Methods and compositions for treatment of disease

Abstract

The present disclosure provides methods for treating an inflammatory disease or disorder, wherein the inflammatory disease or disorder is a neurodegenerative and / or neuroinflammatory disease or disorder, comprising administration of a GLP-1 receptor agonist (e.g., semaglutide, exendin-4), and an IL-2 protein (e.g., aldesleukin) to a subject. Also presented herein are compositions for use with the methods disclosed herein and kits for administering a GLP-1 receptor agonist (e.g., semaglutide, ex endin-4), and an IL-2 protein (e.g., aldesleukin).

Description

Attorney Docket No.14678-029-228 METHODS AND COMPOSITIONS FOR TREATMENT OF DISEASE 1. CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No.63 / 677,244 filed July 30, 2024 and U.S. Provisional Application No.63 / 761,800 filed February 21, 2025, both of which are incorporated by reference herein in their entirety. 2. REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY

[0002] This application contains an electronic Sequence Listing which has been submitted in XML file format with this application, the entire content of which is incorporated by reference herein in its entirety. The Sequence Listing XML file submitted with this application is entitled “14678-029-228_SEQLISTING.xml”, was created on July 15, 2025, and is 29,014 bytes in size. 3. FIELD

[0003] The present disclosure relates, in part, to methods and compositions for therapeutic use of low dose IL-2 protein in combination with a glucagon-like peptide-1 (GLP-1) receptor agonist. 4. BACKGROUND

[0004] Inflammatory mechanisms contribute to a wide variety of devastating diseases. Currently, no disease-modifying treatments for such diseases are available. Anti-inflammatory treatments have been utilized for decades in attempting to ameliorate a multitude of such diseases. Little progress, however, has been made with single drug / single target approaches.

[0005] Increasingly, studies point to immune system involvement in the etiology of diseases and point to dysfunction of immune cells as a chief mediator of disease pathogenesis. The complex signaling mechanisms and built-in redundancies of the immune system and its constituents may help explain the ineffectiveness of such single drug / single target anti- inflammatory approaches.

[0006] Recently, great promise has been demonstrated with regulatory T cell (Treg) cell therapy, which may represent a more global approach to suppressing and / or modulating immune system dysfunction contributing to disease. Nonetheless, there still exists a need for development of additional treatments that can suppress inflammatory and / or promote anti- inflammatory immune system components. 1 NAI-5002088184v1Attorney Docket No.14678-029-228 5. SUMMARY

[0007] In an aspect, the present disclosure provides a method of treating an inflammatory disease or disorder in a subject in need thereof, comprising administering to the subject: (a) a GLP-1 receptor agonist; and (b) an IL-2 protein.

[0008] In certain embodiments, the method mitigates one or more symptoms associated with the inflammatory disease or disorder in the treated subject. In certain embodiments, the method attenuates or stops progression of the inflammatory disease or disorder in the treated subject.

[0009] In certain embodiments, the GLP-1 receptor agonist comprises the amino acid sequence of SEQ ID NO: 3. In certain embodiments, the GLP-1 receptor agonist comprises the amino acid sequence of SEQ ID NO: 4. In certain embodiments, the GLP-1 receptor agonist is semaglutide. In certain embodiments, the GLP-1 receptor agonist is exendin-4.

[0010] In certain embodiments, the IL-2 protein is a human IL-2 protein. In certain embodiments, the human IL-2 protein comprises a serine at the amino acid position corresponding to native mature human IL-2 amino acid residue 125. In certain embodiments, the human IL-2 protein lacks an N-terminal alanine amino acid. In certain embodiments, the human IL-2 protein comprises the amino acid sequence of SEQ ID NO: 26. In certain embodiments, the IL-2 protein is not glycosylated. In certain embodiments, the IL-2 protein is aldesleukin. In certain embodiments, the IL-2 protein comprises the amino acid sequence of aldesleukin.

[0011] In certain embodiments, the GLP-1 receptor agonist is administered by injection or infusion. In certain embodiments, the GLP-1 receptor agonist is administered subcutaneously. In certain embodiments, the GLP-1 receptor agonist is administered intravenously. In certain embodiments, the GLP-1 receptor agonist is administered orally.

[0012] In certain embodiments, the IL-2 protein is administered by injection or infusion. In certain embodiments, the IL-2 protein is administered subcutaneously. In certain embodiments, the IL-2 protein is administered intravenously.

[0013] In certain embodiments, the GLP-1 receptor agonist and the IL-2 protein are administered subcutaneously. In certain embodiments, the GLP-1 receptor agonist and the IL-2 protein are administered intravenously. In certain embodiments, the GLP-1 receptor agonist is administered orally and the IL-2 protein are administered intravenously. In certain 2 NAI-5002088184v1Attorney Docket No.14678-029-228 embodiments, the GLP-1 receptor agonist is administered orally and the IL-2 protein are administered subcutaneously.

[0014] In certain embodiments, the GLP-1 receptor agonist is administered weekly. In certain embodiments, the GLP-1 receptor agonist is administered daily. In certain embodiments, the GLP-1 receptor agonist is administered once daily, twice daily, three times daily, or four times daily.

[0015] In certain embodiments, the IL-2 protein is administered daily. In certain embodiments, the IL-2 protein is administered once daily for 2 to 7 consecutive days. In certain embodiments, the IL-2 protein is administered once daily for 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days.

[0016] In certain embodiments, (a) the GLP-1 receptor agonist is administered once every two weeks; and (b) the IL-2 protein is administered once daily for 2-7 consecutive days beginning on the day the GLP-1 receptor agonist is administered.

[0017] In certain embodiments, (a) the GLP-1 receptor agonist is administered once every week; and (b) the IL-2 protein is administered once daily for 2-7 consecutive days beginning on the day the GLP-1 receptor agonist is administered.

[0018] In certain embodiments, (a) the GLP-1 receptor agonist is administered daily; and (b) the IL-2 protein is administered once daily for 2-7 consecutive days beginning on the day the GLP-1 receptor agonist is administered.

[0019] In certain embodiments, the GLP-1 receptor agonist is administered in an amount in the range of 0.05 mg to about 4 mg per week.

[0020] In certain embodiments, the IL-2 protein is administered in an amount in the range of 500,000 units to 3,000,000 units. In certain embodiments, the IL-2 protein is administered in an amount in the range of 500,000 units to 2,000,000 units. In certain embodiments, the IL-2 protein is administered in an amount of 1,000,000 units.

[0021] In certain embodiments, the inflammatory disease or disorder is a neurodegenerative or neuroinflammatory disease or disorder. In certain embodiments, the neurodegenerative disease or disorder is amyotrophic lateral sclerosis, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, frontotemporal dementia or Huntington’s disease.

[0022] In certain embodiments, the neuroinflammatory disease or disorder is associated with stroke, acute disseminated encephalomyelitis, acute optic neuritis, acute inflammatory 3 NAI-5002088184v1Attorney Docket No.14678-029-228 demyelinating polyradiculoneuropathy, chronic inflammatory demyelinating polyradiculoneuropathy, Guillain-Barre syndrome, transverse myelitis, neuromyelitis optica, epilepsy, traumatic brain injury, spinal cord injury, encephalitis, central nervous system vasculitis, neurosarcoidosis, autoimmune or post-infectious encephalitis or chronic meningitis.

[0023] In certain embodiments, the method further comprises performing an additional therapeutic intervention comprising a cognitive rehabilitation program, a neurostimulation technique, or a combination thereof. In certain embodiments, the cognitive rehabilitation program is a computer-implemented cognitive rehabilitation program. In certain embodiments, the neurostimulation technique is an invasive brain stimulation (IBS) technique. In certain embodiments, the neurostimulation technique is a non-invasive brain stimulation (NIBS) technique. In certain embodiments, the IBS technique is selected from the group consisting of: deep brain stimulation (DBS) and invasive vagus nerve stimulation (VNS). In certain embodiments, the NIBS technique is selected from the group consisting of transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), electroconvulsive treatment (ECT), magnetic seizure therapy (MST), cranial electrostimulation (CES), and non-invasive VNS.

[0024] In another aspect, the present disclosure provides for kits for use with the methods disclosed herein. In certain embodiments, a kit provided by the present disclosure comprises, in separate containers, (i) a GLP-1 receptor agonist, and (ii) an IL-2 protein.

[0025] In certain embodiments, the GLP-1 receptor agonist is suitable for oral administration. In certain embodiments, the GLP-1 receptor agonist is suitable for subcutaneous administration. In certain embodiments, the GLP-1 receptor agonist is suitable for intravenous administration.

[0026] In certain embodiments, the IL-2 protein is suitable for subcutaneous administration. In certain embodiments, the IL-2 protein is suitable for intravenous administration.

[0027] In certain embodiments, the GLP-1 receptor agonist comprises the amino acid sequence of SEQ ID NO: 3. In certain embodiments, the GLP-1 receptor agonist comprises the amino acid sequence of SEQ ID NO: 4. In certain embodiments, the GLP-1 receptor agonist comprises semaglutide. In certain embodiments, the GLP-1 receptor agonist comprises exendin-4.

[0028] In certain embodiments, the IL-2 protein comprises the amino acid sequence of SEQ 4 NAI-5002088184v1Attorney Docket No.14678-029-228 ID NO: 26. In certain embodiments, the IL-2 protein is aldesleukin. In certain embodiments, the IL-2 protein comprises the amino acid sequence of aldesleukin.

[0029] In certain embodiments, the GLP-1 receptor agonist and the formulation of one or more doses of IL-2 protein are solutions. In certain embodiments, the GLP-1 receptor agonist is a tablet and the formulation of one or more doses of IL-2 protein is a solution. 6. BRIEF DESCRIPTION OF THE FIGURES

[0030] FIGS.1A-1B show graphs depicting suppression of pro-inflammatory myeloid cells in in vitro co-culture paradigms of Treg and myeloid cells treated with GLP-1 receptor agonists and / or low dose IL-2. A “+” sign along the x-axis indicates the addition of either myeloid cells (M1), Tregs, IL-2 (50 IU / mL), and / or GLP-1 receptor agonist to the co-culture paradigms whereas a “-” indicates the absence of said component in the co-culture experiment. Treg suppression of pro-inflammatory myeloid cells is demonstrated by the percent suppression of IL- 6 protein measured in the treated myeloid cells (M1). Data represents n=2 patients who sourced the isolated Treg cells and monocytes. Graphs shown depict data averages ± SEM. In FIG.1A, semaglutide was added individually at either 100 nM (left graph) or 1 µM (right graph) and in combination with low dose IL-2 to the Treg / myeloid cell co-culture. In FIG.1B, exendin-4 (Ex4) was added individually at either 100 nM (left graph) or 1 µM (right graph) and in combination with low dose IL-2 to the Treg / myeloid cell co-culture.

[0031] FIGS.2A-2B show graphs depicting RNA levels of pro-inflammatory and anti- inflammatory transcripts as measured from RNA isolated from pro-inflammatory myeloid cells from in vitro co-culture paradigms of Treg and myeloid cells treated with GLP-1 receptor agonists and / or low dose IL-2. The myeloid cells (M1) from which the RNA was harvested from were either untreated or treated with Tregs, low dose IL-2 (50 IU / mL) only, semaglutide (1 µM) only, semaglutide (1 µM) in combination with Tregs and low dose IL-2 (50 IU / mL), exendin-4 (Ex4) (1 µM) only, and Ex4 (1 µM) in combination with Tregs and low dose IL-2 (50 IU / mL). The levels of RNA transcripts are demonstrated as M1 fold RNA levels. FIG.2A depicts the levels of pro-inflammatory myeloid cell RNA transcripts for IL-6 (left graph), IL-1β (middle graph), and TNF (right graph). FIG.2B depicts the levels of pro-inflammatory myeloid cell RNA transcripts for the anti-inflammatory IL-10 (left graph), and anti-inflammatory M2- associated myeloid cell markers of mannose receptor (CD206 / MRC1) (middle graph) and arginase 1 (ARG1) (right graph). 5 NAI-5002088184v1Attorney Docket No.14678-029-228

[0032] FIG.3 shows a graph depicting suppression of responder T-cell (Tresp) proliferation. Shown are CD4+CD25+ Treg cells and CD4+CD25-T effector cells isolated from patient (human) blood and plated in a ratio of 1:1 / 2 T effector:Treg cells at 5 x 104. The cells were treated with either Tregs, low dose IL-2 (1 IU / mL), and / or different concentrations of semaglutide (10 nM, 100 nM, 1 µM). A “+” sign along the x-axis indicates the addition of either Tregs, IL-2, and / or semaglutide agonist to the cells whereas a “-“ indicates the absence of said component in the experiment.

[0033] FIGS.4A-4B shows graphs depicting suppression of pro-inflammatory myeloid cells in in vitro co-culture paradigms of Treg and myeloid cells treated with GLP-1 receptor agonists and / or low dose IL-2. A “+” sign along the x-axis indicates the addition of either myeloid cells (M1), Tregs, IL-2 (50 IU / mL), and / or GLP-1 receptor agonist to the co-culture paradigms whereas a “-“: indicates the absence of said component in the co-culture experiment. Data represents n=6 patients who sourced the isolated Treg cells and monocytes. Graphs shown depict data mean ± SEM. Data were analyzed by a one-way ANOVA with Tukey’s multiple comparisons testing (*p<0.05; **p<0.01; ***p<0.001). In FIG.4A, semaglutide was added individually at either 100 nM (left graph) or 1 µM (right graph) and in combination with low dose IL-2 to the Treg / myeloid cell co-culture. In FIG.4B, exendin-4 (Ex4) was added individually at either 100 nM (left graph) or 1 µM (right graph) and in combination with low dose IL-2 to the Treg / myeloid cell co-culture.

[0034] FIGS.5A-5B show graphs depicting RNA levels of pro-inflammatory and anti- inflammatory transcripts as measured from RNA isolated from pro-inflammatory myeloid cells from in vitro co-culture paradigms of Treg and myeloid cells treated with GLP-1 receptor agonists and / or low dose IL-2. The myeloid cells (M1) from which the RNA was harvested from were either untreated or treated with Tregs, low dose IL-2 (50 IU / mL) only, semaglutide (1 µM) only, semaglutide (1 µM) in combination with Tregs and low dose IL-2 (50 IU / mL), exendin-4 (Ex4) (1 µM) only, and Ex4 (1 µM) in combination with Tregs and low dose IL-2 (50 IU / mL). The levels of RNA transcripts are demonstrated as M1 fold RNA levels. Data represents n=5 healthy controls with graphs depicting data mean ± SEM. Data analyzed by one-way ANOVA with Tukey’s multiple comparisons testing (*p<0.05; **p<0.01; ***p<0.001). FIG.5A depicts the levels of pro-inflammatory myeloid cell RNA transcripts for IL-6 (left graph), IL-1β (middle graph), and TNF (right graph). FIG.5B depicts the levels of pro-inflammatory myeloid cell 6 NAI-5002088184v1Attorney Docket No.14678-029-228 RNA transcripts for the anti-inflammatory IL-10 (left graph), and anti-inflammatory M2- associated myeloid cell markers of arginase 1 (ARG1) (middle graph) and mannose receptor (CD206 / MRC1) (right graph).

[0035] FIGS.6A-6B show graphs depicting suppression of responder T-cell (Tresp) proliferation. Shown are CD4+CD25+ Treg cells and CD4+CD25-T effector cells isolated from patient (human) blood and plated in a ratio of 1:1 / 2 T effector:Treg cells at 5 x 104. The cells were treated with either Tregs, low dose IL-2 (1 IU / mL), and / or different concentrations of semaglutide (100 nM, 1 µM) or exendin-4. A “+” sign along the x-axis indicates the addition of either Tregs, IL-2, and / or semaglutide agonist to the cells whereas a “-“ indicates the absence of said component in the experiment. Data represents n=5 healthywith graphs depicting data mean ± SEM. Data analyzed by one-way ANOVA with Tukey’s multiple comparisons testing (*p<0.05; **p<0.01; ***p<0.001). FIG.6A depicts cells treated with either semaglutide or exendin-4 at a concentration of 100 nM. FIG.6B depicts cells treated with either semaglutide or exendin-4 at a concentration of 1 µM.

[0036] FIGS.7A-7G show Treg-associated survival and functional transcripts after treatment with semaglutide (1 µM) only, low dose IL-2 (50 IU / mL) only, or semaglutide (1 µM) in combination with low dose IL-2 (50 IU / mL) at 3 and 18 hours after isolation. Data represents n=5 healthy controls with graphs depicting data mean ± SEM. Data analyzed by one-way ANOVA with Tukey’s multiple comparisons testing (*p<0.05; **p<0.01; ***p<0.001). FIG. 7A depicts the effects of treatment of transcription levels of FOXP3. FIG.7B depicts the effects of treatment of transcription levels of IL2RA / CD25. FIG.7C depicts the effects of treatment of transcription levels of CLTA-4. FIG.7D depicts the effects of treatment of transcription levels of IL-10. FIG.7E depicts the effects of treatment of transcription levels of TGF-β. FIG.7F depicts the effects of treatment of transcription levels of BAX. FIG.7G depicts the effects of treatment of transcription levels of BCL-2. 7. DETAILED DESCRIPTION DETAILED DESCRIPTION

[0037] The present disclosure relates, in part, to compositions and kits comprising low dose IL-2 protein and at least one GLP-1 receptor agonist. The present disclosure further relates, in part, to methods for administering low dose IL-2 protein and at least one GLP-1 receptor agonist to a subject in need thereof. In some embodiments, the low dose IL-2 protein is administered together with the GLP-1 receptor agonist as part of a pharmaceutical composition. In some 7 NAI-5002088184v1Attorney Docket No.14678-029-228 embodiments, the low dose IL-2 protein is administered separately from the GLP-1 receptor agonist, e.g., as part of a separate pharmaceutical composition. The GLP-1 receptor agonists provided herein can be administered prior to, subsequent to, or simultaneously with administration of the low dose IL-2 protein. In specific embodiments, the GLP-1 receptor agonist is semaglutide. In specific embodiments, the GLP-1 receptor agonist is exendin-4. In specific embodiments, the low dose IL-2 protein comprises the amino acid sequence of SEQ ID NO: 26. In specific embodiments, the low dose IL-2 protein is aldesleukin. In specific embodiments, the low dose IL-2 protein comprises the amino acid sequence of aldesleukin.

[0038] Also provided herein, are methods of treating an inflammatory disease or disorder, comprising: administering to a subject in need thereof: (a) IL-2 protein, and (b) at least one GLP- 1 receptor agonist. In certain embodiments, the inflammatory disease or disorder is a neurodegenerative or neuroinflammatory disease or disorder, e.g., Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), Huntington’s disease, Parkinson’s disease, disease, multiple sclerosis (MS), or frontotemporal dementia. In certain embodiments, the IL-2 protein comprises the amino acid sequence of SEQ ID NO: 26. In certain embodiments, the IL-2 protein is aldesleukin. In certain embodiments, the IL-2 protein comprises the amino acid of aldesleukin. In specific embodiments, the GLP-1 receptor agonist is semaglutide. In specific embodiments, the GLP-1 receptor agonist is exendin-4.

[0039] Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein.

[0040] Unless specifically stated or apparent from context, as used herein, the terms “a”, “an”, and “the” are understood to be singular or plural, and denote “one or more.” Unless specifically stated or apparent from context, as used herein, the term “or” is understood to denote “and / or.”

[0041] The terms “include,” “such as,” and the like are intended to convey inclusion without limitation, unless otherwise specifically indicated.

[0042] The description herein of any aspect or embodiment of the invention using terms such as “comprising”, “having”, “including” or “containing” with reference to an element or elements is intended to provide support for a similar aspect or embodiment of the invention that “consists 8 NAI-5002088184v1Attorney Docket No.14678-029-228 of’, “consists essentially of’, or “substantially comprises” that particular element or elements, unless otherwise stated or clearly contradicted by context (e.g., a composition described herein as comprising a particular element should be understood as also describing a composition consisting of that element, unless otherwise stated or clearly contradicted by context).

[0043] The terms “about” and “approximately” as used herein, are interchangeable, and should generally be understood to refer to a range of numbers around a given number, as well as to all numbers in a recited range of numbers (e.g., “about 5 to 15” means “about 5 to about 15” unless otherwise stated). Moreover, all numerical ranges herein should be understood to include each whole integer within the range. In particular, unless otherwise noted the terms mean within plus or minus 10% of a given value or range. In instances where an integer is required, the terms mean within plus or minus 10% of a given value or range, rounded either up or down to the nearest integer.

[0044] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which the invention pertains. Otherwise, certain terms used herein have the meanings as set forth in the specification. All patents, published patent applications and publications cited herein are incorporated by reference as if set forth fully herein. For purposes of interpreting this specification, the following description of terms will apply and whenever appropriate, terms used in the singular will also include the plural and vice versa. In the event that any description of a term set forth conflicts with any document incorporated herein by reference, the description of the term set forth below shall control. 7.1 GLP-1 Receptor Agonists

[0045] The methods and compositions presented herein comprise or utilize a GLP-1 receptor agonist, for example, a human GLP-1 receptor agonist. A GLP-1 receptor agonist is a molecule that increases the level and / or activity of a GLP-1 receptor. GLP-1 receptor agonists are well known, and may, e.g., be a small molecule or a proteinaceous molecule, such as a peptide or a polypeptide.

[0046] In certain embodiments, a GLP-1 receptor agonist suitable for use with the methods and compositions disclosed herein comprises a GLP-1 receptor agonist that may include one or more from those provided in Table 1. 9 NAI-5002088184v1Attorney Docket No.14678-029-228 TABLE 1: GLP-1 Receptor Agonists GLP-1 Unique Ingredient Identifier Receptor (UNII) / Chemical AbstractsAmino Acid SequenceSEQ IDA onist Service (CAS) NumberNO10 NAI-5002088184v1Attorney Docket No.14678-029-228 GLP-1 Unique Ingredient Identifier Receptor (UNII) / Chemical AbstractsAmino Acid SequenceSEQ IDA onist Service (CAS) NumberNO11 NAI-5002088184v1Attorney Docket No.14678-029-228 GLP-1 Unique Ingredient Identifier Receptor (UNII) / Chemical AbstractsAmino Acid SequenceSEQ IDA onist Service (CAS) NumberNO, s and compositions disclosed herein comprise an exendin, e.g., a naturally occurring (or synthetic version of a naturally occurring) exendin peptide.

[0048] In some embodiments, a GLP-1 receptor agonist comprises exendin-4, a peptide found in the saliva of the Gila monster, Heloderma suspectum. In some embodiments, a GLP-1 receptor agonist disclosed herein comprises a peptide having about 40%, 45%, 50%,55%, 60%, 65% 70%, 75%, 80%, 85% 90%, 95%, or 99% sequence identity to the amino acid sequence of 12 NAI-5002088184v1Attorney Docket No.14678-029-228 SEQ ID NO: 1. In some embodiments, a GLP-1 receptor agonist disclosed herein comprises a peptide comprising the amino acid sequence of SEQ ID NO: 1.

[0049] In some embodiments, a GLP-1 receptor agonist comprises exendin-3, a peptide found in the saliva of the beaded lizard, Heloderma horridum. In some embodiments, a GLP-1 receptor agonist disclosed herein comprises a peptide having about 40%, 45%, 50%,55%, 60%, 65% 70%, 75%, 80%, 85% 90%, 95%, or 99% identity to the amino acid sequence of SEQ ID NO: 2. In some embodiments, a GLP-1 receptor agonist comprises a comprising the amino acid sequence of SEQ ID NO: 2.

[0050] In certain embodiments, a GLP-1 receptor agonist comprises a peptide comprising the amino acid sequence of any one of any one of SEQ ID NOs: 3-24. In some embodiments, a GLP-1 receptor agonist disclosed herein comprises a peptide having about 80%, 85% 90%, 95%, or 99% identity to the amino acid sequence of any one of SEQ ID NOs: 3-24.

[0051] In certain embodiments, a GLP-1 receptor agonist comprises a peptide comprising the amino acid sequence of any one of SEQ ID NOs: 1-24, wherein the amino acid sequence comprises: (1) one or more (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid residues substituted by other amino acid residues; (2) one or more (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) amino acid residues have been deleted; (3) one or more (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10) amino acid residues have been inserted; or (4) any combination of (1)-(3).

[0052] In certain embodiments, a GLP-1 receptor agonist comprises a peptide GLP-1 receptor agonist having at least one modification. Non-limiting examples of such modifications include inclusion of amides, carbohydrates, alkyl groups, acyl groups, esters and the like to the peptide sequence. In certain embodiments, a GLP-1 receptor agonist described herein, e.g., a GLP-1 receptor agonist that comprises the amino acid sequence of any one of SEQ ID NOs: 1- 24, having a C-terminal functional group modification (e.g., amides, esters, and C-terminal ketone modifications) and / or a N-terminal functional group modification (e.g., acylated amines, Schiff bases, cyclization). In certain embodiments, a GLP-1 receptor agonist comprises a glycosylated amino acid sequence. In certain embodiments, a GLP-1 receptor agonist comprises an acylated amino acid sequence.

[0053] In certain embodiments, a GLP-1 receptor agonist comprises the amino acid sequence of SEQ ID NO: 3. In certain embodiments, a GLP-1 receptor is semaglutide. In certain 13 NAI-5002088184v1Attorney Docket No.14678-029-228 embodiments, a GLP-1 receptor agonist comprises the amino acid sequence of SEQ ID NO: 4. In certain embodiments, a GLP-1 receptor is exendin-4.

[0054] In certain embodiments, a GLP-1 receptor agonist suitable for use with the methods and compositions disclosed herein comprises a small molecule and / or chemical compound. Non-limiting examples include: Danuglipron Tromethamine (PF-06882961; UNII: 2HJV78O0SS); Avexitide (exendin 9-39; UNII: 5313W10MYT); and Orforglipron (LY- 3502970; UNII: 7ZW40D021M).

[0055] In certain embodiments, a GLP-1 receptor agonist is part of a dual, triple or multiple action moiety. For example, in certain embodiments, a GLP-1 receptor agonist is part of a fusion protein, for example a dual fusion protein comprising a GLP-1 receptor agonist, e.g. is a tirzepatide dual fusion protein. In certain other embodiments, a GLP-1 receptor agonist may be part of a dual or triple action moiety such as dual gastric inhibitory polypeptide (GIP) / / GLP-1 receptor agonists, dual gastric inhibitory polypeptide receptor (GIPR) / GLP-1 receptor agonists, dual GLP-1 / glucagon receptor agonists (GCGR), dual GLP-1 / amylin receptor agonists, dual GLP-1 / PYY (Peptide YY) agonists, triple GIP / GLP-1 receptor / glucagon receptor agonists, dual GLP-1 receptor / fibroblast growth factor receptor (FGFR) agonists, and triple GLP-1 receptor / GCGR / FGFR agonists such as those included in Table 2 below. TABLE 2: Agonists Agonist Name Agonist Target(s)Company / ManufacturerYH 25724 GLP-1 / FGFR agonist Boehringer Ingelheim / Yuhan14 NAI-5002088184v1Attorney Docket No.14678-029-228 Agonist Name Agonist Target(s)Company / ManufacturerHRS-9531 GLP-1 / GIP agonist Jiangsu Hengrui Pharmaceuticals Co. / Fujian S di Ph ti l Cany of the GLP-1 receptor agonists contemplated herein for peripheral administration, such as parenteral (e.g., subcutaneous, intravenous, intramuscular), a continuous infusion (e.g., intravenous drip, intravenous bolus, intravenous infusion), topical, nasal, or oral administration. Suitable pharmaceutically acceptable carriers and formulations comprising thereof are known the art and can be found at least in, for example, REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (A. Adejare, Ed.; 23rd edition) Academic Press (2020). 7.2 IL-2 Protein

[0057] The methods and compositions presented herein comprise or utilize an IL-2 protein, for example, a human IL-2 protein, e.g. a recombinant human IL-2 protein. In certain aspects, the IL-2 protein utilized herein is a low dose IL-2 protein.

[0058] IL-2 proteins are well known. See, e.g., UniProtKB identifier Q0GK43.

[0059] In certain embodiments, the IL-2 protein is a human IL-2 protein. For example, in certain embodiments, the IL-2 protein is or is derived from the following native mature human IL-2 amino acid sequence: APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCL EEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNR WITFCQSIISTLT (SEQ ID NO: 25).

[0060] In certain embodiments, the IL-2 protein contains one or more mutations relative to the native mature human IL-2 polypeptide. For example, in certain embodiments, the human IL- 2 protein lacks an N-terminal alanine amino acid. In particular embodiments, the human IL-2 15 NAI-5002088184v1Attorney Docket No.14678-029-228 protein comprises a mutation at the amino acid position corresponding to native mature human IL-2 amino acid residue 125 (underlined in the above sequence). For example, in particular embodiments, the IL-2 protein contains a serine at the amino acid position corresponding to native mature human IL-2 amino acid residue 125. In particular embodiments, the human IL-2 protein lacks an N-terminal alanine amino acid and comprises a serine at the amino acid position corresponding to native mature human IL-2 amino acid residue 125.

[0061] In specific embodiments, the IL-2 protein is not glycosylated.

[0062] In particular embodiments, the human IL-2 protein lacks an N-terminal alanine amino acid, comprises a serine at the amino acid position corresponding to native mature human IL-2 amino acid residue 125 and is not glycosylated.

[0063] In certain embodiments, the IL-2 protein is aldesleukin (des-alanyl-1, serine-125 human interleukin-2; trade name PROLEUKIN), which is well-known.

[0064] In certain embodiments, the human IL-2 protein comprises the following amino acid sequence: PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLE EELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRW ITFSQSIISTLT (SEQ ID NO: 26).

[0065] In certain embodiments, the IL-2 protein comprises one or more modifications, e.g., mutations, compared to that of mature human IL-2 and exhibits reduced binding to IL-2 receptor (IL-2R) alpha subunit (CD25) relative to that of native mature IL-2 protein. In certain embodiments, the IL-2 protein comprises one or more modifications, e.g., mutations, compared to that of mature human IL-2 and exhibits reduced binding to IL-2 receptor beta subunit (CD122) relative to that of native IL-2 protein. In certain embodiments, the IL-2 protein comprises one or more modifications, e.g., mutations, compared to that of mature human IL-2 and reduced binding to IL-2 receptor gamma subunit (CD132) relative to that of wild-type IL-2 protein. In particular embodiments, the IL-2 protein comprises one or more modifications, e.g., mutations, compared to that of mature human IL-2 and exhibits reduced binding to IL-2 receptor beta and gamma subunits relative to that of native mature IL-2 protein. In particular embodiments, the IL-2 protein comprises one or more modifications, e.g., mutations, compared to that of mature human IL-2 and exhibits reduced binding to IL-2 receptor alpha and beta subunits relative to that of native mature IL-2 protein. In particular embodiments, the IL-2 protein comprises one or more 16 NAI-5002088184v1Attorney Docket No.14678-029-228 modifications, e.g., mutations, compared to that of mature human IL-2 and exhibits reduced binding to IL-2 receptor beta subunit but not reduced binding to IL-2 receptor subunit alpha relative to that of native mature IL-2 protein. In particular embodiments, the IL-2 protein comprises one or more modifications, e.g., mutations, compared to that of mature human IL-2 and exhibits reduced binding to IL-2 receptor alpha, beta and gamma subunits relative to that of native mature IL-2 protein.

[0066] In certain embodiments, the IL-2 protein comprises one or more modifications, e.g., mutations, compared to that of mature human IL-2 and exhibits reduced IL-2 receptor-mediated signaling activity relative to that of native mature IL-2 protein. IL-2 receptor-mediated signaling activity may be assayed using routine, well known techniques, for example may be assayed via an assessment of STAT5 phosphorylation. See, e.g., Ghelani et al. (2020) Front. Immunol. 11:1106, which is incorporated herein in its entirety.

[0067] In certain embodiments, the IL-2 protein comprises one or more modifications, e.g., mutations, compared to that of mature human IL-2 and exhibits selectivity for (e.g., preferential activation of) T regulatory (Treg) cells, for example selectivity over natural killer cells and / or T effector cells, as assessed, e.g., by Treg cell proliferation assays, Treg-mediated suppressor function, and / or lineage and / or phenotypic marker expression. Such assays are well-known. See, e.g., Ghelani (2020) Id.

[0068] In some embodiments, the IL-protein is an IL-2 mutein (that is, an IL-2 protein comprising one or more mutations relative to native mature IL-2 protein) comprising an amino acid sequence corresponding to native mature human IL-2, which further comprises a replacement substitution or deletion at one or more amino acid positions, e.g., A1 (deletion); P2 (e.g., deletion); T3 (e.g., T3C, T3A, T3G, T3Q, T3E, T3N, T3D, T3R, T3K, T3P, or deletion); S4 (e.g., deletion); S5 (e.g., deletion); S6 (e.g., deletion); H16 (e.g., H16E, H16R), L18 (e.g., L18R, L18G, L18M, L18F, L18E, L18H, L18W, L18K, L18Q, L18S, L18V, L18I, L18Y, L18H, L18D, L18T); D20 (e.g., D20A, D20G, D20H, D20W); Q22 (e.g., Q22F, Q22E, Q22G, Q22A, Q22L, Q22M, Q22F, Q22W, Q22K, Q22S, Q22V, Q22I, Q22Y, Q22H, Q22R, Q22N, Q22D, Q22T, Q22F); K35 (e.g., K35E); R38 (e.g., R38A, R38G); M39 (e.g., M39L, M39V); F42 (e.g., F42A, F42L, F42Y); Y45 e.g., Y45A); H55 (e.g., H55Y); C58 (e.g., deletion); E61 (e.g., E61Q); E62 (e.g., E62A); I86 (e.g., I86V); N88 (e.g., N88I, N88G, N88D, N88K, N88R); I89 (e.g., I89V); V91 (e.g., V91D, V91K); I92 (I92F); K97 (e.g, K97Q); M104 (e.g., M104A, M104T, 17 NAI-5002088184v1Attorney Docket No.14678-029-228 M104V); D109 (e.g, D109C or substituted with a non-natural amino acid with an activated side chain); T113 (e.g, T113N); C125 (e.g., C125A, C125S); Q126 (e.g., Q126H, Q126M, Q126K, Q126C, Q126D, Q126E, Q126G, Q126I, Q126R, Q126S, Q126T); or S130 (e.g., S130T, S130G, S130R).

[0069] In certain embodiments, the human IL-2 protein comprises the following amino acid sequence: PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQLEE ELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWI TFSQSIISTLT (SEQ ID NO: 26).

[0070] In some embodiments, the IL-protein is an IL-2 mutein that comprises an amino acid sequence corresponding to native mature human IL-2 and which further comprises D20A and H16E mutations; D20A and M104T mutations; H16E and E61Q mutations; V91K, D20A and M104V mutations; a D20G mutation; a D20W mutation; an F42Y mutation; an N88K mutation; or D20A, H16R and E61Q mutations.

[0071] In some embodiments, the IL-2 protein is an IL-2 mutein that comprises an amino acid sequence corresponding to native mature human IL-2 and which further comprises a D20, N88 and / or Q126 mutation. For example, in certain embodiments, an IL-2 protein may comprise a D20H mutation, an N88R, N88I or N88G mutation, and / or a Q126D mutation. See, e.g., US6955807.

[0072] In some embodiments, the IL-2 protein is an IL-2Ra / IL-2Rb biased IL-2 protein. For example, in certain embodiments, the IL-12 is STK-012 (Emmerich, J. et al. Cancer Res 2021;81(13_Suppl):Abstract nr 1744.

[0073] In certain embodiments, the IL-2 protein is fused or conjugated to one or more additional moieties. In some embodiments, the IL-2 protein is fused or conjugated to one or more polymers, e.g., one or more polymers having a weight average molecular weight of from about 250 Daltons to about 50,000 Daltons. In some embodiments, the IL-2 protein is pegylated. See, e.g., WO202114636. In particular embodiments, the IL-2 protein or IL-2 mutein is pegylated at a tyrosine residue. In specific embodiments, the pegylated tyrosine residue is Y45 or F42Y. In some embodiments, the IL-2 protein is a modified IL-2 polypeptide as described in PCT Publication No. WO2021140416. In some embodiments, the IL-2 protein is IL-2 clinical candidate BPT-143 (Bright Peak). 18 NAI-5002088184v1Attorney Docket No.14678-029-228

[0074] In some embodiments, the IL-2 protein is conjugated to one or more water-soluble polymers. In some embodiments, the water-soluble polymer is conjugated at the unnatural amino acid. In some embodiments, the water-soluble polymer comprises polyethylene glycol (PEG), poly(propylene glycol) (PPG), copolymers of ethylene glycol and propylene glycol, poly(oxyethylated polyol), poly(olefinic alcohol), poly(vinylpyrrolidone), poly(hydroxyalkylmethacrylamide), poly(hydroxyalkylmethacrylate), poly(saccharides), poly(a- hydroxy acid), poly(vinyl alcohol), polyphosphazene, polyoxazolines (POZ), poly(N- acryloylmorpholine), poly[oligo(ethylene glycol)methyl methacrylate] (POEGMA), or a combination thereof. In specific embodiments, the water-soluble polymer is PEG and has an average molecular weight of from about 100 Daltons to about 150,000 Daltons.

[0075] In some embodiments, the IL-2 protein is conjugated via releasable linkage to one or more poly(ethylene)glycol (PEG) polymers, for example to one to seven PEG polymers, e.g., branched PEG. In particular embodiments, the PEG polymers are branched polymers each having a weight average molecular weight of from about 20,000 Daltons to 85,000 Daltons. In some embodiments, the releasable branched PEG is attached at an amino group of a lysine of the IL-2 protein. In some embodiments, there is a plurality of conjugates that is a mixture of monopegylated, dipeglated and tripegylated conjugates. In some embodiments, the IL-2 protein is a conjugate of IL-2 protein as described in US Patent Nos.9,861,705, 10,960,079 or PCT Publication No. WO2012065086. In some embodiments, the IL-2 protein is clinical candidate NKTR-214 (bempagaldesleukin; Nektar Therapeutics).

[0076] In some embodiments, the IL-2 protein is fused or conjugated to an antibody or fragment thereof. In some embodiments, the antibody or fragment thereof binds to human IL-2 (e.g., an anti-hIL-2 antibody). In some embodiments, the antibody binds to human IL-2Ra. In some embodiments, the antibody binds to human IL-2Ra. In some embodiments, the antibody is a whole antibody. In some embodiments, the antibody fragment is an antigen binding domain. In some embodiments, the antibody fragment is an Fc domain, for example, a human Fc domain, e.g., a human IgG Fc domain. In particular embodiments, the IL-2 protein comprises an N- terminal or C-terminal human Fc domain fusion or conjugation, e.g., a human IgG Fc domain. In some embodiments, such moieties are directly attached to the IL-2 protein. In other embodiments, such moieties are attached to the IL-2 protein indirectly, for example via linker, 19 NAI-5002088184v1Attorney Docket No.14678-029-228 e.g., via a GSSSS-containing linker, for example, a GSSS, (GSSSS)2, (GSSSS)3 or (GSSSS)4- containing liker.

[0077] In particular embodiments, the IL-protein is an IL-2 mutein that comprises an amino acid sequence corresponding to native mature human IL-2 and which further comprises: i) mutations at one or more of L53 (e.g., L53I), L56 (e.g., L56I), L80 (e.g., L80I), andL118 (e.g., L118I); and, optionally, mutations at one or more of V69 (e.g., V69A), Q74 (e.g., Q74P), N88 (e.g., N88D), and C125 (e.g., C125S), for example, L53I, N88D, V69A, Q74P, and C125S mutations; L56I, N88D, V69A, Q74P, and C125S mutations; L80I, N88D, V69A, Q74P, and C125S mutations; or L118I, N88D, V69A, Q74P, and C125S mutations; and ii) optionally an Fc domain, for example, a human IgG1 Fc domain, e.g., an N-terminal human IgG1 Fc domain.

[0078] In some embodiments, the IL-2 protein is an IL-2 mutein comprising: i) an amino acid sequence corresponding to native mature human IL-2, which further comprises a replacement substitution at one or more positions: E15 (e.g., E15Q); H16 (e.g., H16N); Q22 (e.g., Q22E); N29 (e.g., N29S); Y31 (e.g., Y31S, Y31H); K35 (e.g., K35R); T37 (e.g., T37A); K48 (e.g., K48E); V69 (e.g., V69A); N71 (e.g., N71R); Q74 (e.g., Q74P); D84 (e.g., D84N); N88 (e.g., N88D, N88R); E95 (e.g., E95Q); C125 (e.g., C125A, C125S); or Q126 (e.g., Q126E); and ii) optionally is fused or conjugated to an antibody or antigen-binding fragment that binds to MAdCAM, OAT1, OCT2, FXYD2, TSPAN7, DPP6, HEPACAM2, TMEM27, or GPR119.

[0079] In some embodiments, the IL-2 protein or IL-2 mutein, e.g., IL-2 mutein fused or conjugated one or more additional moieties, e.g., an antibody, antigen-binding fragment of an antibody, or an Fc domain, are as described in US Patent Nos.10,174,091, 10,174,092, 10,946,068, 11,091,526, or 11,091,527 or PCT Publication Nos. WO2019112852 or WO2019112854.

[0080] In some embodiments, the IL-2 protein is PT101 / MK-6194 (Pandion Therapeutics / Merck & Co).

[0081] In some embodiments, the IL-2 protein is an IL-2 mutein conjugated to an antibody or fragment thereof as described in PCT Publication No. WO2020247843.

[0082] In some embodiments, the IL-2 protein is IL-2 clinical candidate AB248 (Asher Bio).

[0083] In some embodiments, the IL-2 protein is ANV419 (Anaveon).

[0084] In certain embodiments, the IL-2 protein comprises one or more non-standard or non- natural amino acids. For example, in particular embodiments, the IL-2 protein may comprise an 20 NAI-5002088184v1Attorney Docket No.14678-029-228 amino acid sequence corresponding to the mature human IL-2 protein and may further comprise one or more amino acids other than the standard twenty amino acids found in the majority of proteins.

[0085] For example, in some embodiments, the IL-protein is an IL-2 mutein comprising a homoserine (Hse) substitution at any one of residues 35-45, 61-81, or 94-114. In some embodiments, the IL-2 mutein comprises Hse41, Hse71, Hse104, or a combination thereof. In some embodiments, the IL-2 mutein comprises norleucine substitution at positions 23, 39, or 46.

[0086] In some embodiments, the IL-2 protein comprises at least one non-natural amino acid. In some embodiments, the at least one non-natural amino acid is a replacement substitution at an amino acid position corresponding to native mature human IL-2 selected from T37, R38, T41, F42, K43, F44, Y45, E60, E61, E62, K64, P65, E68, V69, N71, L72, M104, C105, or Y107. In some embodiments, the unnatural amino acid is a lysine derivative or comprises an aromatic side chain. In some embodiments, the unnatural amino acid is N6-[(2-azidoethoxy)carbonyl]-l- lysine.

[0087] In some embodiments, the IL-2 protein comprises at least one unnatural amino acid. In some embodiments, the at least one unnatural amino acid is a replacement substitution at an amino acid position corresponding to native mature human IL-2 selected from T37, R38, T41, F42, K43, F44, Y45, E60, E61, E62, K64, P65, E68, V69, N71, L72, M104, C105, or Y107. In some embodiments, the unnatural amino acid is a lysine derivative or comprises an aromatic side chain. In some embodiments, the unnatural amino acid is N6-[(2-azidoethoxy)carbonyl]-l- lysine. In some embodiments, the IL-2 protein is a conjugate of an IL-2 mutein comprising at least one unnatural amino acid as described in US Patent Nos.10,610,571 or PCT Publication Nos. WO2019028419 or WO2019028425; PCT Publication No. WO19165453; US Patent No. 11,077,195 or PCT Publication No. WO2020163532; PCT Publication No. WO2021030706; PCT Publication No. WO2021050554; or PCT Publication No. WO2021263026. In some embodiments, the IL-2 protein is THOR-707 (Sanofi).

[0088] In some embodiments, the IL-2 protein is an IL-2 mimetic (e.g., a de novo protein that mimics the activity of IL-2). In some embodiments, the IL-2 protein is an IL-2 mimetic as described in PCT Publication No WO2021081193 or PCT Publication No WO2021188374. In some embodiments, the IL-2 mimetic induces the hetero-dimerization of two IL-2 cell membrane receptors. In some embodiments, the IL-2 mimetic is Neoleukin-2 / 15. In some embodiments, 21 NAI-5002088184v1Attorney Docket No.14678-029-228 the IL-2 protein is IL-2 clinical candidate NL-201 (Neoleukin Therapeutics).

[0089] In certain aspects, the IL-2 protein is a low dose IL-2 protein, e.g., is an amount of IL- 2 protein that upon administration to a subject increases the number and function of regulatory T cells (Tregs) without substantially increasing the pool of effector T cells and / or B cells in a subject when compared to the levels of Tregs, T cells, and / or B cells in the subject prior to the administration of IL-2. In certain embodiments, low dose IL-2 protein ranges from about 0.01x106International Units (IU) per administration to about 5x106IU per administration. In certain embodiments, low dose IL-2 protein ranges from about 0.3 µg -1.0 µg per administration to about 150 µg -500 µg per administration. In certain embodiments, low dose IL-2 protein is administered in a monthly amount of about 0.01x106IU to about 150x106IU. In certain embodiments, low dose IL-2 protein is administered in a monthly amount of about 0.3 µg -1.0 µg to about 4,500 µg -15,000 µg.

[0090] Pharmaceutical compositions disclosed herein can be formulated for administering any of the IL-2 proteins contemplated herein for peripheral administration, such as parenteral (e.g., subcutaneous, intravenous, intramuscular), a continuous infusion (e.g., intravenous drip, intravenous bolus, intravenous infusion), topical, nasal, or oral administration. Suitable pharmaceutically acceptable carriers and formulations comprising thereof are known the art and can be found at least in, for example, REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (A. Adejare, Ed.; 23rd edition). Academic Press (2020). 7.3 Methods of Use

[0091] In one aspect, presented herein is a method for administering IL-2 protein and at least one GLP-1 receptor agonist to a subject in need thereof. A subject in need of the methods disclosed herein is diagnosed with or is suspected of having a disorder that would benefit from downregulation of the immune system or reducing inflammation. A subject in need of treatment can be a subject diagnosed with or suspected of having a disease or disorder as described herein. A subject in need of treatment can be a subject diagnosed with or suspected of having an inflammatory disease or disorder as described herein. A subject in need of the methods and / or compositions disclosed herein can be one as described in Section 7.3.1.

[0092] In some embodiments, the IL-2 protein is administered together with the GLP-1 receptor agonist as part of a pharmaceutical composition. In some embodiments, the IL-2 protein is administered separately from the GLP-1 receptor agonist, e.g., as part of a separate 22 NAI-5002088184v1Attorney Docket No.14678-029-228 pharmaceutical composition. The GLP-1 receptor agonists provided herein can be administered prior to, subsequent to, or simultaneously with administration of the IL-2 protein. In certain embodiments, GLP-1 receptor agonists provided herein can be administered prior to administration of the IL-2 protein according to the methods disclosed herein. In specific embodiments, the GLP-1 receptor agonist is semaglutide.

[0093] In a specific embodiment of a method for administering IL-2 protein and at least one GLP-1 receptor agonist to a subject in need thereof, the GLP-1 receptor agonist is semaglutide. In a particular embodiment, the semaglutide is Ozempic®. In another particular embodiment, the semaglutide is Rybelsus®. In yet another particular embodiment the semaglutide is Wegovy®. In in another specific embodiment, the GLP-1 receptor agonist is exendin- 4 / exenatide. In a particular embodiment the exendin-4 / exenatide is Byetta™. In another particular embodiment, the exendin-4 / exenatide is Bydureon.® In yet another particular embodiment, the GLP-1 receptor agonist is tirzepatide. In a particular embodiment, the tirzepatide is Mounjaro®. In another particular embodiment, the tirzepatide is Zepbound®. In another specific embodiment, the GLP-1 receptor agonist is liraglutide. In a particular embodiment, the liraglutide is Victoza®. In another particular embodiment, the liraglutide is Saxenda® In another specific embodiment, the GLP-1 receptor agonist is dulaglutide. In a particular embodiment, the dulaglutide is Trulicity®.

[0094] In a specific embodiment of a method for administering IL-2 protein and at least one GLP-1 receptor agonist to a subject in need thereof, the IL-2 protein is aldesleukin. In a specific embodiment of a method for administering IL-2 protein and at least one GLP-1 receptor agonist to a subject in need thereof, the IL-2 protein comprises the amino acid sequence of SEQ ID NO:26. In a specific embodiment of a method for administering IL-2 protein and at least one GLP-1 receptor agonist to a subject in need thereof, the IL-2 protein comprises the amino acid sequence of aldesleukin.

[0095] In a specific embodiment of a method for administering IL-2 protein and at least one GLP-1 receptor agonist to a subject in need thereof, the GLP-1 receptor agonist is semaglutide and the IL-2 protein comprises the amino acid sequence of SEQ ID NO:26. In a particular embodiment of such a method, the semaglutide is Ozempic®. In another particular embodiment of such a method, the semaglutide is Rybelsus®. In yet another particular embodiment of such a method, the semaglutide is Wegovy®. 23 NAI-5002088184v1Attorney Docket No.14678-029-228

[0096] In a specific embodiment of a method for administering IL-2 protein and at least one GLP-1 receptor agonist to a subject in need thereof, the GLP-1 receptor agonist is semaglutide and the IL-2 protein is aldesleukin. In a particular embodiment of such a method, the semaglutide is Ozempic®. In another particular embodiment of such a method, the semaglutide is Rybelsus®. In yet another particular embodiment of such a method, the semaglutide is Wegovy®.

[0097] In a specific embodiment of a method for administering IL-2 protein and at least one GLP-1 receptor agonist to a subject in need thereof, the GLP-1 receptor agonist is semaglutide and the IL-2 protein comprises the amino acid sequence of aldesleukin. In a particular embodiment of such a method, the semaglutide is Ozempic®. In another particular embodiment of such a method, the semaglutide is Rybelsus®. In yet another particular embodiment of such a method, the semaglutide is Wegovy®.

[0098] In a specific embodiment of a method for administering IL-2 protein and at least one GLP-1 receptor agonist to a subject in need thereof, the GLP-1 receptor agonist is exendin- 4 / exenatide and the IL-2 protein comprises the amino acid sequence of SEQ ID NO:26. In a particular embodiment of such a method, the exendin-4 / exenatide is Byetta™. In another particular embodiment of such a method, the exendin-4 / exenatide is Bydureon®.

[0099] In a specific embodiment of a method for administering IL-2 protein and at least one GLP-1 receptor agonist to a subject in need thereof, the GLP-1 receptor agonist is exendin- 4 / exenatide and the IL-2 protein is aldesleukin. In a particular embodiment of such a method, the exendin-4 / exenatide is Byetta™. In another particular embodiment of such a method, the exendin-4 / exenatide is Bydureon®.

[0100] In a specific embodiment of a method for administering IL-2 protein and at least one GLP-1 receptor agonist to a subject in need thereof, the GLP-1 receptor agonist is exendin- 4 / exenatide and the IL-2 protein comprises the amino acid sequence of aldesleukin. In a particular embodiment of such a method, the exendin-4 / exenatide is Byetta™. In another particular embodiment of such a method, the exendin-4 / exenatide is Bydureon®.

[0101] In a specific embodiment of a method for administering IL-2 protein and at least one GLP-1 receptor agonist to a subject in need thereof, the GLP-1 receptor agonist is tirzepatide and the IL-2 protein comprises the amino acid sequence of SEQ ID NO:26. In a particular 24 NAI-5002088184v1Attorney Docket No.14678-029-228 embodiment of such a method, the tirzepatide is Mounjaro®. In another particular embodiment of such a method, the tirzepatide is Zepbound®.

[0102] In a specific embodiment of a method for administering IL-2 protein and at least one GLP-1 receptor agonist to a subject in need thereof, the GLP-1 receptor agonist is tirzepatide and the IL-2 protein is aldesleukin. In a particular embodiment of such a method, the tirzepatide is Mounjaro®. In another particular embodiment of such a method, the tirzepatide is Zepbound®.

[0103] In a specific embodiment of a method for administering IL-2 protein and at least one GLP-1 receptor agonist to a subject in need thereof, the GLP-1 receptor agonist is tirzepatide and the IL-2 protein comprises the amino acid sequence of aldesleukin. In a particular embodiment of such a method, the tirzepatide is Mounjaro®. In another particular embodiment of such a method, the tirzepatide is Zepbound®.

[0104] In a specific embodiment of a method for administering IL-2 protein and at least one GLP-1 receptor agonist to a subject in need thereof, the GLP-1 receptor agonist is liraglutide and the IL-2 protein comprises the amino acid sequence of SEQ ID NO:26. In a particular embodiment of such a method, the liraglutide is Victoza®. In another particular embodiment of such a method, the liraglutide is Saxenda®.

[0105] In a specific embodiment of a method for administering IL-2 protein and at least one GLP-1 receptor agonist to a subject in need thereof, the GLP-1 receptor agonist is liraglutide and the IL-2 protein is aldesleukin. In a particular embodiment of such a method, the liraglutide is Victoza®. In another particular embodiment of such a method, the liraglutide is Saxenda®.

[0106] In a specific embodiment of a method for administering IL-2 protein and at least one GLP-1 receptor agonist to a subject in need thereof, the GLP-1 receptor agonist is liraglutide and the IL-2 protein comprises the amino acid sequence of aldesleukin. In a particular embodiment of such a method, the liraglutide is Victoza®. In another particular embodiment of such a method, the liraglutide is Saxenda®.

[0107] In a specific embodiment of a method for administering IL-2 protein and at least one GLP-1 receptor agonist to a subject in need thereof, the GLP-1 receptor agonist is dulaglutide and the IL-2 protein comprises the amino acid sequence of SEQ ID NO: 26. In a particular embodiment of such a method, the dulaglutide is Trulicity®.

[0108] In a specific embodiment of a method for administering IL-2 protein and at least one GLP-1 receptor agonist to a subject in need thereof, the GLP-1 receptor agonist is dulaglutide 25 NAI-5002088184v1Attorney Docket No.14678-029-228 and the IL-2 protein is aldesleukin. In a particular embodiment of such a method, the dulaglutide is Trulicity®.

[0109] In a specific embodiment of a method for administering IL-2 protein and at least one GLP-1 receptor agonist to a subject in need thereof, the GLP-1 receptor agonist is dulaglutide and the IL-2 protein comprises the amino acid sequence of aldesleukin. In a particular embodiment of such a method, the dulaglutide is Trulicity®.

[0110] In one aspect, presented herein is a method for administering low dose IL-2 protein and at least one GLP-1 receptor agonist to a subject in need thereof. In some embodiments, the low dose IL-2 protein is administered together with the GLP-1 receptor agonist as part of a pharmaceutical composition. In some embodiments, the low dose IL-2 protein is administered separately from the GLP-1 receptor agonist, e.g., as part of a separate pharmaceutical composition. The GLP-1 receptor agonists provided herein can be administered prior to, subsequent to, or simultaneously with administration of the IL-2 protein. In specific embodiments, the GLP-1 receptor agonist is semaglutide. In specific embodiments, the GLP-1 receptor agonist is exendin-4. In specific embodiments, the IL-2 protein comprises the amino acid sequence of SEQ ID NO: 26. In specific embodiments, the IL-2 protein is aldesleukin. In specific embodiments, the IL-2 protein comprises the amino acid sequence of aldesleukin.

[0111] Also provided herein, are methods of treating a disease or disorder in a subject in need thereof, for example, a disease or disorder described herein, comprising: administering to a subject in need thereof: (a) IL-2 protein, and (b) at least one GLP-1 receptor agonist. In certain embodiments, the IL-2 protein comprises the amino acid sequence of SEQ ID NO: 26. In certain embodiments, the IL-2 protein is aldesleukin. In certain embodiments, the IL-2 protein comprises the amino acid sequence of aldesleukin. In specific embodiments, the IL-2 protein is low dose IL-2 protein. In specific embodiments, the GLP-1 receptor agonist is semaglutide. In specific embodiments, the GLP-1 receptor agonist is exendin-4.

[0112] In certain embodiments, a method of treatment provided herein can resolve at least one sign or symptom of an existing disease or condition of a subject. In certain embodiments, a method of treatment provided herein can at least temporarily restore the health of a subject, e.g., to restore to the health of the subject prior to the subject's development of the disease or condition. In certain embodiments, a method of treatment provided herein can slow the rate of progression of the disease or condition of a subject. In certain embodiments, a method of 26 NAI-5002088184v1Attorney Docket No.14678-029-228 treatment provided herein can result in stabilization of, or prevent progression of, the disease or condition of a subject, e.g., can result in no functional decline in, or maintain the severity of, the disease or condition in the subject comparable to that of the subject before the method of treatment is administered according to the present disclosure. In certain embodiments, the effect of a method of treatment provided herein may be assessed by monitoring clinical signs and symptoms of the disease to be treated (See Section 7.3.2).

[0113] GLP-1 receptor agonists and IL-2 proteins suitable for use with the methods disclosed herein are described in Sections 7.1 and 7.2, respectively. In certain embodiments, the GLP-1 receptor agonist comprises the amino acid sequence of SEQ ID NO: 3. In certain embodiments, the GLP-1 receptor agonist is semaglutide. In certain embodiments, the GLP-1 receptor agonist comprises the amino acid sequence of SEQ ID NO: 4. In certain embodiments, the GLP-1 receptor agonist is exendin-4. In certain embodiments, the IL-2 protein comprises the amino acid sequence of SEQ ID NO: 25. In certain embodiments, the IL-2 protein comprises the amino acid sequence of SEQ ID NO: 26. In In certain embodiments, the IL-2 protein is aldesleukin. In certain embodiments, the IL-2 protein comprises the amino acid sequence of aldesleukin.

[0114] In certain embodiments, the GLP-1 receptor agonist comprises the amino acid sequence of SEQ ID NO: 3 and the IL-2 protein comprises the amino acid sequence of SEQ ID NO: 26. In certain embodiments, the GLP-1 receptor agonist comprises the amino acid sequence of SEQ ID NO: 4 and the IL-2 protein comprises the amino acid sequence of SEQ ID NO: 26. In certain embodiments, the GLP-1 receptor agonist is semaglutide and the IL-2 protein comprises the amino acid sequence of SEQ ID NO: 26. In certain embodiments, the semiglutide is WEGOVY®. In certain embodiments, the semiglutide is OZEMPIC®. In certain embodiments, the semiglutide is RYBELSUS®. In certain embodiments, the GLP-1 receptor agonist is exendin-4 and the IL-2 protein comprises the amino acid sequence of SEQ ID NO: 26. In certain embodiments, the exendin-4 is BYETTA®. In certain embodiments, the exendin-4 is BYDUREON®.

[0115] In certain embodiments, the GLP-1 receptor agonist comprises the amino acid sequence of SEQ ID NO: 3 and the IL-2 protein is aldesleukin. In certain embodiments, the GLP-1 receptor agonist comprises the amino acid sequence of SEQ ID NO: 4 and the IL-2 protein is aldesleukin. In certain embodiments, the GLP-1 receptor agonist is semaglutide and the IL-2 protein is aldesleukin. In certain embodiments, the semiglutide is WEGOVY®. In 27 NAI-5002088184v1Attorney Docket No.14678-029-228 certain embodiments, the semiglutide is OZEMPIC®. In certain embodiments, the semiglutide is RYBELSUS®. In certain embodiments, the GLP-1 receptor agonist is exendin-4 and the IL-2 protein is aldesleukin. In certain embodiments, the exendin-4 is BYETTA®. In certain embodiments, the exendin-4 is BYDUREON®.

[0116] In certain embodiments, the GLP-1 receptor agonist comprises the amino acid sequence of SEQ ID NO: 3 and the IL-2 protein comprises the amino acid sequence of aldesleukin. In certain embodiments, the GLP-1 receptor agonist comprises the amino acid sequence of SEQ ID NO: 4 and the IL-2 protein comprises the amino acid sequence of aldesleukin. In certain embodiments, the GLP-1 receptor agonist is semaglutide and the IL-2 protein comprises the amino acid sequence of aldesleukin. In certain embodiments, the semiglutide is WEGOVY®. In certain embodiments, the semiglutide is OZEMPIC®. In certain embodiments, the semiglutide is RYBELSUS®. In certain embodiments, the GLP-1 receptor agonist is exendin-4 and the IL-2 protein comprises the amino acid sequence of aldesleukin. In certain embodiments, the exendin-4 is BYETTA®. In certain embodiments, the exendin-4 is BYDUREON®.

[0117] In certain embodiments, the GLP-1 receptor agonist and the IL-2 protein are administered to the subject separately.

[0118] In certain embodiments, the GLP-1 receptor agonist is administered by injection or infusion. In certain embodiments, the GLP-1 receptor agonist is administered subcutaneously. In certain embodiments, the GLP-1 receptor agonist is administered orally. In certain embodiments, the IL-2 protein is administered by injection or infusion. In certain embodiments, the IL-2 protein is administered subcutaneously. In certain embodiments, the GLP-1 receptor agonist and the IL-2 protein are administered by injection or infusion. In particular embodiments, the GLP-1 receptor agonist and the IL-2 protein are administered subcutaneously.

[0119] In certain embodiments, according to the GLP-1 receptor agonist / IL-2 methods provided herein, the GLP-1 receptor agonist is administered to the subject daily. In some embodiments, the GLP-1 receptor agonist is administered to the subject at least once a day, at least twice a day, at least 3 times a day, at least 4 times a day, or more than 4 times a day. In certain embodiments, according to the methods provided herein, the GLP-1 receptor agonist is administered to the subject every other day. In certain embodiments, according to the methods provided herein, the GLP-1 receptor agonist is administered to the subject every other third day. 28 NAI-5002088184v1Attorney Docket No.14678-029-228 In certain embodiments, according to the methods provided herein, the GLP-1 receptor agonist is administered to the subject weekly. In certain embodiments, according to the methods provided herein, the GLP-1 receptor agonist is administered to the subject at least once a week, at least twice a week, at least three times a week, or more than three times a week. In certain embodiments, according to the methods provided herein, the GLP-1 receptor agonist is administered to the subject once every week. In certain embodiments, according to the methods provided herein, the GLP-1 receptor agonist is administered to the subject monthly.

[0120] In certain embodiments, according to the GLP-1 receptor agonist / IL-2 methods provided herein, the GLP-1 receptor agonist is administered to the subject daily via injection or infusion. In certain embodiments, according to the methods provided herein, the GLP-1 receptor agonist is administered to the subject at least once a day, at least twice a day, at least 3 times a day, at least 4 times a day, or more than 4 times a day via injection or infusion. In certain embodiments, according to the methods provided herein, the GLP-1 receptor agonist is administered to the subject every other day via injection or infusion. In certain embodiments, according to the methods provided herein, the GLP-1 receptor agonist is administered to the subject every other third day via injection or infusion. In certain embodiments, according to the methods provided herein, the GLP-1 receptor agonist is administered to the subject weekly via injection or infusion. In certain embodiments, according to the methods provided herein, the GLP-1 receptor agonist is administered to the subject once every week via injection or infusion. In certain embodiments, according to the methods provided herein, the GLP-1 receptor agonist is subcutaneously administered to the subject daily. In certain embodiments, according to the methods provided herein, the GLP-1 receptor agonist is subcutaneously administered to the subject weekly. In certain embodiments, according to the methods provided herein, the GLP-1 receptor agonist is subcutaneously administered to the subject once every week. In certain embodiments, according to the methods provided herein, the GLP-1 receptor agonist is subcutaneously administered to the subject at least once a day, at least twice a day, at least 3 times a day, at least 4 times a day, or more than 4 times a day via injection or infusion. In certain embodiments, according to the methods provided herein, the GLP-1 receptor agonist is subcutaneously administered to the subject at least once a day. In certain embodiments, according to the methods provided herein, the GLP-1 receptor agonist is subcutaneously administered to the subject at least twice a day. In certain embodiments, according to the 29 NAI-5002088184v1Attorney Docket No.14678-029-228 methods provided herein, the GLP-1 receptor agonist is subcutaneously administered to the subject once every week wherein the GLP-1 receptor agonist comprises the amino acid sequence of SEQ ID NO: 3. In certain embodiments, according to the methods provided herein, the GLP- 1 receptor agonist is subcutaneously administered to the subject once every week wherein the GLP-1 receptor agonist is semaglutide. In certain embodiments, according to the methods provided herein, the GLP-1 receptor agonist is subcutaneously administered to the subject daily wherein the GLP-1 receptor agonist comprises the amino acid sequence of SEQ ID NO: 4. In certain embodiments, according to the methods provided herein, the GLP-1 receptor agonist is subcutaneously administered to the subject daily wherein the GLP-1 receptor agonist is exendin-4.

[0121] In certain embodiments, according to the methods provided herein, the GLP-1 receptor agonist is administered to the subject daily via an oral route (e.g., via a tablet). In certain embodiments, according to the methods provided herein, the GLP-1 receptor agonist is administered to the subject once daily via an oral route. In certain embodiments, according to the methods provided herein, semaglutide is administered to the subject once daily via an oral route. In certain embodiments, according to the methods provided herein, semaglutide is administered to the subject once daily via an oral route. In certain embodiments, according to the methods provided herein, a GLP-1 receptor agonist comprising the amino acid sequence of SEQ ID NO: 3 is administered to the subject once daily via an oral route.

[0122] In certain embodiments, a method of treatment of an inflammatory disease or disorder in a subject in need thereof, as provided herein, comprises: (a) administering a GLP-1 receptor agonist to the subject daily; and (b) administering an IL-2 protein to the subject weekly. In certain embodiments, a method of treatment of an inflammatory disease or disorder in a subject in need thereof, as provided herein, comprises: (a) administering a GLP-1 receptor agonist to the subject daily; and (b) administering an IL-2 protein to the subject every two weeks. In certain embodiments, a method of treatment of an inflammatory disease or disorder in a subject in need thereof, as provided herein, comprises: (a) a daily administration of a GLP-1 receptor agonist to the subject, wherein the GLP-1 receptor agonist is administered to the subject once a day; and (b) a weekly administration of an IL-2 protein to the subject, wherein the IL-2 protein is administered to the subject once per week or is administered once daily for 2-7 consecutive days. In certain embodiments, a method of treatment of an inflammatory disease or disorder in a 30 NAI-5002088184v1Attorney Docket No.14678-029-228 subject in need thereof, as provided herein, comprises: (a) a daily administration of a GLP-1 receptor agonist to the subject, wherein the GLP-1 receptor agonist is administered to the subject twice a day; and (b) a weekly administration of an IL-2 protein to the subject, wherein the IL-2 protein is administered to the subject once per week or is administered once daily for 2-7 consecutive days.

[0123] In certain embodiments, a method of treatment of an inflammatory disease or disorder in a subject in need thereof, as provided herein, comprises: (a) administering a GLP-1 receptor agonist to the subject weekly; and (b) administering an IL-2 protein to the subject weekly. In certain embodiments, a method of treatment of an inflammatory disease or disorder in a subject in need thereof, as provided herein, comprises: (a) administering a GLP-1 receptor agonist to the subject weekly; and (b) administering an IL-2 protein to the subject weekly, wherein the GLP-1 receptor agonist and the IL-2 protein are administered on the same weeks.

[0124] In certain embodiments, a method of treatment of an inflammatory disease or disorder in a subject in need thereof, as provided herein, comprises: (a) administering a GLP-1 receptor agonist to the subject weekly; and (b) administering an IL-2 protein to the subject every two weeks. In certain embodiments, a method of treatment of an inflammatory disease or disorder in a subject in need thereof, as provided herein, comprises: (a) administering a GLP-1 receptor agonist to the subject weekly, beginning on week 1; and (b) administering an IL-2 protein to the subject every two weeks, beginning on week 1. In certain embodiments, a method of treatment of an inflammatory disease or disorder in a subject in need thereof, as provided herein, comprises: (a) administering a GLP-1 receptor agonist to the subject weekly, beginning on week 1; and (b) administering an IL-2 protein to the subject every two weeks, beginning on week 2.

[0125] In certain embodiments, a method of treatment of an inflammatory disease or disorder in a subject in need thereof, as provided herein, comprises: (a) a weekly administration of a GLP- 1 receptor agonist to the subject, wherein the GLP-1 receptor agonist is administered to the subject once per week; and (b) a weekly administration of an IL-2 protein to the subject, wherein the IL-2 protein is administered to the subject once per week or is administered once daily for 2- 7 consecutive days. In particular embodiments, the GLP-1 receptor agonist and the IL-2 protein are administered to the subject on the same weeks.

[0126] In certain embodiments, a method of treatment of an inflammatory disease or disorder in a subject in need thereof, as provided herein, comprises: (a) a weekly administration of a GLP- 31 NAI-5002088184v1Attorney Docket No.14678-029-228 1 receptor agonist to the subject, wherein the GLP-1 receptor agonist is administered to the subject once per week; and (b) administration of an IL-2 protein to the subject every two weeks, wherein on a week the IL-2 protein is administered to the subject, the IL-2 protein is administered once during the week or is administered once daily during the week for 2-7 consecutive days. In certain embodiments, the weekly GLP-1 receptor agonist administration begins on week 1; and (b) the administration of the IL-2 protein every two weeks, begins on week 1.

[0127] In certain embodiments, a method of treatment of an inflammatory disease or disorder in a subject in need thereof, as provided herein, comprises: (a) a weekly administration of a GLP- 1 receptor agonist to the subject, wherein the GLP-1 receptor agonist is administered to the subject once per week; and (b) administration of an IL-2 protein to the subject every two weeks, wherein on a week the IL-2 protein is administered to the subject, the IL-2 protein is administered once during the week or is administered once daily during the week for 2-7 consecutive days. In certain embodiments, the weekly GLP-1 receptor agonist administration begins on week 1; and (b) the administration of the IL-2 protein every two weeks, begins on week 2.

[0128] In certain embodiments, a method of treatment of an inflammatory disease or disorder in a subject in need thereof, as provided herein, comprises: (a) a weekly administration of a GLP- 1 receptor agonist to the subject, wherein the GLP-1 receptor agonist is administered to the subject once per week on day 1 of each week; and (b) a weekly administration of an IL-2 protein to the subject, wherein the IL-2 protein is administered to the subject once per week on day 1 of each week or is administered to the subject once daily for 2-7 consecutive days, beginning on day 1 of each week. In particular embodiments, the GLP-1 receptor agonist and the IL-2 protein are administered to the subject on the same weeks. In certain embodiments, a method of treatment of an inflammatory disease or disorder in a subject in need thereof, as provided herein, comprises: (a) a weekly administration of a GLP-1 receptor agonist to the subject, wherein the GLP-1 receptor agonist is administered to the subject once per day of the week; and (b) a weekly administration of an IL-2 protein to the subject, wherein the IL-2 protein is administered to the subject once per week on day 1 of each week or is administered to the subject once daily for 2-7 consecutive days, beginning on day 1 of each week. 32 NAI-5002088184v1Attorney Docket No.14678-029-228

[0129] In certain embodiments, a method of treatment of an inflammatory disease or disorder in a subject in need thereof, as provided herein, comprises: (a) a weekly administration of a GLP- 1 receptor agonist to the subject, wherein the GLP-1 receptor agonist is administered to the subject once per week on day 1 of each week; and (b) administration of an IL-2 protein to the subject every two weeks, wherein on a week the IL-2 protein is administered to the subject, the IL-2 protein is administered once during the week on day 1 of the week, or is administered once daily during the week for 2-7 consecutive days, beginning on day 1 of the week.

[0130] In certain embodiments, a method of treatment of an inflammatory disease or disorder in a subject in need thereof, as provided herein, comprises: (a) a weekly administration of a GLP- 1 receptor agonist to the subject, wherein the GLP-1 receptor agonist is administered to the subject once per day of the week; and (b) administration of an IL-2 protein to the subject every two weeks, wherein on a week the IL-2 protein is administered to the subject, the IL-2 protein is administered once during the week on day 1 of the week, or is administered once daily during the week for 2-7 consecutive days, beginning on day 1 of the week.

[0131] In certain embodiments, a method of treatment of an inflammatory disease or disorder in a subject in need thereof, as provided herein, comprises a dosing cycle that comprises administering a GLP-1 receptor agonist weekly and an IL-2 protein to the subject weekly for 2, 3, 4, 5 or 6 consecutive weeks. In certain embodiments, a method of treatment of an inflammatory disease or disorder in a subject in need thereof, as provided herein, comprises a dosing cycle that comprises administering a GLP-1 receptor agonist daily and an IL-2 protein to the subject weekly for 2, 3, 4, 5 or 6 consecutive weeks.

[0132] In certain embodiments, a method of treatment of an inflammatory disease or disorder in a subject in need thereof, as provided herein, comprises a dosing cycle that comprises administering a GLP-1 receptor agonist to the subject weekly for 2, 3, 4, 5 or 6 consecutive weeks, and administration of IL-2 protein to the subject every two weeks for 2, 4, or 6 weeks. In certain embodiments, a method of treatment of an inflammatory disease or disorder in a subject in need thereof, as provided herein, comprises a dosing cycle that comprises administering a GLP-1 receptor agonist to the subject daily for 2, 3, 4, 5 or 6 consecutive weeks, and administration of IL-2 protein to the subject every two weeks for 2, 4, or 6 weeks.

[0133] In certain embodiments, a method of treatment of an inflammatory disease or disorder in a subject in need thereof, as provided herein, comprises a dosing cycle that comprises i) 33 NAI-5002088184v1Attorney Docket No.14678-029-228 administering a GLP-1 receptor agonist to the subject weekly for 2, 3, 4, 5 or 6 consecutive weeks, beginning on week 1, and administration of IL-2 protein to the subject every two weeks for 2, 4, or 6 weeks, beginning on week 1. In certain embodiments, a method of treatment of an inflammatory disease or disorder in a subject in need thereof, as provided herein, comprises a dosing cycle that comprises i) administering a GLP-1 receptor agonist to the subject daily for 2, 3, 4, 5 or 6 consecutive weeks, beginning on week 1, and administration of IL-2 protein to the subject every two weeks for 2, 4, or 6 weeks, beginning on week 1.

[0134] In certain embodiments, a method of treatment of an inflammatory disease or disorder in a subject in need thereof, as provided herein, comprises a dosing cycle that comprises i) administering a GLP-1 receptor agonist to the subject weekly for 2, 3, 4, 5 or 6 consecutive weeks, beginning on week 1, and administration of IL-2 protein to the subject every two weeks for 2, 4, or 6 weeks, beginning on week 2. In certain embodiments, a method of treatment of an inflammatory disease or disorder in a subject in need thereof, as provided herein, comprises a dosing cycle that comprises i) administering a GLP-1 receptor agonist to the subject daily for 2, 3, 4, 5 or 6 consecutive weeks, beginning on week 1, and administration of IL-2 protein to the subject every two weeks for 2, 4, or 6 weeks, beginning on week 2.

[0135] In certain embodiments, a method of treatment of an inflammatory disease or disorder in a subject in need thereof, as provided herein, comprises a dosing cycle that comprises administering a GLP-1 receptor agonist and an IL-2 protein to the subject weekly for 2, 3, 4, 5 or 6 consecutive weeks, wherein the GLP-1 receptor agonist is administered to the subject once per week, and the IL-2 protein is administered to the subject once per week or once daily for 2-7 consecutive days. In certain embodiments, a method of treatment of an inflammatory disease or disorder in a subject in need thereof, as provided herein, comprises a dosing cycle that comprises administering a GLP-1 receptor agonist to the subject daily for 2, 3, 4, 5 or 6 consecutive weeks, wherein the GLP-1 receptor agonist is administered to the subject 1-4 times per day (e.g., once, twice, three times, or four times a day), and the IL-2 protein is administered to the subject once per week for 2, 3, 4, 5 or 6 consecutive weeks for 2-7 consecutive days.

[0136] In certain embodiments, a method of treatment of an inflammatory disease or disorder in a subject in need thereof, as provided herein, comprises a dosing cycle that comprises administering a GLP-1 receptor agonist once per week on day 1 of the week, and an IL-2 protein to the subject weekly for 2, 3, 4, 5 or 6 consecutive weeks, wherein the GLP-1 receptor agonist is 34 NAI-5002088184v1Attorney Docket No.14678-029-228 administered to the subject once per week and the IL-2 protein is administered to the subject once per week on day 1 of the week or once daily for 2-7 consecutive days beginning on day 1 of the week. In certain embodiments, a method of treatment of an inflammatory disease or disorder in a subject in need thereof, as provided herein, comprises a dosing cycle that comprises administering a GLP-1 receptor agonist daily on day 1 of the week, and an IL-2 protein to the subject weekly for 2, 3, 4, 5 or 6 consecutive weeks, wherein the GLP-1 receptor agonist is administered to the subject 1-4 times per day (e.g., once, twice, three times, or four times a day), and the IL-2 protein is administered to the subject once per week on day 1 of the week or once daily for 2-7 consecutive days beginning on day 1 of the week.

[0137] In certain embodiments, a method of treatment of a disease or disorder in a subject in need thereof that comprises a dosing cycle, as provided herein, the dosing cycle is repeated at least 1-12 times. In certain embodiments, the dosing cycle is repeated at least 1-6 times. In certain embodiments, the dosing cycle is repeated at least once. In certain embodiments, the dosing cycle is repeated at least twice. In certain embodiments, the dosing cycle is repeated at least 3 times. In certain embodiments, the dosing cycle is repeated at least 4 times. In certain embodiments, the dosing cycle is repeated at least 5 times. In certain embodiments, the dosing cycle is repeated at least 6 times. In certain embodiments, the dosing cycle is repeated at least 7 times. In certain embodiments, the dosing cycle is repeated at least 8 times. In certain embodiments, the dosing cycle is repeated at least 9 times. In certain embodiments, the dosing cycle is repeated at least 10 times. In certain embodiments, the dosing cycle is repeated at least 11 times. In certain embodiments, the dosing cycle is repeated at least 12 times. In certain embodiments, the dosing cycle is repeated 1-12 times. In certain embodiments, the dosing cycle is repeated at least 1-12 (e.g., 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, 1-11 or 1-12) times in a 26- or 52- week period.

[0138] In certain embodiments, the dosing cycle is repeated once. In certain embodiments, the dosing cycle is repeated twice. In certain embodiments, the dosing cycle is repeated 3 times. In certain embodiments, the dosing cycle is repeated 4 times. In certain embodiments, the dosing cycle is repeated 5 times. In certain embodiments, the dosing cycle is repeated 6 times. In certain embodiments, the dosing cycle is repeated 7 times. In certain embodiments, the dosing cycle is repeated 8 times. In certain embodiments, the dosing cycle is repeated 9 times. In 35 NAI-5002088184v1Attorney Docket No.14678-029-228 certain embodiments, the dosing cycle is repeated 10 times. In certain embodiments, the dosing cycle is repeated 11 times. In certain embodiments, the dosing cycle is repeated 12 times.

[0139] In certain embodiments wherein a dosing cycle is repeated, each repeated dosing cycle begins the day following the end of the previous dosing cycle. In certain embodiments, each repeated dosing cycle begins the week following the end of the previous dosing cycle.

[0140] In some embodiments, according to the methods provided herein, the GLP-1 receptor agonist is administered to the subject as described in any of the embodiments presented herein in an amount in the range of about 0.05 mg to about 3 mg per week. In some embodiments, according to the methods provided herein, the GLP-1 receptor agonist is semaglutide (e.g., WEGOVY®, OZEMPIC®) and is administered to the subject as described in any of the embodiments presented herein in an amount in the range of about 0.05 mg to about 3 mg per week. In some embodiments, according to the methods provided herein, the GLP-1 receptor agonist is exendin-4 (e.g., BYETTA®or BYDUREON®) and is administered to the subject as described in any of the embodiments presented herein in an amount in the range of about 0.05 mg to about 3 mg per week.

[0141] In certain embodiments, according to the methods provided herein, the GLP-1 receptor agonist is administered to the subject as described in any of the embodiments presented herein in an amount of about 0.07 mg per week. In some embodiments, according to the methods provided herein, the GLP-1 receptor agonist is exendin-4 (e.g., BYETTA® ®or BYDUREON®) and is administered to the subject as described in any of the embodiments presented herein in an amount of about 0.07 mg per week.

[0142] In certain embodiments, according to the methods provided herein, the GLP-1 receptor agonist is administered to the subject as described in any of the embodiments presented herein in an amount of about 0.14 mg per week. In some embodiments, according to the methods provided herein, the GLP-1 receptor agonist is exendin-4 (e.g., BYETTA®or BYDUREON®) and is administered to the subject as described in any of the embodiments presented herein in an amount of about 0.14 mg per week.

[0143] In certain embodiments, according to the methods provided herein, the GLP-1 receptor agonist is administered to the subject as described in any of the embodiments presented herein in an amount of about 0.25 mg per week. In some embodiments, according to the methods provided herein, the GLP-1 receptor agonist is semaglutide (e.g., WEGOVY®, 36 NAI-5002088184v1Attorney Docket No.14678-029-228 OZEMPIC®) and is administered to the subject as described in any of the embodiments presented herein in an amount of about 0.25 mg per week.

[0144] In some embodiments, according to the methods provided herein, the GLP-1 receptor agonist is administered to the subject as described in any of the embodiments presented herein in an amount in the range of about 0.5 mg to about 2.4 mg per week.

[0145] In certain embodiments, according to the methods provided herein, the GLP-1 receptor agonist is administered to the subject as described in any of the embodiments presented herein in an amount of about 0.5 mg per week. In some embodiments, according to the methods provided herein, the GLP-1 receptor agonist is semaglutide (e.g., WEGOVY®, OZEMPIC®) and is administered to the subject as described in any of the embodiments presented herein in an amount of about 0.5 mg per week.

[0146] In certain embodiments, according to the methods provided herein, the GLP-1 receptor agonist is administered to the subject as described in any of the embodiments presented herein in an amount of about 1 mg per week. In some embodiments, according to the methods provided herein, the GLP-1 receptor agonist is semaglutide (e.g., WEGOVY®, OZEMPIC®) and is administered to the subject as described in any of the embodiments presented herein in an amount of about 1 mg per week.

[0147] In certain embodiments, according to the methods provided herein, the GLP-1 receptor agonist is administered to the subject as described in any of the embodiments presented herein in an amount of about 1.7 mg per week. In some embodiments, according to the methods provided herein, the GLP-1 receptor agonist is semaglutide (e.g., WEGOVY®) and is administered to the subject as described in any of the embodiments presented herein in an amount of about 1.7 mg per week. In certain embodiments, according to the methods provided herein, the GLP-1 receptor agonist is administered to the subject as described in any of the embodiments presented herein in an amount of about 2 mg per week. In some embodiments, according to the methods provided herein, the GLP-1 receptor agonist is semaglutide (e.g., OZEMPIC®) and is administered to the subject as described in any of the embodiments presented herein in an amount of about 2 mg per week.

[0148] In certain embodiments, according to the methods provided herein, the GLP-1 receptor agonist is administered to the subject as described in any of the embodiments presented herein in an amount of about 2.4 mg per week. In some embodiments, according to the methods 37 NAI-5002088184v1Attorney Docket No.14678-029-228 provided herein, the GLP-1 receptor agonist is semaglutide (e.g., WEGOVY®, OZEMPIC®) and is administered to the subject as described in any of the embodiments presented herein in an amount of about 2.4 mg per week.

[0149] In some embodiments, according to the methods provided herein, the GLP-1 receptor agonist is administered to the subject at an escalating dosage regimen over a period of time until a maintenance dosage is reached. In some embodiments, according to the methods provided herein, the GLP-1 receptor agonist is administered to the subject at an escalating dosage regimen over a period of time until a maintenance dosage is reached wherein the amount of GLP-1 receptor agonist increases at 4 week intervals until a maintenance dosage is reached.

[0150] In some embodiments, according to the methods provided herein, the GLP-1 receptor agonist is administered to the subject at 0.005 mg (5 mcg per dose) at least twice a day. In some embodiments, according to the methods provided herein, the GLP-1 receptor agonist is exendin- 4 (e.g., BYETTA®or BYDUREON®) and is administered to the subject at 0.005 mg (5 mcg per dose) at least twice a day. In some embodiments, according to the methods provided herein, the GLP-1 receptor agonist is administered to the subject at 0.010 mg (10 mcg per dose) at least twice a day. In some embodiments, according to the methods provided herein, the GLP-1 receptor agonist is exendin-4 (e.g., BYETTA®or BYDUREON®) and is administered to the subject at 0.010 mg (10 mcg per dose) at least twice a day. In some embodiments, according to the methods provided herein, the GLP-1 receptor agonist is administered to the subject at 0.005 mg (5 mcg per dose) at least twice a day for 30 days before increasing to administered to the subject at 0.010 mg (10 mcg per dose) at least twice a day. In some embodiments, according to the methods provided herein, the GLP-1 receptor agonist is exendin-4 (e.g., BYETTA®or BYDUREON®) and is administered to the subject at 0.005 mg (5 mcg per dose) at least twice a day for 30 days before increasing to administered to the subject at 0.010 mg (10 mcg per dose) at least twice a day.

[0151] In some embodiments, according to the methods provided herein, the GLP-1 receptor agonist is administered to the subject daily, e.g., as described in any of the embodiments presented herein in an amount in the range of about 3 mg to about 14 mg per day. In some embodiments, according to the methods provided herein, the GLP-1 receptor agonist is semaglutide (e.g., RYBELSUS®) and is administered to the subject daily, e.g., as described in any of the embodiments presented herein in an amount in the range of about 3 mg to about 14 38 NAI-5002088184v1Attorney Docket No.14678-029-228 mg per day. In certain embodiments, according to the methods provided herein, the GLP-1 receptor agonist is administered to the subject daily, e.g., as described in any of the embodiments presented herein in an amount of about 3 mg per day. In some embodiments, according to the methods provided herein, the GLP-1 receptor agonist is semaglutide (e.g., RYBELSUS®) and is administered to the subject daily, e.g., as described in any of the embodiments presented herein in an amount of about 3 mg per day. In certain embodiments, according to the methods provided herein, the GLP-1 receptor agonist is administered to the subject daily, e.g., as described in any of the embodiments presented herein in an amount of about 7 mg per day. In some embodiments, according to the methods provided herein, the GLP-1 receptor agonist is semaglutide (e.g., RYBELSUS®) and is administered to the subject daily, e.g., as described in any of the embodiments presented herein in an amount of about 7 mg per day. In certain embodiments, according to the methods provided herein, the GLP-1 receptor agonist is administered to the subject daily, e.g., as described in any of the embodiments presented herein in an amount of about 14 mg per day. In some embodiments, according to the methods provided herein, the GLP-1 receptor agonist is semaglutide (e.g., RYBELSUS®) and is administered to the subject daily, e.g., as described in any of the embodiments presented herein in an amount of about 14 mg per day.

[0152] In some embodiments, according to the methods provided herein, the GLP-1 receptor agonist is administered to the subject daily at an escalating dosage regimen over a period of time until a maintenance dosage is reached wherein the amount of GLP-1 receptor agonist (e.g., semaglutide (e.g., RYBELSUS®)) increases at 30 day intervals until a maintenance dosage is reached. In some embodiments, according to the methods provided herein, the GLP-1 receptor agonist is semaglutide (e.g., RYBELSUS®) and is administered to the subject daily at 3 mg once daily for 30 days before increasing the increase the dosage to 7 mg once daily. In some embodiments, according to the methods provided herein, the GLP-1 receptor agonist is semaglutide (e.g., RYBELSUS®) and is administered to the subject daily at 3 mg once daily for 30 days, followed by administration to the subject daily at 7 mg once daily for at least 30 days, before administering to the subject daily at 14 mg once daily. In some embodiments, the maintenance dosage is 7 mg once daily. In some embodiments, the maintenance dosage is 14 mg once daily. 39 NAI-5002088184v1Attorney Docket No.14678-029-228

[0153] In certain embodiments, according to the methods provided herein, the GLP-1 receptor agonist is administered to the subject subcutaneously once per week in the amount of about 0.25 mg to about 2.4 mg (e.g., 0.25 mg, 0.5 mg, 1.0 mg, 1.7 mg, 2.0 mg, 2.4 mg) wherein the GLP-1 receptor agonist comprises the amino acid sequence of SEQ ID NO: 3 (e.g., WEGOVY®, OZEMPIC®). In certain embodiments, according to the methods provided herein, the GLP-1 receptor agonist is administered to the subject subcutaneously once per week in the amount of about 0.25 mg to about 2.4 mg (e.g., 0.25 mg, 0.5 mg, 1.0 mg, 1.7 mg, 2.0 mg, 2.4 mg) wherein the GLP-1 receptor agonist is semaglutide (e.g., WEGOVY®, OZEMPIC®).

[0154] In some embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject daily. In some embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject daily for 3 days, for example, 3 days per week, such as 3 consecutive days per week, e.g., for 12 days per month. In some embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject daily for 5 days, for example, 5 days per week, such as 5 consecutive days per week, e.g., for 20 days per month. In some embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject every other day, e.g., 14, 15 or 16 times per month. In some embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject once weekly, e.g., 4 times per month. In some embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject monthly. In some embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject twice monthly. In some embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly.

[0155] In some embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, e.g., as described in any of the embodiments presented herein in an amount ranging from about 2.5 x 106International Units (IU) to about 1 x 107IU per week. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, e.g., as described in any of the embodiments presented herein in an amount of about 2.5 x 106IU per week. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, e.g., as described in any of the embodiments presented herein in an amount of about 5.0 x 106IU per week. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the 40 NAI-5002088184v1Attorney Docket No.14678-029-228 subject weekly, e.g., as described in any of the embodiments presented herein in an amount of about 7.5 x 106IU per week. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, e.g., as described in any of the embodiments presented herein in an amount of about 1.0 x 107IU per week. In certain embodiments, the IL-2 protein is administered subcutaneously. In certain embodiments, the IL-2 protein is administered subcutaneously in a volume of 0.5 mL to 1.5 mL. In certain embodiments, the IL-2 protein is administered subcutaneously in a volume of about 0.5 mL. In certain embodiments, the IL-2 protein is administered subcutaneously in a volume of about 1.0 mL. In certain embodiments, the IL-2 protein is administered subcutaneously in a volume of about 0.5 mL. In certain embodiments, the IL-2 protein comprises the amino acid sequence of SEQ ID NO: 26. In certain embodiments, the IL-2 protein is aldesleukin. In certain embodiments, the IL-2 protein comprises the amino acid sequence of aldesleukin.

[0156] In some embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, once per week, e.g., as described in any of the embodiments presented herein in an amount ranging from about 2.5 x 106International Units (IU) to about 1 x 107IU. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly once per week, e.g., as described in any of the embodiments presented herein in an amount of about 2.5 x 106IU. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly once per week, e.g., as described in any of the embodiments presented herein in an amount of about 5.0 x 106IU. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly once per week, e.g., as described in any of the embodiments presented herein in an amount of about 7.5 x 106IU. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly once per week, e.g., as described in any of the embodiments presented herein in an amount of about 1.0 x 107IU. In certain embodiments, the IL-2 protein is administered subcutaneously in a volume of 0.5 mL to 1.5 mL. In certain embodiments, the IL-2 protein is administered subcutaneously in a volume of about 0.5 mL. In certain embodiments, the IL-2 protein is administered subcutaneously in a volume of about 1.0 mL. In certain embodiments, the IL-2 protein is administered subcutaneously in a volume of about 0.5 mL. In certain embodiments, the IL-2 protein comprises the amino acid sequence of SEQ ID NO: 26. In certain embodiments, the IL-2 41 NAI-5002088184v1Attorney Docket No.14678-029-228 protein is aldesleukin. In certain embodiments, the IL-2 protein comprises the amino acid sequence of aldesleukin.

[0157] In some embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily administration for 2-7 (e.g., 2-5) consecutive days, e.g., as described in any of the embodiments presented herein in a weekly amount ranging from about 2.5 x 106International Units (IU) to about 1 x 107IU, divided equally among the daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 2-7 (e.g., 2- 5) consecutive days, e.g., as described in any of the embodiments presented herein in a weekly amount of about 2.5 x 106IU, divided equally among the once daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 2-7 (e.g., 2-5) consecutive days, e.g., as described in any of the embodiments presented herein in an amount of about 5.0 x 106IU, divided equally among the once daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 2-7 (e.g., 2-5) consecutive days, e.g., as described in any of the embodiments presented herein in a weekly amount of about 7.5 x 106IU, divided equally among the once daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 2-7 (e.g., 2-5) consecutive days, e.g., as described in any of the embodiments presented herein in an amount of about 1.0 x 107IU, divided equally amount the once daily administrations. In certain embodiments, the IL-2 protein is administered subcutaneously. In certain embodiments, the once daily IL-2 protein administration is administered subcutaneously in a volume of 0.5 mL to 1.5 mL. In certain embodiments, the once daily IL-2 protein administration is administered subcutaneously in a volume of about 0.5 mL. In certain embodiments, the once daily IL-2 protein administration is administered subcutaneously in a volume of about 1.0 mL. In certain embodiments, the once daily IL-2 protein administration is administered subcutaneously in a volume of about 0.5 mL. In certain embodiments, the IL-2 protein comprises the amino acid sequence of SEQ ID NO: 26. 42 NAI-5002088184v1Attorney Docket No.14678-029-228 In certain embodiments, the IL-2 protein is aldesleukin. In certain embodiments, the IL-2 protein comprises the amino acid sequence of aldesleukin.

[0158] In some embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily administration for 5 consecutive days, e.g., as described in any of the embodiments presented herein in a weekly amount ranging from about 2.5 x 106International Units (IU) to about 1 x 107IU, divided equally among the daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 5 consecutive days, e.g., as described in any of the embodiments presented herein in a weekly amount of about 2.5 x 106IU, divided equally among the once daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 5 consecutive days, e.g., as described in any of the embodiments presented herein in an amount of about 5.0 x 106IU, divided equally among the once daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 5 consecutive days, e.g., as described in any of the embodiments presented herein in a weekly amount of about 7.5 x 106IU, divided equally among the once daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 5 consecutive days, e.g., as described in any of the embodiments presented herein in an amount of about 1.0 x 107IU, divided equally amount the once daily administrations. In certain embodiments, the IL-2 protein is administered subcutaneously. In certain embodiments, the once daily IL-2 protein administration is administered subcutaneously in a volume of 0.5 mL to 1.5 mL. In certain embodiments, the once daily IL-2 protein administration is administered subcutaneously in a volume of about 0.5 mL. In certain embodiments, the once daily IL-2 protein administration is administered subcutaneously in a volume of about 1.0 mL. In certain embodiments, the once daily IL-2 protein administration is administered subcutaneously in a volume of about 0.5 mL. In certain embodiments, the IL-2 protein comprises the amino acid sequence of SEQ ID NO: 26. In certain 43 NAI-5002088184v1Attorney Docket No.14678-029-228 embodiments, the IL-2 protein is aldesleukin. In certain embodiments, the IL-2 protein comprises the amino acid sequence of aldesleukin.

[0159] In particular embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, in a weekly amount of 5 x 106International Units (IU), wherein the weekly IL-2 administration comprises once daily subcutaneous administration of 1 x 106IU for 5 consecutive days, and wherein the IL-2 protein comprises the amino acid sequence of SEQ ID NO: 26. In particular embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, in a weekly amount of 5 x 106International Units (IU), wherein the weekly IL-2 administration comprises once daily subcutaneous administration of 1 x 106IU in a 1.0 mL volume for 5 consecutive days, and wherein the IL-2 protein comprises the amino acid sequence of SEQ ID NO: 26.

[0160] In particular embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, in a weekly amount of 5 x 106International Units (IU), wherein the weekly IL-2 administration comprises once daily subcutaneous administration of 1 x 106IU for 5 consecutive days, and wherein the IL-2 protein is aldesleukin. In particular embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, in a weekly amount of 5 x 106International Units (IU), wherein the weekly IL-2 administration comprises once daily subcutaneous administration of 1 x 106IU in a 1.0 mL volume for 5 consecutive days, and wherein the IL-2 protein is aldesleukin.

[0161] In particular embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, in a weekly amount of 5 x 106International Units (IU), wherein the weekly IL-2 administration comprises once daily subcutaneous administration of 1 x 106IU for 5 consecutive days, and wherein the IL-2 protein comprises the amino acid sequence of aldesleukin. In particular embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, in a weekly amount of 5 x 106International Units (IU), wherein the weekly IL-2 administration comprises once daily subcutaneous administration of 1 x 106IU in a 1.0 mL volume for 5 consecutive days, and wherein the IL-2 protein comprises the amino acid sequence of aldesleukin.

[0162] In some embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, e.g., as described in any of the embodiments presented herein in an amount ranging from about 0.25 mg to about 1.0 mg per week. In certain embodiments, 44 NAI-5002088184v1Attorney Docket No.14678-029-228 according to the methods provided herein, the IL-2 protein is administered to the subject weekly, e.g., as described in any of the embodiments presented herein in an amount of about 0.25 mg per week. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, e.g., as described in any of the embodiments presented herein in an amount of about 0.5 mg per week. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, e.g., as described in any of the embodiments presented herein in an amount of about 0.75 mg per week. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, e.g., as described in any of the embodiments presented herein in an amount of about 1.0 mg per week. In certain embodiments, the IL-2 protein is administered subcutaneously. In certain embodiments, the IL-2 protein is administered subcutaneously in a volume of 0.5 mL to 1.5 mL. In certain embodiments, the IL-2 protein is administered subcutaneously in a volume of about 0.5 mL. In certain embodiments, the IL-2 protein is administered subcutaneously in a volume of about 1.0 mL. In certain embodiments, the IL-2 protein is administered subcutaneously in a volume of about 0.5 mL. In certain embodiments, the IL-2 protein comprises the amino acid sequence of SEQ ID NO: 26. In certain embodiments, the IL-2 protein is aldesleukin. In certain embodiments, the IL-2 protein comprises the amino acid sequence of aldesleukin.

[0163] In some embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, once per week, e.g., as described in any of the embodiments presented herein in an amount ranging from about 0.25 mg to about 1.0 mg. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly once per week, e.g., as described in any of the embodiments presented herein in an amount of about 0.25 mg. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly once per week, e.g., as described in any of the embodiments presented herein in an amount of about 0.5 mg. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly once per week, e.g., as described in any of the embodiments presented herein in an amount of about 0.75 mg. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly once per week, e.g., as described in any of the embodiments presented herein in an amount of about 1.0 mg. In certain embodiments, the IL-2 45 NAI-5002088184v1Attorney Docket No.14678-029-228 protein is administered subcutaneously in a volume of 0.5 mL to 1.5 mL. In certain embodiments, the IL-2 protein is administered subcutaneously in a volume of about 0.5 mL. In certain embodiments, the IL-2 protein is administered subcutaneously in a volume of about 1.0 mL. In certain embodiments, the IL-2 protein is administered subcutaneously in a volume of about 0.5 mL. In certain embodiments, the IL-2 protein comprises the amino acid sequence of SEQ ID NO: 26. In certain embodiments, the IL-2 protein is aldesleukin. In certain embodiments, the IL-2 protein comprises the amino acid sequence of aldesleukin.

[0164] In some embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily administration for 2-7 (e.g., 2-5) consecutive days, e.g., as described in any of the embodiments presented herein in a weekly amount ranging from about 0.25 mg to about 1.0 mg, divided equally among the daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 2-7 (e.g., 2-5) consecutive days, e.g., as described in any of the embodiments presented herein in a weekly amount of about 0.25 mg, divided equally among the once daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 2-7 (e.g., 2-5) consecutive days, e.g., as described in any of the embodiments presented herein in an amount of about 0.5 mg, divided equally among the once daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 2-7 (e.g., 2- 5) consecutive days, e.g., as described in any of the embodiments presented herein in a weekly amount of about 0.75 mg, divided equally among the once daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 2-7 (e.g., 2-5) consecutive days, e.g., as described in any of the embodiments presented herein in an amount of about 1.0 mg, divided equally amount the once daily administrations. In certain embodiments, the IL-2 protein is administered subcutaneously. In certain embodiments, the once daily IL-2 protein administration is administered subcutaneously in a volume of 0.5 mL to 1.5 mL. In certain embodiments, the once daily IL-2 protein 46 NAI-5002088184v1Attorney Docket No.14678-029-228 administration is administered subcutaneously in a volume of about 0.5 mL. In certain embodiments, the once daily IL-2 protein administration is administered subcutaneously in a volume of about 1.0 mL. In certain embodiments, the once daily IL-2 protein administration is administered subcutaneously in a volume of about 0.5 mL. In certain embodiments, the IL-2 protein comprises the amino acid sequence of SEQ ID NO: 26. In certain embodiments, the IL-2 protein is aldesleukin. In certain embodiments, the IL-2 protein comprises the amino acid sequence of aldesleukin.

[0165] In some embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily administration for 5 consecutive days, e.g., as described in any of the embodiments presented herein in a weekly amount ranging from about 0.25 mg to about 1.0 mg, divided equally among the daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 5 consecutive days, e.g., as described in any of the embodiments presented herein in a weekly amount of about 0.25 mg, divided equally among the once daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 5 consecutive days, e.g., as described in any of the embodiments presented herein in an amount of about 0.5 mg, divided equally among the once daily administrations. In certain embodiments, according to the methods provided herein, the IL- 2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 5 consecutive days, e.g., as described in any of the embodiments presented herein in a weekly amount of about 0.75 mg, divided equally among the once daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 5 consecutive days, e.g., as described in any of the embodiments presented herein in an amount of about 1.0 mg, divided equally amount the once daily administrations. In certain embodiments, the IL-2 protein is administered subcutaneously. In certain embodiments, the once daily IL-2 protein administration is administered subcutaneously in a volume of 0.5 mL to 1.5 mL. In certain embodiments, the once daily IL-2 protein administration is administered subcutaneously in a volume of about 0.5 mL. In certain 47 NAI-5002088184v1Attorney Docket No.14678-029-228 embodiments, the once daily IL-2 protein administration is administered subcutaneously in a volume of about 1.0 mL. In certain embodiments, the once daily IL-2 protein administration is administered subcutaneously in a volume of about 0.5 mL. In certain embodiments, the IL-2 protein comprises the amino acid sequence of SEQ ID NO: 26. In certain embodiments, the IL-2 protein is aldesleukin. In certain embodiments, the IL-2 protein comprises the amino acid sequence of aldesleukin.

[0166] In particular embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, in a weekly amount of 0.5 mg, wherein the weekly IL-2 administration comprises once daily subcutaneous administration of 0.1 mg IL-2 for 5 consecutive days, and wherein the IL-2 protein comprises the amino acid sequence of SEQ ID NO: 26. In particular embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, in a weekly amount of 0.5 mg, wherein the weekly IL-2 administration comprises once daily subcutaneous administration of 0.1 mg IL-2 in a 1.0 mL volume for 5 consecutive days, and wherein the IL-2 protein comprises the amino acid sequence of SEQ ID NO: 26.

[0167] In particular embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, in a weekly amount of 0.5 mg, wherein the weekly IL-2 administration comprises once daily subcutaneous administration of 0.1 mg IL-2 for 5 consecutive days, and wherein the IL-2 protein is aldesleukin. In particular embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, in a weekly amount of 0.5 mg, wherein the weekly IL-2 administration comprises once daily subcutaneous administration of 0.1 mg IL-2 in a 1.0 mL volume for 5 consecutive days, and wherein the IL-2 protein is aldesleukin.

[0168] In particular embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, in a weekly amount of 0.5 mg, wherein the weekly IL-2 administration comprises once daily subcutaneous administration of 0.1 mg IL-2 for 5 consecutive days, and wherein the IL-2 protein comprises the amino acid sequence of aldesleukin. In particular embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, in a weekly amount of 0.5 mg, wherein the weekly IL-2 administration comprises once daily subcutaneous administration of 0.1 mg IL-2 in a 1.0 48 NAI-5002088184v1Attorney Docket No.14678-029-228 mL volume for 5 consecutive days, and wherein the IL-2 protein comprises the amino acid sequence of aldesleukin.

[0169] In some embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, e.g., as described in any of the embodiments presented herein in an amount ranging from about 0.01 x 106IU to about 3.5 x 107IU per week.

[0170] In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, e.g., as described in any of the embodiments presented herein in an amount of about 0.01 x 106IU per week. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, e.g., as described in any of the embodiments presented herein in an amount of about 0.1 x 106IU per week. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, e.g., as described in any of the embodiments presented herein in an amount of about 0.5 x 106IU per week. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, e.g., as described in any of the embodiments presented herein in an amount of about 1.0 x 106IU per week. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, e.g., as described in any of the embodiments presented herein in an amount of about 1.5 x 106IU per week. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, e.g., as described in any of the embodiments presented herein in an amount of about 2.0 x 106IU per week. In certain embodiments, the IL-2 protein is administered subcutaneously. In certain embodiments, the IL-2 protein is administered subcutaneously in a volume of 0.5 mL to 1.5 mL. In certain embodiments, the IL-2 protein is administered subcutaneously in a volume of about 0.5 mL. In certain embodiments, the IL-2 protein is administered subcutaneously in a volume of about 1.0 mL. In certain embodiments, the IL-2 protein is administered subcutaneously in a volume of about 0.5 mL. In certain embodiments, the IL-2 protein comprises the amino acid sequence of SEQ ID NO: 26. In certain embodiments, the IL-2 protein is aldesleukin. In certain embodiments, the IL-2 protein comprises the amino acid sequence of aldesleukin.

[0171] In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, e.g., as described in any of the embodiments presented herein in an amount of about 1.5 x 107IU per week. In certain embodiments, according to the methods 49 NAI-5002088184v1Attorney Docket No.14678-029-228 provided herein, the IL-2 protein is administered to the subject weekly, e.g., as described in any of the embodiments presented herein in an amount of about 2.0 x 107IU per week. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, e.g., as described in any of the embodiments presented herein in an amount of about 2.5 x 107IU per week. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, e.g., as described in any of the embodiments presented herein in an amount of about 3.0 x 107IU per week. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, e.g., as described in any of the embodiments presented herein in an amount of about 3.5 x 107IU per week. In certain embodiments, the IL-2 protein is administered subcutaneously. In certain embodiments, the IL-2 protein is administered subcutaneously in a volume of 0.5 mL to 1.5 mL. In certain embodiments, the IL-2 protein is administered subcutaneously in a volume of about 0.5 mL. In certain embodiments, the IL-2 protein is administered subcutaneously in a volume of about 1.0 mL. In certain embodiments, the IL-2 protein is administered subcutaneously in a volume of about 0.5 mL. In certain embodiments, the IL-2 protein comprises the amino acid sequence of SEQ ID NO: 26. In certain embodiments, the IL-2 protein is aldesleukin. In certain embodiments, the IL-2 protein comprises the amino acid sequence of aldesleukin.

[0172] In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, once per week, e.g., as described in any of the embodiments presented herein in an amount of about 0.01 x 106IU per week. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, once per week, e.g., as described in any of the embodiments presented herein in an amount of about 0.1 x 106IU per week. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, once per week, e.g., as described in any of the embodiments presented herein in an amount of about 0.5 x 106IU per week. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, once per week, e.g., as described in any of the embodiments presented herein in an amount of about 1.0 x 106IU per week. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, once per week, e.g., as described in any of the embodiments presented herein in an amount of about 1.5 x 106IU per 50 NAI-5002088184v1Attorney Docket No.14678-029-228 week. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, once per week, e.g., as described in any of the embodiments presented herein in an amount of about 2.0 x 106IU per week. In certain embodiments, the IL-2 protein is administered subcutaneously. In certain embodiments, the IL-2 protein is administered subcutaneously in a volume of 0.5 mL to 1.5 mL. In certain embodiments, the IL-2 protein is administered subcutaneously in a volume of about 0.5 mL. In certain embodiments, the IL-2 protein is administered subcutaneously in a volume of about 1.0 mL. In certain embodiments, the IL-2 protein is administered subcutaneously in a volume of about 0.5 mL. In certain embodiments, the IL-2 protein comprises the amino acid sequence of SEQ ID NO: 26. In certain embodiments, the IL-2 protein is aldesleukin. In certain embodiments, the IL-2 protein comprises the amino acid sequence of aldesleukin.

[0173] In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, once per week, e.g., as described in any of the embodiments presented herein in an amount of about 1.5 x 107IU per week. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, once per week, e.g., as described in any of the embodiments presented herein in an amount of about 2.0 x 107IU per week. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, e.g., once per week, as described in any of the embodiments presented herein in an amount of about 2.5 x 107IU per week. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, e.g., once per week, as described in any of the embodiments presented herein in an amount of about 3.0 x 107IU per week. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, once per week, e.g., as described in any of the embodiments presented herein in an amount of about 3.5 x 107IU per week. In certain embodiments, the IL-2 protein is administered subcutaneously. In certain embodiments, the IL-2 protein is administered subcutaneously in a volume of 0.5 mL to 1.5 mL. In certain embodiments, the IL-2 protein is administered subcutaneously in a volume of about 0.5 mL. In certain embodiments, the IL-2 protein is administered subcutaneously in a volume of about 1.0 mL. In certain embodiments, the IL-2 protein is administered subcutaneously in a volume of about 0.5 mL. In certain embodiments, the IL-2 protein comprises the amino acid 51 NAI-5002088184v1Attorney Docket No.14678-029-228 sequence of SEQ ID NO: 26. In certain embodiments, the IL-2 protein is aldesleukin. In certain embodiments, the IL-2 protein comprises the amino acid sequence of aldesleukin.

[0174] In some embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily administration for 2-7 (e.g., 2-5) consecutive days, e.g., as described in any of the embodiments presented herein in a weekly amount ranging from about 0.01 x 106IU to about 3.5 x 107IU, divided equally among the daily administrations.

[0175] In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 2-7 (e.g., 2-5) consecutive days, e.g., as described in any of the embodiments presented herein in a weekly amount of about 0.01 x 106IU, divided equally among the once daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 2-7 (e.g., 2-5) consecutive days, e.g., as described in any of the embodiments presented herein in a weekly amount of about 0.05 x 106IU, divided equally among the once daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 2-7 (e.g., 2-5) consecutive days, e.g., as described in any of the embodiments presented herein in an amount of about 0.1 x 106IU, divided equally among the once daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 2-7 (e.g., 2-5) consecutive days, e.g., as described in any of the embodiments presented herein in a weekly amount of about 0.5 x 106IU, divided equally among the once daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 2-7 (e.g., 2-5) consecutive days, e.g., as described in any of the embodiments presented herein in an amount of about 1.0 x 106IU, divided equally amount the once daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 2-7 (e.g., 2-5) consecutive days, e.g., 52 NAI-5002088184v1Attorney Docket No.14678-029-228 as described in any of the embodiments presented herein in an amount of about 1.5 x 106IU, divided equally amount the once daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 2-7 (e.g., 2-5) consecutive days, e.g., as described in any of the embodiments presented herein in an amount of about 2.0 x 106IU, divided equally amount the once daily administrations. In certain embodiments, the IL-2 protein is administered subcutaneously. In certain embodiments, the once daily IL-2 protein administration is administered subcutaneously in a volume of 0.5 mL to 1.5 mL. In certain embodiments, the once daily IL-2 protein administration is administered subcutaneously in a volume of about 0.5 mL. In certain embodiments, the once daily IL-2 protein administration is administered subcutaneously in a volume of about 1.0 mL. In certain embodiments, the once daily IL-2 protein administration is administered subcutaneously in a volume of about 0.5 mL. In certain embodiments, the IL-2 protein comprises the amino acid sequence of SEQ ID NO: 26. In certain embodiments, the IL-2 protein is aldesleukin. In certain embodiments, the IL-2 protein comprises the amino acid sequence of aldesleukin.

[0176] In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 2-7 (e.g., 2-5) consecutive days, e.g., as described in any of the embodiments presented herein in a weekly amount of about 1.5 x 107IU, divided equally among the once daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 2-7 (e.g., 2-5) consecutive days, e.g., as described in any of the embodiments presented herein in a weekly amount of about 2.0 x 107IU, divided equally among the once daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 2-7 (e.g., 2-5) consecutive days, e.g., as described in any of the embodiments presented herein in an amount of about 2.5 x 107IU, divided equally among the once daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 2-7 (e.g., 2-5) consecutive days, e.g., as described in any of the embodiments 53 NAI-5002088184v1Attorney Docket No.14678-029-228 presented herein in a weekly amount of about 3.0 x 107IU, divided equally among the once daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 2-7 (e.g., 2-5) consecutive days, e.g., as described in any of the embodiments presented herein in an amount of about 3.0 x 107IU, divided equally amount the once daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 2-7 (e.g., 2-5) consecutive days, e.g., as described in any of the embodiments presented herein in an amount of about 3.5 x 107IU, divided equally amount the once daily administrations. In certain embodiments, the IL-2 protein is administered subcutaneously. In certain embodiments, the once daily IL-2 protein administration is administered subcutaneously in a volume of 0.5 mL to 1.5 mL. In certain embodiments, the once daily IL-2 protein administration is administered subcutaneously in a volume of about 0.5 mL. In certain embodiments, the once daily IL-2 protein administration is administered subcutaneously in a volume of about 1.0 mL. In certain embodiments, the once daily IL-2 protein administration is administered subcutaneously in a volume of about 0.5 mL. In certain embodiments, the IL-2 protein comprises the amino acid sequence of SEQ ID NO: 26. In certain embodiments, the IL-2 protein is aldesleukin. In certain embodiments, the IL-2 protein comprises the amino acid sequence of aldesleukin.

[0177] In some embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily administration for 5 consecutive days, e.g., as described in any of the embodiments presented herein in a weekly amount ranging from about 0.01 x 106IU to about 3.5 x 107IU, divided equally among the daily administrations.

[0178] In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 5 consecutive days, e.g., as described in any of the embodiments presented herein in a weekly amount of about 0.01 x 106IU, divided equally among the once daily administrations. In certain embodiments, according to the methods provided herein, the IL- 2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 5 consecutive days, e.g., as described in any of the 54 NAI-5002088184v1Attorney Docket No.14678-029-228 embodiments presented herein in a weekly amount of about 0.05 x 106IU, divided equally among the once daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 5 consecutive days, e.g., as described in any of the embodiments presented herein in an amount of about 0.1 x 106IU, divided equally among the once daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 5 consecutive days, e.g., as described in any of the embodiments presented herein in a weekly amount of about 0.5 x 106IU, divided equally among the once daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 5 consecutive days, e.g., as described in any of the embodiments presented herein in an amount of about 1.0 x 106IU, divided equally amount the once daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 5 consecutive days, e.g., as described in any of the embodiments presented herein in an amount of about 1.5 x 106IU, divided equally amount the once daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 5 consecutive days, e.g., as described in any of the embodiments presented herein in an amount of about 2.0 x 106IU, divided equally amount the once daily administrations. In certain embodiments, the IL-2 protein is administered subcutaneously. In certain embodiments, the once daily IL-2 protein administration is administered subcutaneously in a volume of 0.5 mL to 1.5 mL. In certain embodiments, the once daily IL-2 protein administration is administered subcutaneously in a volume of about 0.5 mL. In certain embodiments, the once daily IL-2 protein administration is administered subcutaneously in a volume of about 1.0 mL. In certain embodiments, the once daily IL-2 protein administration is administered subcutaneously in a volume of about 0.5 mL. In certain embodiments, the IL-2 protein comprises the amino acid sequence of SEQ ID NO: 26. In 55 NAI-5002088184v1Attorney Docket No.14678-029-228 certain embodiments, the IL-2 protein is aldesleukin. In certain embodiments, the IL-2 protein comprises the amino acid sequence of aldesleukin.

[0179] In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 5 consecutive days, e.g., as described in any of the embodiments presented herein in a weekly amount of about 1.5 x 107IU, divided equally among the once daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 5 consecutive days, e.g., as described in any of the embodiments presented herein in a weekly amount of about 2.0 x 107IU, divided equally among the once daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 5 consecutive days, e.g., as described in any of the embodiments presented herein in an amount of about 2.5 x 107IU, divided equally among the once daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 5 consecutive days, e.g., as described in any of the embodiments presented herein in a weekly amount of about 3.0 x 107IU, divided equally among the once daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 5 consecutive days, e.g., as described in any of the embodiments presented herein in an amount of about 3.0 x 107IU, divided equally amount the once daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 5 consecutive days, e.g., as described in any of the embodiments presented herein in an amount of about 3.5 x 107IU, divided equally amount the once daily administrations. In certain embodiments, the IL-2 protein is administered subcutaneously. In certain embodiments, the once daily IL-2 protein administration is administered subcutaneously in a volume of 0.5 mL to 1.5 mL. In certain embodiments, the once daily IL-2 protein administration is administered subcutaneously in a volume of about 0.5 mL. In certain 56 NAI-5002088184v1Attorney Docket No.14678-029-228 embodiments, the once daily IL-2 protein administration is administered subcutaneously in a volume of about 1.0 mL. In certain embodiments, the once daily IL-2 protein administration is administered subcutaneously in a volume of about 0.5 mL. In certain embodiments, the IL-2 protein comprises the amino acid sequence of SEQ ID NO: 26. In certain embodiments, the IL- 2 protein is aldesleukin. In certain embodiments, the IL-2 protein comprises the amino acid sequence of aldesleukin.

[0180] In some embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, e.g., as described in any of the embodiments presented herein in an amount ranging from about 0.25 mg to about 1.0 mg per week. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, e.g., as described in any of the embodiments presented herein in an amount of about 0.25 mg per week. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, e.g., as described in any of the embodiments presented herein in an amount of about 0.5 mg per week. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, e.g., as described in any of the embodiments presented herein in an amount of about 0.75 mg per week. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, e.g., as described in any of the embodiments presented herein in an amount of about 1.0 mg per week. In certain embodiments, the IL-2 protein is administered subcutaneously. In certain embodiments, the IL-2 protein is administered subcutaneously in a volume of 0.5 mL to 1.5 mL. In certain embodiments, the IL-2 protein is administered subcutaneously in a volume of about 0.5 mL. In certain embodiments, the IL-2 protein is administered subcutaneously in a volume of about 1.0 mL. In certain embodiments, the IL-2 protein is administered subcutaneously in a volume of about 0.5 mL. In certain embodiments, the IL-2 protein comprises the amino acid sequence of SEQ ID NO: 26. In certain embodiments, the IL-2 protein is aldesleukin. In certain embodiments, the IL-2 protein comprises the amino acid sequence of aldesleukin.

[0181] In some embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, once per week, e.g., as described in any of the embodiments presented herein in an amount ranging from about 0.25 mg to about 1.0 mg. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the 57 NAI-5002088184v1Attorney Docket No.14678-029-228 subject weekly once per week, e.g., as described in any of the embodiments presented herein in an amount of about 0.25 mg. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly once per week, e.g., as described in any of the embodiments presented herein in an amount of about 0.5 mg. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly once per week, e.g., as described in any of the embodiments presented herein in an amount of about 0.75 mg. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly once per week, e.g., as described in any of the embodiments presented herein in an amount of about 1.0 mg. In certain embodiments, the IL-2 protein is administered subcutaneously in a volume of 0.5 mL to 1.5 mL. In certain embodiments, the IL-2 protein is administered subcutaneously in a volume of about 0.5 mL. In certain embodiments, the IL-2 protein is administered subcutaneously in a volume of about 1.0 mL. In certain embodiments, the IL-2 protein is administered subcutaneously in a volume of about 0.5 mL. In certain embodiments, the IL-2 protein comprises the amino acid sequence of SEQ ID NO: 26. In certain embodiments, the IL-2 protein is aldesleukin. In certain embodiments, the IL-2 protein comprises the amino acid sequence of aldesleukin.

[0182] In some embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily administration for 2-7 (e.g., 2-5) consecutive days, e.g., as described in any of the embodiments presented herein in a weekly amount ranging from about 0.25 mg to about 1.0 mg, divided equally among the daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 2-7 (e.g., 2-5) consecutive days, e.g., as described in any of the embodiments presented herein in a weekly amount of about 0.25 mg, divided equally among the once daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 2-7 (e.g., 2-5) consecutive days, e.g., as described in any of the embodiments presented herein in an amount of about 0.5 mg, divided equally among the once daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 2-7 (e.g., 2- 58 NAI-5002088184v1Attorney Docket No.14678-029-228 5) consecutive days, e.g., as described in any of the embodiments presented herein in a weekly amount of about 0.75 mg, divided equally among the once daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 2-7 (e.g., 2-5) consecutive days, e.g., as described in any of the embodiments presented herein in an amount of about 1.0 mg, divided equally amount the once daily administrations. In certain embodiments, the IL-2 protein is administered subcutaneously. In certain embodiments, the once daily IL-2 protein administration is administered subcutaneously in a volume of 0.5 mL to 1.5 mL. In certain embodiments, the once daily IL-2 protein administration is administered subcutaneously in a volume of about 0.5 mL. In certain embodiments, the once daily IL-2 protein administration is administered subcutaneously in a volume of about 1.0 mL. In certain embodiments, the once daily IL-2 protein administration is administered subcutaneously in a volume of about 0.5 mL. In certain embodiments, the IL-2 protein comprises the amino acid sequence of SEQ ID NO: 26. In certain embodiments, the IL- 2 protein is aldesleukin. In certain embodiments, the IL-2 protein comprises the amino acid sequence of aldesleukin.

[0183] In some embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily administration for 5 consecutive days, e.g., as described in any of the embodiments presented herein in a weekly amount ranging from about 0.25 mg to about 1.0 mg, divided equally among the daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 5 consecutive days, e.g., as described in any of the embodiments presented herein in a weekly amount of about 0.25 mg, divided equally among the once daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 5 consecutive days, e.g., as described in any of the embodiments presented herein in an amount of about 0.5 mg, divided equally among the once daily administrations. In certain embodiments, according to the methods provided herein, the IL- 2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 5 consecutive days, e.g., as described in any of the 59 NAI-5002088184v1Attorney Docket No.14678-029-228 embodiments presented herein in a weekly amount of about 0.75 mg, divided equally among the once daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 5 consecutive days, e.g., as described in any of the embodiments presented herein in an amount of about 1.0 mg, divided equally amount the once daily administrations. In certain embodiments, the IL-2 protein is administered subcutaneously. In certain embodiments, the once daily IL-2 protein administration is administered subcutaneously in a volume of 0.5 mL to 1.5 mL. In certain embodiments, the once daily IL-2 protein administration is administered subcutaneously in a volume of about 0.5 mL. In certain embodiments, the once daily IL-2 protein administration is administered subcutaneously in a volume of about 1.0 mL. In certain embodiments, the once daily IL-2 protein administration is administered subcutaneously in a volume of about 0.5 mL. In certain embodiments, the IL-2 protein comprises the amino acid sequence of SEQ ID NO: 26. In certain embodiments, the IL- 2 protein is aldesleukin. In certain embodiments, the IL-2 protein comprises the amino acid sequence of aldesleukin.

[0184] In particular embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, in a weekly amount of 0.5 mg, wherein the weekly IL-2 administration comprises once daily subcutaneous administration of 0.1 mg IL-2 for 5 consecutive days, and wherein the IL-2 protein comprises the amino acid sequence of SEQ ID NO: 26. In particular embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, in a weekly amount of 0.5 mg, wherein the weekly IL-2 administration comprises once daily subcutaneous administration of 0.1 mg IL-2 in a 1.0 mL volume for 5 consecutive days, and wherein the IL-2 protein comprises the amino acid sequence of SEQ ID NO: 26.

[0185] In particular embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, in a weekly amount of 0.5 mg, wherein the weekly IL-2 administration comprises once daily subcutaneous administration of 0.1 mg IL-2 for 5 consecutive days, and wherein the IL-2 protein is aldesleukin. In particular embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, in a weekly amount of 0.5 mg, wherein the weekly IL-2 administration comprises once daily 60 NAI-5002088184v1Attorney Docket No.14678-029-228 subcutaneous administration of 0.1 mg IL-2 in a 1.0 mL volume for 5 consecutive days, and wherein the IL-2 protein is aldesleukin.

[0186] In particular embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, in a weekly amount of 0.5 mg, wherein the weekly IL-2 administration comprises once daily subcutaneous administration of 0.1 mg IL-2 for 5 consecutive days, and wherein the IL-2 protein comprises the amino acid sequence of aldesleukin. In particular embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, in a weekly amount of 0.5 mg, wherein the weekly IL-2 administration comprises once daily subcutaneous administration of 0.1 mg IL-2 in a 1.0 mL volume for 5 consecutive days, and wherein the IL-2 protein comprises the amino acid sequence of aldesleukin.

[0187] In some embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, e.g., as described in any of the embodiments presented herein in an amount ranging from about 0.3 µg to about 200 µg per week. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, e.g., as described in any of the embodiments presented herein in an amount of about 0.3 µg to about 1.0 µg per week. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, e.g., as described in any of the embodiments presented herein in an amount of about 3.0 µg to about 10 µg per week. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, e.g., as described in any of the embodiments presented herein in an amount of about 15 µg to about 50 µg per week. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, e.g., as described in any of the embodiments presented herein in an amount of about 30 µg to about 100 µg per week. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, e.g., as described in any of the embodiments presented herein in an amount of about 45 µg to about 150 µg per week. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, e.g., as described in any of the embodiments presented herein in an amount of about 60 µg to about 200 µg per week. In certain embodiments, the IL-2 protein is administered subcutaneously. In certain embodiments, the IL-2 protein is administered subcutaneously in a volume of 0.5 mL to 1.5 mL. In certain 61 NAI-5002088184v1Attorney Docket No.14678-029-228 embodiments, the IL-2 protein is administered subcutaneously in a volume of about 0.5 mL. In certain embodiments, the IL-2 protein is administered subcutaneously in a volume of about 1.0 mL. In certain embodiments, the IL-2 protein is administered subcutaneously in a volume of about 0.5 mL. In certain embodiments, the IL-2 protein comprises the amino acid sequence of SEQ ID NO: 26. In certain embodiments, the IL-2 protein is aldesleukin. In certain embodiments, the IL-2 protein comprises the amino acid sequence of aldesleukin.

[0188] In some embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, e.g., as described in any of the embodiments presented herein in an amount ranging from about 1.25 mg to about 2.5 mg per week. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, e.g., as described in any of the embodiments presented herein in an amount of about 1.25 mg per week. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, e.g., as described in any of the embodiments presented herein in an amount of about 1.5 mg per week. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, e.g., as described in any of the embodiments presented herein in an amount of about 1.75 mg per week. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, e.g., as described in any of the embodiments presented herein in an amount of about 2.0 mg per week. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, e.g., as described in any of the embodiments presented herein in an amount of about 2.5 mg per week. In certain embodiments, the IL-2 protein is administered subcutaneously. In certain embodiments, the IL-2 protein is administered subcutaneously in a volume of 0.5 mL to 1.5 mL. In certain embodiments, the IL-2 protein is administered subcutaneously in a volume of about 0.5 mL. In certain embodiments, the IL-2 protein is administered subcutaneously in a volume of about 1.0 mL. In certain embodiments, the IL-2 protein is administered subcutaneously in a volume of about 0.5 mL. In certain embodiments, the IL-2 protein comprises the amino acid sequence of SEQ ID NO: 26. In certain embodiments, the IL-2 protein is aldesleukin. In certain embodiments, the IL-2 protein comprises the amino acid sequence of aldesleukin.

[0189] In some embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, once per week, e.g., as described in any of the embodiments 62 NAI-5002088184v1Attorney Docket No.14678-029-228 presented herein in an amount ranging from about 0.3 µg to about 200 µg per week. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, once per week, e.g., as described in any of the embodiments presented herein in an amount of about 0.3 µg to about 1.0 µg per week. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, once per week, e.g., as described in any of the embodiments presented herein in an amount of about 3.0 µg to about 10 µg per week. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, once per week, e.g., as described in any of the embodiments presented herein in an amount of about 15 µg to about 50 µg per week. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, once per week, e.g., as described in any of the embodiments presented herein in an amount of about 30 µg to about 100 µg per week. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, once per week, e.g., as described in any of the embodiments presented herein in an amount of about 45 µg to about 150 µg per week. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, once per week, e.g., as described in any of the embodiments presented herein in an amount of about 60 µg to about 200 µg per week. In certain embodiments, the IL-2 protein is administered subcutaneously. In certain embodiments, the IL-2 protein is administered subcutaneously in a volume of 0.5 mL to 1.5 mL. In certain embodiments, the IL-2 protein is administered subcutaneously in a volume of about 0.5 mL. In certain embodiments, the IL-2 protein is administered subcutaneously in a volume of about 1.0 mL. In certain embodiments, the IL-2 protein is administered subcutaneously in a volume of about 0.5 mL In certain embodiments, the IL-2 protein comprises the amino acid sequence of SEQ ID NO: 26. In certain embodiments, the IL-2 protein is aldesleukin. In certain embodiments, the IL-2 protein comprises the amino acid sequence of aldesleukin.

[0190] In some embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, once per week, e.g., as described in any of the embodiments presented herein in an amount ranging from about 1.25 mg to about 2.5 mg per week. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, once per week, e.g., as described in any of the embodiments presented herein in an amount of about 1.25 mg per week. In certain embodiments, according to the methods 63 NAI-5002088184v1Attorney Docket No.14678-029-228 provided herein, the IL-2 protein is administered to the subject weekly, once per week, e.g., as described in any of the embodiments presented herein in an amount of about 1.5 mg per week. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, once per week, e.g., as described in any of the embodiments presented herein in an amount of about 1.75 mg per week. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, once per week, once per week, e.g., as described in any of the embodiments presented herein in an amount of about 2.0 mg per week. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, once per week, e.g., as described in any of the embodiments presented herein in an amount of about 2.5 mg per week. In certain embodiments, the IL-2 protein is administered subcutaneously. In certain embodiments, the IL-2 protein is administered subcutaneously in a volume of 0.5 mL to 1.5 mL. In certain embodiments, the IL-2 protein is administered subcutaneously in a volume of about 0.5 mL. In certain embodiments, the IL-2 protein is administered subcutaneously in a volume of about 1.0 mL. In certain embodiments, the IL-2 protein is administered subcutaneously in a volume of about 0.5 mL. In certain embodiments, the IL-2 protein comprises the amino acid sequence of SEQ ID NO: 26. In certain embodiments, the IL-2 protein is aldesleukin. In certain embodiments, the IL-2 protein comprises the amino acid sequence of aldesleukin.

[0191] In some embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily administration for 2-7 (e.g., 2-5) consecutive days, e.g., as described in any of the embodiments presented herein in a weekly amount ranging from about 0.3 µg to about 200 µg, divided equally among the daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 2-7 (e.g., 2-5) consecutive days, e.g., as described in any of the embodiments presented herein in a weekly amount of about 0.3 µg to about 1.0 µg, divided equally among the once daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 2-7 (e.g., 2- 5) consecutive days, e.g., as described in any of the embodiments presented herein in an amount of about 3.0 µg to about 10 µg, divided equally among the once daily administrations. In certain 64 NAI-5002088184v1Attorney Docket No.14678-029-228 embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 2-7 (e.g., 2-5) consecutive days, e.g., as described in any of the embodiments presented herein in a weekly amount of about 15 µg to about 50 µg, divided equally among the once daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 2-7 (e.g., 2-5) consecutive days, e.g., as described in any of the embodiments presented herein in an amount of about 30 µg to about 100 µg, divided equally amount the once daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 2-7 (e.g., 2-5) consecutive days, e.g., as described in any of the embodiments presented herein in an amount of about 45 µg to about 150 µg, divided equally amount the once daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 2-7 (e.g., 2-5) consecutive days, e.g., as described in any of the embodiments presented herein in an amount of about 60 µg to about 200 µg, divided equally amount the once daily administrations. In certain embodiments, the IL-2 protein is administered subcutaneously. In certain embodiments, the once daily IL-2 protein administration is administered subcutaneously in a volume of 0.5 mL to 1.5 mL. In certain embodiments, the once daily IL-2 protein administration is administered subcutaneously in a volume of about 0.5 mL. In certain embodiments, the once daily IL-2 protein administration is administered subcutaneously in a volume of about 1.0 mL. In certain embodiments, the once daily IL-2 protein administration is administered subcutaneously in a volume of about 0.5 mL. In certain embodiments, the IL-2 protein comprises the amino acid sequence of SEQ ID NO: 26. In certain embodiments, the IL- 2 protein is aldesleukin. In certain embodiments, the IL-2 protein comprises the amino acid sequence of aldesleukin.

[0192] In some embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily administration for 2-7 (e.g., 2-5) consecutive days, e.g., as described in any of the embodiments presented herein in a weekly amount ranging from about 1.25 mg to about 2.5 mg, divided 65 NAI-5002088184v1Attorney Docket No.14678-029-228 equally among the daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 2-7 (e.g., 2-5) consecutive days, e.g., as described in any of the embodiments presented herein in a weekly amount of about 1.25 mg, divided equally among the once daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 2-7 (e.g., 2-5) consecutive days, e.g., as described in any of the embodiments presented herein in an amount of about 1.5 mg, divided equally among the once daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 2-7 (e.g., 2- 5) consecutive days, e.g., as described in any of the embodiments presented herein in a weekly amount of about 1.75 mg, divided equally among the once daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 2-7 (e.g., 2-5) consecutive days, e.g., as described in any of the embodiments presented herein in an amount of about 2.0 mg, divided equally amount the once daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 2-7 (e.g., 2-5) consecutive days, e.g., as described in any of the embodiments presented herein in an amount of about 2.5 mg, divided equally amount the once daily administrations. In certain embodiments, the IL-2 protein is administered subcutaneously. In certain embodiments, the once daily IL-2 protein administration is administered subcutaneously in a volume of 0.5 mL to 1.5 mL. In certain embodiments, the once daily IL-2 protein administration is administered subcutaneously in a volume of about 0.5 mL. In certain embodiments, the once daily IL-2 protein administration is administered subcutaneously in a volume of about 1.0 mL. In certain embodiments, the once daily IL-2 protein administration is administered subcutaneously in a volume of about 0.5 mL. In certain embodiments, the IL-2 protein comprises the amino acid sequence of SEQ ID NO: 26. In certain embodiments, the IL-2 protein is aldesleukin. In certain embodiments, the IL-2 protein comprises the amino acid sequence of aldesleukin. 66 NAI-5002088184v1Attorney Docket No.14678-029-228

[0193] In some embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily administration for 5 consecutive days, e.g., as described in any of the embodiments presented herein in a weekly amount ranging from about 0.3 µg to about 200 µg, divided equally among the daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 5 consecutive days, e.g., as described in any of the embodiments presented herein in a weekly amount of about 0.3 µg to about 1.0 µg, divided equally among the once daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 5 consecutive days, e.g., as described in any of the embodiments presented herein in an amount of about 3.0 µg to about 10 µg, divided equally among the once daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 5 consecutive days, e.g., as described in any of the embodiments presented herein in a weekly amount of about 15 µg to about 50 µg, divided equally among the once daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 5 consecutive days, e.g., as described in any of the embodiments presented herein in an amount of about 30 µg to about 100 µg, divided equally amount the once daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 5 consecutive days, e.g., as described in any of the embodiments presented herein in an amount of about 45 µg to about 150 µg, divided equally amount the once daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 5 consecutive days, e.g., as described in any of the embodiments presented herein in an amount of about 60 µg to about 200 µg, divided equally amount the once daily administrations. In certain embodiments, the IL-2 protein is administered subcutaneously. In certain embodiments, the once daily IL-2 protein administration is 67 NAI-5002088184v1Attorney Docket No.14678-029-228 administered subcutaneously in a volume of 0.5 mL to 1.5 mL. In certain embodiments, the once daily IL-2 protein administration is administered subcutaneously in a volume of about 0.5 mL. In certain embodiments, the once daily IL-2 protein administration is administered subcutaneously in a volume of about 1.0 mL. In certain embodiments, the once daily IL-2 protein administration is administered subcutaneously in a volume of about 0.5 mL. In certain embodiments, the IL-2 protein comprises the amino acid sequence of SEQ ID NO: 26. In certain embodiments, the IL-2 protein is aldesleukin. In certain embodiments, the IL-2 protein comprises the amino acid sequence of aldesleukin.

[0194] In some embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily administration for 5 consecutive days, e.g., as described in any of the embodiments presented herein in a weekly amount ranging from about 1.25 mg to about 2.5 mg, divided equally among the daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 5 consecutive days, e.g., as described in any of the embodiments presented herein in a weekly amount of about 1.25 mg, divided equally among the once daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 5 consecutive days, e.g., as described in any of the embodiments presented herein in an amount of about 1.5 mg, divided equally among the once daily administrations. In certain embodiments, according to the methods provided herein, the IL- 2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 5 consecutive days, e.g., as described in any of the embodiments presented herein in a weekly amount of about 1.75 mg, divided equally among the once daily administrations. In certain embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 5 consecutive days, e.g., as described in any of the embodiments presented herein in an amount of about 2.0 mg, divided equally amount the once daily administrations. In certain embodiments, according to the methods provided herein, the IL- 2 protein is administered to the subject weekly, wherein the weekly IL-2 administration comprises once daily IL-2 administration for 5 consecutive days, e.g., as described in any of the 68 NAI-5002088184v1Attorney Docket No.14678-029-228 embodiments presented herein in an amount of about 2.0 mg, divided equally amount the once daily administrations. In certain embodiments, the IL-2 protein is administered subcutaneously. In certain embodiments, the once daily IL-2 protein administration is administered subcutaneously in a volume of 0.5 mL to 1.5 mL. In certain embodiments, the once daily IL-2 protein administration is administered subcutaneously in a volume of about 0.5 mL. In certain embodiments, the once daily IL-2 protein administration is administered subcutaneously in a volume of about 1.0 mL. In certain embodiments, the once daily IL-2 protein administration is administered subcutaneously in a volume of about 0.5 mL. In certain embodiments, the IL-2 protein comprises the amino acid sequence of SEQ ID NO: 26. In certain embodiments, the IL- 2 protein is aldesleukin. In certain embodiments, the IL-2 protein comprises the amino acid sequence of aldesleukin.

[0195] In certain embodiments, the administration methods described herein may be repeated. For example, an administration method described herein may be repeated at least once. In certain embodiments, an administration method described herein may be repeated at least 1-6, at least 1-12, at least 1-16, at least 1-20, at least 1-26 or more times. In certain embodiments, an administration method described herein may be repeated 1-6, 1-12, 1-16, 1-20, 1-26 or more times. In certain embodiments, an administration method described herein may be repeated at least 1, at least 2, at least 3, or at least four times. In certain embodiments, an administration method described herein may be repeated 1, 2, 3, or 4 times.

[0196] In particular embodiments, an administration method as described herein may be repeated at least once during a 26- or 52-week period. In certain embodiments, an administration method described herein may be repeated at least 1-6, at least 1-12, at least 1-16, at least 1-20, at least 1-26 or more times during a 26- or 52-week period. In certain embodiments, an administration method described herein may be repeated 1-6, 1-12, 1-16, 1-20, 1-26 or more times during a 26- or 52-week period. In certain embodiments, an administration method described herein may be repeated at least 1, at least 2, at least 3, or at least four times during a 26- or 52-week period. In certain embodiments, an administration method described herein may be repeated 1, 2, 3, or 4 times during a 26- or 52-week period.

[0197] In certain embodiments, when an administration method is repeated, a subsequent administration method may begin the week following the completion of the previous administration method. In certain embodiments, when an administration method is repeated, a 69 NAI-5002088184v1Attorney Docket No.14678-029-228 subsequent administration method may begin the day following the completion of the previous administration method. In certain embodiments, when a weekly administration method is repeated, a subsequent administration method may begin the week following the completion of the previous administration method. In certain embodiments, when a weekly administration method is repeated, a subsequent administration method may begin the day following the completion of the previous administration method.

[0198] In certain embodiments, a weekly administration of a GLP-1 receptor agonist and an IL-2 protein as described herein may be followed by 1 or more weeks wherein a subject does not receive a GLP-1 receptor agonist or IL-2 protein. For example, a subject may receive a weekly administration of a GLP-1 receptor agonist and IL-2 protein for 1 week or for 2, 3, 4, 5, or 6 consecutive weeks followed by 1 or 2 weeks wherein the subject does not receive a GLP-1 receptor agonist or IL-2 protein.

[0199] In some embodiments, the GLP-1 receptor agonist and / or IL-2 protein is administered with an autoinjector, which may for example, be a delivery pen with a mechanism for automation. Such an autoinjector may use any mechanism for automation known in the art (e.g., a spring-loaded needle or a liquefied gas, such as liquefied hydrofluoroalkane). One of skill in the art will appreciate that in some embodiments, in using an autoinjector, a subject may actuate drug delivery without activating a push-button (e.g., solely through the application of pressure on the injection site). In some embodiments, an autoinjector may be a device that wholly or partially replaces the activities involved in drug delivery from a standard syringe. As a non- limiting example, these activities may include removing the protective syringe cap, inserting a needle into the skin of the patient, injecting medication, removing the needle, shielding the needle, and preventing reuse of the device.

[0200] Non-limiting examples of devices suitable for use in conjunction with administration methods described herein include a pre-filled syringe, an injection device (e.g., an INJECT- EASE™ or a GENJECT™ device), an infusion pump (e.g. an Accu-Chek™ infusion pump), an injector pen (e.g., a GENPEN™ injector pen), a needleless device (e.g., a MEDDECTOR™ or BIOJECTOR™ needless device), or an autoinjector (e.g., a ClickJectTM autoinjector).

[0201] In some embodiments, administration of the GLP-1 receptor agonist and / or the IL-2 protein is self-administration by the subject. In some embodiments, administration of the GLP-1 receptor agonist and / or the IL-2 protein is self-administration by the subject via a self- 70 NAI-5002088184v1Attorney Docket No.14678-029-228 administration device. In some embodiments, the self-administration device, for example, the injection device (e.g., autoinjector, such as autoinjector pen) is mechanical. In some embodiments, the injection device (e.g., autoinjector, such as autoinjector pen) is electronic. Such injection devices may be provided separate from a pharmaceutical composition comprising the GLP-1 receptor agonist or IL-2 protein or pre-filled with the pharmaceutical composition. In some embodiments, the injection device is pre-filled. In some embodiments, the device is empty and can be filled using cassette or cartridges.

[0202] In some embodiments, a device suitable for self-administration, e.g., subcutaneous administration, is provided in a single-use container (e.g., a single-use vial, ampoule, syringe, or autoinjector). In some embodiments, a single-use container can be disposable. In some embodiments, an injection device suitable for self-administration, e.g., subcutaneous administration, be provided pre-filled with a pharmaceutical composition held in a reservoir within the device, and once the reservoir is emptied of the pharmaceutical composition, the entire device can be discarded.

[0203] In some embodiments, a device suitable for self-administration, e.g., subcutaneous administration, is reusable. As a non-limiting example, in some embodiments, a reusable autoinjector delivery device may utilize a replaceable cartridge that contains a pharmaceutical composition comprising a GLP-1 receptor agonist or IL-2 protein, and once the pharmaceutical composition within the cartridge has been administered and the cartridge is empty or no longer needed, the cartridge can be discarded and replaced with a new cartridge that contains a pharmaceutical composition.

[0204] In certain embodiments, any pen and / or autoinjector injection device known in the art may be used for the subcutaneous delivery in conjunction with any of the administration methods described herein. 7.3.1. Subjects

[0205] Described herein are methods and compositions for treating or preventing treating an inflammatory disease or disorder in a subject in need thereof. A subject in need of treatment can be a subject diagnosed with or suspected of having a disease or disorder as described herein. For example, in some embodiments, the disease or disorder is associated with Treg dysfunction and the subject is diagnosed with or is suspected of having a disorder associated with Treg dysfunction. In some embodiments, the disease or disorder is associated with Treg deficiency 71 NAI-5002088184v1Attorney Docket No.14678-029-228 and the subject is diagnosed with or is suspected of having a disorder associated with Treg deficiency. In some embodiments, the disease or disorder is a condition driven by a T cell response and the subject is diagnosed with or is suspected of having a condition driven by a T cell response. In certain embodiments, a subject in need thereof is diagnosed as having or is suspected of having an inflammatory disease or disorder that is a neurodegenerative or neuroinflammatory disorder. The term “subject” and “patient” are used interchangeably throughout the present disclosure. Subjects for whom the methods provided herein can be used are diagnosed and selected based on assessing diagnostic criteria and / or biomarkers associated with the inflammatory disorder or disease according to the methods described in herein.

[0206] In some embodiments, the inflammatory disorder or disease is a neurodegenerative disease and the subject is diagnosed with or is suspected of having a neurodegenerative disease. In some embodiments, the subject is diagnosed with or is suspected of having Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Huntington’s disease, Parkinson’s disease (PD), or frontotemporal dementia.

[0207] In some embodiments, the subject is diagnosed with or is suspected of having Alzheimer’s disease (AD). In some embodiments, the subject is diagnosed with or is suspected of having late-onset AD. In some embodiments, the subject is diagnosed with or is suspected of having early-onset AD. In general, AD diagnosed as beginning after age 65 is considered late- onset disease whereas an AD diagnosis before age 55 is considered early-onset disease. In some embodiments, the subject is diagnosed with or is suspected of having sporadic AD. In some embodiments, the subject is diagnosed with or is suspected of having familial AD. In some embodiments, the subject diagnosed with or suspected of having familial AD has a genetic mutation in one or more of the following genes: APP, PSEN1 and PSEN2.

[0208] In some embodiments, the subject is diagnosed with or is suspected of having amyotrophic lateral sclerosis (ALS). In some embodiments, the subject is diagnosed with or is suspected of having juvenile amyotrophic lateral sclerosis (JALS). In some embodiments, the subject is diagnosed with or is suspected of having sporadic ALS. In some embodiments, the subject is diagnosed with or is suspected of having familial ALS. In some embodiments, the subject diagnosed with or suspected of having familial ALS has a genetic mutation in one or more of the following genes: C9orf72, SOD1, TARDBP and / or FUS. In some embodiments, the subject is diagnosed with or is suspected of amyotrophic lateral sclerosis (ALS). In some 72 NAI-5002088184v1Attorney Docket No.14678-029-228 embodiments, the subject is diagnosed with or is suspected of Definite ALS, Probable ALS, Probable ALS - Laboratory Results Supported, or Possible ALS according to El Escorial diagnostic criteria (see Table 3). TABLE 3: El Escorial Diagnostic Categories and Inclusion Criteria Diagnostic Category Inclusion Criteria orHuntington’s disease (HD). In some embodiments, the subject is diagnosed with or is suspected of having late-onset HD. In general, HD diagnosed as beginning after age 60 is considered late- onset disease. In some embodiments, the subject is diagnosed with or is suspected of having juvenile HD (diagnosed before the age of 20 years).

[0210] In some embodiments, the subject is diagnosed with or is suspected of having Parkinson’s disease (PD). In some embodiments, the subject is diagnosed with or is suspected of having late-onset PD. In some embodiments, the subject is diagnosed with or is suspected of having early-onset PD. In general, PD diagnosed as beginning after age 50 is considered late- onset disease whereas a PD diagnosis before age 20 is considered early-onset disease and is sometimes referred to as juvenile-onset Parkinson disease. In some embodiments, the subject is diagnosed with or is suspected of having sporadic PD. In some embodiments, the subject is diagnosed with or is suspected of having familial PD. In some embodiments, the subject diagnosed with or suspected of having familial PD has a genetic mutation in one or more of the following genes: GBA, LRRK2, PARK7, PINK1, PRKN, SNCA, and VPS3.

[0211] In some embodiments, the subject is diagnosed with or is suspected of having frontotemporal dementia (FTD). In some embodiments, the subject is diagnosed with or is 73 NAI-5002088184v1Attorney Docket No.14678-029-228 suspected of having sporadic FTD. In some embodiments, the subject is diagnosed with or is suspected of having familial FTD. In some embodiments, the subject diagnosed with or suspected of having familial FTD has a genetic mutation in one or more of the following genes: C9ORF72, MAPT, GRN, TARDBP, VCP, CHMP2B, SQSTM1, UBQLN1 and TBK1.

[0212] In some embodiments, the disease or disorder is neuroinflammation or is a disease or disorder associated with neuroinflammation, and the subject is diagnosed with or suspected of having neuroinflammation. The neuroinflammation may be associated, for example, with stroke, acute disseminated encephalomyelitis (ADEM), acute optic neuritis, transverse myelitis, neuromyelitis optica (NMO), epilepsy, traumatic brain injury, spinal cord injury, encephalitis central nervous system (CNS) vasculitis, neurosarcoidosis, autoimmune or post-infectious encephalitis, or chronic meningitis. 7.3.2. Methods of Determining Treatment Effect

[0213] The effect of a method of treatment provided herein can be assessed by monitoring clinical signs and symptoms of the disease to be treated.

[0214] The efficacy of a method of treatment described herein may, for example, be assessed at about 4 weeks, about 8 weeks, about 16 weeks, about 20 weeks, about 24 weeks, about 28 weeks, about 32 weeks, about 36 weeks, about 40 weeks, about 44 weeks, about 48 weeks, about 52 weeks, about 56 weeks, about 60 weeks, about 64 weeks, about 68 weeks, about 72 weeks, about 76 weeks, about 80 weeks, about 84 weeks, about 88 weeks, about 92 weeks, about 96 weeks, about 100 weeks, at about 2-3 months, 3-4 months, 4-5 months, 5-6 months, 6-7 months, 7-8 months, 8-9 months, about 9-10 months, about 10-11 months, about 11-12 months, about 12- 18 months, about 18-24 months, about 1-2 years, about 2-3 years, about 3-4 years, about 4-5 years, about 5-6 years, about 6-7 years, about 7-8 years, about 8-9 years, or about 9-10 years after initiation of treatment in accordance with the method described herein.

[0215] In some embodiments, method of treatment provided herein results in a change in the mini-mental state examination (MMSE) score compared to baseline. In the context of an assessment of the effect of a method of treatment, the term “baseline” refers to a measurement pre-treatment. The MMSE score measures overall Alzheimer’s disease symptoms. In some embodiments, the MMSE score increases in a subject treated in accordance with a method provided herein compared to baseline, indicating an improvement of symptoms. In other embodiments, the MMSE score remains unchanged in a subject treated in accordance with a 74 NAI-5002088184v1Attorney Docket No.14678-029-228 method provided herein compared to baseline.

[0216] In some embodiments, method of treatment provided herein results in a change in the Appel ALS (AALS) score compared to baseline. In the context of an assessment of the effect of a method of treatment, the term “baseline” refers to a measurement pre-treatment. The AALS scale consists of 5 subscales (Bulbar Function, Respiratory Function, Overall Muscle Strength, Upper Extremity, and Lower Extremity Function) with scores ranging from 30 (Normal) to 164 (Maximal Dysfunction). See Haverkamp, Appel, and Appel. Brain.1995 Jun;118 (Pt 3):707-19. A total AALS score (sum of the scores from all 5 subscales) score measures overall progression of disability or altered function. In some embodiments, the Appel ALS score decreases in a subject treated in accordance with a method provided herein compared to baseline, indicating an improvement of symptoms. In other embodiments, the Appel ALS score remains unchanged in a subject treated in accordance with a method provided herein compared to baseline. In some embodiments, a method of treatment provided herein results in an ALSFRS-R rate of decline that is greater than about three points per month (point / month). In some embodiments, a method of treatment provided herein results in a decline in ALSFRS-R score greater than about 1 to about 3 points / month, e.g., greater than about 1 point / month, greater than about 1.2 points / month, greater than about 1.4 points / month, greater than about 1.6 points / month, greater than about 1.8 points / month, greater than about 2 points / month, greater than about 2.2 points / month, greater than about 2.4 points / month, greater than about 2.6 points / month, greater than about 2.8 points / month, or greater than about 3.0 points / month.

[0217] In some embodiments, a method of treatment provided herein results in a change in the Amyotrophic Lateral Sclerosis Functional Rating Scale-revised (ALSFRS-R) score compared to baseline. The ALSFRS-R score assesses the progression of disability or altered function. ALSFRS-R is a 12-item scale assessing motor impairment with regard to bulbar function, hand and arm function, walking / gross motor abilities, and respiration. The ALSFRS-R includes 12 questions, each being rated on a five-point scale from 0=cannot do, to 4=normal ability. Individual item scores are summed to produce a reported score of between 0=worst and 48=best. See Cedarbaum JM, J Neurol Sci 1999; 169: 13-21. In some embodiments, the ALSFRS-R score increases in a subject treated in accordance with a method provided herein compared to baseline, indicating an improvement of symptoms. In other embodiments, the Appel ALSFRS-R score remains unchanged in a subject treated in accordance with a method 75 NAI-5002088184v1Attorney Docket No.14678-029-228 provided herein compared to baseline. On average, in ALS clinical trials, there is approximately a one point drop every month (Castrillo-Viguera C et al., Amyotroph Lateral Scler.2010;11(1- 2):178-180). In some embodiments, a method of treatment provided herein results in an ALSFRS-R rate of decline that is less than about one point per month (point / month). In some embodiments, a method of treatment provided herein results in a decline in ALSFRS-R score of less than about 1.0 to less than about 0.2 points per month (points / month), e.g., less than about 1.0 point / month, less than about 0.9 points / month, less than about 0.8 points / month, less than about 0.7 points / month, less than about 0.6 points / month, less than about 0.5 points / month, less than about 0.4 points / month, less than about 0.3 points / month, or less than about 0.2 points / month.

[0218] In some embodiments, a method of treatment provided herein results in a change in forced vital capacity (FVC; strength of muscles used with expiration) compared to baseline, where the highest number is the strongest measurement. In some embodiments, FVC increases in a subject treated in accordance with a method provided herein compared to baseline. In other embodiments, FVC remains unchanged in a subject treated in accordance with a method provided herein compared to baseline.

[0219] In some embodiments, a method of treatment provided herein results in a change in Maximum Inspiratory Pressure (MIP; strength of muscles used with inspiration) compared where the highest number is the strongest measurement. In some embodiments, MIP increases in a subject treated in accordance with a method provided herein compared to baseline. In other embodiments, MIP remains unchanged in a subject treated in accordance with a method provided herein compared to baseline.

[0220] In some embodiments, a method of treatment provided herein results in a change in Neuropsychiatric Inventory Questionnaire (NPI-Q) compared to baseline. The NPI-Q provides symptom Severity and Distress ratings for each symptom reported, and total Severity and Distress scores reflecting the sum of individual domain scores. In some embodiments, the NPI- Q score decreases in a subject treated in accordance with a method provided herein compared to baseline. In other embodiments, NPI-Q score remains unchanged in a subject treated in accordance with a method provided herein compared to baseline.

[0221] In some embodiments, a method of treatment provided herein results in a decrease in the frequency of GI symptoms, anaphylaxis or seizures compared to baseline. 76 NAI-5002088184v1Attorney Docket No.14678-029-228

[0222] In some embodiments, a method of treatment provided herein results in a change in the levels of CSF amyloid and / or CSF tau protein (CSF-tau) compared to baseline. In some embodiments, the levels of CSF amyloid and / or CSF tau protein decreases in a subject treated in accordance with a method provided herein compared to baseline. In other embodiments, the levels of CSF amyloid and / or CSF tau protein remains unchanged in a subject treated in accordance with a method provided herein compared to baseline.

[0223] In some embodiments, a method of treatment provided herein results in a change in the levels of at least one serum biomarker associated with ALS compared to baseline. In some embodiments, a method of treatment provided herein results in a change in the serum level of neurofilament light chain (NfL) compared to baseline. In some embodiments, a method of treatment provided herein maintains the serum level of NfL compared to baseline. In some embodiments, a method of treatment provided herein results in a change in the serum level of oxidized low-density lipoprotein (ox-LDL). In some embodiments, a method of treatment provided herein maintains the serum level of ox-LDL compared to baseline. In some embodiments, a method of treatment provided herein results in a change in the serum level of 4- hydroxynonenol (4-HNE) compared to baseline. In some embodiments, a method of treatment provided herein maintains the serum level of 4-HNE compared to baseline.

[0224] In some embodiments, a method of treatment provided herein results in a change in Clinical Dementia Rating (CDR) compared to baseline. The CDR rates memory, orientation, judgment and problem-solving, community affairs, home and hobbies, and personal care, and a global rating is then generated, ranging from 0-no impairment to 3-severe impairment. In some embodiments, the CDR decreases in a subject treated in accordance with the methods provided herein compared to baseline. In other embodiments, the CDR remains unchanged in a subject treated in accordance with a method provided herein compared to baseline.

[0225] In certain embodiments, a method of treatment provided herein results in a change in Alzheimer's Disease Assessment Scale–Cognitive Subscale (ADAS-cog) score compared to baseline. See, e.g., Kueper JK et al., J Alzheimers Dis.2018;63(2):423-444. ADAS-cog tests cognitive performance and has an upper limit of 85 (poor performance) and lower limit of zero (best performance). In some embodiments, the ADAS-cog score decreases in a subject treated in accordance with a method provided herein compared to baseline. In other embodiments, the ADAS-cog score remains unchanged in a subject treated in accordance with a method provided 77 NAI-5002088184v1Attorney Docket No.14678-029-228 herein. In some embodiments, a method of treatment provided herein results in a change in ADAS-cog3 score compared to baseline. In some embodiments, a method of treatment provided herein results in a change in ADAS-cog11 score compared to baseline. In some embodiments, a method of treatment provided herein results in a change in ADAS-cog12 score compared to baseline. In some embodiments, a method of treatment provided herein results in a change in ADAS-cog13 score compared to baseline. In some embodiments, a method of treatment provided herein results in a change in ADAS-cog-IRT score compared to baseline. In some embodiments, a method of treatment provided herein results in a change in ADAS-cog-5-subset score compared to baseline. In some embodiments, a method of treatment provided herein results in a change in ADAS-cog-6-subset score compared to baseline.

[0226] In certain embodiments, a method of treatment provided herein reduces or mitigates at least one sign or symptom of an existing disease or condition (e.g., a neurodegenerative or neuroinflammatory disease) of a subject. In certain embodiments, a method of treatment provided herein mitigates one or more symptoms associated with the neurodegenerative or neuroinflammatory disease or disorder in the treated subject. In certain embodiments, a method of treatment provided herein mitigates one or more symptoms associated with neurodegenerative or neuroinflammatory disease in the treated subject. For example, in certain embodiments, a method of treatment provided herein can reduce the duration or severity of at least one sign or symptom of an existing disease or condition of a subject.

[0227] For example, in certain embodiments, the ADAS-cog score of a subject remains unchanged, or is not statistically different, in the subject treated in accordance with a method provided herein compared to baseline. For example, in certain embodiments, the MMSE score of a subject remains unchanged, or is not statistically different, in the subject treated in accordance with a method provided herein compared to baseline. For example, in certain embodiments, the ALSFRS-R score of a subject with ALS remains unchanged, or is not statistically different, in the subject treated in accordance with a method provided herein compared to baseline. For example, in certain embodiments, in a subject with ALS, the Appel ALS score remains unchanged or is not statistically different in the subject treated in accordance with a method provided herein compared to baseline. In certain embodiments, a method of treatment is provided herein wherein at least one sign or symptom of an existing disease or condition (e.g., a neurodegenerative or neuroinflammatory disease, for example ALS) of a 78 NAI-5002088184v1Attorney Docket No.14678-029-228 subject does not worsen. 7.4 Additional Therapies

[0228] In some embodiments, a subject treated in accordance with the method of treatment described herein further receives one or more additional therapy or additional therapies known in the art for treating diseases such as neurodegenerative and neuroinflammatory diseases.

[0229] In some embodiments, the subject treated in accordance with the methods described herein receives one or more additional therapies that are for the treatment of Alzheimer’s. Addition therapies for the treatment of Alzheimer’s may include acetylcholinesterase inhibitors (e.g., donepezil (Aricept®), galantamine (Razadyne®), or rivastigmine (Exelon®)) or NMDA receptor antagonists (e.g., Memantine (Akatinol®, Axura®, Ebixa® / Abixa®, Memox®and Namenda®). Additional therapies may also include anti-inflammatory agents (e.g., nonsteroidal anti-inflammatory drugs (NSAID) such as ibuprofen, indomethacin, and sulindac sulfide), neuronal death associated protein kinase (DAPK) inhibitors such as derivatives of 3-amino pyridazine, Cyclooxygenases (COX-1 and -2) inhibitors, or antioxidants such as vitamins C and E. In some embodiments, a subject treated in accordance with the methods described herein receives one or more additional therapies for the treatment of ALS. Additional therapies for the treatment of ALS may include riluzole (Rilutek®, Tiglutik®, or Exservan™).

[0230] In some embodiments, a subject treated in accordance with the methods described herein receives one or more additional therapy, which can include, but is not limited to: (a) a TNF alpha inhibitor (e.g., infliximab, adalimumab (Humira®), etanercept, golimumab, or certolizumab); (b) an IL-6 inhibitor (e.g., siltuximab, tocilizumab, olokizumab, elsilimomab, clazakizumab, or sirukumab); (c) an IL-23 inhibitor (e.g., tildrakizumab, guselkumab, or risankizumab); (d) an IL-17 inhibitor (e.g., secukinumab, ixekizumab, or brodalumab); (e) an IL-12 / IL-23 subunit p40 inhibitor (e.g., ustekinumab or briakinumab); (f) an IL-1 inhibitor (e.g., anakinra (Kineret®), canakinumab, or rilonacept); (g) a C3-targeted complement inhibitor (e.g., pegcetacoplan); (h) a C5-targeted complement inhibitor (e.g., ravulizumab or eculizumab); (i) a JAK inhibitor (e.g., baricitinib, tofacitinib, or upadacitinib); (j) an anti-CD40 CD40L (e.g., toralizumab, dapirolizumab pegol, or ruplizumab); or 79 NAI-5002088184v1Attorney Docket No.14678-029-228 (k) a CD14 inhibitor (e.g., IC14).

[0231] In some embodiments, a subject treated in accordance with the method of treatment described herein further receives regulatory T cell (Treg) therapy. A Treg cell therapy is described, for instance, in WO 2021 / 113685 A2, which is incorporated herein in its entirety for all purposes.

[0232] In some embodiments, a subject treated in accordance with the method of treatment described herein further receives extracellular vesicles (EVs) that are derived from ex vivo- expanded human Tregs as therapy (“Treg EV therapy”). Treg EV therapy is described, for instance, in International Application No. PCT / US2022 / 017990, filed February 25, 2022, which is incorporated herein in its entirety for all purposes.

[0233] In some embodiments, a subject treated in accordance with the method of treatment described herein further receives one or more additional therapies, wherein the one or more additional therapies does not comprise an anti-thymocyte globulin (ATG or Thymoglobulin®). In some embodiments, a subject treated in accordance with the method of treatment described herein further receives one or more additional therapies, wherein the one or more additional therapies does not comprise adalimumab (Humira®). In some embodiments, a subject treated in accordance with the method of treatment described herein further receives one or more additional therapies, wherein the one or more additional therapies does not comprise pegfilgrastim (Neulasta®). In some embodiments, a subject treated in accordance with the method of treatment described herein further receives one or more additional therapies, wherein the one or more additional therapies does not comprise clozapine. In some embodiments, a subject treated in accordance with the method of treatment described herein further receives one or more additional therapies, wherein the one or more additional therapies does not comprise olanzapine. In some embodiments, a subject treated in accordance with the method of treatment described herein further receives one or more additional therapies, wherein the one or more additional therapies does not comprise an anti-inflammatory agent (e.g., an agent targeting IL-1β and / or TNF-α). In some embodiments, a subject treated in accordance with the method of treatment described herein further receives one or more additional therapies, wherein the one or more additional therapies does not comprise an immunomodulating agent (e.g., anti-CD3, anti- CD20, co-stimulation blockage, ATG). In some embodiments, a subject treated in accordance with the method of treatment described herein further receives one or more additional therapies, 80 NAI-5002088184v1Attorney Docket No.14678-029-228 wherein the one or more additional therapies does not comprise an agent that drives Tregs (e.g., GCSF, Treg infusion). In some embodiments, a subject treated in accordance with the method of treatment described herein further receives one or more additional therapies, wherein the one or more additional therapies does not comprise a diabetes-related antigen (e.g., oral insulin, GAD vaccine). 7.5 Additional Therapeutic Interventions

[0234] In some embodiments, the methods disclosed herein can be employed with one or more additional therapeutic interventions known in the art for treating diseases such as neurodegenerative and neuroinflammatory diseases, for example, ALS or Alzheimer’s disease. As a non-limiting example, in some embodiments the additional therapeutic intervention may comprise a cognitive rehabilitation program, neurostimulation technique, or a combination thereof.

[0235] Any cognitive rehabilitation program known in the art can be used with the methods disclosed herein. Cognitive training, stimulation, and rehabilitation methods and software provided via digital devices are used in the art to improve the cognitive function in subjects with neurodegenerative and neuroinflammatory diseases, for example, Alzheimer’s disease (Irazoki, E. et al., Front. Psychol.11:648 (2020)). In some embodiments, the cognitive rehabilitation program is a computer-implemented cognitive rehabilitation program. As a non-limiting example, in some embodiments the computer-implemented cognitive rehabilitation program may include: FesKits (Gaitán et al., 2012, Int. J. Geriatr. Psychiatry 28, 91–99); SOCIABLE (Barban et al., 2015, Int. J. Geriatr. Psychiatry 31, 340–348 and Danassi, 2015, Adv. Exp. Med. Biol.821, 129–130); Brainer (Cavallo et al., 2016, Arch. Clin. Neuropsychol.31, 868–876 and Cavallo and Angilletta, 2018, J. Appl. Gerontol.38, 1035–1044); NeuronUp (Mendoza Laiz et al., 2018, Restor. Neurol. Neurosci.36, 207–213); and ComCog (Hwang et al., 2015, J. Phys. Ther. Sci. 27, 2921–2923).

[0236] In some embodiments, the neurostimulation technique is a non-invasive brain stimulation (NIBS). In some embodiments, the neurostimulation technique is an invasive brain stimulation (IBS). Any neurostimulation techniques known in the art can be used with the methods disclosed herein. As a non-limiting example, IBS includes deep brain stimulation (DBS), and invasive vagus nerve stimulation (VNS), and NIBS includes transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), transcranial alternating current 81 NAI-5002088184v1Attorney Docket No.14678-029-228 stimulation (tACS), electroconvulsive treatment (ECT), magnetic seizure therapy (MST), cranial electrostimulation (CES), and / or non-invasive VNS. In some embodiments, the neurostimulation technique is invasive vagus nerve stimulation or non-invasive VNS. As a non- limiting example, in some embodiments, the additional therapeutic intervention is implantation and use of a vagus stimulator (e.g., NeuroCybernetic Prosthesis, Cyberonics Inc., Houston TX.) See, e.g., Sjogren, MJ et al., J Clin Psychiatry. (2002) 63(11):972-80. In some embodiments, any methods known in the art to use vagus nerve stimulation to enhance cognition in a subject may be used (e.g., by programming a pulse generator that delivers electrical signals using parameters known in the art). 7.6 Kits

[0237] In an aspect, provided herein is a kit comprising a GLP-1 receptor agonist and IL-2 protein as described herein. In a specific embodiment of a kit comprising IL-2 protein and at least one GLP-1 receptor agonist, the GLP-1 receptor agonist is semaglutide. In a particular embodiment, the semaglutide is Ozempic®. In another particular embodiment, the semaglutide is Rybelsus®. In yet another particular embodiment the semaglutide is Wegovy®.

[0238] In another specific embodiment of a kit comprising IL-2 protein and at least one GLP-1 receptor agonist, the GLP-1 receptor agonist is exendin-4 / exenatide. In a particular embodiment, the exendin-4 / exenatide is Byetta™. In another particular embodiment, the exendin-4 / exenatide is Bydureon.®

[0239] In a specific embodiment of a kit comprising IL-2 protein and at least one GLP1 receptor agonist, the GLP-1 receptor agonist is tirzepatide. In a particular embodiment, the tirzepatide is Mounjaro®. In another particular embodiment, the tirzepatide is Zepbound®.

[0240] In another specific embodiment of a kit comprising IL-2 protein and at least one GLP-1 receptor agonist, the GLP-1 receptor agonist is liraglutide. In a particular embodiment, the liraglutide is Victoza®. In another particular embodiment, the liraglutide is Saxenda®

[0241] In yet another specific embodiment of a kit comprising IL-2 protein and at least one GLP-1 receptor agonist, the GLP-1 receptor agonist is dulaglutide. In a particular embodiment, the dulaglutide is Trulicity®.

[0242] In a specific embodiment of a kit comprising IL-2 protein and at least one GLP-1 receptor agonist, the IL-2 protein comprises the amino acid sequence of SEQ ID NO:26. In a specific embodiment of a kit comprising IL-2 protein and at least one GLP-1 receptor agonist, 82 NAI-5002088184v1Attorney Docket No.14678-029-228 the IL-2 protein is aldesleukin. In a specific embodiment of a kit comprising IL-2 protein and at least one GLP-1 receptor agonist, the IL-2 protein comprises the amino acid sequence of aldesleukin.

[0243] In a specific embodiment of a kit comprising IL-2 protein and at least one GLP-1 receptor agonist, the GLP-1 receptor agonist is semaglutide and the IL-2 protein comprises the amino acid sequence of SEQ ID NO:26. In a particular embodiment of such a kit, the semaglutide is Ozempic®. In another particular embodiment of such a kit, the semaglutide is Rybelsus®. In yet another particular embodiment of such a kit, the semaglutide is Wegovy®.

[0244] In a specific embodiment of a kit comprising IL-2 protein and at least one GLP-1 receptor agonist, the GLP-1 receptor agonist is semaglutide and the IL-2 protein is aldesleukin. In a particular embodiment of such a kit, the semaglutide is Ozempic®. In another particular embodiment of such a kit, the semaglutide is Rybelsus®. In yet another particular embodiment of such a kit, the semaglutide is Wegovy®.

[0245] In a specific embodiment of a kit comprising IL-2 protein and at least one GLP-1 receptor agonist, the GLP-1 receptor agonist is semaglutide and the IL-2 protein comprises the amino acid sequence of aldesleukin. In a particular embodiment of such a kit, the semaglutide is Ozempic®. In another particular embodiment of such a kit, the semaglutide is Rybelsus®. In yet another particular embodiment of such a kit, the semaglutide is Wegovy®.

[0246] In a specific embodiment of a kit comprising IL-2 protein and at least one GLP-1 receptor agonist, the GLP-1 receptor agonist is exendin-4 / exenatide and the IL-2 protein comprises the amino acid sequence of SEQ ID NO:26. In a particular embodiment of such a kit, the exendin-4 / exenatide is Byetta™. In another particular embodiment of such a kit, the exendin-4 / exenatide is Bydureon®.

[0247] In a specific embodiment of a kit comprising IL-2 protein and at least one GLP-1 receptor agonist, the GLP-1 receptor agonist is exendin-4 / exenatide and the IL-2 protein is aldesleukin. In a particular embodiment of such a kit, the exendin-4 / exenatide is Byetta™. In another particular embodiment of such a kit, the exendin-4 / exenatide is Bydureon®.

[0248] In a specific embodiment of a kit comprising IL-2 protein and at least one GLP-1 receptor agonist, the GLP-1 receptor agonist is exendin-4 / exenatide and the IL-2 protein comprises the amino acid sequence of aldesleukin. In a particular embodiment of such a kit, the 83 NAI-5002088184v1Attorney Docket No.14678-029-228 exendin-4 / exenatide is Byetta™. In another particular embodiment of such a kit, the exendin- 4 / exenatide is Bydureon®.

[0249] In a specific embodiment of a kit comprising IL-2 protein and at least one GLP-1 receptor agonist, the GLP-1 receptor agonist is tirzepatide and the IL-2 protein comprises the amino acid sequence of SEQ ID NO:26. In a particular embodiment of such a kit, the tirzepatide is Mounjaro®. In another particular embodiment of such a kit, the tirzepatide is Zepbound®.

[0250] In a specific embodiment of a kit comprising IL-2 protein and at least one GLP-1 receptor agonist to a subject in need thereof, the GLP-1 receptor agonist is tirzepatide and the IL- 2 protein is aldesleukin. In a particular embodiment of such a kit, the tirzepatide is Mounjaro®. In another particular embodiment of such a kit, the tirzepatide is Zepbound®.

[0251] In a specific embodiment of a kit comprising IL-2 protein and at least one GLP-1 receptor agonist, the GLP-1 receptor agonist is tirzepatide and the IL-2 protein comprises the amino acid sequence of aldesleukin. In a particular embodiment of such a kit, the tirzepatide is Mounjaro®. In another particular embodiment of such a kit, the tirzepatide is Zepbound®.

[0252] In a specific embodiment of a kit comprising IL-2 protein and at least one GLP-1 receptor agonist, the GLP-1 receptor agonist is liraglutide and the IL-2 protein comprises the amino acid sequence of SEQ ID NO:26. In a particular embodiment of such a kit, the liraglutide is Victoza®. In another particular embodiment of such a kit, the liraglutide is Saxenda®.

[0253] In a specific embodiment of a kit comprising IL-2 protein and at least one GLP-1 receptor agonist, the GLP-1 receptor agonist is liraglutide and the IL-2 protein is aldesleukin. In a particular embodiment of such a kit, the liraglutide is Victoza®. In another particular embodiment of such a kit, the liraglutide is Saxenda®.

[0254] In a specific embodiment of a kit comprising IL-2 protein and at least one GLP-1 receptor agonist, the GLP-1 receptor agonist is liraglutide and the IL-2 protein comprises the amino acid sequence of aldesleukin. In a particular embodiment of such a kit, the liraglutide is Victoza®. In another particular embodiment of such a kit, the liraglutide is Saxenda®.

[0255] In a specific embodiment of a kit comprising IL-2 protein and at least one GLP-1 receptor agonist, the GLP-1 receptor agonist is dulaglutide and the IL-2 protein comprises the amino acid sequence of SEQ ID NO: 26. In a particular embodiment of such a kit, the dulaglutide is Trulicity®. 84 NAI-5002088184v1Attorney Docket No.14678-029-228

[0256] In a specific embodiment of a kit comprising IL-2 protein and at least one GLP-1 receptor agonist, the GLP-1 receptor agonist is dulaglutide and the IL-2 protein is aldesleukin. In a particular embodiment of such a kit, the dulaglutide is Trulicity®.

[0257] In a specific embodiment of a kit comprising IL-2 protein and at least one GLP-1 receptor agonist, the GLP-1 receptor agonist is dulaglutide and the IL-2 protein comprises the amino acid sequence of aldesleukin. In a particular embodiment of such a kit, the dulaglutide is Trulicity®.

[0258] In certain embodiments, a kit provided herein comprises instructions for use, additional reagents (e.g., sterilized water or saline solutions for dilution of the compositions), or components, such as tubes, containers or syringes for collection of biological samples, processing of biological samples, and / or reagents for quantitating the amount of one or more surface markers in a sample (e.g., detection reagents, such as antibodies).

[0259] In some embodiments, the kits contain one or more containers containing a GLP-1 receptor agonist formulation and an IL-2 protein formulation for use in the methods provided herein. In some embodiments, the kits contain one or more containers containing a GLP-1 receptor agonist formulation and a low dose IL-2 protein formulation for use in the methods provided herein. In some embodiments, kits for use in the methods provided herein contain a GLP-1 receptor agonist formulation that is separate from an IL-2 protein formulation. The one or more containers holding the GLP-1 receptor agonist formulation can be a single-use vial or a multi-use vial. The one or more containers holding the IL-2 protein (e.g., aldesleukin) formulation can be a single-use vial or a multi-use vial. In some embodiments, the article of manufacture or kit can further comprise a third container comprising a suitable diluent. In some embodiments, the kit contains instruction for use (e.g., dilution and / or administration) of the GLP-1 receptor agonist formulation and / or the IL-2 protein (e.g., aldesleukin) formulation provided herein.

[0260] In some embodiments, a kit provided herein comprises multiple doses or administration units of one or more pharmaceutical together with one or more devices for application (e.g., syringe(s), injection pen(s) and / or autoinjector(s)). In some embodiments, such devices may be provided separate from a pharmaceutical composition or prefilled with the pharmaceutical composition. In some embodiments, a kit provided herein comprises one or more doses of a pharmaceutical composition and / or formulation in separate containers. In some 85 NAI-5002088184v1Attorney Docket No.14678-029-228 embodiments, the containers are enclosed in an injection device or can be inserted into an injection device (e.g., disposable dose cassettes or cartridges that can be inserted into an autoinjector device for administration).

[0261] In one aspect, presented herein is a kit comprising, in one container, a pharmaceutical composition comprising one or more doses of GLP-1 receptor agonist (e.g., semaglutide, exendin-4), and an IL-2 protein (e.g., aldesleukin). In some embodiments, the kit further comprises instructions for use, additional reagents (e.g., sterilized water or saline solutions for dilution of the compositions), or components, such as tubes, containers or syringes for collection of biological samples, processing of biological samples, reagents for quantitating the amount of one or more surface markers in a sample (e.g., detection reagents, such as antibodies), and / or one or more devices for administration (e.g., syringe(s), injection pen(s) and / or autoinjector(s)).

[0262] In certain embodiments, provided herein is a kit for administering a GLP-1 receptor agonist and IL-2 protein that comprises weekly administration of the GLP-1 receptor agonist and the IL-2 protein. In certain embodiments, provided herein is a kit for administering a GLP-1 receptor agonist and IL-2 protein that comprises weekly administration of the GLP-1 receptor agonist and the IL-2 protein, wherein the GLP-1 receptor agonist is administered once per week and the IL-2 protein is administered 2-7 times per week, e.g., 5 times per week.

[0263] In certain embodiments, provided herein is a kit for administering a GLP-1 receptor agonist and IL-2 protein that comprises daily administration of the GLP-1 receptor agonist and the IL-2 protein. In certain embodiments, provided herein is a kit for administering a GLP-1 receptor agonist and IL-2 protein that comprises daily administration of the GLP-1 receptor agonist and the IL-2 protein, wherein the GLP-1 receptor agonist is administered once per week and the IL-2 protein is administered 2-7 times per week, e.g., 5 times per week.

[0264] In certain embodiments, presented herein is a kit for administering a GLP-1 receptor agonist and IL-2 protein, comprising: (a) a pre-filled syringe containing a solution comprising a GLP-1 receptor agonist, wherein the solution is suitable for subcutaneous administration to a human subject; and (b) a vial containing a solution comprising an IL-2 protein, wherein the solution is suitable for subcutaneous administration to a human subject. In certain embodiments, the pre-filled syringe contains a solution that comprises a sufficient amount of the GLP-1 receptor agonist, and the vial contains a solution that comprises a sufficient amount of the IL-2 protein for a week of a weekly GLP-1 receptor agonist and IL2 protein administration method 86 NAI-5002088184v1Attorney Docket No.14678-029-228 described herein. In certain embodiments, the pre-filled syringe contains a solution that comprises a sufficient amount of the GLP-1 receptor agonist, and the vial contains a solution that comprises a sufficient amount of low dose IL-2 protein for a week of a weekly GLP-1 receptor agonist and IL2 protein administration method described herein. In certain embodiments, the pre-filled syringe contains a solution that comprises a sufficient amount of the GLP-1 receptor agonist, and the vial contains a solution that comprises a sufficient amount of the IL-2 protein for a week of a daily GLP-1 receptor agonist and IL2 protein administration method described herein. In certain embodiments, the pre-filled syringe contains a solution that comprises a sufficient amount of the GLP-1 receptor agonist, and the vial contains a solution that comprises a sufficient amount of the low dose IL-2 protein for a week of a daily GLP-1 receptor agonist and IL2 protein administration method described herein.

[0265] In some embodiments, the kits contain one or more containers containing a GLP-1 receptor agonist formulation and an IL-2 protein formulation (e.g., a low dose IL-2 protein formulation) for use in the methods provided herein wherein the kit can further comprise one or more additional therapies such as those disclosed herein (see e.g., Section 7.4). In some embodiments, the kits contain one or more containers containing a GLP-1 receptor agonist formulation and an IL-2 protein formulation (e.g., a low dose IL-2 protein formulation) for use in the methods provided herein wherein the kit does not further comprise an anti-inflammatory agent (e.g., an agent targeting IL-1β and / or TNF-α). In some embodiments, the kits contain one or more containers containing a GLP-1 receptor agonist formulation and an IL-2 protein formulation (e.g., a low dose IL-2 protein formulation) for use in the methods provided herein wherein the kit does not further comprise an immunomodulating agent (e.g., anti-CD3, anti- CD20, co-stimulation blockage, ATG). In some embodiments, the kits contain one or more containers containing a GLP-1 receptor agonist formulation and an IL-2 protein formulation (e.g., a low dose IL-2 protein formulation) for use in the methods provided herein wherein the kit does not further comprise an agent that drives Tregs (e.g., GCSF, Treg infusion). In some embodiments, the kits contain one or more containers containing a GLP-1 receptor agonist formulation and an IL-2 protein formulation (e.g., a low dose IL-2 protein formulation) for use in the methods provided herein wherein the kit does not further comprise a diabetes-related antigen (e.g., oral insulin, GAD vaccine). 87 NAI-5002088184v1Attorney Docket No.14678-029-228 8. EXAMPLES 8.1 Example 1: Effects of GLP-1 Receptor Agonists on IL-2-induced Treg Suppression of Pro-inflammatory Myeloid Cells

[0266] Myeloid cell co-culture experiments were performed to determine the effects of glucagon-like peptide-1 (GLP-1) agonists on pro-inflammatory myeloid cells and the synergistic functions of adding low dose IL-2 plus Treg cells to the system.

[0267] In brief, Tregs and monocytes were isolated from patient (human) blood. The myeloid cells (monocyte / macrophages just isolated) were cultured in 96 well flat bottom tissue culture plates. Myeloid cells were activated using 0.1 ng / mL lipopolysaccharide (LPS) and 0.2 ng / mL interferon gamma (IFNγ) to produce pro-inflammatory M1 myeloid cells. Following 1 hour activation, test articles of low dose IL-2 (50 IU / mL) and / or GLP-1 receptor agonists (semaglutide (OZEMPIC®) or exendin-4 (BYETTA®)) were added to the culture paradigm along with patient-derived Treg cells. The amount of IL-2 used in this exemplary study herein was low enough to not cause significant effector T cell (Teff) proliferation, but was provided at a concentration high enough to result in a Treg receptor-mediated boost in suppressive function. Co-cultures of myeloid cells, Tregs, IL-2, and / or GLP-1 receptor agonists were incubated overnight (~16-18 hours post pro-inflammatory stimulus) and the media was collected along with RNA isolated from the pro-inflammatory myeloid cells. Pro-inflammatory and anti- inflammatory cytokine analysis was performed on the collected conditioned media. For example, protein levels of IL-6, TNF, Il-1b, IL-10, and the like were measured by standard ELISA techniques. Using the isolated RNA, an RT-PCR analysis of myeloid transcripts for pro- inflammatory, anti-inflammatory, and oxidative stress markers was performed. Antioxidant and lipid peroxidation assays were also performed according to standard techniques known in the art.

[0268] As demonstrated in FIGS.1A-1B, addition of GLP-1 receptor agonists enhanced IL- 2-induced Treg suppression of pro-inflammatory myeloid cells. Semaglutide and exendin-4 (Ex4) were added individually and in combination with low dose IL-2 to the Treg / myeloid cell co-culture at either 100 nM or 1 µM amounts. Semaglutide showed an anti-inflammatory effect alone in suppressing pro-inflammatory IL-6 protein and an enhanced anti-inflammatory effect in combination with low dose IL-2 in this paradigm (FIG.1A). In the same way, exendin-4 (Ex4) suppressed IL-6 protein in the co-culture paradigm. Ex4 showed an anti-inflammatory effect alone and an enhanced anti-inflammatory effect in combination with low dose IL2 in this 88 NAI-5002088184v1Attorney Docket No.14678-029-228 paradigm (FIG.1B).

[0269] In the same in vitro co-culture paradigm of Treg and myeloid cells as depicted in FIGS.1A-1B, RNA was isolated from myeloid cells to examine reduction in pro-inflammatory transcripts and any enhancement in anti-inflammatory transcripts. Data showed reductions in pro-inflammatory myeloid cell transcripts of IL-6, IL-1β, and TNF with addition of Treg+IL2, GLP-1 receptor agonist alone (semaglutide or Ex4), and enhancement of suppression with combination Treg / IL2 / GLP1 agonist together (FIG.2A). The combination of GLP1 agonist and Treg+IL2 treatments demonstrated an increase in anti-inflammatory IL-10 cytokine transcript from myeloid cells along with increases in anti-inflammatory, M2-associated myeloid cell markers of mannose receptor (CD206 / MRC1) and arginase 1 (ARG1) (FIG.2B). These data demonstrated that combination therapeutic approach of low dose IL-2 and GLP-1 agonism not only reduces pro-inflammatory signaling, but this combination can enhance the anti- inflammatory potential of the resulting myeloid cell. 8.2 Example 2: Effects of GLP-1 Receptor Agonists on Treg Suppression of T cell Proliferation

[0270] T cell proliferation experiments were performed to determine if GLP-1 receptor agonists alone or in combination with low dose IL-2 can enhance Treg suppressive function.

[0271] In brief, CD4+CD25+ Treg cells and CD4+CCD25-T effector cells were isolated from patient (human) blood. Cells were co-cultured in a 96 well round bottom tissue culture plate at a ratio of 1:1 / 2 T effector:Treg cells (Teff:Treg). Wells are treated with low dose IL-2 (1 IU / mL) and / or GLP-1 receptor agonist (semaglutide) at different concentrations (100 nM, 1 µM, 10 µM). Following 5 days incubation and subsequent T cell proliferation, Treg and test article suppression of T cell proliferation is read out using a tritium incorporation assay according to standard techniques known in the art.

[0272] FIG.3 shows that low dose IL-2 enhanced endogenous Treg suppressive function and that the addition of different concentrations of GLP-1 receptor agonists added to the suppressive function of the Treg suppressive capabilities. In sum, the data demonstrated that GLP-1 receptor agonists enhance Treg suppressive function of T cell proliferation. 89 NAI-5002088184v1Attorney Docket No.14678-029-228 8.3 Example 3: Further Effects of GLP-1 Receptor Agonists on IL-2-induced Treg Suppression of Pro-inflammatory Myeloid Cells

[0273] Examples 3-5, presented herein, further demonstrate that combination treatment with low dose IL2 and GLP-1 receptor agonists enhances Treg suppressive function, reduces pro- inflammatory signaling and promotes Treg survival. For example, the results of these experiments demonstrate the combination treatment enhances Treg suppression of IL-6 production by pro-inflammatory myeloid cells, reduces myeloid cell pro-inflammatory transcripts of IL-6 and TNF, and increases anti-inflammatory myeloid marker transcripts of ARG1. The results also demonstrate that Tresp proliferation is more effectively suppressed by the combination than either agent alone. For example, Tregs treated with low dose IL2 and GLP-1 receptor agonist exhibited increased FOXP3, IL2RA / CD25, and CTLA-4 expression, along with enhanced anti-apoptotic BCL-2 and reduced pro-apoptotic BAX transcripts.

[0274] In this Example, additional myeloid cell co-culture experiments were performed in an expanded cohort to further characterize the effects of GLP-1 receptor agonists on pro- inflammatory myeloid cells and adding low dose IL-2 plus Treg cells to the system.

[0275] Immune cells were isolated from peripheral blood of healthy donors using a Lymphoprep (Stemcell) density gradient, followed by positive or negative selection using bead- based, magnetic columns (Miltenyi Biotec). Peripheral monocytes were isolated using Human Pan Monocyte Isolation Kit (Miltenyi Biotec) to obtain CD14+ / CD16+ pan-monocytes. Regulatory T Cell Isolation Kit (Miltenyi Biotec) was used to isolate CD4+CD25+ Treg cells and CD4+CD25- responder T (Tresp) cells.

[0276] For pro-inflammatory myeloid cell cultures with / without Tregs, pan-monocytes were plated immediately after isolation in 96-well flat bottom plates at 50,000 cells per well. The plated myeloid cells were then activated to become pro-inflammatory with 0.1 ng / mL lipopolysaccharide (LPS) + 0.2 ng / mL IFN-γ or 1 hour in 37 °C in a cell culture incubator prior to addition of Treg cells and / or test article treatments. Following pro-inflammatory myeloid activation, a recombinant human low dose IL-2 (MW app.15.3 kD; 50 IU / mL) and / or GLP-1 receptor agonists (semaglutide (OZEMPIC®) or exendin-4 (BYETTA®) (0.1-1 uM)) were added to the cultures followed by 50,000 isolated Tregs per well to complete a 1:1 M1:Treg co-culture. Cells and test articles were incubated together overnight (18 hours) followed by sampling the 90 NAI-5002088184v1Attorney Docket No.14678-029-228 conditioned media for cytokine analysis and isolating mRNA from the pro-inflammatory myeloid cells for inflammatory transcript analysis.

[0277] As shown in FIGS.4A-4B, following pro-inflammatory activation of the myeloid cells, co-culture with isolated Treg cells at a 1:1 ratio produced an approximate 7% suppression of pro-inflammatory IL-6 protein. Adding low dose IL-2 to the co-culture enhanced Treg suppression to 15%. When low dose IL-2 and a GLP-1 receptor agonist, semaglutide, were combined, a significant increase in IL-6 suppression was observed (31% at 100 nM concentration, p < 0.05 and 42% at 1 uM concentration, p < 0.001) (FIG.4A). Treatment of activated myeloid cells with only semaglutide induced direct suppression of IL-6 at 17-20% at those concentrations. Another GLP-1 receptor agonist, exendin-4 (ex4), was able to induce 29% and 34% suppression of IL-6 release when combined with low dose IL-2 in the Treg:M1 co- cultures, while treatment of ex4 alone on myeloid cells resulted in 20% suppression of IL-6 (FIG.4B). At the higher dose of ex4, the increase in suppression on M1 cells when combined with low dose IL-2 was significant compared to ex4 alone on M1 cells and Treg+IL-2 treatment.

[0278] In the same in vitro co-culture paradigm of Treg and myeloid cells as depicted in FIGS.4A-4B, messenger RNA expression levels from treated M1 cells were examined to assess additional pro-inflammatory and anti-inflammatory transcripts following single and combination treatments. Consistent with the previous co-culture cytokine data, the most pronounced pro- inflammatory transcript change was with IL-6. Treg suppression of M1 IL-6 RNA was enhanced with low dose IL-2 treatment, increasing from 4% to 28% (FIG.5A left). When the GLP-1 receptor agonist semaglutide was added at 1µM in combination with low dose IL-2 and Tregs, M1 IL-6 RNA was reduced by 65% (FIG.5A left). A similar effect was seen when adding 1µM Ex4 GLP-1 receptor agonist to Treg+ low dose IL-2 on M1 cells as there was a 46% reduction in M1 IL-6 transcripts (FIG.5A left). GLP-1 receptor agonists alone induced modest suppression of M1 IL-6 RNA, with semaglutide and Ex4 reducing by 22% and 17%, respectively (FIG.5A left).

[0279] Additional pro-inflammatory transcripts for M1 IL-1β and TNF were assayed following treatment with the low dose IL-2 and GLP-1 receptor agonists. GLP-1 receptor agonists demonstrated enhanced suppression of these transcripts when added to the M1:Treg co- culture. Treg+IL-2 suppression of IL-1β was 19% and increased to 36.5% when 1µM semaglutide was added (FIG.5A middle). With 1uM of Ex4, suppression was increased to 31% 91 NAI-5002088184v1Attorney Docket No.14678-029-228 of IL-1β and 51% of TNF transcripts (FIG.5A middle, right). Individually, 1µM semaglutide induced only 4% suppression of IL-1β and no suppression of TNF transcripts. Ex4 only treatment of M1 cells demonstrated 7% suppression of IL-1β and no suppression of TNF (FIG. 5A middle, right).

[0280] GLP-1 receptor agonists could enhance anti-inflammatory IL-10 transcripts and specific mRNA markers of alternative activation of an anti-inflammatory myeloid phenotype (M2), compared to their individual treatments (FIG.5B left). Although not significant, IL-10 transcript production in the activated myeloid cells increased by 1.4-fold when treated with Treg+IL-2. This IL-10 production increased in the combination Treg+IL-2+GLP-1 receptor agonist treatments with a 1.9-fold increase with semaglutide and 1.3-fold increase with Ex4 (FIG.5B left). With Arg1 transcripts, we found a robust increase in transcripts following combination GLP-1 receptor agonists+Treg+IL-2 treatment of M1 cells. A 5.0-fold increase of Arg1 mRNA in treated M1 cells was seen with combination of semiglutide+IL-2 +Treg and 6.5- fold increase with Ex4 combination treatment (FIG.5B middle). Mannose receptor (CD206), another alternative activation marker of myeloid cells, demonstrated a 3.9- fold and 3.0-fold increase with semaglutide or Ex4, respectively, to the Treg+IL-2 co-cultures (FIG.5B right).

[0281] Taken together, these results demonstrate that combination low dose IL-2 and GLP-1 receptor agonists enhance Treg suppression of pro-inflammatory myeloid cells and provides synergistic immune modulation of myeloid cell inflammatory transcripts. 8.4 Example 4: Responder T cell Proliferation is Suppressed with Low Dose IL-2 and GLP-1 Receptor Agonists Combination with Treg

[0282] Responder T cell experiments were performed to assess the effect of low dose IL-2 and GLP-1 receptor agonism on responder T cell proliferation.

[0283] CD4+CD25+ Treg cells and CD4+CD25- Tresp cells were isolated from healthy control blood and co-cultured in 96-well round bottom tissue culture plates at a ratio of 50,000 Tresp cells to 25,000 Treg cells (1: 1 / 2 ratio). Addition of low dose IL-2 (1 IU / mL) alone or in combination with varying concentrations of a GLP-1 receptor agonist were added to the co- culture followed by activation of T cell proliferation. Following 5 days incubation, suppression of T cell proliferation was assessed using a tritium incorporation assay.

[0284] Data shows that low dose IL-2 enhances endogenous Treg suppressive function (FIG. 6). Treg suppression of Tresp proliferation was 24% in this assay with culturing Tresp / Treg cells 92 NAI-5002088184v1Attorney Docket No.14678-029-228 at a ratio of 1:1 / 2. Titration of low dose IL-2 into Tresp:Treg cocultures was previously performed to find a dose of IL-2 that stimulated enhanced Treg suppression without inducing Tresp proliferation (data not shown). When Tresp / Tregs were co-cultured with 1 IU / mL IL-2, Treg suppression increased to 34%. The combination of low dose IL-2 and semaglutide at 100nM concentration increased Tresp suppression to 52% (FIG.6A) while the combination with 1µM concentration increased suppression to 58% (FIG.6B), a significant synergistic enhancement of suppression of Tresp proliferation compared to low dose IL-2 or semaglutide alone.

[0285] Taken together, these results demonstrate that combination low dose IL-2 and GLP-1 receptor agonists suppresses Tresp proliferation. 8.5 Example 5: Combination of Low Dose IL-2 and GLP-1 Receptor Agonists Increases Health and Function Transcripts in Tregs and Protects Against Apoptosis Transcript Signature

[0286] Transcript analysis was performed to determine the effect of low dose IL-2 and GLP- 1 receptor agonists on Treg health and functional transcripts.

[0287] In brief, CD4+CD25+ Tregs were isolated from healthy controls. Tregs were plated in 96-well, round bottom plates and treated with low dose IL-2 (50 IU / mL), GLP-1 receptor agonist (semaglutide at 1µM), or a combination IL-2 / GLP-1 receptor agonist at 3 hours and 18 hours. Tregs were then isolated for transcript analysis and media was frozen for future studies. Transcripts, such as FOXP3, IL2RA / CD25, and CTLA-4, were analyzed as surrogate markers of Treg survival and function.

[0288] RNA was isolated using Trizol reagent followed by Direct-zol RNA MiniPrep Plus Kit (Zymo Research). Quality and concentration of RNA was assessed using Nanodrop spectrophotometer. Quantitative RT-PCR (qPCR) experiments were performed using a One-Step RT-PCR kit with SYBR Green and a Bio-Rad iQ5 Multicolor Real-Time PCR Detection System. Primers for the study were acquired from BioRad and the relative expression of each mRNA was calculated using the ΔΔCt method with normalization to β-actin.

[0289] FOXP3 is a master regulator of immune suppression in Treg cells and is directly correlated with Treg suppressive activity. Low dose IL-2 induced Treg FOXP3 transcripts by 2.6-fold at the 3 hours post-treatment and GLP-1 receptor agonist (semaglutide) increased FOXP3 by 1.5-fold (FIG.7A). Combination of low dose IL-2 and GLP-1 receptor agonist 93 NAI-5002088184v1Attorney Docket No.14678-029-228 additively enhanced FOXP3 significantly to a 3.8-fold increase. Following overnight culture in which Tregs are known to die and lose function in culture without optimal stimulation, FOXP3 levels remained significantly increased at 2.6-fold with the combination of low dose IL-2 and GLP-1 receptor agonist while all other groups decreased below the normalized level at 3 hr (FIG.7A).

[0290] IL2RA / CD25 is the critical receptor for Treg survival, expansion, and suppressive function. After 3 hrs of treatment, both low dose IL-2 and the low dose IL-2 / GLP-1 receptor agonist combination treatment provided robust increases in CD25 transcript levels with fold increases of 4.7 and 4.9, respectively (FIG.7B). Following overnight stimulation, low dose IL-2 treatment elevated CD25 transcripts (2.8-fold) as did the combination treatment (3.9-fold). The combination treatment resulted in higher CD25 transcript levels than GLP-1 receptor agonist alone and low dose IL-2 alone.

[0291] CTLA-4, a critical receptor in Treg suppressive function, demonstrated marginal increases with low dose IL-2 alone and further increases with the combination of low-dose IL-2 and GLP-1 receptor agonist at the 3-hour timepoint (FIG.7C). The significant increases in CTLA-4 occurred at the 18-hour timepoint with combination treatment retaining its roughly 2.4- fold increase which was higher than Tregs or low dose IL-2 treatment alone. Under inflammatory conditions, IL-10 and TGF-β are cytokines produced by Tregs to limit immune responses and modulate pro-inflammatory cells. Overnight treatment with GLP-1 receptor agonist induced IL-10 transcript production alone and in combination with low dose IL-2 to approximately 2.4-fold each (FIG.7D). Low dose IL-2 treatment did not induce IL-10 transcripts at either timepoint. TGF-β transcripts saw moderate increases at 3-hour timepoint with GLP-1 receptor agonist and low dose IL-2 treatment alone while enhancement was seen in the combination of low dose IL-2 and GLP-1 receptor agonist (FIG.7E). Following overnight culture, TGF-β mRNA levels dropped across all treated groups, but remained above transcript levels of Tregs without treatments (FIG.7E).

[0292] Treg apoptosis can occur with prolonged exposure to pro-inflammatory and oxidative environments in vivo. The BAX / BCL2 axis regulates apoptosis as BAX is a pro-apoptotic protein while BCL-2 inhibits apoptosis. These transcripts were examined in the Treg co cultures following treatments with low dose IL-2 and / or GLP-1 receptor agonist (FIGS.7F - 7G). It was found that overnight cultures of the Tregs without any treatment increased Treg pro-apoptotic 94 NAI-5002088184v1Attorney Docket No.14678-029-228 BAX transcripts to roughly 2.5-fold levels. As seen with treatments of GLP-1 receptor agonist and the combination of GLP-1 receptor agonist and low dose IL-2, BAX mRNA levels did not increase at the overnight timepoint (FIG, 7F). When looking at anti-apoptotic BCL-2 at the 3- hour timepoint, it was found that low dose IL-2 treatment increased BCL-2 levels to 3.3-fold while low dose IL-2 and GLP-1 receptor agonist combination treatment increased BCL-2 levels to 4-fold (FIG.7G) Additionally, the levels of BCL-2 remained elevated overnight in the combination treatment group. Overall, the combination treatment showed an anti-apoptotic effect through increased BAX expression and enhanced BCL-2 transcripts.

[0293] Taken together, these results demonstrate that combination of low dose IL-2 and GLP-1 receptor agonists increase health and functional transcripts in Tregs and protects against apoptosis transcript signatures. 8.6 Example 6: Combination of Low Dose IL-2 and GLP-1 Receptor Agonists in a Mouse Model of Peripheral and Neuroinflammation

[0294] The studies described in this Example are designed to evaluate the immunomodulatory and neuroprotective effects of low-dose IL-2 and GLP-1 receptor agonist combination therapy in a validated preclinical model of systemic and neuroinflammation.

[0295] Animals: C57BL / 6J wild-type mice (Jackson Laboratories), a well-characterized strain commonly employed in neuroinflammation and immunology research due to its consistent immune and behavioral profiles. Age of mice at study initiation is 8–12 weeks, corresponding to young adult mice, which minimizes variability related to aging. Expected weight range at the time of dosing is 20–28 grams. Both male and female mice are included to evaluate potential sex-specific responses, with animals housed in same-sex cages under standard conditions in the vivarium. Mice are acclimated for a minimum of 72 hours prior to any experimental procedures to reduce stress-related variability and ensure baseline health before study initiation.

[0296] Low-dose IL-2 (LD-IL2): Clinical-grade investigational product formulated at 1,000,000 IU / mL in phosphate buffer with mannitol and sodium dodecyl sulfate (SDS) in a good manufacturing practices (GMP) facility. The solution is diluted to the appropriate dose using sterile 0.9% saline immediately before injection. Low-dose IL-2 is administered intraperitoneally (IP) at 30,000 IU per mouse per day, diluted appropriately to achieve the target dose in a 100 µL injection volume. Dose is given daily, starting three days before lipopolysaccharide (LPS) administration. 95 NAI-5002088184v1Attorney Docket No.14678-029-228

[0297] GLP-1 receptor agonist (GLP-1RA): Research-grade semaglutide (MedChemExpress (MCE; Cat. No. HY-114118)) with verified purity suitable for in vivo administration is used The semaglutide is reconstituted per manufacturer instructions before dilution in sterile saline to the target working concentration. The semaglutide is administered intraperitoneally at 25 nmol / kg / day in a 100 µL injection volume, beginning three days before LPS administration, and continuing daily throughout the LPS treatment period.

[0298] LPS is used to induce systemic and neuroinflammation in a reproducible, translational preclinical model. LPS (Escherichia coli O111:B4 LPS; Sigma-Aldrich, Product No. L3024), purified by ion-exchange chromatography and validated for consistent endotoxin activity is utilized. This preparation is widely utilized in neuroinflammation models to induce peripheral immune activation and subsequent CNS inflammatory responses without the acute toxicity associated with high-dose paradigms. This subacute LPS dosing regimen effectively models the chronic peripheral immune activation and neuroinflammatory processes relevant to neurodegenerative disease pathology.

[0299] Pilot phase: In the pilot phase, LPS is reconstituted in sterile saline to achieve the required working concentration and administered intraperitoneally at 0.25 mg / kg and 0.5 mg / kg for 5 consecutive days to determine the optimal dosing for consistent inflammation while maintaining animal welfare. The pilot phase consists of 3 experimental groups with, e.g., 6 mice per group (3 male, 3 female) for a total of 18 mice. The mice are randomly divided into either Group 1: vehicle control IP (no LPS); Group 2: LPS 0.25 mg / kg only IP (Days 0–4; 5 days total); or Group 3: LPS 0.5 mg / kg only IP (Days 0–4; 5 days total). Following pilot confirmation, the main study proceeds using the selected dose for 5 consecutive days.

[0300] Main study: The main study phase consists of 6 experimental groups of mice with, e.g., 10 mice per group (5 male, 5 female) for a total of 60 mice. Mice are randomly divided into either Group 1: Vehicle Control (no LPS, no treatment); Group 2: LPS only (confirmed dose, Days 0-4); Group 3: LPS + low dose IL-2 (30,000 IU / mouse / day); Group 4: LPS + GLP-1 receptor agonist (semaglutide, 25 nmol / kg / day); Group 5: LPS + low dose IL-2 + GLP-1 receptor agonist (combination therapy); or Group 6: LPS + low dose IL-2 + GLP-1 receptor agonist (no LPS). As illustrated in Table 4, during the main study, mice receive daily intraperitoneal injections of either vehicle control or LPS at the optimal dosing as determined by the pilot phase (e.g., 0.5 mg / kg) for five consecutive days (Days 0–4) to induce a moderate but 96 NAI-5002088184v1Attorney Docket No.14678-029-228 sustained inflammatory response that models chronic neuroinflammation relevant to neurodegenerative disease. Low-dose IL-2 (30,000 IU per mouse, IP) and / or GLP-1 receptor agonist (semaglutide, 25 nmol / kg, IP) is administered daily beginning three days prior to LPS exposure (Days -3 to -1) and continued throughout the LPS treatment period (Days 0–4) to assess treatment effects on peripheral and central inflammation. Mice undergo daily welfare checks and body weight monitoring throughout the study to ensure animal health and adherence to humane endpoints. On Day 5, within 24 hours of the final LPS dose, mice are sacrificed for comprehensive tissue and blood collection, enabling downstream analysis of inflammatory gene and protein expression in brain regions and peripheral immune organs, as well as serum cytokine profiling. TABLE 4: Dosing Paradigm Day -4 -3 -2 -1 0 1 2 3 4 5LPS 0.5 mg / kg IP X X X X XX X X X X X X Xanalysis. For example, brain regions and spinal cord may be assessed, e.g., for inflammatory cytokines, glial activation markers, and neuroprotective factors. Lymph nodes and spleen may be assessed for systemic immune modulation and, e.g., changes in cytokine profiles, immune cell activation, and trafficking signatures relevant to systemic inflammation contributing to central nervous system (CNS) pathology. CD11b+ Myeloid Cells may be isolated from spleen to assess innate immune cell activation and inflammatory signatures. Tregs (CD4+CD25+) and Teff (CD4+CD25-) cells may be isolated to assess adaptive immune modulation, Treg stability, and Teff activation profiles in response to treatment. Blood collected at sacrifice is processed for serum isolation to quantify systemic cytokines, chemokines, and additional biomarkers indicative of systemic immune responses and treatment effects. 9. ILLUSTRATIVE EMBODIMENTS

[0302] The present disclosure provides the following non-limiting embodiments: 97 NAI-5002088184v1Attorney Docket No.14678-029-228 1. A method of treating an inflammatory disease or disorder in a subject in need thereof, comprising administering to the subject: (a) a GLP-1 receptor agonist; and (b) an IL-2 protein. 2. The method of embodiment 1, wherein the method mitigates one or more symptoms associated with the inflammatory disease or disorder in the treated subject. 3. The method of embodiment 1 or embodiment 2, wherein the method attenuates or stops progression of the inflammatory disease or disorder in the treated subject. 4. The method of any one of embodiments 1-3, wherein the GLP-1 receptor agonist comprises the amino acid sequence of SEQ ID NO: 3. 5. The method of any one of embodiments 1-3, wherein the GLP-1 receptor agonist comprises the amino acid sequence of SEQ ID NO: 4. 6. The method of any one of embodiments 1-3, wherein the GLP-1 receptor agonist is semaglutide. 7. The method of any one of embodiments 1-3, wherein the GLP-1 receptor agonist is exendin-4. 8. The method of any one of embodiments 1-7, wherein the IL-2 protein is a human IL-2 protein. 9. The method of embodiment 8, wherein the human IL-2 protein comprises a serine at the amino acid position corresponding to native mature human IL-2 amino acid residue 125. 10. The method of embodiment 8 or 9, wherein the human IL-2 protein lacks an N-terminal alanine amino acid. 11. The method of any one of embodiments 8-10, wherein the human IL-2 protein comprises the amino acid sequence of SEQ ID NO: 26. 12. The method of any one of embodiments 1-11, wherein the IL-2 protein is not glycosylated. 13. The method of embodiment 8, wherein the IL-2 protein is aldesleukin. 14. The method of any one of embodiments 1-13, wherein the GLP-1 receptor agonist is administered by injection or infusion. 15. The method of embodiment 14, wherein the GLP-1 receptor agonist is administered subcutaneously. 98 NAI-5002088184v1Attorney Docket No.14678-029-228 16. The method of embodiment 14, wherein the GLP-1 receptor agonist is administered intravenously. 17. The method of any one of embodiments 1-13, wherein the GLP-1 receptor agonist is administered orally. 18. The method of any one of embodiments 1-17, wherein the IL-2 protein is administered by injection or infusion. 19. The method of embodiment 18, wherein the IL-2 protein is administered subcutaneously. 20. The method of embodiment 18, wherein the IL-2 protein is administered intravenously. 21. The method of any one of embodiments 1-13, wherein the GLP-1 receptor agonist and the IL-2 protein are administered subcutaneously. 22. The method of any one of embodiments 1-13, wherein the GLP-1 receptor agonist and the IL-2 protein are administered intravenously. 23. The method of any one of embodiments 1-13, wherein the GLP-1 receptor agonist is administered orally and the IL-2 protein are administered intravenously. 24. The method of any one of embodiments 1-13, wherein the GLP-1 receptor agonist is administered orally and the IL-2 protein are administered subcutaneously. 25. The method of any one of embodiments 1-24, wherein the GLP-1 receptor agonist is administered weekly. 26. The method of any one of embodiments 1-24, wherein the GLP-1 receptor agonist is administered daily. 27. The method of embodiment 26, wherein the GLP-1 receptor agonist is administered once daily, twice daily, three times daily, or four times daily. 28. The method of any one of embodiments 1-27, wherein the IL-2 protein is administered once daily for 2 to 7 consecutive days. 29. The method of embodiment 28, wherein the IL-2 protein is administered once daily for 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days. 30. The method of any one of embodiments 1-29, wherein: (a) the GLP-1 receptor agonist is administered once every two weeks; and (b) the IL-2 protein is administered once daily for 2-7 consecutive days beginning on the day the GLP-1 receptor agonist is administered. 99 NAI-5002088184v1Attorney Docket No.14678-029-228 31. The method of any one of embodiments 1-29, wherein: (a) the GLP-1 receptor agonist is administered once every week; and (b) the IL-2 protein is administered once daily for 2-7 consecutive days beginning on the day the GLP-1 receptor agonist is administered. 32. The method of any one of embodiments 1-29, wherein: (a) the GLP-1 receptor agonist is administered daily; and (b) the IL-2 protein is administered once daily for 2-7 consecutive days beginning on the day the GLP-1 receptor agonist is administered. 33. The method of any one of embodiments 1-32, wherein the GLP-1 receptor agonist is administered in an amount in the range of 0.05 mg to about 4 mg per week. 34. The method of any one of embodiments 1-33, wherein the IL-2 protein is administered in an amount in the range of 500,000 units to 3,000,000 units. 35. The method of embodiment 34, wherein the IL-2 protein is administered in an amount in the range of 500,000 units to 2,000,000 units. 36. The method of embodiment 35, wherein the IL-2 protein is administered in an amount of 1,000,000 units. 37. The method of any one of embodiments 1-36, wherein the inflammatory disease or disorder is a neurodegenerative or neuroinflammatory disease or disorder. 38. The method of embodiment 37, wherein the neurodegenerative disease or disorder is amyotrophic lateral sclerosis, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, frontotemporal dementia or Huntington’s disease. 39. The method of embodiment 37 or embodiment 38, wherein the neuroinflammatory disease or disorder is associated with stroke, acute disseminated encephalomyelitis, acute optic neuritis, acute inflammatory demyelinating polyradiculoneuropathy, chronic inflammatory demyelinating polyradiculoneuropathy, Guillain-Barre syndrome, transverse myelitis, neuromyelitis optica, epilepsy, traumatic brain injury, spinal cord injury, encephalitis, central nervous system vasculitis, neurosarcoidosis, autoimmune or post-infectious encephalitis or chronic meningitis. 40. The method of any one of embodiments 1-39, wherein the method further comprises performing an additional therapeutic intervention comprising a cognitive rehabilitation program, a neurostimulation technique, or a combination thereof. 100 NAI-5002088184v1Attorney Docket No.14678-029-228 41. The method of embodiment 40, wherein the cognitive rehabilitation program is a computer-implemented cognitive rehabilitation program. 42. The method of embodiment 40 or 41, wherein the neurostimulation technique is an invasive brain stimulation (IBS) technique. 43. The method of embodiment 40 or 41, wherein the neurostimulation technique is a non- invasive brain stimulation (NIBS) technique. 44. The method of embodiment 42, wherein the IBS technique is selected from the group consisting of: deep brain stimulation (DBS) and invasive vagus nerve stimulation (VNS). 45. The method of embodiment 43, wherein the NIBS technique is selected from the group consisting of transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), electroconvulsive treatment (ECT), magnetic seizure therapy (MST), cranial electrostimulation (CES), and non-invasive VNS. 46. A kit, comprising, in separate containers, (i) a GLP-1 receptor agonist, and (ii) an IL-2 protein. 47. The kit of embodiment 46, wherein the GLP-1 receptor agonist is suitable for oral administration. 48. The kit of embodiment 46, wherein the GLP-1 receptor agonist is suitable for subcutaneous administration. 49. The kit of embodiment 46, wherein the GLP-1 receptor agonist is suitable for intravenous administration. 50. The kit of any one of embodiments 46-49, wherein the IL-2 protein is suitable for subcutaneous administration. 51. The kit of any one of embodiments 46-49, wherein the IL-2 protein is suitable for intravenous administration. 52. The kit of any one of embodiments 46-51, wherein the GLP-1 receptor agonist comprises the amino acid sequence of SEQ ID NO: 3. 53. The kit of any one of embodiments 46-51, wherein the GLP-1 receptor agonist comprises the amino acid sequence of SEQ ID NO: 4. 54. The kit of any one of embodiments 46-51, wherein the GLP-1 receptor agonist comprises semaglutide. 101 NAI-5002088184v1Attorney Docket No.14678-029-228 55. The kit of any one of embodiments 46-51, wherein the GLP-1 receptor agonist comprises exendin-4. 56. The kit of any one of embodiments 46-55, wherein the IL-2 protein comprises the amino acid sequence of SEQ ID NO: 26. 57. The kit of any one of embodiments 46-55, wherein the IL-2 protein comprises the amino acid sequence of aldesleukin. 58. The kit of any one of embodiments 46-57, wherein both the GLP-1 receptor agonist and the formulation of one or more doses of IL-2 protein are solutions. 59. The kit of any one of embodiments 46-57, wherein the GLP-1 receptor agonist is a tablet and the formulation of one or more doses of IL-2 protein is a solution. 10. EQUIVALENTS

[0303] All patents and publications mentioned in this specification are incorporated herein by reference in their entireties. From the foregoing description, it will be apparent that variations and modifications can be made to the invention described herein to adopt it to various uses and conditions. Such embodiments are also within the scope of the following claims. 102 NAI-5002088184v1

Claims

Attorney Docket No.14678-029-228 What is claimed is:

1. A method of treating an inflammatory disease or disorder in a subject in need thereof, comprising administering to the subject: (a) a GLP-1 receptor agonist; and (b) an IL-2 protein.

2. The method of claim 1, wherein the method mitigates one or more symptoms associated with the inflammatory disease or disorder in the treated subject.

3. The method of claim 1 or claim 2, wherein the method attenuates or stops progression of the inflammatory disease or disorder in the treated subject.

4. The method of any one of claims 1-3, wherein the GLP-1 receptor agonist comprises the amino acid sequence of SEQ ID NO:

3.

5. The method of any one of claims 1-3, wherein the GLP-1 receptor agonist comprises the amino acid sequence of SEQ ID NO:

4.

6. The method of any one of claims 1-3, wherein the GLP-1 receptor agonist is semaglutide.

7. The method of any one of claims 1-3, wherein the GLP-1 receptor agonist is exendin-4.

8. The method of any one of claims 1-7, wherein the IL-2 protein is a human IL-2 protein.

9. The method of claim 8, wherein the human IL-2 protein comprises a serine at the amino acid position corresponding to native mature human IL-2 amino acid residue 125.

10. The method of claim 8 or 9, wherein the human IL-2 protein lacks an N-terminal alanine amino acid.

11. The method of any one of claims 8-10, wherein the human IL-2 protein comprises the amino acid sequence of SEQ ID NO:

26.

12. The method of any one of claims 1-11, wherein the IL-2 protein is not glycosylated. 103 NAI-5002088184v1Attorney Docket No.14678-029-228 13. The method of claim 8, wherein the IL-2 protein is aldesleukin.

14. The method of any one of claims 1-13, wherein the GLP-1 receptor agonist is administered by injection or infusion.

15. The method of claim 14, wherein the GLP-1 receptor agonist is administered subcutaneously.

16. The method of claim 14, wherein the GLP-1 receptor agonist is administered intravenously.

17. The method of any one of claims 1-13, wherein the GLP-1 receptor agonist is administered orally.

18. The method of any one of claims 1-17, wherein the IL-2 protein is administered by injection or infusion.

19. The method of claim 18, wherein the IL-2 protein is administered subcutaneously.

20. The method of claim 18, wherein the IL-2 protein is administered intravenously.

21. The method of any one of claims 1-13, wherein the GLP-1 receptor agonist and the IL-2 protein are administered subcutaneously.

22. The method of any one of claims 1-13, wherein the GLP-1 receptor agonist and the IL-2 protein are administered intravenously.

23. The method of any one of claims 1-13, wherein the GLP-1 receptor agonist is administered orally and the IL-2 protein are administered intravenously.

24. The method of any one of claims 1-13, wherein the GLP-1 receptor agonist is administered orally and the IL-2 protein are administered subcutaneously.

25. The method of any one of claims 1-24, wherein the GLP-1 receptor agonist is administered weekly. 104 NAI-5002088184v1Attorney Docket No.14678-029-228 26. The method of any one of claims 1-24, wherein the GLP-1 receptor agonist is administered daily.

27. The method of claim 26, wherein the GLP-1 receptor agonist is administered once daily, twice daily, three times daily, or four times daily.

28. The method of any one of claims 1-27, wherein the IL-2 protein is administered once daily for 2 to 7 consecutive days.

29. The method of claim 28, wherein the IL-2 protein is administered once daily for 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days.

30. The method of any one of claims 1-29, wherein: (a) the GLP-1 receptor agonist is administered once every two weeks; and (b) the IL-2 protein is administered once daily for 2-7 consecutive days beginning on the day the GLP-1 receptor agonist is administered.

31. The method of any one of claims 1-29, wherein: (a) the GLP-1 receptor agonist is administered once every week; and (b) the IL-2 protein is administered once daily for 2-7 consecutive days beginning on the day the GLP-1 receptor agonist is administered.

32. The method of any one of claims 1-29, wherein: (a) the GLP-1 receptor agonist is administered daily; and (b) the IL-2 protein is administered once daily for 2-7 consecutive days beginning on the day the GLP-1 receptor agonist is administered.

33. The method of any one of claims 1-32, wherein the GLP-1 receptor agonist is administered in an amount in the range of 0.05 mg to about 4 mg per week.

34. The method of any one of claims 1-33, wherein the IL-2 protein is administered in an amount in the range of 500,000 units to 3,000,000 units.

35. The method of claim 34, wherein the IL-2 protein is administered in an amount in the range of 500,000 units to 2,000,000 units. 105 NAI-5002088184v1Attorney Docket No.14678-029-228 36. The method of claim 35, wherein the IL-2 protein is administered in an amount of 1,000,000 units.

37. The method of any one of claims 1-36, wherein the inflammatory disease or disorder is a neurodegenerative or neuroinflammatory disease or disorder.

38. The method of claim 37, wherein the neurodegenerative disease or disorder is amyotrophic lateral sclerosis, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, frontotemporal dementia or Huntington’s disease.

39. The method of claim 37 or claim 38, wherein the neuroinflammatory disease or disorder is associated with stroke, acute disseminated encephalomyelitis, acute optic neuritis, acute inflammatory demyelinating polyradiculoneuropathy, chronic inflammatory demyelinating polyradiculoneuropathy, Guillain-Barre syndrome, transverse myelitis, neuromyelitis optica, epilepsy, traumatic brain injury, spinal cord injury, encephalitis, central nervous system vasculitis, neurosarcoidosis, autoimmune or post-infectious encephalitis or chronic meningitis.

40. The method of any one of claims 1-39, wherein the method further comprises performing an additional therapeutic intervention comprising a cognitive rehabilitation program, a neurostimulation technique, or a combination thereof.

41. The method of claim 40, wherein the cognitive rehabilitation program is a computer- implemented cognitive rehabilitation program.

42. The method of claim 40 or 41, wherein the neurostimulation technique is an invasive brain stimulation (IBS) technique.

43. The method of claim 40 or 41, wherein the neurostimulation technique is a non-invasive brain stimulation (NIBS) technique.

44. The method of claim 42, wherein the IBS technique is selected from the group consisting of: deep brain stimulation (DBS) and invasive vagus nerve stimulation (VNS). 106 NAI-5002088184v1Attorney Docket No.14678-029-228 45. The method of claim 43, wherein the NIBS technique is selected from the group consisting of transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), electroconvulsive treatment (ECT), magnetic seizure therapy (MST), cranial electrostimulation (CES), and non-invasive VNS.

46. A kit, comprising, in separate containers, (i) a GLP-1 receptor agonist, and (ii) an IL-2 protein.

47. The kit of claim 46, wherein the GLP-1 receptor agonist is suitable for oral administration.

48. The kit of claim 46, wherein the GLP-1 receptor agonist is suitable for subcutaneous administration.

49. The kit of claim 46, wherein the GLP-1 receptor agonist is suitable for intravenous administration.

50. The kit of any one of claims 46-49, wherein the IL-2 protein is suitable for subcutaneous administration.

51. The kit of any one of claims 46-49, wherein the IL-2 protein is suitable for intravenous administration.

52. The kit of any one of claims 46-51, wherein the GLP-1 receptor agonist comprises the amino acid sequence of SEQ ID NO:

3.

53. The kit of any one of claims 46-51, wherein the GLP-1 receptor agonist comprises the amino acid sequence of SEQ ID NO:

4.

54. The kit of any one of claims 46-51, wherein the GLP-1 receptor agonist comprises semaglutide.

55. The kit of any one of claims 46-51, wherein the GLP-1 receptor agonist comprises exendin-4. 107 NAI-5002088184v1Attorney Docket No.14678-029-228 56. The kit of any one of claims 46-55, wherein the IL-2 protein comprises the amino acid sequence of SEQ ID NO:

26.

57. The kit of any one of claims 46-55, wherein the IL-2 protein comprises the amino acid sequence of aldesleukin.

58. The kit of any one of claims 46-57, wherein both the GLP-1 receptor agonist and the formulation of one or more doses of IL-2 protein are solutions.

59. The kit of any one of claims 46-57, wherein the GLP-1 receptor agonist is a tablet and the formulation of one or more doses of IL-2 protein is a solution. 108 NAI-5002088184v1

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