clobetasone butyrate and triamcinolone acetonide. Class I TCS (weak or mild) include hydrocortisone, prednisolone, and methylprednisolone.

[0170] The term "topical calcineurin inhibitors" or "TCIs" as used herein includes pimecrolimus, tacrolimus, and other inhibitors that suppress calcineurin activity and that can be applied topically to a patient's skin.

[0171] In embodiments relating to methods of treatment described herein, such embodiments are also further embodiments for use in that treatment or alternatively for use in the manufacture of a medicament for use in that treatment.

[0172] RUR 20kD -Preparation and manufacturing example of IL-2 selective Treg stimulating agent composition RUR 20kDThe IL-2-selective Treg stimulator composition drug substance is a PEGylated conjugate composition consisting of recombinant human interleukin-2 (rhIL-2, aldesleukin sequence) conjugated to multiple polyethylene glycol (PEG) moieties covalently linked at lysine groups. The number of PEG moieties per rhIL-2 molecule (PEGylation degree) is a distribution of primarily 2 and 3 PEG moieties per molecule (di- or tri-PEGylation), with minor species including 1 PEG (mono-PEGylation) and 4 PEG (tetra-PEGylation) as well as higher PEGylated molecules, resulting in an average of approximately 2.5 PEG moieties per rhIL-2. Each PEG moiety has a nominal molecular weight of 20 kDa, and rhIL-2 has a molecular weight of 15.3 kDa, resulting in a nominal RUR. 20kD - The molecular weight of the IL-2 selective Treg stimulator composition will be 65 kDa. Unless otherwise specified, RUR 20kD The concentrations, amounts, and dosage levels of the IL-2-selective Treg stimulator composition are described on a protein basis, which counts only the mass contributed by the protein component and not the mass contributed by the PEG chains. By using a protein basis, only the rhIL-2 protein is counted, so the effective molecular weight, when used in dosage and concentration calculations, remains constant at 15.3 kDa and is not affected by the distribution of PEGylated rhIL-2 molecules.

[0173] The preparations and examples are illustrative and not limiting, and various modifications may be made by those skilled in the art. 20kDMethods for preparing selective Treg stimulator compositions, including IL-2 embodiments and related compositions, are described in WO 2019 / 226,538 (incorporated herein by reference), described herein, or are well known to those of skill in the art. Reagents and starting materials are readily available or can be easily synthesized by those of skill in the art. Suitable conditions for these method steps are well known, and appropriate substitutions of buffers and reagents are within the skill of those of skill in the art. Furthermore, those of skill in the art will understand that the steps and order in which the compositions are prepared may be varied depending on the circumstances, as would be well understood by a biochemist. Similarly, it will be understood that preparations may be isolated and / or purified by various well-known techniques, as necessary or desired.

[0174] Preparation of IL-2 intermediate: The IL-2 moiety can be obtained from non-recombinant and / or recombinant methods, and the present disclosure is not limited in this regard. The IL-2 moiety can be obtained from human, animal, and plant sources. For example, IL-2 can be isolated from biological systems or otherwise obtained from culture media. See, e.g., U.S. Pat. No. 4,401,756 and the procedures described in Pauly et al. (1984) J. Immunol Methods 75(1):73-84. Exemplary IL-2 moieties are described in the literature, e.g., U.S. Pat. Nos. 5,116,943, 5,153,310, 5,635,597, 7,101,965, and 7,567,215, and U.S. Patent Application Publication Nos. 2010 / 0036097 and 2004 / 0175337. A preferred IL-2 moiety has the amino acid sequence provided in Figure 2, which represents the amino acid sequence of aldesleukin as used herein.

[0175] Methods for producing and expressing recombinant polypeptides in vitro and in prokaryotic and eukaryotic host cells are well known to those of skill in the art, see, for example, U.S. Patent No. 5,614,185. The IL-2 moiety can be expressed in bacterial [e.g., E. coli, see e.g., Fischer et al. (1995) Biotechnol. Appl. BioIL-2m. 21(3):295-311], mammalian [see e.g., Kronman et al. (1992) Gene 121:295-304], yeast [e.g., Pichia pastoris, see e.g., Morel et al. (1997) Biochem. J. 328(1):121-129], and plant [see e.g., Mor et al. (2001) Biotechnol. Bioeng. 75(3):259-266] expression systems. While recombinant-based methods for preparing proteins can vary, recombinant methods typically involve constructing a nucleic acid encoding the desired polypeptide or fragment, cloning the nucleic acid into an expression vector, transforming a host cell (e.g., a plant, bacteria, yeast, transgenic animal cell, or mammalian cell such as Chinese hamster ovary cell or baby hamster kidney cell), and expressing the nucleic acid to produce the desired polypeptide or fragment. Various methods of protein purification can be used to purify the compositions of the present disclosure and are known in the art and described, for example, in Scopes, Protein Purification: Principles and Practice, 3rd Edition, Springer, NY (1994). To facilitate identification and purification of the recombinant polypeptide, a nucleic acid sequence encoding an epitope tag or other affinity binding sequence can be inserted or added in frame with the coding sequence, thereby producing a fusion protein consisting of the desired polypeptide and a polypeptide suitable for binding.

[0176] RUR 20kD -Preparation of selective Treg stimulator compositions containing IL-2 embodiments and related compositions: RUR 20kD An exemplary selective Treg stimulator composition for IL-2 is generally prepared by reacting purified IL-2 with a molar excess of a PEG reagent (molar equivalent excess relative to IL-2), mPEG2(20 kD)-butanoic acid, N-hydroxysuccinimide ester (or any other suitably activated ester) (1,3-bis(methoxypoly(ethylene glycol) MW 10,000 carbamoyl)-2-propanoxy)-4-succinimidyl butanoate, in a bicine solution at a high pH of about 9. The reactants are generally mixed under mild conditions, e.g., from about 20°C to about 65°C, or from about 20°C to about 40°C, or at ambient or room temperature, for about 30 minutes to about 5 hours, or from about 30 minutes to about 4 hours, or from about 30 minutes to about 2 hours, or from about 30 minutes to about 1 hour. The reaction is quenched by acidifying to a low pH with the addition of a suitable acid, such as acetic acid.

[0177] The PEGylated rIL-2 reaction product is then purified by an appropriate method, such as ion exchange chromatography. For example, when ion exchange chromatography is used, the RUR 20kD The IL-2 composition is bound to the resin and then eluted with a suitable gradient, such as a sodium chloride gradient. The chromatographic product pool is then concentrated and double filtered, for example, using tangential flow filtration (TFF), into a suitable formulation buffer (e.g., sodium acetate buffer containing sucrose).

[0178] If desired, the product pool can be further separated into positional isomers by reversed-phase chromatography using a suitable column (e.g., a C18 column or a C3 column commercially available from companies such as Amersham Biosciences or Vydac) by reversed-phase high performance liquid chromatography (RP-HPLC) or by ion-exchange chromatography using an ion-exchange column, e.g., a Sepharose™ ion-exchange column commercially available from Amersham Biosciences. Either technique can be used to separate macromolecular active agent isomers having the same molecular weight (i.e., positional isomers).

[0179] RUR 20kD -Selective Treg stimulator compositions, including IL-2 embodiments and related compositions, can be characterized by a variety of analytical and bioassay techniques described herein and / or known to those skilled in the art, including analytical HPLC, SDS-Page, LCMS, and bioassays such as CTLL-2 proliferation, in vivo Treg induction, etc.

[0180] Embodiments of the RUR20kD-IL-2 Selective Treg Stimulator Composition RUR 20kD The IL-2-selective Treg stimulator composition comprises recombinant human interleukin-2 (rhIL-2, specifically the aldesleukin amino acid sequence without any additional or substitution amino acid mutations), stably covalently attached to a 20 kDa polyethylene glycol (PEG) moiety, where the mixture has a defined fraction containing a particular degree of PEGylation per IL-2 moiety. The compositions of the present disclosure comprise selected mixtures of IL-2 PEG conjugates having a defined fraction consisting primarily of di- and tri-PEGylated IL-2 and a lesser defined fraction of mono- and / or tetra- or higher-PEGylated IL-2.

[0181] An embodiment of the present disclosure is a compound of the formula: [ka] (wherein IL-2 is interleukin-2, n is an integer of about 3 to about 4000, and n' is 1, 2, or 3.) The polymer moiety of formula (I) is also referred to as 1,3-bis(methoxypoly(ethylene glycol) MW 10,000 carbamoyl)-2-propanoxy)-4-butanoyl (up to and including the carbonyl group covalently attached to the amino nitrogen of the IL-2 moiety).

[0182] The embodiments of the present disclosure are 20kDFurther provided are selective Treg stimulator compositions, including IL-2 embodiments and related compositions, and preferred embodiments of the compositions include aldesleukin. In certain embodiments of the compositions, the nominal average molecular weight of each branched polyethylene glycol moiety is about 20,000 daltons. In further specific embodiments of the compositions, the PEGylated IL-2 conjugate of the composition has a PEG moiety attached at lysine 31. The mixed compositions according to formula (I) are generally referred to herein as RUR-IL2, which encompasses various PEG sizes.

[0183] Exemplary ranges of n include, for example, about 3 to about 4000, as well as about 5 to about 2000, or about 10 to about 1000, or about 10 to about 750, or about 10 to about 500, or about 10 to about 400, or about 10 to about 300, or about 10 to about 250, or about 20 to about 250. In some embodiments, n averages about 226.

[0184] In some embodiments, a selective Treg stimulator composition of Formula I comprises an IL-2R stably covalently linked branched polyethylene glycol moiety, wherein the number of branched PEG moieties per IL-2 moiety (degree of PEGylation) is a distribution of primarily 2- and 3-mers (di- and tri-PEGylated) in a mixture with a smaller fraction comprising 1-mers (mono-PEGylated) and 4-mers (tetra-PEGylated). Thus, in some embodiments, a smaller fraction in a composition according to Formula I comprises conjugates where n' is 1, 4, 5, or more, but not greater than 11. As used herein, higher order PEGylated conjugates refer to 4-11 or 4-7.

[0185] In some preferred embodiments provided herein, the compositions comprise aldesleukin conjugates with individual covalently attached PEG attachments having a combined nominal molecular weight of about 20 kD. These compositions further comprise a selected mixture of IL-2 PEG conjugates having a defined fraction of primarily di- and tri-PEGylated IL-2 and a lesser defined fraction of mono-PEGylated IL-2 and / or tetra- or higher-PEGylated IL-2. 20kDSpecific preparations of IL-2 compositions are described below and throughout this application. As used herein, an RUR of formula A 20kD - a composition of IL-2, RUR of formula B 20kD - a composition of IL-2, RUR of formula C 20kD - a composition of IL-2, RUR of formula D 20kD - a composition of IL-2 and / or a RUR of formula E 20kD - a composition of IL-2 and / or a RUR of formula F 20kD -The composition of IL-2 is a selective Treg stimulator RUR 20kD - represents a specific embodiment of IL-2 and related compositions, in which the IL-2 moiety is aldesleukin (as described herein). Optionally, these compositions include pharmaceutically acceptable salts thereof.

[0186] In one embodiment, the RUR of formula A 20kD Provided herein are compositions of IL-2, the compositions comprising, on a molar basis, about 5 mol% or less of mono-PEGylated IL-2 conjugates, about 28 mol% to about 60 mol% of di-PEGylated IL-2 conjugates, about 24 mol% to about 65 mol% of tri-PEGylated IL-2 conjugates, and about 12 mol% or less of higher order PEGylated IL-2 conjugates, wherein each branched polyethylene glycol moiety has a nominal average molecular weight of about 20,000 daltons. Preferably, the RUR of Formula A 20kD The composition of IL-2 comprises 80 mole % or more of conjugated di- and tri-PEGylated IL-2 conjugates.

[0187] In one embodiment, the RUR of formula B 20kD Provided herein are compositions of IL-2, which comprise, on a molar basis, about 2.5 to about 4.5 mole % of a mono-PEGylated IL-2 conjugate, about 35 to about 50 mole % of a di-PEGylated IL-2 conjugate, about 38 to about 46 mole % of a tri-PEGylated IL-2 conjugate, and about 3 to about 10 mole % of a higher order PEGylated IL-2 conjugate, wherein each branched polyethylene glycol moiety has a nominal average molecular weight of about 20,000 daltons. Preferably, the RUR of Formula B 20kDThe IL-2 composition comprises a total of about 80 to about 95 mole % di-PEGylated and tri-PEGylated IL-2 conjugates.

[0188] In one embodiment, an RUR of formula C 20kD Provided herein are compositions of IL-2, which comprise, on a molar basis, about 2.8 to about 3.8 mole % of a mono-PEGylated IL-2 conjugate, about 44 to about 48 mole % of a di-PEGylated IL-2 conjugate, about 41 to about 44 mole % of a tri-PEGylated IL-2 conjugate, and about 7 to about 9 mole % of a higher order PEGylated IL-2 conjugate, wherein each branched polyethylene glycol moiety has a nominal average molecular weight of about 20,000 daltons. Preferably, the RUR of Formula C is 20kD The composition of IL-2 comprises a total of about 87 to about 90 mole % di-PEGylated and tri-PEGylated IL-2 conjugates.

[0189] In one embodiment, a RUR of formula D 20kD Provided herein is a composition of IL-2, the composition comprising, on a molar basis, about 2.8 to about 3.8 mole % of a mono-PEGylated IL-2 conjugate, about 44 to about 48 mole % of a di-PEGylated IL-2 conjugate, about 41 to about 44 mole % of a tri-PEGylated IL-2 conjugate, and about 7 to about 9 mole % of a higher order PEGylated IL-2 conjugate, the composition comprising a mixture of mono-PEGylated IL-2 conjugates having a PEG moiety attached at one of lysines K7, or K8, or K31, or K75, and each branched polyethylene glycol moiety having a nominal average molecular weight of about 20,000 daltons. Preferably, the composition is a RUR of Formula D 20kD The composition of IL-2 comprises a total of about 87 to about 90 mole % di-PEGylated and tri-PEGylated IL-2 conjugates.

[0190] In one embodiment, an RUR of formula E 20kDProvided herein is a composition of IL-2, the composition comprising, on a molar basis, about 2.8 to about 3.8 mole % of a mono-PEGylated IL-2 conjugate, about 44 to about 48 mole % of a di-PEGylated IL-2 conjugate, about 41 to about 44 mole % of a tri-PEGylated IL-2 conjugate, and about 7 to about 9 mole % of a higher order PEGylated IL-2 conjugate, the composition comprising a mono-PEGylated IL-2 conjugate having a PEG moiety attached at lysine K7, and each branched polyethylene glycol moiety having a nominal average molecular weight of about 20,000 daltons. Preferably, the composition is a RUR of Formula E 20kD The composition of IL-2 comprises a total of about 87 to about 90 mole % di-PEGylated and tri-PEGylated IL-2 conjugates.

[0191] In one embodiment, a RUR of formula F 20kD Provided herein are compositions of IL-2, the compositions comprising, on a molar basis, about 2-4 mol% or less of mono-PEGylated IL-2 conjugates, about 35 mol% to about 55 mol% of di-PEGylated IL-2 conjugates, about 35 mol% to about 55 mol% of tri-PEGylated IL-2 conjugates, and about 12 mol% or less of higher order PEGylated IL-2 conjugates, wherein each branched polyethylene glycol moiety has a nominal average molecular weight of about 20,000 daltons. Preferably, the RUR of formula F 20kD The composition of IL-2 comprises 80 mole % or more of conjugated di- and tri-PEGylated IL-2 conjugates.

[0192] As used herein, "RUR" 20kD -IL-2 and related compositions" refers to a RUR of formula A 20kD -IL-2, and / or RUR of formula B 20kD -IL-2, and / or RUR of formula C 20kD -IL-2, and / or RUR of formula D 20kD -IL-2, and / or RUR of formula E 20kD -IL-2, and / or RUR of formula F 20kDThe preparations of Example 1 and / or Example 1A may refer to one or more compositions according to the "RUR" method of the present disclosure. 20kD -IL-2 and related compositions.

[0193] Further embodiments of the selective Treg stimulator compositions provided herein: The compositions provided herein can include conjugates where n is equal to 2, e.g., di-PEGylated conjugates, where each is 1,3-bis(methoxypoly(ethylene glycol)) as shown above. 10kD Two branched polyethylene glycol polymers having a (carbamoyl)-2-propanoxy)-4-butanoyl structure are attached at the same relative positions for substantially all di-PEGylated IL-2 conjugates in the composition. Alternatively, the di-PEGylated conjugates may comprise a mixture of di-PEGylated conjugates, e.g., a mixture of di-PEGylated conjugates in which the attachment of the branched polyethylene glycol moieties occurs at two sites on IL-2, in which case the specific attachment site is not the same for all di-PEGylated IL-2 conjugates contained in the composition. Thus, such di-PEGylated compositions are homogeneous with respect to the degree of PEGylation, particularly the number of attached branched PEG moieties (e.g., dimers), but heterogeneous with respect to the position of PEG attachment on the IL-2 molecule, in which case they exhibit positional isomers of PEG attachment.

[0194] The composition may also include a single conjugate where n is equal to 3, e.g., a tri-PEGylated conjugate in which three branched polyethylene glycol moieties are attached at the same relative positions for substantially all IL-2 conjugates in the composition. Alternatively, the tri-PEGylated conjugate may include a mixture of tri-PEGylated conjugates, e.g., a mixture of tri-PEGylated conjugates in which the attachment sites of the branched polyethylene glycol moieties are present at different sites on IL-2 for the conjugates included in the composition. Thus, such tri-PEGylated compositions are homogeneous with respect to the degree of PEGylation, particularly the number of attached branched PEG moieties, but heterogeneous with respect to the position of PEG attachment on the IL-2 molecule, in which case they exhibit positional isomers of PEG attachment. As used herein, a "higher-order PEGylated IL-2 conjugate" refers to four or more branched polyethylene glycol moieties attached to IL-2, e.g., 4 to 11 attached moieties.

[0195] The composition can also include a single conjugate where n equals 1, e.g., a mono-PEGylated conjugate in which one branched polyethylene glycol moiety is attached at the same relative position for substantially all IL-2 conjugates in the composition. Alternatively, the mono-PEGylated conjugate can include a mixture of mono-PEGylated conjugates, e.g., a mixture of mono-PEGylated conjugates in which the attachment site of the branched polyethylene glycol moiety is present at different sites on IL-2 for the conjugates included in the composition. Thus, such mono-PEGylated compositions are homogeneous with respect to the degree of PEGylation, particularly the number of branched PEG moieties attached, but heterogeneous with respect to the position of PEG attachment on the IL-2 molecule, in which case they exhibit positional isomers of PEG attachment.

[0196] Certain positions of PEG attachment on the IL-2 molecule are more common in the compositions described herein. For example, lysines K7 or K8 or K31 or K75 are common PEGylation sites. 20kD - Compositions of IL-2 and related compositions may include conjugates in which lysine K7 or K8 or K31 or K75 is the PEGylation site.20kD Compositions of IL-2 and related compositions may include mono-PEGylated conjugates in which lysine K7 or K8 or K31 or K75 is the PEGylation site. 20kD Compositions of IL-2 and related compositions may include mono-PEGylated conjugates in which lysine K7 is the PEGylation site. 20kD Compositions of -IL-2 and related compositions may include mono-PEGylated conjugates in which lysine K31 is the PEGylation site.

[0197] In some embodiments, when the compositions are considered collectively and are encompassed by formula (I) (where n' is an integer selected from 1, 4, 5, or 6 or greater), the compositions contain about 20 mol% or less, preferably about 15 mol% or less, of the conjugate, where the molar percentages are based on the total PEG-IL-2 conjugates. In some embodiments, when the compositions are considered collectively and are encompassed by formula (I) (where n' is an integer selected from 1, 4, 5, or 6 or greater), the compositions contain about 10 mol% or less of the conjugate, where the molar percentages are based on the total PEG-IL-2 conjugates. In some other embodiments, the compositions comprise about 10 mol% or less of the monomer, preferably about 7 mol% or less of the monomer, or about 5 mol% or less of the monomer (i.e., according to structure (I) where n is equal to 1). In some further embodiments, the composition comprises about 10 mol% or less of tetramer, preferably about 7 mol% or less of tetramer, or about 5 mol% or less of tetramer (i.e., according to structure (I) where n equals 4). In certain other embodiments, the composition comprises about 10 mol% or less of monomer and about 10 mol% or less of tetramer. Alternatively, the composition can comprise about 7 mol% or less of monomer and about 7 mol% or less of tetramer, or about 5 mol% or less of monomer and about 5 mol% or less of tetramer.

[0198] In some embodiments, with respect to the PEGylated IL-2 in the composition, the composition generally meets one or more of the following characteristics: at least about 80% of the conjugates in the composition comprise a mixture of di-PEGylated and tri-PEGylated conjugates, some having two branched polymers having the structure shown in Formula (I) attached to the IL-2 moiety and some having three branched polymers; at least about 85% of the conjugates in the composition comprise a mixture of di-PEGylated and tri-PEGylated conjugates, some having two branched polymers having the structure shown in Formula (I) attached to the IL-2 moiety and some having three branched polymers; at least about 90% of the conjugates in the composition comprise a mixture of di-PEGylated and tri-PEGylated conjugates, some having two branched polymers having the structure shown in Formula (I) attached to the IL-2 moiety and some having three branched polymers. at least about 95% of the conjugates in the composition comprise a mixture of di-PEGylated and tri-PEGylated conjugates, some having two branched polymers and some having three branched polymers attached to the IL-2 moiety; no more than about 20% of the conjugates in the composition have one, four or more branched polymers having the structure shown in Formula (I) attached to the IL-2 moiety; no more than about 15% of the conjugates in the composition have one, four or more branched polymers having the structure shown in Formula (I) attached to the IL-2 moiety; no more than about 10% of the conjugates in the composition have one, four or more branched polymers having the structure shown in Formula (I) attached to the IL-2 moiety; no more than about 7% of the conjugates in the composition have one, four or more branched polymers having the structure shown in Formula (I) above attached to the IL-2 moiety.

[0199] In some embodiments, when the compositions are considered collectively and encompassed by formula (I) (where n' is an integer selected from 1, 4, 5, or 6 or greater), the compositions contain about 20 mol% or less, preferably about 15 mol% or less, of compounds encompassed by formula (I), where n' is an integer selected from 1, 4, 5, or 6 or greater, and the molar percentages are based on the total PEG-IL-2 conjugates. In some embodiments, when the compositions are considered collectively and encompassed by formula (I) (where n' is an integer selected from 1, 4, 5, or 6 or greater), the compositions contain about 10 mol% or less of conjugates, and the molar percentages are based on the total PEG-IL-2 conjugates. In some other embodiments, the compositions comprise about 10 mol% or less of monomers, preferably about 7 mol% or less of monomers or about 5 mol% or less of monomers (i.e., according to structure (I) where n is equal to 1). In some further embodiments, the composition comprises about 10 mol% or less of tetramer, preferably about 7 mol% or less of tetramer, or about 5 mol% or less of tetramer (i.e., according to structure (I) where n equals 4). In certain other embodiments, the composition comprises about 10 mol% or less of monomer and about 10 mol% or less of tetramer. Alternatively, the composition can comprise about 7 mol% or less of monomer and about 7 mol% or less of tetramer, or about 5 mol% or less of monomer and about 5 mol% or less of tetramer.

[0200] In some other embodiments, the composition comprises approximately equimolar amounts of: [ka] Includes.

[0201] For example, exemplary compositions may include any one or more of the following approximate ratios of di-PEGylated species to tri-PEGylated species: 1.4:1; 1.3:1; 1.2:1; 1.1:1; 1:1; 1:1.1; 1:1.2; 1:1.3; or 1:1.4. The average number of PEG moieties per IL-2 in such compositions is selected from, for example, 2; 2.1; 2.2; 2.3; 2.4; 2.5; 2.6; 2.7; 2.8; 2.9; and 3. In certain embodiments, the average number of PEG moieties per IL-2 is about 2.5.

[0202] For example, in some embodiments, compositions are considered collectively and have the formula: [ka] (wherein n' is an integer selected from 1, 4, 5, or 6 or greater). When included in the formula, the composition comprises 20 mole percent (mol %) or less of the IL-2 conjugate.

[0203] Also in some embodiments, compositions are considered collectively and have the formula: [ka] and n' is an integer selected from 1, 4, 5, or 6 or greater, the composition comprises 15 mole percent (mol %) or less of an IL-2 conjugate.

[0204] Also in some embodiments, compositions are considered collectively and have the formula: [ka] and n' is an integer selected from 1, 4, 5, or 6 or greater, the composition comprises 10 mole percent (mol %) or less of an IL-2 conjugate.

[0205] In some additional embodiments of the foregoing, the composition comprises about 10 mol% or less of an IL-2 conjugate, where n' is equal to 1. In yet some other embodiments, the composition comprises about 7 mol% or less of an IL-2 conjugate (where n' is equal to 1).

[0206] In yet some other embodiments, the composition comprises about 5 mol% or less of an IL-2 conjugate, where n' is equal to 1. In yet some alternative embodiments, the composition comprises less than about 5 mol% of an IL-2 conjugate (where n' is equal to 1).

[0207] In some further embodiments related to any one or more of the above, the composition comprises about 10 mol% or less of an IL-2 conjugate (n' equals 4). Alternatively, in some other embodiments, the composition comprises about 7 mol% or less of an IL-2 conjugate (n' equals 4). In yet some further embodiments, the composition comprises about 5 mol% or less of an IL-2 conjugate (n' equals 4).

[0208] As used herein, approximately equimolar amounts of [ka] Also provided is a composition comprising:

[0209] In some other embodiments, the formula: [ka] wherein the molar ratio of di-PEG / tri-PEG conjugates is selected from the group consisting of 1.4:1; 1.3:1; 1.2:1; 1.1:1; 1:1; 1:1.1; 1:1.2; 1:1.3; and 1:1.4. Provided herein are compositions comprising an IL-2 conjugate of the formula:

[0210] In yet some further embodiments, the composition has an average number of branched polyethylene glycol moieties (having the structure shown above) per IL-2 residue selected from the group consisting of 2; 2.1; 2.2; 2.3; 2.4; 2.5; 2.6; 2.7; 2.8; 2.9; and 3. In certain embodiments, the average number of branched polyethylene glycol moieties (having the structure shown above) per IL-2 moiety is about 2.5. In some embodiments related to one or more of the above, the value of n is 5 to 2000. In some other embodiments, the value of n is in the range of 10 to 1000. In yet some additional embodiments, the value of n is 10 to 750. In some embodiments, the value of n is 10 to 500 or 20 to 250.

[0211] The value of n in the embodiments described herein can vary independently at each occurrence. In one or more embodiments described herein, the value of n in each of the polyethylene glycol arms of the branched polymer is substantially the same. In some other embodiments, the value of n in each of the polymer arms comprising the branched polymer is about 170 to 285. In yet some other embodiments, the value of n in each of the polymer arms comprising the branched polymer is about 204 to about 250. In one or more specific embodiments, the value of n in each of the polymer arms comprising the branched polymer is about 226.

[0212] In one or more embodiments related to any one or more of the aspects or embodiments provided herein, the nominal average molecular weight of each branched polyethylene glycol moiety is from about 250 daltons to about 90,000 daltons. In some other embodiments, the nominal average molecular weight of each branched polyethylene glycol moiety is from about 1000 daltons to about 60,000 daltons. In yet other embodiments, the nominal average molecular weight of each branched polyethylene glycol moiety is from about 5,000 daltons to about 60,000 daltons. In some other embodiments, the nominal average molecular weight of each branched polyethylene glycol moiety is from about 10,000 daltons to about 55,000 daltons.

[0213] In yet some additional embodiments, the nominal average molecular weight of each branched polyethylene glycol moiety is from about 15,000 daltons to about 25,000 daltons. In yet one or more other embodiments, the nominal average molecular weight of each branched polyethylene glycol moiety is within the range of from about 18,000 daltons to about 22,000 daltons. In yet some other embodiments, the nominal average molecular weight of each branched polyethylene glycol moiety is about 20,000 daltons.

[0214] Additional exemplary compositions include compositions according to the above formula, wherein the entire polymeric portion of the molecule has a nominal average molecular weight of from about 250 daltons to about 90,000 daltons. Additional suitable ranges for the polymeric portion of the molecule include nominal average molecular weights in ranges selected from about 1,000 daltons to about 60,000 daltons, about 5,000 daltons to about 60,000 daltons, about 10,000 daltons to about 55,000 daltons, about 15,000 daltons to about 50,000 daltons, and about 20,000 daltons to about 50,000 daltons.

[0215] Further exemplary weight average molecular weights of the polyethylene glycol polymer moiety are about 200 daltons, about 300 daltons, about 400 daltons, about 500 daltons, about 600 daltons, about 700 daltons, about 750 daltons, about 800 daltons, about 900 daltons, about 1,000 daltons, about 1,500 daltons, about 2,000 daltons, about 2,200 daltons, about 2,500 daltons, about 3,000 daltons, about 4,000 daltons, about 4,400 daltons, about 4,500 daltons, about 5,000 daltons, about 5,500 daltons, about 6,000 daltons, about 7,000 daltons, about 8,000 daltons, about 9,000 daltons, about 10,000 daltons, about 11,000 daltons, about 12,000 daltons, about 13,000 daltons, about 14,000 daltons, about 15,000 daltons, about 16,000 daltons, about 17,000 daltons, about 18,000 daltons, about 19,000 daltons, about 20,000 daltons, about 21,000 daltons, about 22,000 daltons, about 25,000 daltons, about 26,000 daltons, about 27,000 daltons, about 28,000 daltons, about 29 ,500 Daltons, about 8,000 Daltons, about 9,000 Daltons, about 10,000 Daltons, about 11,000 Daltons, about 12,000 Daltons, about 13,000 Daltons, about 14,000 Daltons, about 15,000 Daltons, about 20,000 Daltons, about 22,500 Daltons, about 25,000 Daltons, about 30,000 Daltons, about 35,000 Daltons, about 40,000 Daltons, about 45,000 Daltons, about 50,000 Daltons, about 55,000 Daltons, about 60,000 Daltons, about 65,000 Daltons, about 70,000 Daltons, and about 75,000 Daltons. In some preferred embodiments, the weight average molecular weight of the branched polyethylene glycol polymer is about 20,000 Daltons. In some particular embodiments where each branched PEG moiety has a nominal molecular weight of about 20,000 daltons, the resulting composition has a molecular weight range of about 55-75 kDa when characterized across the entire composition.

[0216] Further embodiments of the selective Treg stimulating agent compositions provided herein include pharmaceutically acceptable salts thereof. As mentioned above, the IL-2 conjugate compositions may be in the form of pharmaceutically acceptable salts. Typically, such salts are formed by reaction with a pharmaceutically acceptable acid or acid equivalent. In this regard, the term "pharmaceutically acceptable salts" generally refers to relatively non-toxic inorganic and organic acid addition salts. These salts can be prepared in situ during the administration vehicle or dosage form manufacturing process or by separately reacting a long-acting interleukin-2 composition as described herein with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, oxylate, mesylate, glucoheptonate, lactobionate, and lauryl sulfonate (see, e.g., Berge et al. (1977) "Pharmaceutical Salts," J. Pharm. Sci. 66:1-19). Thus, the salts described may be derived from inorganic acids such as hydrochloride, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; or may be prepared from organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isothionine acid, and the like. As used herein, the RURs described herein are intended to be salts of RURs of the invention. 20kD The term "composition" or "compositions," including IL-2 embodiments and related compositions, includes pharmaceutically acceptable salts of any and / or all PEGylated IL-2 conjugates. This description applies whether or not the term "or a pharmaceutically acceptable salt thereof" is added to the description of the composition. [Brief explanation of the drawings]

[0217] [Figure 1A-1B] 1 is a representative reverse-phase HPLC plot illustrating the general composition of the RUR20kD-IL-2 composition, the preparation of which is described in Examples 1 and 1A. Moving from left to right along the x-axis (elution time, minutes), the purified conjugate composition contains primarily di- and tri-PEGylated rIL-2. [Figure 2] 1 is the amino acid sequence of aldesleukin (125-L-serine-2-133 interleukin-2, recombinant non-glycosylated interleukin-2 expressed in E. coli). [Figure 3] Interim analysis results from a Phase 1b study (NCT04081350) in patients with moderate to severe atopic dermatitis receiving respegaldesleukin, a RUR20kD-IL-2-selective Treg-stimulating composition. The results show the mean percent change from baseline in EASI scores over time in a subset of patients. Patients with moderate to severe atopic dermatitis treated with 24 μg / kg respegaldesleukin administered subcutaneously every two weeks for 12 weeks demonstrated a more robust effect on EASI scores compared with placebo patients. Patients were required to be EASI-50 responders at Week 19 to continue in the study. (EASI = Eczema Area and Severity Index). See also Example 2. [Figure 4] Study Schedule Protocol J1P-MC-KFAD: Treatment and initial follow-up. [Figure 5] Same as above. [Figure 6] Study Schedule Protocol J1P-MC-KFAD: Clinical response follow-up for EASI50 responders at 19-week safety follow-up. [Figure 7] Phase 1b, double-blind, placebo-controlled study KFAD (NCT04081350): Showing change from baseline in EASI scores. [Figure 8A]Changes from baseline in (A) total Treg cells and (B) CD25bright Treg cells in PBO, 12 μg / kg, and 24 μg / kg cohorts are shown. [Figure 8B] Same as above. [Figure 9A] (A) Change from baseline in PASI score from W12 to W19 in the PBO and 24 μg / kg cohorts. (B) Percentage of patients achieving PASI-50 and (C) PASI-75 responses by W19 in the PBO and 24 μg / kg cohorts. [Figure 9B] Same as above. [Figure 9C] Same as above. [Figure 10] Changes from baseline in (A) total Treg cells, (B) CD25bright Treg cells, and (C) Tcon cells in the PBO 24 μg / kg cohort are shown. [Figure 11] 1 shows the J1P-MC-KFAJ trial schema, a phase 2 trial evaluating the efficacy and safety of respegaldesleukin in adults with systemic lupus erythematosus. [Figure 12A]

[0023] Figure 5 shows the study schema for Example 5A Phase 2, randomized, double-blind, parallel-group, placebo-controlled, 52-week study to evaluate the efficacy of respegaldesleukin (LY3471851, NKTR-358) in treating adult patients with moderate to severe atopic dermatitis. [Figure 12B] Same as above. [Figure 13] An overview of the KFAD study design is shown. (a) Full study design not shown; the LY3471851 10 μg / kg cohort was not included in this analysis. (b) Total of 7 doses / patient. EASI50 = 50% improvement from baseline in Eczema Area and Severity Index; PBO = placebo; Q2W = once every 2 weeks; SC = subcutaneous; W = week. [Figure 14]Atopic Dermatitis KFAD Study Results - A dose-dependent trend in percent change from baseline in EASI was observed with respegaldesleukin (LY3471851) compared with PBO through week 48. n = number of patients assessed at visit; EASI = Eczema Area and Severity Index; PBO = placebo; SD = standard deviation. [Figure 15] Results of the KFAD study of atopic dermatitis - Through week 48, a dose-dependent trend in EASI75 response was observed with respegaldesleukin (LY3471851) versus PBO. n = number of responders; EASI75 = 75% improvement from baseline in Eczema Area and Severity Index score; NRI = non-responder imputation; PBO = placebo. [Figure 16] Results of the KFAD study of atopic dermatitis - Up to week 48, a dose-dependent trend in vIGA-AD(0,1) responders was observed with respegaldesleukin (LY3471851) compared with PBO. [Figure 17] Results of the KFAD atopic dermatitis trial - persistence of vIGA-AD(0,1) in week 16 responders. A high percentage of week 16 vIGA-AD(0,1) responders maintained response through week 48 with LY3471851 24 μg / kg. Analysis includes patients who achieved vIGA-AD(0,1) at week 16. n = number of responders, PBO = placebo. [Figure 18] Atopic Dermatitis KFAD Study Results - Itch NRS ≥ 4-point improvement. Through week 48, a dose-dependent trend in itch NRS responders was observed with LY3471851 compared with placebo. N = number of responders; NRI = nonresponder imputation; NRS = numerical rating scale; placebo = placebo. [Figure 19] Summary of KFAC study design: 7 doses total / patient, PBO = placebo; Q2W = once every 2 weeks; SC = subcutaneous; W = week. [Figure 20] Results of the KFAC Psoriasis Trial - Percent Change from Baseline in PASI. PASI improved with LY3471851 versus PBO, and this was maintained through week 19. [Figure 21]Study schema for Example 5A Phase 2, randomized, double-blind, parallel-group, placebo-controlled, 52-week study to evaluate the efficacy of respegaldesleukin (LY3471851, NKTR-358) in the treatment of adult patients with moderate to severe atopic dermatitis, including biologic-naive and biologic-experienced patients. DETAILED DESCRIPTION OF THE INVENTION

[0218] RUR for use in the dosing regimens of the present disclosure 20kD - Preparation and Examples of IL-2-Selective Treg Stimulator Compositions and Formulations It should be understood that the foregoing description and subsequent examples are intended to illustrate, but not limit, the scope of the disclosure provided herein. Other aspects, advantages, and modifications within the scope of the present disclosure will be apparent to those skilled in the art to which the present disclosure pertains. The RUR20kD-IL-2-selective Treg stimulating agent compositions, their formulation preparations, and embodiments described in the Examples set forth below are useful as compositions for use in the therapeutic and / or prophylactic regimens described herein. [Example]

[0219] Materials and Methods Recombinant human IL-2 with an amino acid sequence identical to that of aldesleukin (des-alanyl-1, serine-125 human interleukin-2, see FIG. 2) was cloned, expressed, and used to generate the RUR 20kDAn exemplary selective Treg stimulator composition designated IL-2 is prepared. The sequence is derived from the native mature human IL-2 sequence by removing amino acid #1 (alanine) and by mutating cysteine ​​to serine at amino acid #125. The first amino acid in the sequence is a methionine for direct bacterial expression (no signal peptide is encoded). Upon expression, the N-terminal methionine is removed by host methionine aminopeptidase. A single disulfide bond is formed between the cysteines at amino acid positions #58 and #105. This protein is derived from E. coli and is therefore not glycosylated. In some descriptions, the conjugated IL-2 composition may be described in some respects as (1,3-bis(methoxypoly(ethylene glycol)carbamoyl)-2-propanoxy)-4-butanamide) interleukin-2, but it should be noted that this nomenclature does not fully describe the PEGylation pattern or mixture.

[0220] Polyethylene glycol reagent, mPEG2 (20 kD)-butanoic acid, N-hydroxysuccinimide ester (1,3-bis(methoxypoly(ethylene glycol) 10kD Carbamoyl)-2-propanoxy)-4-succinimidyl butanoate (also referred to herein as mPEG2-ru-20K NHS) is prepared as described in Example 2 of U.S. Pat. No. 7,887,789. Appearance: White to off-white granular powder; molecular weight (Mn) 18-22 kDa (depending on polymer polydispersity). 1,3-bis(methoxypoly(ethylene glycol) 10kD The structure of (carbamoyl)-2-propanoxy)-4-succinimidyl butanoate is shown below. [ka]

[0221] Unless otherwise specified, the RURs provided herein 20kD- Concentrations, amounts, and dosage levels of selective Treg stimulator compositions, such as IL-2 embodiments and related compositions, are reported on a protein basis, which counts only the mass contributed by the protein component and not the mass contributed by the PEG moiety. Using a protein basis reduces the effective RUR used in the calculation. 20kD The molecular weight of the rIL-2 composition is 15.3 kDa, even though it is a mixture of conjugated rIL-2 molecules with various degrees of PEGylation, since only the rIL-2 protein is counted.

[0222] RUR 20kD The IL-2-related composition is a PEGylated conjugate mixture composition consisting of rhIL-2 (preferably, aldesleukin sequences) conjugated to multiple polyethylene glycol (PEG) moieties covalently linked at lysine groups. The number of PEG moieties (degree of PEGylation) per rhIL-2 molecule is primarily a distribution of 2 and 3 PEG moieties per molecule (di- or tri-PEGylation), with minor species containing 1 PEG (mono-PEGylation) and 4 PEG (tetra-PEGylation) and / or higher PEGylated molecules, resulting in an average of approximately 2.5 PEG moieties per rhIL-2. Preferably, each PEG moiety has a nominal molecular weight of 20 kDa, and rhIL-2 has a molecular weight of 15.3 kDa, resulting in a nominal RUR 20kD -IL-2 has a molecular weight of approximately 65 kDa.

[0223] Example 1 RUR 20kD -Preparation of IL-2 and related compositions A stock solution of mPEG2-ru-20K NHS (100 mg / mL) is prepared in 2 mM HCl. A typical PEGylation reaction of IL-2 is performed as follows: 115 mL of IL-2 (aldesleukin) stock solution (1.3 mg / mL) is transferred to a 250 mL plastic bottle, and 15 mL of 0.5 M bicine (N,N-bis(2-hydroxyethyl)glycine), pH 9.2, and 0.5 mL of water are added to the IL-2 solution. PEGylation is initiated by adding 19.5 mL of mPEG2-ru-20K NHS stock solution dropwise to the IL-2-containing solution. The resulting reaction mixture contains 1 mg / mL IL-2, 50 mM bicine, and 10 molar equivalents of mPEG2-ru-20K NHS (relative to the protein), with a pH of 8.7. The reaction is allowed to proceed for 40 minutes at ambient temperature under gentle agitation. The reaction is stopped by adding 2.2 mL of acetic acid to lower the reaction pH to 4.1.

[0224] The resulting IL-2 conjugate product is purified by cation exchange chromatography using SP FF Sepharose. After completion of the conjugation reaction, the reaction mixture is dialyzed against 20 volumes of 10 mM sodium acetate buffer (pH 4.0). The dialyzed sample is diluted 1:4 with water and loaded onto a column packed with SP FF Sepharose resin. The buffers used for cation exchange chromatography are as follows: Buffer A: 10 mM sodium acetate (pH 4.0) and Buffer B: 10 mM sodium acetate, 1.0 M sodium chloride (pH 4.0). Before loading the sample, the resin is washed with Buffer B and equilibrated with Buffer A. After loading, the resin is washed with 3 column volumes of Buffer A. Conjugated and unconjugated IL-2 are eluted at a flow rate of 28 cm / h using a four-step gradient consisting of 0-50% buffer B over 5 column volumes, 25%-50% buffer B over 1 column volume, 50% buffer B over 1 column volume, 50%-100% buffer B over 1 column volume, and 100% buffer B over 1 column volume at a flow rate of 28 cm / h. Fractions containing IL-2 conjugates with degrees of PEGylation (dP) of 2 and 3 (i.e., dimers and trimers) are identified by SDS-PAGE and pooled.

[0225] The pooled dimer- and trimer-containing fractions were concentrated using a stirred ultrafiltration cell (Amicon) and nitrogen gas. The composition of the final product was determined by RP-HPLC using a mobile phase (A = 0.09% TFA in water, B = 0.04% TFA in acetonitrile) on an Intrada WP-RP C18 column (3 × 150 mm) at a flow rate of 0.5 ml / min and a column temperature of 50°C. The purified conjugate mixture was found to contain approximately 4.6% (mol) mono-PEGylated rIL-2, approximately 47.7% (mol) di-PEGylated rIL-2, approximately 42.9% (mol) tri-PEGylated rIL-2, and approximately 4.8% (mol) tetra-PEGylated IL-2. See Figure 1 (elution times are displayed on the x-axis). The average degree of PEGylation of the final product mixture was determined to be 2.48 (i.e., approximately 2.5). No free IL-2 is detected in the final product mixture. This preparation is a RUR of formula A 20kD -An example of a composition of IL-2.

[0226] Example 1-A RUR 20kD - Alternative preparations of IL-2 and related compositions Desired RUR 20kD - Preparation of IL-2 and related compositions involves fermentation and purification of rhIL-2 protein process intermediates, conjugation of rhIL-2 with the PEG reagent starting material mPEG2-ru-20K NHS, purification of IL-2 conjugate fractions with a designated degree of PEGylation, and final formulation of the PEGylated rhIL-2 conjugate to produce IL-2 with a desired distribution of RUR according to embodiments described herein. 20kD - producing an IL-2 composition.

[0227] Desired RUR 20kD -IL-2 composition is 1,3-bis(methoxypoly(ethylene glycol) 10kDCarbamoyl)-2-propanoxy)-4-succinimidyl butanoate (also referred to herein as mPEG2-ru-20K NHS) was prepared by reacting with lysine residues on the interleukin-2 (IL-2) protein (aldesleukin sequence), resulting in a distribution of PEGylated IL-2 conjugates. The products contain primarily di- and tri-PEGylated species, with smaller amounts of mono- and / or tetra-PEGylated species.

[0228] Frozen IL-2 starting material (purified recombinant IL-2 (aldesleukin sequence) in 10 mM acetate, 5% trehalose, pH 4.5 buffer stored at -70 °C) is thawed to room temperature. The PEG reactant, mPEG2-ru-20K NHS (powder), is solubilized by adding it to approximately 90 g / L of 2 mM HCl solution at room temperature and stirred for a minimum of 15 minutes. This solution is then charged into a reaction vessel. The thawed IL-2 is added to the reaction vessel and appropriately diluted with water, followed by the addition of 0.75 M bicine pH 9.7 buffer. The final IL-2 concentration in the reaction mixture is approximately 1.0 g / L, and the bicine concentration is approximately 50 mM to achieve a target pH of 8.7. Generally, to PEGylate proteins, the mass ratio of PEG:rhIL-2 is approximately 10:1 to 13:1 in a bicine buffer solution at pH 8.5-9.5. The reaction is incubated with continuous stirring at 22°C for 40 minutes, measured from the completion of the addition of the mPEG2-ru-20K NHS solution. At the end of the incubation period, the reaction is quenched by adding 1N acetic acid to rapidly lower the pH, followed immediately by a further stepwise titration to pH 4.0 with additional 1N acetic acid. The quenched reaction is diluted 10-fold by the addition of water. The diluted quenched reaction is filtered through a 0.22 μm filter to obtain the crude product.

[0229] The crude product was then subjected to SP SEPHAROSE® Fast Flow cation exchange chromatography to partially separate the PEGylation reaction fraction. The SP SEPHAROSE® Fast Flow cation exchange chromatography column was equilibrated and loaded with the feed material at room temperature with a residence time of approximately 5 minutes, followed by a 5 CV (column volume) wash with loading buffer. PEGylated rhIL-2 binds to the resin, while free PEG is washed away. The product was then eluted with a linear gradient elution using 0 to 500 mM sodium chloride in a 10 mM sodium acetate pH 4.0 buffer background. Elution began at approximately 1 CV, and fractions of 0.15 CV each were collected. Fraction collection was terminated when the absorbance at 280 nm was less than 5% of the peak maximum. The concentration of the PEGylated fraction (i.e., mono-PEGylated IL-2 (monomer), di-PEGylated IL-2 (dimer), tri-PEGylated IL-2 (trimer), tetra-PEGylated IL-2 (tetramer), etc.) in each fraction is measured by absorbance at 280 nm. The distribution of PEGylated fractions is measured by RP-HPLC, as described herein or otherwise known to those skilled in the art, to identify fractions containing mono-PEG, di-PEG, tri-PEG, and higher components and use them to perform RUR as provided herein. 20kD - determining the repooling of fractions necessary to produce an IL-2 composition, particularly a composition with a target PEGylated fraction distribution profile as described in Formulas A-F. After calculating selected fractions of the identified composition, e.g., di-PEG-IL-2 and tri-PEG-IL-2 and / or mono-PEG or higher PEG aliquots, to achieve the target profile as provided herein, RUR having a product with a desired distribution of PEGylated fractions. 20kD- Repooling as needed to obtain the IL-2 composition. Alternatively, purification schemes can be devised that allow for elution and collection to obtain the desired profile according to the embodiments described herein without the need for repooling. The desired (and / or repooled) chromatographically purified preparation is then concentrated and double filtered using tangential flow filtration (TFF) into 10 mM sodium acetate, 150 mM sodium chloride, 2% w / v sucrose, pH 5.0, followed by RUR. 20kD - Achieve a final target concentration of IL-2 composition drug substance: 1 mg / mL (protein basis).

[0230] The repooled and / or target product is analyzed to verify the composition distribution by methods described herein, including RP-HPLC, to assess the PEG fraction profile. 20kD Preparation of compositions according to the specifications herein for IL-2 compositions is exemplified by example product batches numbered 1-4 listed in Table 1 below. Assays for attributes are known to those skilled in the art and / or are assay methods described herein or described, for example, in WO 2019 / 226,538. Suitable historical reference sample compositions have been established and are used for comparison in subsequent preparations.

[0231] [Table 1-1-1]

[0232] [Table 1-1-2]

[0233] [Table 1-1-3]

[0234] In some embodiments, RUR 20kDThe product IL-2 composition contains, on a molar basis, less than 1% free, unconjugated IL-2 (more preferably, no detectable free IL-2), 5% or less mono-PEGylated IL-2, 28% to about 60% di-PEGylated IL-2, about 24% to about 65% tri-PEGylated IL-2, 12% or less higher PEGylated IL-2 species, and a combination of 80% or more di- and tri-PEGylated IL-2 species.

[0235] In some embodiments, RUR 20kD The IL-2 composition product contains, for example, less than 0.5 mol % free IL-2, about 2.5 to about 4.5 mol % mono-PEGylated IL-2, about 35 to about 50 mol % di-PEGylated IL-2, about 38 to about 46 mol % tri-PEGylated IL-2, and about 3 to about 10 mol % higher PEGylated IL-2 species, for a total of about 80 to about 95 mol % combination of di-PEGylated IL-2 and tri-PEGylated IL-2.

[0236] In some embodiments, RUR 20kD The product IL-2 composition may contain, for example, on a molar basis, 5% or less mono-PEGylated IL-2, about 28% to about 60% di-PEGylated IL-2, about 24% to about 65% tri-PEGylated IL-2, and up to 12% higher PEGylated IL-2 species. Preferably, the composition contains a combination of 80% or more di- and tri-PEGylated IL-2 species.

[0237] In some embodiments, RUR 20kD The IL-2 composition product may contain, for example, about 2.5 to about 4.5 mol % mono-PEGylated IL-2, about 35 to about 50 mol % di-PEGylated IL-2, about 38 to about 46 mol % tri-PEGylated IL-2, and about 3 to about 10 mol % higher PEGylated IL-2 species. Preferably, the composition contains a total of about 80 to about 95 mol % di-PEGylated IL-2 and tri-PEGylated IL-2 in combination.

[0238] In some embodiments, RUR 20kDThe IL-2 composition product may contain, for example, about 2.8 to about 3.8 mol % mono-PEGylated IL-2, about 44 to about 48 mol % di-PEGylated IL-2, about 41 to about 44 mol % tri-PEGylated IL-2, and about 7 to about 9 mol % higher PEGylated IL-2 species. Preferably, the composition contains a total of about 87 to about 90 mol % of a combination of di-PEGylated and tri-PEGylated IL-2.

[0239] In some embodiments, RUR 20kD The IL-2 composition product may comprise, for example, about 2.8 to about 3.8 mol % mono-PEGylated IL-2, about 44 to about 48 mol % di-PEGylated IL-2, about 41 to about 44 mol % tri-PEGylated IL-2, and about 7 to about 9 mol % higher PEGylated IL-2 species, the composition comprising a mixture of mono-PEGylated IL-2 conjugates having a PEG moiety attached at one of lysines K7, or K8, or K31, or K75. Preferably, the composition comprises a total of about 87 to about 90 mol % di-PEGylated and tri-PEGylated IL-2 combination.

[0240] In some embodiments, RUR 20kD The IL-2 composition product may comprise, for example, about 2.8 to about 3.8 mol % mono-PEGylated IL-2, about 44 to about 48 mol % di-PEGylated IL-2, about 41 to about 44 mol % tri-PEGylated IL-2, and about 7 to about 9 mol % higher PEGylated IL-2 species, the composition including a mono-PEGylated IL-2 conjugate having a PEG moiety attached at lysine K7. Preferably, the composition comprises a total of about 87 to about 90 mol % di-PEGylated and tri-PEGylated IL-2 combination.

[0241] In some embodiments, RUR 20kDThe IL-2 composition product may contain, for example, about 2-4 mol% or less of mono-PEGylated IL-2 conjugates, about 35 mol% to about 55 mol% of di-PEGylated IL-2 conjugates, about 35 mol% to about 55 mol% of tri-PEGylated IL-2 conjugates, and about 12 mol% or less of higher order PEGylated IL-2 conjugates, wherein each branched polyethylene glycol moiety has a nominal average molecular weight of about 20,000 daltons.

[0242] In some embodiments, RUR 20kD Embodiments of IL-2 and related compositions are referred to herein as "Respegaldesleukin," which are prepared according to the methods described herein and / or in WO 2019 / 226,538 (incorporated herein by reference), and "Respegaldesleukin" compositions correspond, for example, to compositions of Formula A, which comprise, on a molar basis, about 5 mole % or less of a mono-PEGylated IL-2 conjugate, 28 mole % to about 60 mole % of a di-PEGylated IL-2 conjugate, about 24 mole % to about 65 mole % of a tri-PEGylated IL-2 conjugate, and about 12 mole % or less of a higher order PEGylated IL-2 conjugate, each branched polyethylene glycol and / or the "Respegaldesleukin" composition corresponds, for example, to a composition of Formula F, which comprises, on a molar basis, about 2-4 mol % or less of mono-PEGylated IL-2 conjugates, about 35 mol % to about 55 mol % of di-PEGylated IL-2 conjugates, about 35 mol % to about 55 mol % of tri-PEGylated IL-2 conjugates, and about 12 mol % or less of higher-PEGylated IL-2 conjugates, wherein the nominal average molecular weight of each branched polyethylene glycol moiety is about 20,000 daltons; and / or the "Respegaldesleukin" composition is exemplified, for example, by Batches 1-4 listed in Table 1 above. The "Respegaldesleukin" conjugate composition has been assigned CAS Registry Number 2641686-76-0.

[0243] Example 1-B RUR by reversed-phase high-performance liquid chromatography 20kD- Purity and characterization of IL-2 compositions RUR was analyzed using reversed-phase high-performance liquid chromatography (RP-HPLC) on an Agilent 1200 series instrument equipped with a diode array detector (UV at 215 nm). 20kD The chromatographic purity and identity of the IL-2 composition sample is evaluated. The column used is an ACE 3 Phenyl-300 column (Mac-Mod Analytical Inc.) (or other suitable column), with an eluent flow rate of 0.6 mL / min. RP25-HPLC is performed using a gradient containing a mixture of two mobile phases: (1) mobile phase A, 0.1% formic acid in water, and (2) mobile phase B, 0.1% formic acid in acetonitrile. The linear gradient varied from 60% mobile phase A / 40% mobile phase B to 40% mobile phase A / 60% mobile phase B to 20% mobile phase A / 80% mobile phase B to 60% mobile phase A / 40% mobile phase B. The dilution / formulation buffer contains 10 mM sodium acetate, 200 mM sodium chloride, and 2% sucrose at pH 5.0.

[0244] Freezing RUR 20kD - Thaw IL-2 composition standards and samples and dilute to 1.0 mg / mL in formulation buffer. 20kD To ensure that there is no interference in the analysis of the IL-2 composition-related peaks, first, a blank control consisting of one formulation buffer is injected onto the RP-HPLC. 20kD - IL-2 composition standard or control was injected five times. 20kD - Inject the IL-2 composition sample. 20kD - IL-2 composition calibrator / control is injected after every 6 sample injections as well as at the end of the injection sequence.

[0245] Di-PEGylated (di-PEG) and tri-PEGylated (tri-PEG) RUR 20kD The relative standard deviation (RSD) % of retention times for the first five standard injections containing the IL-2 composition is less than or equal to 2.0%. All standards RUR for di-PEG and tri-PEG components 20kD- The RSD area percent (%) of the IL-2 composition injection is less than or equal to 5.0%. All RURs from standard and sample injections 20kD - IL-2 composition peak is integrated. Specifically, RUR at 1.0 mg / mL concentration 20kD - For IL-2 compositions, di-PEG and tri-PEG RUR greater than 0.5% limit of detection (LOD) 20kD -IL-2 composition species and rhIL-2 peaks above 0.3% LOD were integrated. RUR at 1.0 mg / mL concentration 20kD For IL-2, the limit of quantitation (LOQ) was 1.08 for di-PEG and tri-PEG RUR 20kD - 1.0% for IL-2 species and 0.5% for rhIL-2. The analytical results are shown in Table 2 (6 samples) and Table 3 (12 samples) below.

[0246] [Table 2-2]

[0247] [Table 3-1]

[0248] Example 1-C RUR by size-exclusion high-performance liquid chromatography 20kD - Purity and characterization of IL-2 compositions Size-exclusion high-performance liquid chromatography (SEC-HPLC) was used to analyze the RUR using an Agilent 1200 series instrument equipped with a diode array detector (UV at 280 nm) and a Yarra SEC-2000 column (Phenomenex) with an eluent flow rate of 0.225 mL / min. 20kD The purity of the IL-2 composition can also be determined and characterized. The mobile phase was 0.2 M ammonium acetate (pH 5.5) in an 80:20 volume ratio with acetonitrile. The dilution / formulation buffer contained 10 mM sodium acetate, 200 mM sodium chloride, and 2% sucrose at pH 5.0. Frozen RUR 20kD- Thaw IL-2 formulation standards and analytical samples and dilute to 1.0 mg / mL in formulation buffer. Samples are stable in solution at 5°C for up to 5 days.

[0249] The procedure is as follows: 20kD To ensure that there is no interference in the analysis of the IL-2-related peak, first, at least one blank control consisting of the formulation buffer is injected onto the RP-HPLC. 20kD - IL-2 composition, system compatible solution is injected to prevent aggregates or higher molecular weight species from forming tetra-PEG-RUR 20kD - Ensure that the IL-2 fraction is separated from the IL-2 fraction. 20kD - 5 injections of IL-2 composition standard or control. Then RUR 20kD - Inject the IL-2 composition sample. 20kD - IL-2 composition calibrator / control is injected after every 6 sample injections as well as at the end of the injection sequence.

[0250] Di-PEG and Tri-PEG RUR 20kD - The %RSD of the retention time of the IL-2 fraction is ≤ 2.0% for the first five standard injections. Di-PEG and Tri-PEG RUR for all standard injections 20kD - The RSD area percent (%) of IL-2 is 5.0% or less. All RURs from standard and sample injections 20kD - IL-2 fraction peak is integrated. Specifically, RUR at 1.0 mg / mL concentration 20kD - For IL-2 compositions, di-PEG and tri-PEG RUR above 1.0% limit of detection (LOD) 20kD -Integrate the IL-2 fraction. RUR at a concentration of 1.0 mg / mL 20kD In the case of -IL-, only di-PEG and tri-PEG RUR20kD-IL-2 were reported to exceed the LOQ of 3.0%.

[0251] RUR 20kD -Analysis of replicate samples of IL-2 composition is shown in Tables 4 and 5 below, where RUR 20kDPeak areas are provided for the mono-PEG, di-PEG, tri-PEG, tetra-PEG and penta-PEG fractions of the -IL-2 composition.

[0252] [Table 4]

[0253] [Table 5]

[0254] RUR by both RP-HPLC and SEC-HPLC 20kD A summary of representative analyses of various IL-2 compositions is shown in Table 1. As can be seen, RUR 20kD -IL-2 composition preparations show good batch-to-batch consistency with respect to the mixture of PEGylated fractions (i.e., mono-PEGylated, di-PEGylated, tri-PEGylated, tetra-PEGylated, penta-PEGylated, etc.).

[0255] Example 1-D SDS-Page RUR 20kD - To confirm the identity of the IL-2 composition, SDS-PAGE is used. 20kD -IL-2 composition, molecular weight markers and appropriate RUR 20kD Samples of the IL-2 composition standard are loaded onto a NuPAGE Bis-Tris gel and run through the gel. After electrophoresis, the gel is stained with GelCode™ Blue Safe Protein Stain. The identity of the sample is confirmed by comparing the gel banding pattern with that of the standard and confirming the absence of new bands in the sample. The two most intense bands may correspond to the tri-PEGylated and di-PEGylated fractions. The top band in the lane corresponds to the highly PEGylated variant, and the bottom band corresponds to the mono-PEGylated variant.

[0256] Example 1-E CTLL-2 cell proliferation assay In the cell proliferation assay, samples and standards are incubated for approximately 26 hours, after which cell proliferation is measured in vitro using CTLL-2 cells, in this case by a luminescent adenosine triphosphate-based assay (CellTiter-Glo®, Promega, WI). For example, this cell-based proliferation assay uses the CTLL-2 cell line, which exhibits a dose-dependent proliferative response to rhIL-2 protein. rhIL-2 is used as an assay control, and in this method, RUR 20kD -IL-2 compositions are prepared at different concentrations. The assay is performed in a 96-well plate format. CTLL-2 cells are starved of rhIL-2 in starvation medium and incubated overnight at 37°C and in a 5% CO2 incubator for 20±3 hours. Starved cells are plated in 96-well plates and RUR 20kD - Cells are fed with serial dilutions of the IL-2 composition and incubated for an additional 25±3 hours in a 37°C, 5% CO2 incubator. 20kD -IL-2 composition-induced cell proliferation is measured using the CellTiter Glo® detection kit from Promega. CellTiter Glo® generates a luminescent signal proportional to the amount of ATP present in each well, which is directly proportional to the viable cells present. The luminescent signal is read on a SpectraMax M5 plate reader. RUR is determined by plotting the luminescent signal (y-axis) against the concentration (x-axis). 20kD Dose-response curves for the IL-2 composition standard and each sample are generated. The plots are fitted to a four-parameter logistic nonlinear regression model. Parallel Line Analysis (PLA) software is used to perform a test of equivalence of slopes (parallelism), assess the significance of the regression, and calculate the potency ratio of the sample to the standard within the same plate.

[0257] Example 1-F Phospho-STAT5 activation In the phospho-STAT5 assay, downstream cell signaling following receptor binding activates signal transducer and activator of transcription 5 (STAT5) via phosphorylation, promoting gene expression and inducing cell proliferation. Activation of phospho-STAT5 is measured in CTLL-2 cells, an IL-2-dependent murine T lymphocyte cell line, using a phospho-STAT5 / total STAT5 multiplex assay (Meso Scale Discovery, MD) following approximately 10 minutes of sample and standard treatment.

[0258] RUR 20kD -IL-2 selective Treg stimulator composition formulations and delivery devices In one or more further embodiments provided herein, a selective Treg stimulating agent composition is provided, comprising the IL-2 conjugate composition described herein and a pharmaceutically acceptable excipient, and as such, is provided as a selective Treg stimulating agent composition comprising an IL-2 conjugate composition described herein and a pharmaceutically acceptable excipient, and as such ... 20kD -IL-2 embodiments and related compositions.

[0259] A "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" refers to an ingredient that can be included in the compositions described herein and that does not cause significant adverse toxic effects in a subject. Additional suitable pharmaceutically acceptable excipients include, for example, those described in Handbook of Pharmaceutical Excipients, 7th ed., Rowe, R.C., Ed., Pharmaceutical Press, 2012. The compositions of the present disclosure are preferably formulated as pharmaceutical compositions to be administered by any route that makes the composition bioavailable, such as parenteral administration, including intravenous, intramuscular, or subcutaneous administration.

[0260] Subcutaneous administration is preferred for embodiments of the present disclosure. Such pharmaceutical compositions and processes for preparing them are known in the art (see, for example, Remington: The Science and Practice of Pharmacy (DB Troy, Editor, 21st Edition, Lippincott, Williams & Wilkins, 2006)). Useful formulations are described in WO 2019 / 226,538. Further preferred formulations are described below.

[0261] In some embodiments, respegaldesleukin or a pharmaceutical formulation containing respegaldesleukin (e.g., 5 mM sodium acetate, 25 mM sodium chloride, 7.5% (w / v) sucrose, pH 5.0, etc.) is administered to a patient using a subcutaneous administration device. The subcutaneous administration device can be selected from a pre-filled syringe, a disposable pen injection device, a microneedle device, a microinfuser device, a needleless injection device, or an auto-injection device. Various subcutaneous administration devices, including self-injection devices, are known in the art and are commercially available. Exemplary devices include, but are not limited to, pre-filled syringes (such as BD HYPAK SCF®, READYFILL™, and STERIFILL SCF™ from Becton Dickinson; CLEARSHOT™ copolymer pre-filled syringes from Baxter; and Daikyo Seiko CRYSTAL ZENITH® pre-filled syringes available from West Pharmaceutical Services); disposable pen injection devices such as the BD Pen from Becton Dickinson; ultra-sharp devices and microneedle devices (such as the INJECT-EASET™ and micro-infuser devices available from Becton Dickinson and the H-PATCH™ available from Valeritas), as well as needle-free injection devices (such as BIOJECTOR® and IJECT® available from Bioject; and SOF-SERTER® and patch devices available from Medtronic).

[0262] RURs provided herein, including respegaldesleukin 20kD A preferred formulation of the selective Treg stimulator composition, including embodiments of IL-2 and related compositions, is 5 mM sodium acetate, 25 mM sodium chloride, 7.5% (w / v) sucrose, pH 5.0. 20kDThe IL-2 composition can be stored in a sterile, single-use polycarbonate bottle of appropriate volume with a polypropylene cap and silicone liner and is supplied sterile and ready to use. The concentration of the formulation API (e.g., respegaldesleukin) for the 1800 μg dose is selected from 0.9, 1.8, or 3.6 mg / mL protein equivalent, depending on the autoinjector or prefilled syringe used. A preferred delivery device is a 0.5 ml, 1 ml, or 2 ml autoinjector, selected as appropriate for the selected dose, or a prefilled syringe corresponding to the same dose volume. For a 3000 μg dose, the concentration of the formulation API (e.g., respegaldesleukin) will be 1.5, 3.0, or 6.0 mg / mL (depending on the autoinjector or prefilled syringe). Other concentrations required to achieve the required dose and volume can be determined by methods described herein and known to those skilled in the art.

[0263] Respegaldesleukin is being studied in several ongoing or completed trials, including a Phase 2 trial of respegaldesleukin in patients with SLE (NCT04433585), a Phase 2 trial of respegaldesleukin in patients with moderately to severely active ulcerative colitis (NCT04677179), and a Phase 1b trial in patients with atopic dermatitis (NCT04081350) and psoriasis (NCT04119557). Embodiments of the disclosure described herein can be clinically investigated by methods described herein or known to those of skill in the art, such as the study methods described in WO 2019 / 226,538 for SLE patients. The fixed unit dose and / or induction and maintenance dosing regimens described herein can be modified and evaluated in trials for dose, formulation, means of administration, patient selection, dosing frequency, duration of administration, and variations embodied by the induction and maintenance regimens of the disclosure to conform to the limitations of the disclosed embodiments.

[0264] Example 2 A Phase 1, Double-Blind, Randomized, Placebo-Controlled, Multiple-Dose Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Subcutaneous Respegaldesleukin in Patients with Atopic Dermatitis Rationale: The J1P-MC-KFAD study is a phase 1 study designed to evaluate the safety, tolerability, and pharmacokinetics (PK) of multiple subcutaneous (SC) doses of respegaldesleukin in patients with atopic dermatitis (AD). Respegaldesleukin is a recombinant human interleukin-2 (rhIL-2) with a stable, covalently attached polyethylene glycol (PEG) moiety. IL-2 has pleiotropic immunoregulatory functions and plays a specific role in controlling the proliferation and survival of regulatory T (Treg) cells, which are impaired in various autoimmune diseases and inflammatory skin diseases, including AD. Analysis of skin lesions in AD patients has revealed either reduced Treg cell numbers or impaired immunosuppressive function of Treg cells (Nedoszytko et al. 2017). Furthermore, filaggrin-deficient mutations correlate with alterations in circulating Tregs in AD patients (Moosbrugger-Martinz et al. 2018). Dysfunction of Treg cell proliferation and function has been hypothesized to be involved in the pathogenesis of AD and other skin-related inflammatory diseases, and treatment with low-dose IL-2 conjugate therapy (respegaldesleukin) offers the potential to overcome the imbalance between conventional T (Tcon) cells and Treg cells. The goal of respegaldesleukin therapy is to increase the number and function of Treg cells while minimizing effects on Tcon cells in patients with inflammatory diseases such as AD, which may result in beneficial clinical outcomes.

[0265] [Table 7]

[0266] This is a double-blind, randomized, placebo-controlled study evaluating the safety, tolerability, PK, and PD effects of multiple doses of respegaldesleukin in up to two cohorts of patients with AD.

[0267] Treatment Period (through Week 12): Respegaldesleukin or placebo will be administered SC every 2 weeks for a total of 7 doses per patient. The treatment period will be 12 weeks, during which blood and skin samples will be collected, PK and PD measurements will be performed, and physician and patient outcome and safety assessments will be performed. The primary exploratory disease activity assessment will be performed on Day 85 (Week 12) prior to the last dose of study drug.

[0268] Follow-up Period (Weeks 12 to 19): All patients will be monitored for safety, PK, PD, and disease activity assessments until Day 134 (Week 19), 50 days after the last dose of study drug. Patients who do not achieve an Eczema Area and Severity Index (EASI) 50 response on Day 134 will be considered to have completed the study.

[0269] Follow-up period for patients with sustained EASI50 response (Weeks 19 to 48): To assess the durability of response, patients who are EASI50 responders (patient's EASI score has decreased by at least 50% compared to their baseline score) at Day 134 and agree to continue will continue until Week 48 or until they no longer meet the EASI25 response. Patients who continue will visit the clinic every 4 weeks from Week 24 to assess disease activity and PK until Day 337 (Week 48).

[0270] Approximately 50 patients with active AD are planned to be randomly assigned to either the respegaldesleukin group or the placebo group. Each cohort will have up to 20 patients randomly assigned to the respegaldesleukin group and up to 5 patients randomly assigned to the placebo group (matched saline). This will allow approximately 40 patients to complete the study in each cohort. The end of the study will be the date of the last patient visit or last scheduled procedure date as indicated on the last patient activity schedule.

[0271] Statistical Analysis: The safety population will consist of all patients receiving at least one dose of study drug per randomization. The PK population will consist of all randomized patients who received respegaldesleukin and had sufficient PK data to allow meaningful analysis. Adverse events will be classified according to International Medical Dictionary System Organ Class and Preferred Term and summarized by treatment. Other safety data, including vital signs and laboratory values, will be summarized by treatment. Pharmacokinetic parameters will be calculated from plasma concentration-time data after the first dose using standard non-compartmental analytical methods and summarized using descriptive statistics. Data listings and summary statistics will be provided for safety by treatment group over time. For continuous variables, summary statistics will include mean, standard deviation, minimum, maximum, median, and number of observations. For categorical variables, frequency counts and percentages will be provided.

[0272] Activity Schedule Study Schedule Protocol J1P-MC-KFAD: Treatment and First Follow-Up (See Figures 4 and 5) Records of concomitant medications and adverse events will be kept throughout the study period.

[0273] Abbreviations for Figures 4 and 5: BP = blood pressure; BSA = body surface area; C-SSRS = Columbia-Suicide Severity Rating Scale; DLQI = Dermatology Life Quality Index; DNA = deoxyribonucleic acid; EASI = Eczema Area and Severity Index; EASI50 = EASI score in patients with at least a 50% reduction compared to the baseline score; ECG = electrocardiogram; ED = early discontinuation; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; HR = heart rate; IGA = investigator's global assessment; IL = interleukin; IP = investigational drug; mRNA = messenger ribonucleic acid; NRS = pruritus numerical rating scale; PBMC = peripheral blood mononuclear cells; PD = pharmacodynamics; POEM = patient-directed eczema measure; PK = pharmacokinetics; RR = respiratory rate; T = body temperature; TB = tuberculosis; VAS = visual analog scale.

[0274] aOn the day study medication is administered, all procedures are to be completed prior to administration of the dose.

[0275] b Day 85 (Week 12): Key exploratory disease activity assessment and administration of last dose.

[0276] c Day 134 (Week 19): Final study visit for week 12 EASI50 non-responders and week 12 responders who are no longer responding at this visit.

[0277] d A full physical examination, excluding breast and genital examinations, will be performed at screening and at the visit after the last dose of study drug (or ED). A full physical examination will also be required at Visit 14. Symptom-specific physical examinations will be performed at all other scheduled times or as deemed necessary by the investigator.

[0278] e The Self-Harm Follow-Up Form is only required if triggered by the Self-Harm Supplemental Form.

[0279] f A chest radiograph and either a tuberculin skin test or a QuantiFERON®-TB Gold test will be performed.

[0280] g On the day of administration of the study drug, vital signs will be measured before administration and 2 hours ± 15 minutes after administration.

[0281] h On days when ECG or vital signs and blood draws are performed simultaneously, these should be performed at approximately the same time. The ECG should be recorded and vital signs should be measured (in either order) before blood draws. The patient should be in a supine position approximately 5-10 minutes before ECG or vital signs collection and should remain awake in the supine position during ECG collection.

[0282] iThe patient's weight on Day 1 (baseline) will be used to calculate the patient's study drug dose throughout the study.

[0283] j Only collected if ED occurs before week 12 (day 85).

[0284] k To assess acute cardiac effects, ECGs are collected pre-dose and 2 hours (±15 minutes) post-dose.

[0285] l An ECG is collected prior to administration to assess cardiac effects at steady state.

[0286] m Additional laboratory tests, such as local testing, may be performed at any time as determined by the investigator for the emergency management / safety of the patient or as required by local regulations.

[0287] n For blood tests on days 8 and 22, only a 3 mL blood sample is required.

[0288] o A serum pregnancy test will be used at the screening visit; a urine pregnancy test will be performed thereafter.

[0289] p Drug testing may be repeated at the discretion of the investigator.

[0290] q At the end of each designated visit, the investigator will ask the patient if they have any injection site concerns and will record the patient's response according to the Injection Site Assessment and Pain VAS tool, including any new or ongoing injection site reactions or concerns. The Injection Site Assessment and Pain VAS tool will only be completed if there are new injection site concerns and / or reactions or ongoing injection site reactions or concerns from the previous visit.

[0291] rIf an injection site reaction occurs, an optional biopsy can be taken, if needed, at any visit date, preferably Visit 8 (Day 22). Consent must be obtained using the ISR Biopsy Consent Form prior to collection of the ISR biopsy.

[0292] s If an injection site reaction occurs, clinical photography may be used to photograph the injection site, which can be taken at any visit as needed.

[0293] t EASI50 responders will be followed up to week 48.

[0294] Study Schedule Protocol J1P-MC-KFAD: Clinical Response Follow-up for EASI50 Responders at Week 19 Safety Follow-up (See Figure 6) Abbreviations: BP = blood pressure; BSA = body surface area; C-SSRS = Columbia-Suicide Severity Rating Scale; DLQI = Dermatology Life Quality Index; EASI = Eczema Area and Severity Index; ED = early discontinuation; HR = heart rate; IGA = Investigator Global Assessment; NRS = Pruritus Numerical Rating Scale; POEM = Patient-Oriented Eczema Measure; PK = pharmacokinetics.

[0295] Study population: Patient eligibility for inclusion in the study will be based on screening results of medical history, physical examination, vital signs, laboratory tests, and ECG. Vital sign measurements may be repeated once if any measurements are out of range. The nature of any condition present at the time of physical examination and any pre-existing conditions will be recorded. Screening may occur up to 28 days prior to enrollment. Patients not enrolled within 28 days of screening may undergo additional medical evaluation and / or clinical measurements to confirm eligibility. Pre-approved protocol deviations (also known as protocol waivers or exemptions) to recruitment and enrollment criteria will not be permitted.

[0296] Participation criteria: Patients are eligible to participate in this study only if they meet all of the following criteria at screening and / or enrollment: 1. Patients with a diagnosis of AD at least 12 months prior to screening as defined by the American Academy of Dermatology: Clinical Practice Guideline for the Management of Atopic Dermatitis; Section 1. Diagnosis and evaluation of moderate to severe atopic dermatitis, including all of the following (Eichenfield et al., 2014): 2. EASI score ≥ 16 at baseline (Day 1) 3. Investigator Global Assessment (IGA) score ≥ 3 at baseline (Day 1) 4. Baseline (Day 1) body surface area (BSA) lesions ≥ 10% 5. History of an inadequate response to existing topical medications within 6 months prior to screening, as documented by a physician and / or investigator, or history of intolerance to topical therapy as defined by at least one of the following: 6. Failure to achieve good disease control, defined as mild or better (e.g., IGA ≤ 2), after use of at least medium-potency topical corticosteroids (TCS) for at least 4 weeks or the maximum duration recommended by the product prescribing information (e.g., 14 days for extra-potency TCS). (Note: TCS may be used with or without a topical calcineurin inhibitor [TCNI]). or 7. Documented history of clinically significant adverse events from TCS use, such as skin atrophy, allergic reactions, or systemic effects, that, in the opinion of the investigator, outweigh the benefits of retreatment; and / or 8. Within 6 months prior to screening, systemic therapy for AD treatment, such as cyclosporine, methotrexate, azathioprine, and mycophenolate mofetil, has failed (considered to have had an inadequate response to local therapy) 9. Agree to discontinue use of the following excluded medications for at least 2 weeks prior to Baseline (Day 1) and throughout the study: 10. Topical corticosteroids or topical immunomodulators (e.g., tacrolimus or pimecrolimus), and 11. Topical phosphodiesterase type 4 (PDE4) inhibitors (crisaborole) 12.Applied emollients daily for at least 14 days prior to baseline (Day 1) and consented to use emollients throughout the treatment period. 13. Men and women aged 18-70 years at the time of screening who agree to comply with contraception requirements 14. Body mass index (BMI) is 18.0 to 45.0 kg / m 2 is (inclusive) 15. Clinical test results that are within the normal reference range for the population or clinical trial site, or results with acceptable deviations that the investigator deems not clinically significant 16. Sufficient venous access to allow blood sampling 17. Be reliable and willing to be available throughout the study period and to follow study procedures. 18. Willing and able to undergo biopsy of skin lesions on days 1, 22, and 85 of the study 19. Willing and able to give signed informed consent; and 20. Willing and able to participate in the study for up to 6 months.

[0297] Exclusion criteria: Patients will be excluded from study enrollment if they meet any of the following criteria at screening and / or enrollment: 21. Clinical trial site personnel directly involved in this study and their close relatives (spouse, biological or legal guardian, children, or siblings) 22. Lilly employees or employees of third-party organizations involved in this study 23. Individuals currently enrolled in clinical trials involving investigational new drugs (IPs) or other types of medical research that are deemed scientifically or medically incompatible with this study. 24. Subjects who have previously completed or discontinued this study or any other clinical trial investigating respegaldesleukin, or who have previously received IP 25. Known allergy to respegaldesleukin, related compounds, or any component of the preparation 26. Clinically significant ECG abnormalities, including a QT interval corrected using the Fridericia formula >450 msec in men and >470 msec in women 27. History of additional risk factors for Torsades de Pointes (e.g., heart failure, hypokalemia, long QT syndrome) 28. Concomitant use of drugs that prolong the QT / QTc interval (excluding drugs that may be used to treat depression) 29. Clinically relevant blood pressure (BP) and / or heart rate (HR) abnormalities as determined by the investigator 30. Evidence of significant liver or renal dysfunction (including any of the following at screening): 1.Modification of Diet in Renal Disease formula: 1. Glomerular filtration rate (mL / min / 1.73 m2) = 175 × (Scr) - 1.154 × (age) - 0.203 × (0.742 for women) × (1.212 for African Americans) Estimated glomerular filtration rate ≤ 60 mL / min using 2. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), or alkaline phosphatase (ALP) >1.5 times the upper limit of normal (ULN), or 3. Total bilirubin (TBL) > 1.5 times ULN 31. History of significant cardiovascular disease (e.g., myocardial infarction, congestive heart failure, uncontrolled hypertension, cerebrovascular accident), thrombotic episode, or serious medical illness in the opinion of the investigator within the past year. 32. Significant hematological dysfunction at screening, including any of the following: 1. Hemoglobin < 10.0 g / dL 2. Absolute neutrophil count <1.8 × 109 / L 3. White blood cell count (WBC) < 3.6 × 109 / L 4. Absolute lymphocyte count ≤ 0.8 × 109 / L 5. Platelet count <100 × 109 / L, or 6. Eosinophil count > 3000 mL 33.Currently experiencing or having a history of other concomitant skin diseases (e.g., PsO or cutaneous lupus) that may interfere with the evaluation of the effect of the study drug on AD 34. Patients currently experiencing or have a history of erythroderma, refractory, or unstable skin disease requiring frequent hospitalization and / or IV treatment for skin infections, which, in the opinion of the investigator, may preclude participation in this study. 35. History of herpetic eczema within 12 months prior to screening 36. History of 2 or more herpetic eczema episodes 37. Patients currently experiencing a skin infection requiring or currently being treated with topical or systemic antibiotics Note: Patients may not be rescreened until at least 4 weeks have passed since the date of the previous failed screen and at least 2 weeks have passed since the infection was resolved. 38. Serious intercurrent illness (e.g., unstable chronic asthma) that requires the use of systemic corticosteroids or that would otherwise interfere with study participation or require active and frequent monitoring. 39. History of any disease other than AD that required treatment with oral or parenteral corticosteroids for more than 2 weeks within the 24 weeks prior to signing the informed consent form (ICF). 40. History of primary immunodeficiency, splenectomy, or underlying disease that predisposes the subject to infection 41. The exclusion criteria

[33] were removed. 42. Medical history of major surgery within 12 weeks of screening or requiring major surgery during the study 43. Subjects deemed by the investigator to be at significant risk for suicide based on the following criteria: Those who have had suicidal thoughts or behaviors within the past six months and answered "yes" to questions 4 or 5 of the Columbia-Suicide Severity Rating Scale (C-SSRS) for "suicidal thoughts"; or Those who answered "yes" to any suicide-related behavior in the "Suicidal Behavior" question of the C-SSRS 44. Persons who regularly use known drugs of abuse and / or have positive drug screen results. 45. History of alcohol or other drug abuse within the past year 46. ​​Evidence of HIV infection and / or positive human HIV antibody test 47. Evidence of hepatitis B and / or positive hepatitis B surface antigen and / or positive hepatitis B core antibody at screening (even if negative for hepatitis B surface antigen) 48. Evidence of hepatitis C and / or positive hepatitis C antibodies at screening Note Patients previously diagnosed with hepatitis C who have been treated with antiviral therapy and have achieved sustained virologic response may also be eligible to participate in this study if they have undetectable hepatitis C virus (HCV) RNA as screened by this protocol. Sustained virologic response is defined as undetectable HCV RNA 24 weeks after completion of a full documented course of approved antiviral therapy for HCV.

[0298] Patients with spontaneous resolution of HCV infection, defined as: a. HCV antibody test positive, and b. Patients with a negative HCV RNA test and no history of anti-HCV therapy may be eligible to participate in the study if their HCV RNA is undetectable at screening. Patients who exhibit behaviors that put them at risk for reinfection with HCV, as determined by the investigator, may be excluded from the study.

[0299] Patients with a history of HCV infection who achieve elevated ALT levels ≥ 3xULN during the study will undergo HCV RNA testing in addition to a thorough liver evaluation. Any person diagnosed with hepatitis C during the study will be excluded from the study and will be required to receive appropriate follow-up medical care. 49. Breastfeeding women 50.Subjects who have donated more than 500 mL of blood within 4 weeks prior to study screening 51.Subjects who have received blood products within 6 months of screening 52.Subjects who have had symptoms of shingles within 3 months prior to screening 53. Individuals who have documented evidence of active or latent TB from a medical history and chest radiograph (posterior-anterior chest radiograph; interpreted by a radiologist, pulmonologist, or designated physician; lateral chest radiograph may be performed if clinically or radiologically appropriate) and / or a positive TB test, defined as: a positive tuberculin skin test (TST) (defined as a skin induration >5 mm after 48-72 hours with or without BCG (bacille Calmette-Guerin) TB vaccination), or Positive or two consecutive indeterminate QuantiFERON®-TB Gold test results Note The choice of whether to administer the TST or QuantiFERON-TB Gold test will be determined by the investigator according to local approval and standard of care. The QuantiFERON-TB Gold test can only be used in countries where it is approved. 54. Have received a live vaccine (including live attenuated vaccines) within 4 weeks of screening or are willing to receive one during the study and for 5 drug half-lives after the last dose (up to Week 19) 55. Have received BCG vaccination within 12 months of screening or are willing to receive BCG vaccination during the study period and for 5 drug half-lives after the last dose of the study 56. Have received treatment with a biologic (such as a monoclonal antibody, including over-the-counter drugs) within 3 months or 5 half-lives (whichever is longer) prior to administration. Note Patients previously treated with dupilumab must not have received dupilumab within 6 months of baseline (Day 1). 57.Received small molecule IP within 4 weeks or 5 half-lives prior to screening, whichever is longer. 58. A history of clinically significant drug hypersensitivity reactions that, in the opinion of the investigator, may predispose the patient to clinically significant hypersensitivity reactions to respegaldesleukin or its formulation excipients, or 59. Intolerance to TCS 60. Has received parenteral corticosteroids administered by intra-articular, intramuscular, or IV injection within 2 weeks prior to study entry or within 6 weeks prior to the scheduled baseline date (Day 1), or is expected to require parenteral corticosteroids during the study. Note The use of nasal or inhaled steroids is permitted during the study. 61. Received aldesleukin or an investigational IL-2 analog at any time 62. Have received or plan to continue receiving any of the following medications / treatments throughout the study within 4 weeks prior to Baseline (Day 1): 63. Oral systemic corticosteroid and leukotriene inhibitors 64. Systemic immunomodulators (including but not limited to cyclosporine, methotrexate, mycophenolate mofetil, azathioprine, and Janus kinase (JAK) inhibitors (tofacitinib, ruxolitinib)) 65. Other systemic therapies (approved or off-label) used to treat AD or symptoms of AD; or 66. Phototherapy, including therapeutic phototherapy (psoralen + UVA, UVB), excimer laser, or tanning bed 67. Medical history of organ transplant or bone marrow transplant 68. Lymphoma, leukemia, or malignant tumor within the past 5 years (with the following exceptions): Excised basal cell or squamous cell carcinoma of the skin with no evidence of metastasis for 3 years, or Cervical intraepithelial neoplasia with no evidence of recurrence within 5 years prior to baseline 69. Breast cancer within the past 10 years, or 70. In the opinion of the investigator or sponsor, the participant is inappropriate for participation in this study. 71. Current or recent acute active infection. At least 30 days prior to screening, you must have had no significant symptoms, such as fever of 100.5°F (38°C) or higher at screening or baseline, no signs of confirmed or suspected infection, and have completed appropriate anti-infective treatment. 72. Have had any of the following infections within 6 months of screening: 1) Severe infection (requiring hospitalization and / or IV antibiotic treatment) 2) opportunistic infections (as defined by Winthrop et al. 2015 ); 3) Shingles is considered active and ongoing until all vesicles have dried and crusted. 4) Chronic infection (symptoms, signs, and / or treatment for 6 weeks or more) 5) Recurrent infections (including but not limited to herpes simplex, shingles, recurrent cellulitis, and chronic osteomyelitis) Patients with only recurrent, mild, and uncomplicated herpes labialis and / or genital herpes may be discussed with Lilly or a Lilly-designated medical monitor regarding possible immunity to this exclusion criterion.

[0300] Treatment: The respegaldesleukin formulation is a sterile solution for SC injection. The placebo dosing solution is 0.9% sodium chloride injection (USP). Preparation of the respegaldesleukin formulation for injection and the placebo dosing solution will be open-labeled by a pharmacist.

[0301] The study drug is administered as a SC injection. The formulation is administered using no more than four injections, each of no more than 2.0 mL (maximum total volume 8.0 mL). c. The injection site selected for SC administration is the abdominal region approximately 5 cm from the navel, with the needle applied at an angle of approximately 45° while pinching the skin. d. If more than one injection is given per day, administer the injections into the following abdominal quadrants in clockwise order (only one injection per quadrant), with all injections planned to deliver the full intended dose being administered within a maximum of 5 minutes. e. If ISR remains in one abdominal site, do not use that site until the ISR has resolved (to avoid confounding AE assessment). f. Subcutaneous administration of study medication should be limited to a limited number of people to ensure consistency.

[0302] IP will be stored, inventoried, reconstituted, and disposed of in accordance with all applicable regulations. Clinical trial material will be manufactured in accordance with current good manufacturing practice. Respegaldesleukin will be supplied as a solution in vials for use in clinical trials. Each 0.5 mL vial will be manufactured to administer 0.5 mg of respegaldesleukin. Vials will be shipped in cartons containing the appropriate amount for the planned dispensing schedule of IP. Placebo will be 0.9% sodium chloride for all cohorts. When prepared for administration according to the instructions, respegaldesleukin and placebo are indistinguishable. Investigational product will be prepared by unblinded pharmacy staff or pharmacists who are not involved in other study-related procedures.

[0303] On Day 1 of each cohort period, patients who meet all screening and eligibility criteria will be randomized in a 4:1 ratio within treatment arms to either respegaldesleukin or placebo. Treatment assignment will be determined by a computer-generated random sequence using an interactive web response system (IWRS). Block sizes will b...

Claims

1. 1. A method of treating a human subject having an autoimmune disease, comprising administering to a subject a selective Treg stimulatory agent RUR at a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose. ２０ｋＤ - administering to said human subject an IL-2 composition, said composition comprising a composition of formulae A-F.

2. 2. The method of claim 1, wherein the composition is a composition of Formula A, the composition comprising, on a molar basis, about 5 mol % or less of mono-PEGylated IL-2 conjugates, about 28 mol % to about 60 mol % of di-PEGylated IL-2 conjugates, about 24 mol % to about 65 mol % of tri-PEGylated IL-2 conjugates, and about 12 mol % or less of higher order PEGylated IL-2 conjugates, wherein the nominal average molecular weight of each branched polyethylene glycol moiety is about 20,000 Daltons.

3. 2. The method of claim 1, wherein the composition is a composition of Formula F, the composition comprising, on a molar basis, about 2-4 mol % or less of mono-PEGylated IL-2 conjugates, about 35 mol % to about 55 mol % of di-PEGylated IL-2 conjugates, about 35 mol % to about 55 mol % of tri-PEGylated IL-2 conjugates, and about 12 mol % or less of higher order PEGylated IL-2 conjugates, wherein the nominal average molecular weight of each branched polyethylene glycol moiety is about 20,000 Daltons.

4. 2. The method of claim 1, wherein the composition is a composition of Formula B, the composition comprising, on a molar basis, about 2.5 to about 4.5 mole % of a mono-PEGylated IL-2 conjugate, about 35 to about 50 mole % of a di-PEGylated IL-2 conjugate, about 38 to about 46 mole % of a tri-PEGylated IL-2 conjugate, and about 3 to about 10 mole % of a higher order PEGylated IL-2 conjugate, wherein the nominal average molecular weight of each branched polyethylene glycol moiety is about 20,000 Daltons.

5. 2. The method of claim 1, wherein the composition is a composition of Formula C, the composition comprising, on a molar basis, about 2.8 to about 3.8 mole % of a mono-PEGylated IL-2 conjugate, about 44 to about 48 mole % of a di-PEGylated IL-2 conjugate, about 41 to about 44 mole % of a tri-PEGylated IL-2 conjugate, and about 7 to about 9 mole % of a higher order PEGylated IL-2 conjugate, wherein the nominal average molecular weight of each branched polyethylene glycol moiety is about 20,000 Daltons.

6. 2. The method of claim 1, wherein the composition is a composition of Formula C, the composition comprising, on a molar basis, about 2.8 to about 3.8 mol % mono-PEGylated IL-2 conjugates, about 44 to about 48 mol % di-PEGylated IL-2 conjugates, about 41 to about 44 mol % tri-PEGylated IL-2 conjugates, and about 7 to about 9 mol % higher order PEGylated IL-2 conjugates, the composition comprising a mixture of mono-PEGylated IL-2 conjugates having a PEG moiety attached at one of lysines K7, or K8, or K31, or K75, and wherein the nominal average molecular weight of each branched polyethylene glycol moiety is about 20,000 daltons.

7. The method of claim 1 , wherein the composition comprises respegaldesleukin.

8. 10. The method of claim 1, wherein the administration is performed once every two weeks or once every four weeks.

9. 10. The method of claim 1, wherein the administration is performed once every two weeks.

10. 10. The method of claim 1, wherein the administration is performed once every four weeks.

11. 11. The method of any one of claims 1-10, wherein the composition further comprises a formulation of about 5 mM sodium acetate, about 25 mM sodium chloride, about 7.5% (w / v) sucrose at a pH of about 5.

0.

12. The method according to any one of claims 1 to 11, wherein the autoimmune disease is selected from systemic lupus erythematosus (SLE), ulcerative colitis, Crohn's disease, rheumatoid arthritis, atopic dermatitis, systemic sclerosis, ankylosing spondylitis, graft-versus-host disease, polymyositis; type 1 diabetes, Addison's disease, Hashimoto's thyroiditis, Graves' disease, Sjogren's syndrome, vitiligo, pernicious anemia, glomerulonephritis, lupus nephritis, myasthenia gravis, Goodpasture's syndrome, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, peanut allergy, pulmonary fibrosis, celiac disease, alopecia areata, psoriasis, hidradenitis suppurativa, or asthma.

13. 13. The method of any one of claims 1 to 12, wherein the dose is about 450 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg or about 2100 μg per dose.

14. The method of any one of claims 1 to 12, wherein the dose is about 900 μg per dose.

15. The method of any one of claims 1 to 12, wherein the dose is about 1200 μg per dose.

16. The method of any one of claims 1 to 12, wherein the dose is about 1500 μg per dose.

17. The method of any one of claims 1 to 12, wherein the dose is about 1800 μg per dose.

18. The method of any one of claims 1 to 13, wherein the dose is about 2100 μg per dose.

19. The method of any one of claims 1 to 13, wherein the dose is about 2400 μg per dose.

20. The method of any one of claims 1 to 13, wherein the dose is about 2700 μg per dose.

21. The method of any one of claims 1 to 13, wherein the dose is about 3000 μg per dose.

22. The method according to any one of claims 1 to 21, wherein the autoimmune disease is systemic lupus erythematosus (SLE).

23. The method according to any one of claims 1 to 21, wherein the autoimmune disease is atopic dermatitis.

24. The method of any one of claims 1 to 21, wherein the autoimmune disease is atopic dermatitis and the atopic dermatitis patient is biologic experienced.

25. The method according to any one of claims 1 to 21, wherein the autoimmune disease is type 1 diabetes.

26. The method according to any one of claims 1 to 21, wherein the autoimmune disease is peanut allergy.

27. 1. A method of treating a human subject having an autoimmune disease comprising administering to the human subject a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of respegaldesleukin during an induction phase, the method comprising administering to the human subject a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose said respegaldesleukin being administered for a total of 12 weeks, a total of 16 weeks, a total of 20 weeks, or a total of 24 weeks of administration during said induction phase; followed by administration of respegaldesleukin at a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose. a maintenance phase comprising administering to said human subject a pegaldesleukin, said administration occurring once every 2 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 12 weeks, once every 24 weeks, once every 36 weeks, once every 48 weeks or once every 52 weeks; said pegaldesleukin being administered for a total of 4 to 52 weeks of administration or for a total of 1 to 5 years of administration; said autoimmune disease being systemic lupus erythematosus (SLE), ulcerative colitis, , Crohn's disease, rheumatoid arthritis, atopic dermatitis, systemic sclerosis, ankylosing spondylitis, graft versus host disease and polymyositis; type 1 diabetes, Addison's disease, Hashimoto's thyroiditis, Graves' disease, Sjogren's syndrome, vitiligo, pernicious anemia, glomerulonephritis, lupus nephritis, myasthenia gravis, Goodpasture's syndrome, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, peanut allergy, pulmonary fibrosis, celiac disease, alopecia areata, psoriasis, hidradenitis suppurativa or asthma.

28. 28. The method of claim 27, wherein the dose of respegaldesleukin in the induction phase comprises 900 μg.

29. 28. The method of claim 27, wherein the dose of respegaldesleukin in the induction phase comprises 1200 μg.

30. 28. The method of claim 27, wherein the dose of respegaldesleukin in the induction phase comprises 1500 μg.

31. 28. The method of claim 27, wherein the dose of respegaldesleukin in the induction phase comprises 1800 μg.

32. 28. The method of claim 27, wherein the dose of respegaldesleukin in the induction phase comprises 2100 μg.

33. 28. The method of claim 27, wherein the dose of respegaldesleukin in the induction phase comprises 2400 μg.

34. 28. The method of claim 27, wherein the dose of respegaldesleukin in the induction phase comprises 2700 μg.

35. 28. The method of claim 27, wherein the dose of respegaldesleukin in the induction phase comprises 3000 μg.

36. The method of any one of claims 27 to 35, wherein the dose of respegaldesleukin in the maintenance phase comprises 900 μg.

37. The method of any one of claims 27 to 35, wherein the dose of respegaldesleukin in the maintenance phase comprises 1200 μg.

38. The method of any one of claims 27 to 35, wherein the dose of respegaldesleukin in the maintenance phase comprises 1500 μg.

39. The method of any one of claims 27 to 35, wherein the dose of respegaldesleukin in the maintenance phase comprises 1800 μg.

40. The method of any one of claims 27 to 35, wherein the dose of respegaldesleukin in the maintenance phase comprises 2100 μg.

41. The method of any one of claims 27 to 35, wherein the dose of respegaldesleukin in the maintenance phase comprises 2400 μg.

42. The method of any one of claims 27 to 35, wherein the dose of respegaldesleukin in the maintenance phase comprises 2700 μg.

43. The method of any one of claims 27 to 35, wherein the dose of respegaldesleukin in the maintenance phase comprises 3000 μg.

44. 36. The method of any one of claims 27 to 35, wherein the induction dose is administered once every two weeks.

45. 36. The method of any one of claims 27 to 35, wherein the induction dose is administered once every four weeks.

46. 36. The method of any one of claims 27 to 35, wherein the maintenance dose is administered once every four weeks.

47. 36. The method of any one of claims 27 to 35, wherein the maintenance dose is administered once every 8 weeks.

48. 36. The method of any one of claims 27 to 35, wherein the maintenance dose is administered once every 12 weeks.

49. 36. The method of any one of claims 27 to 35, wherein the maintenance dose is administered once every 24 weeks.

50. 36. The method of any one of claims 27 to 35, wherein the maintenance dose is administered once every 36 weeks.

51. 36. The method of any one of claims 27-35, wherein the maintenance dose is administered once every 48 weeks.

52. 36. The method of any one of claims 27-35, wherein the maintenance dose is administered once every 52 weeks.

53. A method of treating moderate to severe atopic dermatitis in a patient in need thereof comprising administering to the human subject a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of respegaldesleukin during an induction phase, which is performed once every week, once every two weeks, once every three weeks, once every four weeks, once every six weeks, or once every eight weeks; wherein the respegaldesleukin is administered for a total of 12 weeks, a total of 16 weeks, a total of 20 weeks, or a total of 24 weeks of administration during the induction phase; and detecting after the induction period that the patient is responsive to the respegaldesleukin. determining whether said patient is a responder to respegaldesleukin; and if said patient is a responder, administering respegaldesleukin to said patient at a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose. and advancing to a maintenance phase comprising administering to the subject once every 2 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 12 weeks, once every 24 weeks, once every 36 weeks, once every 48 weeks, or once every 52 weeks; and the respegaldesleukin is administered for a total of 4 to 52 weeks of administration or for a total of 1 to 5 years of administration.

54. 1. A method of reducing sleep deprivation in a patient having moderate to severe atopic dermatitis in a patient in need thereof, comprising administering to said human subject a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg or about 3600 μg per dose of respegaldesleukin during an induction phase, said respegaldesleukin being administered for a total of 12 weeks, a total of 16 weeks, a total of 20 weeks or a total of 24 weeks of administration during said induction phase; determining whether the patient is a responder to respegaldesleukin; and if said patient is a responder, administering respegaldesleukin at a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose. and advancing to a maintenance phase comprising administering to the human subject once every 2 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 12 weeks, once every 24 weeks, once every 36 weeks, once every 48 weeks, or once every 52 weeks; and the respegaldesleukin is administered for a total of 4 to 52 weeks of administration or for a total of 1 to 5 years of administration.

55. A selective Treg stimulator (RUR) comprising a composition of formulae A-F for use in treating an autoimmune disease in a patient. ２０ｋＤ - IL-2 and related compositions, wherein the patient is administered a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg or about 3600 μg per dose, ２０ｋＤ -IL-2 and related compositions.

56. 56. The use of claim 55, wherein the composition is a composition of Formula A, the composition comprising, on a molar basis, about 5 mol % or less of mono-PEGylated IL-2 conjugates, about 28 mol % to about 60 mol % of di-PEGylated IL-2 conjugates, about 24 mol % to about 65 mol % of tri-PEGylated IL-2 conjugates, and about 12 mol % or less of higher order PEGylated IL-2 conjugates, wherein the nominal average molecular weight of each branched polyethylene glycol moiety is about 20,000 Daltons.

57. 56. The use of claim 55, wherein the composition is a composition of Formula F, the composition comprising, on a molar basis, about 2-4 mol % or less of mono-PEGylated IL-2 conjugates, about 35 mol % to about 55 mol % of di-PEGylated IL-2 conjugates, about 35 mol % to about 55 mol % of tri-PEGylated IL-2 conjugates, and about 12 mol % or less of higher order PEGylated IL-2 conjugates, wherein the nominal average molecular weight of each branched polyethylene glycol moiety is about 20,000 Daltons.

58. 56. The use of claim 55, wherein the composition is a composition of Formula B, the composition comprising, on a molar basis, about 2.5 to about 4.5 mole % of a mono-PEGylated IL-2 conjugate, about 35 to about 50 mole % of a di-PEGylated IL-2 conjugate, about 38 to about 46 mole % of a tri-PEGylated IL-2 conjugate, and about 3 to about 10 mole % of a higher order PEGylated IL-2 conjugate, wherein the nominal average molecular weight of each branched polyethylene glycol moiety is about 20,000 Daltons.

59. 56. The use of claim 55, wherein the composition is a composition of Formula C, the composition comprising, on a molar basis, about 2.8 to about 3.8 mole % of a mono-PEGylated IL-2 conjugate, about 44 to about 48 mole % of a di-PEGylated IL-2 conjugate, about 41 to about 44 mole % of a tri-PEGylated IL-2 conjugate, and about 7 to about 9 mole % of a higher order PEGylated IL-2 conjugate, wherein the nominal average molecular weight of each branched polyethylene glycol moiety is about 20,000 Daltons.

60. 56. The use of claim 55, wherein the composition is a composition of Formula C, the composition comprising, on a molar basis, about 2.8 to about 3.8 mol % mono-PEGylated IL-2 conjugates, about 44 to about 48 mol % di-PEGylated IL-2 conjugates, about 41 to about 44 mol % tri-PEGylated IL-2 conjugates, and about 7 to about 9 mol % higher order PEGylated IL-2 conjugates, the composition comprising a mixture of mono-PEGylated IL-2 conjugates having a PEG moiety attached at one of lysines K7, or K8, or K31, or K75, and wherein the nominal average molecular weight of each branched polyethylene glycol moiety is about 20,000 daltons.

61. 56. The use of claim 55, wherein the composition comprises respegaldesleukin.

62. 56. The use of claim 55, wherein the administration is performed once every two weeks or once every four weeks.

63. 56. The use of claim 55, wherein the administration is performed once every two weeks.

64. 56. The use of claim 55, wherein the administration is performed once every four weeks.

65. 65. The use of any one of claims 55 to 64, wherein the dose further comprises a formulation of 5 mM sodium acetate, 25 mM sodium chloride, 7.5% (w / v) sucrose, pH 5.

0.

66. 65. The use according to any one of claims 55 to 64, wherein the autoimmune disease is selected from systemic lupus erythematosus (SLE), ulcerative colitis, Crohn's disease, rheumatoid arthritis, atopic dermatitis, systemic sclerosis, ankylosing spondylitis, graft versus host disease, polymyositis; type 1 diabetes, Addison's disease, Hashimoto's thyroiditis, Graves' disease, Sjogren's syndrome, vitiligo, pernicious anemia, glomerulonephritis, lupus nephritis, myasthenia gravis, Goodpasture's syndrome, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, peanut allergy, pulmonary fibrosis, celiac disease, alopecia areata, psoriasis, hidradenitis suppurativa or asthma.

67. 67. The use according to any one of claims 55 to 66, wherein the dose is about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg or about 3600 μg per dose.

68. 67. The use according to any one of claims 55 to 66, wherein the dose is about 900 μg per dose.

69. 67. The use according to any one of claims 55 to 66, wherein the dose is about 1200 μg per dose.

70. 67. The use according to any one of claims 55 to 66, wherein the dose is about 1500 μg per dose.

71. 67. The use according to any one of claims 55 to 66, wherein the dose is about 1800 μg per dose.

72. 67. The use according to any one of claims 55 to 66, wherein the dose is about 2100 μg per dose.

73. 67. The use according to any one of claims 55 to 66, wherein the dose is about 2400 μg per dose.

74. 67. The use according to any one of claims 55 to 66, wherein the dose is about 2700 μg per dose.

75. The use according to any one of claims 55 to 66, wherein the dose is about 3000 μg per dose.

76. The use according to any one of claims 55 to 75, wherein the autoimmune disease is systemic lupus erythematosus (SLE).

77. The use according to any one of claims 55 to 75, wherein the autoimmune disease is atopic dermatitis.

78. 76. The use according to any one of claims 55 to 75, wherein the autoimmune disease is atopic dermatitis and the atopic dermatitis patient is biologic experienced.

79. The use according to any one of claims 55 to 75, wherein the autoimmune disease is type 1 diabetes.

80. The use according to any one of claims 55 to 75, wherein the autoimmune disease is peanut allergy.

81. A selective Treg stimulator (RUR) comprising a composition of formulae A-F for use in treating an autoimmune disease in a patient. ２０ｋＤ - IL-2 and related compositions, wherein the patient is administered a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg or about 3600 μg per dose during the induction phase; said administration being performed once every week, once every two weeks, once every three weeks, once every four weeks, once every six weeks or once every eight weeks; The composition is administered for a total of 12 weeks, a total of 16 weeks, a total of 20 weeks, or a total of 24 weeks of administration in the induction phase; followed by a maintenance phase comprising administering to the human subject a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose. wherein the administration is performed once every 2 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 12 weeks, once every 24 weeks, once every 36 weeks, once every 48 weeks, or once every 52 weeks; there is a maintenance phase in which the respegaldesleukin is administered for a total of 4 weeks to 52 weeks of administration or for a total of 1 to 5 years of administration; and the autoimmune disease is systemic lupus erythematosus (SLE), ulcerative colitis, Crohn's disease, rheumatoid arthritis, atopic dermatitis, or other skin diseases. a selective Treg stimulator RUR selected from dermatitis, systemic sclerosis, ankylosing spondylitis, graft-versus-host disease, and polymyositis; type 1 diabetes, Addison's disease, Hashimoto's thyroiditis, Graves' disease, Sjogren's syndrome, vitiligo, pernicious anemia, glomerulonephritis, lupus nephritis, myasthenia gravis, Goodpasture's syndrome, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, peanut allergy, pulmonary fibrosis, celiac disease, alopecia areata, psoriasis, hidradenitis suppurativa, and asthma. ２０ｋＤ -IL-2 and related compositions.

82. 82. The use of claim 81, wherein the dose in the induction phase comprises 900 μg.

83. 82. The use of claim 81, wherein the dose in the induction phase comprises 1200 μg.

84. 82. The use of claim 81, wherein the dose in the induction phase comprises 1500 μg.

85. 82. The use of claim 81, wherein the dose in the induction phase comprises 1800 μg.

86. 82. The use of claim 81, wherein the dose in the induction phase comprises 2100 μg.

87. 82. The use of claim 81, wherein the dose in the induction phase comprises 2400 μg.

88. 82. The use of claim 81, wherein the dose in the induction phase comprises 2700 μg.

89. 82. The use of claim 81, wherein the dose in the induction phase comprises 3000 μg.

90. 90. The use according to any one of claims 81 to 89, wherein the dose in the maintenance phase comprises 900 μg.

91. 90. The use according to any one of claims 81 to 89, wherein the dose in the maintenance phase comprises 1200 μg.

92. 90. The use according to any one of claims 81 to 89, wherein the dose in the maintenance phase comprises 1500 μg.

93. 90. The use according to any one of claims 81 to 89, wherein the dose in the maintenance phase comprises 1800 μg.

94. 90. The use according to any one of claims 81 to 89, wherein the dose in the maintenance phase comprises 2100 μg.

95. 90. The use according to any one of claims 81 to 89, wherein the dose in the maintenance phase comprises 2400 μg.

96. 90. The use according to any one of claims 81 to 89, wherein the dose in the maintenance phase comprises 2700 μg.

97. 90. The use according to any one of claims 81 to 89, wherein the dose in the maintenance phase comprises 3000 μg.

98. 90. The use of any one of claims 81 to 89, wherein the induction dose is administered once every two weeks.

99. 90. The use of any one of claims 81 to 89, wherein the induction dose is administered once every four weeks.

100. 90. The use according to any one of claims 81 to 89, wherein the maintenance dose is administered once every four weeks.

101. 90. The use according to any one of claims 81 to 89, wherein the maintenance dose is administered once every 8 weeks.

102. 90. The use according to any one of claims 81 to 89, wherein the maintenance dose is administered once every 12 weeks.

103. 90. The use according to any one of claims 81 to 89, wherein the maintenance dose is administered once every 24 weeks.

104. 90. The use according to any one of claims 81 to 89, wherein the maintenance dose is administered once every 36 weeks.

105. 90. The use according to any one of claims 81 to 89, wherein the maintenance dose is administered once every 48 weeks.

106. 90. The use according to any one of claims 81 to 89, wherein the maintenance dose is administered once every 52 weeks.

107. The use according to any one of claims 81 to 106, wherein the composition is respegaldesleukin.

108. A selective Treg stimulator RUR comprising a composition of formulas A-F for use in treating severe atopic dermatitis in a patient in need thereof. ２０ｋＤ administering IL-2 and related compositions to the human subject at a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg or about 3600 μg per dose during an induction phase, the administration being performed once every week, once every two weeks, once every three weeks, once every four weeks, once every six weeks or once every eight weeks; the composition is administered for a total of 12 weeks, a total of 16 weeks, a total of 20 weeks or a total of 24 weeks of administration during the induction phase; and determining whether the patient is a responder to the composition after the induction period. and if the patient is a responder, proceeding to a maintenance phase comprising administering to the human subject a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose, wherein the administration occurs once every 2 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 12 weeks, once every 24 weeks, once every 36 weeks, once every 48 weeks, or once every 52 weeks; and the composition is administered for a total of 4 to 52 weeks of administration or a total of 1 to 5 years of administration. ２０ｋＤ -IL-2 and related compositions.

109. The use of claim 108, wherein the composition is respegaldesleukin.

110. A selective Treg stimulator RUR comprising a composition of formulas A-F for use in reducing sleep deprivation in patients with moderate to severe atopic dermatitis in a patient in need thereof. ２０ｋＤ - administering to the human subject a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of respegaldesleukin during an induction phase, which is performed once every week, once every two weeks, once every three weeks, once every four weeks, once every six weeks, or once every eight weeks; the respegaldesleukin is administered for a total of 12 weeks, a total of 16 weeks, a total of 20 weeks, or a total of 24 weeks of administration during the induction phase; and determining after the induction period whether the patient is a responder to the respegaldesleukin. and if the patient is a responder, administering to the human subject a dose of about 300 μg, about 450 μg, about 600 μg, about 900 μg, about 1200 μg, about 1500 μg, about 1800 μg, about 2100 μg, about 2400 μg, about 2700 μg, about 3000 μg, about 3300 μg, or about 3600 μg per dose of respegaldesleukin. and progressing to a maintenance phase including once every 2 weeks, once every 4 weeks, once every 6 weeks, once every 8 weeks, once every 12 weeks, once every 24 weeks, once every 36 weeks, once every 48 weeks, or once every 52 weeks; and the respegaldesleukin is administered for a total of 4 to 52 weeks of administration or for a total of 1 to 5 years of administration. ２０ｋＤ -IL-2 and related compositions.

111. The use of claim 110, wherein the composition is respegaldesleukin.

112. The selective Treg stimulator RUR at a concentration of about 4.0 mg / mL to about 5.0 mg / mL ２０ A pharmaceutical formulation comprising kD-IL-2 and related compositions, sodium acetate in the concentration of about 5 mM, sodium chloride in the concentration of about 25 mM, sucrose in the concentration of about 7.5% (w / v), and a pH of about 5.

0.

113. The selective Treg stimulator RUR ２０ 113. The formulation of claim 112, wherein the kD-IL-2 and related compositions comprise, on a molar basis, about 5 mole percent or less of mono-PEGylated IL-2 conjugates, about 28 mole percent to about 60 mole percent of di-PEGylated IL-2 conjugates, about 24 mole percent to about 65 mole percent of tri-PEGylated IL-2 conjugates, and about 12 mole percent or less of higher order PEGylated IL-2 conjugates, wherein the nominal average molecular weight of each branched polyethylene glycol moiety is about 20,000 Daltons.

114. The selective Treg stimulator RUR ２０ 113. The formulation of claim 112, wherein the kD-IL-2 and related compositions comprise, on a molar basis, from about 2 mole percent to about 4 mole percent mono-PEGylated IL-2 conjugates, from about 35 mole percent to about 55 mole percent di-PEGylated IL-2 conjugates, from about 35 mole percent to about 55 mole percent tri-PEGylated IL-2 conjugates, and up to about 12 mole percent higher order PEGylated IL-2 conjugates, wherein the nominal average molecular weight of each branched polyethylene glycol moiety is about 20,000 Daltons.

115. The selective Treg stimulator RUR ２０ 113. The formulation of claim 112, wherein the kD-IL-2 and related compositions comprise, on a molar basis, from about 2.5 mole percent to about 4.5 mole percent of mono-PEGylated IL-2 conjugates, from about 35 mole percent to about 50 mole percent of di-PEGylated IL-2 conjugates, from about 38 mole percent to about 46 mole percent of tri-PEGylated IL-2 conjugates, and from about 3 mole percent to about 10 mole percent of higher order PEGylated IL-2 conjugates, wherein the nominal average molecular weight of each branched polyethylene glycol moiety is about 20,000 Daltons.

116. The selective Treg stimulator RUR ２０ 113. The formulation of claim 112, wherein the kD-IL-2 and related compositions comprise, on a molar basis, from about 2.8 mole percent to about 3.8 mole percent of mono-PEGylated IL-2 conjugates, from about 44 mole percent to about 48 mole percent of di-PEGylated IL-2 conjugates, from about 41 mole percent to about 44 mole percent of tri-PEGylated IL-2 conjugates, and from about 7 mole percent to about 9 mole percent of higher order PEGylated IL-2 conjugates, wherein the nominal average molecular weight of each branched polyethylene glycol moiety is about 20,000 Daltons.

117. 113. The formulation of claim 112, which is suitable for subcutaneous injection.

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