Methods and Compositions for the Treatment of Disease

Abstract

The present disclosure provides methods of treating diseases such as neurodegenerative and neuroinflammatory diseases, e.g., Alzheimer's disease, comprising administering to a subject a CTLA-4 containing protein, e.g., abatacept, and an IL-2 protein, e.g., aldesleukin, either separately or in a single formulation. Also provided herein are pharmaceutical compositions comprising a CTLA-4 containing protein, e.g., abatacept, and an IL-2 protein, e.g., aldesleukin.

Description

[Technical field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of U.S. Provisional Application No. 63 / 159,919, filed March 11, 2021, U.S. Provisional Application No. 63 / 225,846, filed July 26, 2021, and U.S. Provisional Application No. 63 / 310,839, filed February 16, 2022, each of which is incorporated by reference in its entirety herein.

[0002] (Reference to electronically submitted sequence listing) This application incorporates by reference the Sequence Listing submitted herewith as a text file entitled "14678-014-228_SEQ_LISTING.txt", created on March 9, 2022, and having a size of 12,142 bytes.

[0003] (1. Field) The present disclosure provides methods of treating diseases such as neurodegenerative and neuroinflammatory diseases, e.g., Alzheimer's disease, comprising administering to a subject a CTLA-4 containing protein, e.g., abatacept, and an IL-2 protein, e.g., aldesleukin, either separately or in a single formulation. Also provided herein are pharmaceutical compositions comprising a CTLA-4 containing protein, e.g., abatacept, and an IL-2 protein, e.g., aldesleukin. [Background technology]

[0004] (2.Background) Inflammation and neuroinflammatory mechanisms contribute to a wide variety of devastating diseases, including neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease, and Parkinson's disease, which impose a huge health and economic burden that will only worsen over time.

[0005] Currently, no disease-modifying therapeutics are available for such diseases. Anti-inflammatory therapeutics have been available for decades in an attempt to ameliorate a number of neurodegenerative diseases. However, little progress has been made with single drug / target approaches.

[0006] Increasing studies point to the involvement of the immune system in the pathogenesis of such diseases and to dysfunction of immune cells as key mediators of disease pathogenesis. The complex signaling mechanisms and inherent redundancy of the immune system and its components may help explain the inefficiency of such single drug / single target anti-inflammatory approaches.

[0007] Recently, the use of regulatory T cell (Treg) cell therapy has demonstrated great promise and may represent a more global approach to suppress immune system dysfunction that contributes to the disease. For example, clinical trials involving the administration of expanded autologous Tregs to ALS patients have reported that Treg therapy slows the progression rate at early and late stages of the disease, and that Treg suppressive function correlates with delayed disease progression (Thonhoff, JR et al., 2018, Neurology-Neuroimmunology Neuroinflammation 5(4)).

[0008] Nonetheless, there remains a need for the development of additional therapeutic agents that can suppress inflammation and / or promote anti-inflammatory immune system components. Summary of the Invention Effect of the Invention

[0009] (3. Overview) In one aspect, there is provided a method of treating a neurodegenerative or neuroinflammatory disease or disorder in a subject in need thereof, comprising administering to the subject: i) a CTLA-4 containing protein; and ii) IL-2 protein; Provided herein is a method for alleviating one or more symptoms associated with a neurodegenerative or neuroinflammatory disease or disorder in a treated subject, comprising administering to said subject a CTLA-4 containing protein. In one embodiment, the CTLA-4 containing protein is abatacept. In one embodiment, the IL-2 protein is aldesleukin. In one embodiment, the CTLA-4 containing protein is abatacept and the IL-2 protein is aldesleukin.

[0010] In some embodiments, the CTLA-4 containing protein is administered by injection or infusion. In certain embodiments, the CTLA-4 containing protein is administered subcutaneously. In certain embodiments, the CTLA-4 containing protein is administered intravenously. In some 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. In some embodiments, the CTLA-4 containing protein and the IL-2 protein are administered by injection or infusion. In certain embodiments, the CTLA-4 containing protein and the IL-2 protein are administered subcutaneously. In certain embodiments, the CTLA-4 containing protein and the IL-2 protein are administered intravenously.

[0011] In some embodiments, the CTLA-4 containing protein comprises a human CTLA-4 extracellular domain. In certain embodiments, the CTLA-4 containing protein is a fusion protein, e.g., a fusion protein comprising a human CTLA-4 extracellular domain and a human immunoglobulin Fc domain, e.g., a modified Fc domain comprising an immunoglobulin hinge region, a CH2 region, and a CH3. In certain embodiments, the human immunoglobulin Fc domain is a human IgG1 Fc domain. In some embodiments, the CTLA-4 containing protein is glycosylated.

[0012] In one embodiment, the CTLA-4 containing protein comprises a monomer having the following amino acid sequence: [ka] In a specific embodiment, the CTLA-4 containing protein comprises a homodimer of two monomers, each monomer comprising the amino acid sequence of SEQ ID NO:1.

[0013] In a particular embodiment, the CTLA-4 containing protein is abatacept.

[0014] In one embodiment, the CTLA-4 containing protein comprises a monomer having the following amino acid sequence:

[0015] [ka] In a specific embodiment, the CTLA-4 containing protein comprises a homodimer of two monomers, each monomer comprising the amino acid sequence of SEQ ID NO:2.

[0016] In a particular embodiment, the CTLA-4 containing protein is belatacept.

[0017] 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 naturally occurring 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 lacks an N-terminal alanine amino acid and comprises a serine at the amino acid position corresponding to naturally occurring mature human IL-2 amino acid residue 125.

[0018] In one embodiment, the human IL-2 protein has the following amino acid sequence: [ka] Includes.

[0019] In a specific embodiment, the IL-2 protein is non-glycosylated, hi some embodiments, the IL-2 protein is aldesleukin.

[0020] In one embodiment, the human IL-2 protein has the following amino acid sequence: [ka] Includes.

[0021] In one aspect, there is provided a method of treating a neurodegenerative or neuroinflammatory disease or disorder in a subject in need thereof, comprising administering to the subject: i) abatacept; and ii) Aldesleukin; and alleviating one or more symptoms associated with a neurodegenerative or neuroinflammatory disease or disorder in a treated subject.

[0022] In some embodiments, abatacept is administered by injection or infusion. In certain embodiments, abatacept is administered subcutaneously. In certain embodiments, abatacept is administered intravenously. In some embodiments, aldesleukin is administered by injection or infusion. In certain embodiments, aldesleukin is administered subcutaneously. In certain embodiments, aldesleukin is administered intravenously. In some embodiments, abatacept and aldesleukin are administered by injection or infusion. In certain embodiments, abatacept and aldesleukin are administered subcutaneously. In certain embodiments, abatacept and aldesleukin are administered intravenously.

[0023] In some embodiments, the CTLA-4 containing protein, e.g., abatacept, is administered to the subject for 2 months, 3 months, 4 months, 5 months, 6 months, 1 year, 2 years, 5 years, 10 years or more.

[0024] In some embodiments, the CTLA-4 containing protein, e.g., abatacept, is administered to the subject once every two weeks. In certain embodiments, the CTLA-4 containing protein, e.g., abatacept, is administered subcutaneously to the subject once every two weeks. In some embodiments, the CTLA-4 containing protein, e.g., abatacept, is administered to the subject once every two weeks for 15 weeks, 16 weeks, 4 months, 5 months, 6 months, 1 year, 2 years, 5 years, 10 years or more. In certain embodiments, the CTLA-4 containing protein, e.g., abatacept, is administered subcutaneously to the subject once every two weeks for 15 weeks, 16 weeks, 4 months, 5 months, 6 months, 1 year, 2 years, 5 years, 10 years or more.

[0025] In some embodiments, the CTLA-4 containing protein, e.g., abatacept, is administered to the subject once every three weeks. In certain embodiments, the CTLA-4 containing protein, e.g., abatacept, is administered subcutaneously to the subject once every three weeks. In some embodiments, the CTLA-4 containing protein, e.g., abatacept, is administered to the subject once every three weeks for 15 weeks, 16 weeks, 4 months, 5 months, 6 months, 1 year, 2 years, 5 years, 10 years or more. In certain embodiments, the CTLA-4 containing protein, e.g., abatacept, is administered subcutaneously to the subject once every three weeks for 15 weeks, 16 weeks, 4 months, 5 months, 6 months, 1 year, 2 years, 5 years, 10 years or more.

[0026] In some embodiments, the CTLA-4 containing protein, e.g., abatacept, is administered to the subject once every four weeks. In certain embodiments, the CTLA-4 containing protein, e.g., abatacept, is administered subcutaneously to the subject once every four weeks. In some embodiments, the CTLA-4 containing protein, e.g., abatacept, is administered to the subject once every four weeks for 15 weeks, 16 weeks, 4 months, 5 months, 6 months, 1 year, 2 years, 5 years, 10 years or more. In certain embodiments, the CTLA-4 containing protein, e.g., abatacept, is administered subcutaneously to the subject once every four weeks for 15 weeks, 16 weeks, 4 months, 5 months, 6 months, 1 year, 2 years, 5 years, 10 years or more.

[0027] In some embodiments, the IL-2 protein, e.g., aldesleukin, is administered to a subject once per day for three consecutive days. In certain embodiments, the IL-2 protein, e.g., aldesleukin, is administered subcutaneously to a subject once per day for three consecutive days.

[0028] In one embodiment, the CTLA-4 containing protein, e.g., abatacept, is administered to the subject once every two weeks and the IL-2 protein, e.g., aldesleukin, is administered to the subject once per day for three consecutive days. In one embodiment, the CTLA-4 containing protein, e.g., abatacept, is administered subcutaneously to the subject once every two weeks and the IL-2 protein, e.g., aldesleukin, is administered subcutaneously to the subject once per day for three consecutive days.

[0029] In one embodiment, a CTLA-4 containing protein, e.g., abatacept, is administered to a subject once every two weeks and an IL-2 protein, e.g., aldesleukin, is administered to a subject once per day for three consecutive days beginning on the day that the CTLA-4 containing protein, e.g., abatacept, is administered to the subject. In one embodiment, a CTLA-4 containing protein, e.g., abatacept, is administered subcutaneously to a subject once every two weeks and an IL-2 protein, e.g., aldesleukin, is administered subcutaneously to a subject once per day for three consecutive days beginning on the day that the CTLA-4 containing protein, e.g., abatacept, is administered to a subject.

[0030] In some embodiments, the CTLA-4 containing protein, e.g., abatacept, is administered to the subject once every two weeks for 15 weeks, 16 weeks, 4 months, 5 months, 6 months, 1 year, 2 years, 5 years, 10 years or more, and the IL-2 protein is administered to the subject once a day for three consecutive days starting from the day the CTLA-4 containing protein, e.g., abatacept, is administered to the subject. In certain embodiments, the first administration of the CTLA-4 containing protein to the subject is performed without administration of the IL-2 protein. For example, in some embodiments, the administration of the IL-2 protein, e.g., aldesleukin, to the subject begins in the third week, and the IL-2 protein is administered to the subject daily for three consecutive days starting from the day the CTLA-4 containing protein, e.g., abatacept, is administered to the subject. In some embodiments, the CTLA-4 containing protein, e.g., abatacept, is administered subcutaneously to the subject once every two weeks for 15 weeks, 16 weeks, 4 months, 5 months, 6 months, 1 year, 2 years, 5 years, 10 years or more, and the IL-2 protein is administered subcutaneously to the subject once a day for three consecutive days starting from the day the CTLA-4 containing protein, e.g., abatacept, is administered. In certain embodiments, the first administration of the CTLA-4 containing protein to the subject is performed without administration of the IL-2 protein. For example, in some embodiments, the administration of the IL-2 protein, e.g., aldesleukin, to the subject begins in the third week, and the IL-2 protein is administered subcutaneously to the subject daily for three consecutive days starting from the day the CTLA-4 containing protein, e.g., abatacept, is administered to the subject.

[0031] In one embodiment, the CTLA-4 containing protein, e.g., abatacept, is administered to the subject once every three weeks and the IL-2 protein, e.g., aldesleukin, is administered to the subject once per day for three consecutive days. In one embodiment, the CTLA-4 containing protein, e.g., abatacept, is administered subcutaneously to the subject once every three weeks and the IL-2 protein, e.g., aldesleukin, is administered subcutaneously to the subject once per day for three consecutive days.

[0032] In one embodiment, a CTLA-4 containing protein, e.g., abatacept, is administered to a subject once every three weeks and an IL-2 protein, e.g., aldesleukin, is administered to a subject once per day for three consecutive days beginning on the day that the CTLA-4 containing protein, e.g., abatacept, is administered to the subject. In one embodiment, a CTLA-4 containing protein, e.g., abatacept, is administered subcutaneously to a subject once per week and an IL-2 protein, e.g., aldesleukin, is administered subcutaneously to a subject once per day for three consecutive days beginning on the day that the CTLA-4 containing protein, e.g., abatacept, is administered to a subject.

[0033] In some embodiments, a CTLA-4 containing protein, e.g., abatacept, is administered to a subject once every three weeks for 15 weeks, 16 weeks, 4 months, 5 months, 6 months, 1 year, 2 years, 5 years, 10 years or more, and an IL-2 protein is administered to the subject once a day for three consecutive days from the day the CTLA-4 containing protein, e.g., abatacept, is administered to the subject. In some embodiments, a CTLA-4 containing protein, e.g., abatacept, is administered subcutaneously to a subject once every three weeks for 15 weeks, 16 weeks, 4 months, 5 months, 6 months, 1 year, 2 years, 5 years, 10 years or more, and an IL-2 protein is administered subcutaneously to a subject once a day for three consecutive days from the day the CTLA-4 containing protein, e.g., abatacept, is administered to the subject. In certain embodiments, the initial administration of a CTLA-4 containing protein to a subject is performed without administration of an IL-2 protein.

[0034] In one embodiment, a CTLA-4 containing protein, e.g., abatacept, is administered to a subject once every three weeks and an IL-2 protein, e.g., aldesleukin, is administered to a subject once per day for three consecutive days beginning on the day that the CTLA-4 containing protein, e.g., abatacept, is administered to the subject. In one embodiment, a CTLA-4 containing protein, e.g., abatacept, is administered subcutaneously to a subject once per week and an IL-2 protein, e.g., aldesleukin, is administered subcutaneously to a subject once per day for three consecutive days beginning on the day that the CTLA-4 containing protein, e.g., abatacept, is administered to a subject.

[0035] In some embodiments, the CTLA-4 containing protein, e.g., abatacept, is administered to the subject once every four weeks for 15 weeks, 16 weeks, 4 months, 5 months, 6 months, 1 year, 2 years, 5 years, 10 years or more, and the IL-2 protein is administered to the subject once a day for three consecutive days from the day the CTLA-4 containing protein, e.g., abatacept, is administered to the subject. In some embodiments, the CTLA-4 containing protein, e.g., abatacept, is administered subcutaneously to the subject once every four weeks for 15 weeks, 16 weeks, 4 months, 5 months, 6 months, 1 year, 2 years, 5 years, 10 years or more, and the IL-2 protein is administered subcutaneously to the subject once a day for three consecutive days from the day the CTLA-4 containing protein, e.g., abatacept, is administered to the subject. In certain embodiments, the initial administration of the CTLA-4 containing protein to the subject is performed without administration of the IL-2 protein.

[0036] In some embodiments, about 5 mg to about 200 mg, about 10 mg to about 200 mg, about 15 mg to about 200 mg, about 20 mg to about 200 mg, about 25 mg to about 200 mg, about 50 mg to about 200 mg, about 50 mg to about 175 mg, about 50 mg to about 150 mg, or about 50 mg to about 125 mg of a CTLA-4-containing protein, such as abatacept, is administered to the subject. In certain embodiments, a CTLA-4-containing protein, such as abatacept, is administered subcutaneously to the subject.

[0037] In certain embodiments, about 50 mg of CTLA-4 containing protein, e.g., abatacept, is administered to the subject. In a specific embodiment, about 50 mg of CTLA-4 containing protein, e.g., abatacept, is administered to the subject in a volume of 0.4 mL. In certain embodiments, the CTLA-4 containing protein, e.g., abatacept, is administered subcutaneously to the subject.

[0038] In certain embodiments, about 87.5 mg of the CTLA-4 containing protein, e.g., abatacept, is administered to the subject. In a specific embodiment, about 87.5 mg of the CTLA-4 containing protein, e.g., abatacept, is administered to the subject in a volume of 0.7 mL. In certain embodiments, the CTLA-4 containing protein, e.g., abatacept, is administered subcutaneously to the subject.

[0039] In certain embodiments, about 125 mg of CTLA-4 containing protein, e.g., abatacept, is administered to the subject. In a specific embodiment, about 125 mg of CTLA-4 containing protein, e.g., abatacept, is administered to the subject in a volume of 1.0 mL. In certain embodiments, the CTLA-4 containing protein, e.g., abatacept, is administered subcutaneously to the subject.

[0040] In certain embodiments, about 1 x 10 4 ~ approx. 1x10 7 , about 5x10 4 ~ approx. 1x10 7 , Approx. 1x10 5 ~ approx. 1x10 7 , about 5x10 5 ~ approx. 1x10 7 , 5x10 5 ~about 5x10 6 , 5x10 5 ~about 4x10 6 , 5x10 5 ~about 3x10 6 , 5x10 5 ~about 2x10 6 , about 5x10 5 ~ approx. 1x10 6 Units of an IL-2 protein, such as aldesleukin, are administered to the subject. In certain embodiments, an IL-2 protein, such as aldesleukin, is administered subcutaneously to the subject.

[0041] In a specific embodiment, about 500,000 units to 3,000,000 units of an IL-2 protein, e.g., aldesleukin, are administered to the subject, e.g., subcutaneously to the subject. In a specific embodiment, about 500,000 units to 2,000,000 units of an IL-2 protein, e.g., aldesleukin, are administered to the subject, e.g., subcutaneously to the subject. In a specific embodiment, about 500,000 units to 1,000,000 units of an IL-2 protein, e.g., aldesleukin, are administered to the subject, e.g., subcutaneously to the subject.

[0042] In one aspect, there is provided a method of treating a neurodegenerative or neuroinflammatory disease or disorder in a subject in need thereof, comprising administering to the subject: i) a CTLA-4 containing protein; and ii) IL-2 protein; Provided herein is a method of alleviating one or more symptoms associated with a neurodegenerative or neuroinflammatory disease or disorder in a treated subject, comprising administering a formulation comprising: . The formulation is administered to the subject one or more times. In some embodiments, the formulation is administered to the subject for a period of 2 months, 3 months, 4 months, 5 months, 6 months, 1 year, 2 years, 5 years, 10 years or more. In some embodiments, the CTLA-4 containing protein is abatacept. In some embodiments, the CTLA-4 containing protein is belatacept. In some embodiments, the IL-2 protein is aldesleukin. In some embodiments, the CTLA-4 containing protein is abatacept and the IL-2 protein is aldesleukin.

[0043] In one aspect, a method of treating a neurodegenerative or neuroinflammatory disease or disorder in a subject in need thereof, comprising a dosing cycle beginning on day 1, administering to the subject: i) a CTLA-4 containing protein; and ii) IL-2 protein; Provided herein is a method of alleviating one or more symptoms associated with a neurodegenerative or neuroinflammatory disease or disorder in a treated subject, comprising administering a formulation comprising: The formulation may be administered to the subject one or more times during a dosing cycle.

[0044] The method may include one or more dosing cycles. In some embodiments, the method includes two or more dosing cycles, each dosing cycle being the same. In some embodiments, the method includes two or more dosing cycles, at least one dosing cycle being different from the others. The dosing cycle may be repeated one or more times. There may be a period between the completion of one dosing cycle and the start of the next dosing cycle.

[0045] In some embodiments, the CTLA-4 containing protein is abatacept. In some embodiments, the CTLA-4 containing protein is belatacept. In some embodiments, the IL-2 protein is aldesleukin. In some embodiments, the CTLA-4 containing protein is abatacept and the IL-2 protein is aldesleukin.

[0046] For ease of description, the formulation may be referred to herein as a "CTLA-4-containing protein / IL-2 protein formulation" or an "IL-2 protein / CTLA-4 containing protein formulation." When the CTLA-4 containing protein is abatacept and the IL-2 protein is aldesleukin, the formulation may be referred to herein as an "abatacept / aldesleukin formulation" or an "aldesleukin / abatacept formulation."

[0047] In some embodiments, the CTLA-4 containing protein / IL-2 protein formulation, e.g., abatacept / aldesleukin formulation, is administered to the subject by injection or infusion. In a specific embodiment, the CTLA-4 containing protein / IL-2 protein formulation, e.g., abatacept / aldesleukin formulation, is administered to the subject subcutaneously. In a specific embodiment, the CTLA-4 containing protein / IL-2 protein formulation, e.g., abatacept / aldesleukin formulation, is administered to the subject intravenously.

[0048] In certain embodiments of such methods, a dosing cycle comprises 1 to 10 administrations of a CTLA-4 containing protein / IL-2 protein formulation, such as an abatacept / aldesleukin formulation, to the subject.

[0049] In specific embodiments of the methods described herein, the dosing cycle comprises a single administration of a CTLA-4 containing protein / IL-2 protein formulation, e.g., an abatacept / aldesleukin formulation, to the subject on day 1 of the dosing cycle. In specific embodiments of such methods, the dosing cycle comprises administering a CTLA-4 containing protein / IL-2 protein formulation, e.g., an abatacept / aldesleukin formulation, to the subject daily for two consecutive days starting on day 1 of the dosing cycle. In specific embodiments of such methods, the dosing cycle comprises administering a CTLA-4 containing protein / IL-2 protein formulation, e.g., an abatacept / aldesleukin formulation, to the subject daily for three consecutive days starting on day 1 of the dosing cycle. In specific embodiments of such methods, the dosing cycle comprises administering a CTLA-4 containing protein / IL-2 protein formulation, e.g., an abatacept / aldesleukin formulation, to the subject daily for four consecutive days starting on day 1 of the dosing cycle. In a specific embodiment of such a method, the dosing cycle comprises administering to the subject a CTLA-4 containing protein / IL-2 protein formulation, e.g., an abatacept / aldesleukin formulation, daily for 5 consecutive days beginning on day 1 of the dosing cycle. In a specific embodiment of such a method, the dosing cycle comprises administering to the subject a CTLA-4 containing protein / IL-2 protein formulation, e.g., an abatacept / aldesleukin formulation, daily for 6 consecutive days beginning on day 1 of the dosing cycle. In a specific embodiment of such a method, the dosing cycle comprises administering to the subject a CTLA-4 containing protein / IL-2 protein formulation, e.g., an abatacept / aldesleukin formulation, daily for 7 consecutive days beginning on day 1 of the dosing cycle.

[0050] In specific embodiments of the methods described herein, a dosing cycle comprises administering a CTLA-4 containing protein / IL-2 protein formulation, e.g., an abatacept / aldesleukin formulation, to a subject daily for at least two non-consecutive days. In one non-limiting embodiment, for example, a CTLA-4 containing protein / IL-2 protein formulation, e.g., an abatacept / aldesleukin formulation, is first administered to the subject on day 1, and then administered to the subject on day 3, 4, 5, 6, or 7 of the dosing cycle.

[0051] In certain embodiments of the methods described herein, the method includes 2-13 dosing cycles. In certain embodiments of the methods described herein, the dosing cycle is repeated 1-12 times. In specific embodiments, the method includes 7 dosing cycles, e.g., the dosing cycle is repeated 6 times. In certain embodiments, each dosing cycle, e.g., each repeated dosing cycle, begins 10-28 days after day 1 of the previous dosing cycle. In certain embodiments, each dosing cycle, e.g., each repeated dosing cycle, begins 10-28 days after completion of the previous dosing cycle. In specific embodiments, each dosing cycle, e.g., each repeated dosing cycle, begins 14 days after day 1 of the previous dosing cycle. In certain embodiments, each dosing cycle, e.g., each repeated dosing cycle, begins 14 days after completion of the previous dosing cycle.

[0052] In certain embodiments of the methods described herein, a first dosing cycle comprises administering a CTLA-4 containing protein / IL-2 protein formulation, e.g., an abatacept / aldesleukin formulation, to a subject daily for three consecutive days beginning on day 1 of the dosing cycle, and the first dosing cycle is repeated six times, with each repeat dosing cycle beginning 14 days after day 1 of the previous dosing cycle.

[0053] In certain embodiments of the methods described herein, a dosing cycle comprises about 5 mg to about 125 mg of a CTLA-4-containing protein and about 3x10 4 ~about 3x10 7In one embodiment of the methods described herein, a dosing cycle comprises administering to a subject a CTLA-4-containing protein / IL-2 protein formulation comprising about 5 mg to about 125 mg of abatacept and about 3x10 units of IL-2 protein. 4 ~about 3x10 7 The method includes administering to the subject an abatacept / aldesleukin formulation containing units of aldesleukin.

[0054] In certain embodiments of the methods described herein, a dosing cycle comprises about 8.75 mg to about 87.5 mg of abatacept and about 3x10 4 ~about 3x10 7 The method includes administering to the subject a formulation containing a unit of aldesleukin.

[0055] In certain embodiments of the methods described herein, a dosing cycle comprises about 29.17 mg of abatacept and about 1x10 5 In some embodiments of the methods described herein, a dosing cycle includes administering to a subject a formulation containing about 29.17 mg of abatacept and about 1x10 units of aldesleukin. 6 In some embodiments of the methods described herein, a dosing cycle includes administering to a subject a formulation containing about 29.17 mg of abatacept and about 1x10 units of aldesleukin. 7 The method includes administering to the subject a formulation containing a unit of aldesleukin.

[0056] In certain embodiments of the methods described herein, a dosing cycle comprises about 5 mg to about 50 mg of abatacept and about 3x10 4 ~about 3x10 7 The method includes administering to the subject a formulation containing a unit of aldesleukin.

[0057] In certain embodiments of the methods described herein, a dosing cycle comprises about 16.67 mg of abatacept and about 1x10 5 In some embodiments of the methods described herein, a dosing cycle includes administering to a subject a formulation containing about 16.67 mg of abatacept and about 1x10 units of aldesleukin.6 In some embodiments of the methods described herein, a dosing cycle includes administering to a subject a formulation containing about 16.67 mg of abatacept and about 1x10 units of aldesleukin. 7 The method includes administering to the subject a formulation containing a unit of aldesleukin.

[0058] In certain embodiments of the methods described herein, a dosing cycle comprises about 12.5 mg to about 125 mg of abatacept and about 3x10 4 ~about 3x10 7 The method includes administering to the subject a formulation containing a unit of aldesleukin.

[0059] In one embodiment of the methods described herein, a dosing cycle comprises about 41.67 mg of abatacept and about 1x10 5 In some embodiments of the methods described herein, a dosing cycle comprises administering to a subject a formulation containing about 41.67 mg of abatacept and about 1x10 units of aldesleukin. 6 In some embodiments of the methods described herein, a dosing cycle comprises administering to a subject a formulation containing about 41.67 mg of abatacept and about 1x10 units of aldesleukin. 7 The method includes administering to the subject a formulation containing a unit of aldesleukin.

[0060] In certain embodiments of the methods described herein, a dosing cycle comprises administering to a subject the formulation daily for three consecutive days beginning on day 1 of the dosing cycle, the formulation comprising about 29.17 mg of abatacept and about 1x10 6 In a specific embodiment, the dosing cycle is repeated six times, with each repeated dosing cycle beginning 14 days after day 1 of the previous dosing cycle.

[0061] In certain embodiments of the methods described herein, the dosing cycle continues for a period of 2 months, 3 months, 4 months, 5 months, 6 months, 1 year, 2 years, 5 years, 10 years or more, e.g., the dosing cycle is repeated for a period of 2 months, 3 months, 4 months, 5 months, 6 months, 1 year, 2 years, 5 years, 10 years or more.

[0062] In certain embodiments, the methods described herein further comprise administering a CTLA-4 containing protein formulation, e.g., an abatacept formulation, to the subject prior to the first administration of a CTLA-4 containing / IL-2 protein formulation, e.g., an abatacept / aldesleukin formulation, to the subject. In certain embodiments, the methods described herein further comprise administering a CTLA-4 containing protein formulation, e.g., an abatacept formulation, to the subject 14 days prior to day 1 of the first dosing cycle, i.e., 14 days prior to the first administration of a CTLA-4 containing / IL-2 protein formulation, e.g., an abatacept / aldesleukin formulation, to the subject.

[0063] In a specific embodiment, the CTLA-4-containing protein formulation contains 50 mg to 125 mg of CTLA-4-containing protein, for example, 50 mg of CTLA-4-containing protein, 87.5 mg of CTLA-4-containing protein, or 125 mg of CTLA-4-containing protein. In a specific embodiment, the abatacept formulation contains 50 mg to 125 mg of abatacept, for example, 50 mg of abatacept, 87.5 mg of abatacept, or 125 mg of abatacept. In an embodiment, the CTLA-4-containing protein formulation, for example, the abatacept formulation, is administered to the subject by injection or infusion. In an embodiment, the CTLA-4-containing protein formulation, for example, the abatacept formulation, is administered to the subject subcutaneously or intravenously.

[0064] In certain embodiments of the methods described herein, the neurodegenerative disease or disorder is amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, multiple sclerosis, frontotemporal dementia, or Huntington's disease. In certain embodiments of the methods described herein, the neurodegenerative disease or disorder is Alzheimer's disease.

[0065] In certain embodiments of the methods described herein, 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.

[0066] In some embodiments of the methods described herein, the method further comprises administering an additional therapeutic intervention, where the additional therapeutic intervention comprises a cognitive rehabilitation program, a neurostimulation technique, or a combination thereof. In some embodiments, the cognitive rehabilitation program is a computer-implemented cognitive rehabilitation program. In some embodiments, the neurostimulation technique is an invasive brain stimulation (IBS) technique. In some embodiments, the neurostimulation technique is a non-invasive brain stimulation (NIBS) technique. In some embodiments, the IBS technique is selected from the group consisting of deep brain stimulation (DBS) and invasive vagus nerve stimulation (VNS). In some 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 therapy (ECT), magnetic seizure therapy (MST), cranial electrical stimulation therapy (CES), and non-invasive VNS.

[0067] In one embodiment, a kit is provided herein that includes, in separate containers, i) one or more doses of a formulation comprising 50-125 mg of abatacept, and ii) one or more doses of a formulation comprising 500,000-3,000,000 units of aldesleukin. In some embodiments, the kit includes one or more doses of a formulation comprising 50 mg of abatacept, 87.5 mg of abatacept, or 125 mg of abatacept. In specific embodiments, the one or more doses of abatacept are present in lyophilized form, e.g., as a lyophilized powder or lyophilized cake. In some embodiments, the one or more doses of abatacept formulation are suitable for subcutaneous or intravenous administration. In some embodiments, the kit includes one or more doses of a formulation comprising 500,000-2,000,000 units of aldesleukin, or 1,000,000 units of aldesleukin. In a specific embodiment, the one or more doses of aldesleukin are present in lyophilized form, for example, as a lyophilized powder or lyophilized cake. In some embodiments, the formulation of the one or more doses of aldesleukin is suitable for subcutaneous or intravenous administration.

[0068] In one aspect, provided herein is a pharmaceutical composition comprising a CTLA-4 containing protein and one or more doses of an IL-2 protein (a "CTLA-4 containing protein / IL-2 protein dose"). In certain embodiments, provided herein is a pharmaceutical composition comprising abatacept and one or more doses of aldesleukin (an "abatacept / aldesleukin dose").

[0069] In one embodiment, a pharmaceutical composition comprising one or more abatacept / aldesleukin doses is provided herein, the abatacept / aldesleukin dose being between 5 mg and 125 mg of abatacept and 3x10 4 ~3x10 7 Contains units of aldesleukin.

[0070] In certain embodiments, pharmaceutical compositions comprising one or more abatacept / aldesleukin doses are provided herein, the abatacept / aldesleukin dose being 8.75-87.5 mg of abatacept and 3x10 4~3x10 7 In a specific embodiment, a pharmaceutical composition is provided herein that includes one or more abatacept / aldesleukin doses, the abatacept / aldesleukin doses being 29.17 mg abatacept and 1x10 5 Units of Aldesleukin, 1x10 6 Units of Aldesleukin or 1x10 7 In a specific embodiment, a pharmaceutical composition is provided herein that includes one or more abatacept / aldesleukin doses, the abatacept / aldesleukin doses being 29.17 mg abatacept and 1x10 6 Contains units of aldesleukin.

[0071] In certain embodiments, pharmaceutical compositions comprising one or more abatacept / aldesleukin doses are provided herein, the abatacept / aldesleukin doses being between 5 mg and 50 mg of abatacept and 3x10 4 ~3x10 7 In a specific embodiment, a pharmaceutical composition is provided herein that includes one or more abatacept / aldesleukin doses, the abatacept / aldesleukin doses being 16.67 mg abatacept and 1x10 5 Units of Aldesleukin, 1x10 6 Units of Aldesleukin or 1x10 7 In a specific embodiment, a pharmaceutical composition is provided herein that includes one or more abatacept / aldesleukin doses, the abatacept / aldesleukin doses being 16.67 mg abatacept and 1x10 6 Contains units of aldesleukin.

[0072] In certain embodiments, pharmaceutical compositions comprising one or more abatacept / aldesleukin doses are provided herein, the abatacept / aldesleukin doses being 12.5 mg to 125 mg of abatacept and 3x10 4 ~3x10 7In a specific embodiment, a pharmaceutical composition is provided herein that includes one or more abatacept / aldesleukin doses, the abatacept / aldesleukin doses being 41.67 mg abatacept and 1x10 5 Units of Aldesleukin, 1x10 6 Units of Aldesleukin or 1x10 7 In a specific embodiment, a pharmaceutical composition is provided herein that includes one or more abatacept / aldesleukin doses, the abatacept / aldesleukin doses being 41.67 mg abatacept and 1x10 6 Contains units of aldesleukin.

[0073] In certain embodiments, pharmaceutical compositions comprising one or more abatacept / aldesleukin doses as shown in Table 4 are presented herein.

[0074] In certain embodiments, a pharmaceutical composition comprising one or more abatacept / aldesleukin doses described herein is in lyophilized form, for example, as a lyophilized powder or lyophilized cake.

[0075] In certain embodiments, the pharmaceutical composition comprising one or more abatacept / aldesleukin doses described herein is a solution, e.g., an aqueous solution. In specific embodiments, the one or more abatacept / aldesleukin doses are present in the pharmaceutical composition in a concentration of 1 abatacept / aldesleukin dose / 0.4 ml, 1 abatacept / aldesleukin dose / 0.7 ml, 1 abatacept / aldesleukin dose / 1.0 ml, 1 abatacept / aldesleukin dose / 1.5 ml, or 1 abatacept / aldesleukin dose / 2.0 ml.

[0076] In some embodiments, pharmaceutical compositions comprising one or more abatacept / aldesleukin doses described herein are suitable for subcutaneous administration. In some embodiments, pharmaceutical compositions comprising one or more abatacept / aldesleukin doses described herein are suitable for intravenous administration.

[0077] Further exemplary embodiments are as follows:

[0078] 1. A method of treating a neurodegenerative or neuroinflammatory disease or disorder in a subject in need thereof, comprising administering to the subject: i) a CTLA-4 containing protein; and ii) IL-2 protein; wherein said method comprises administering to said subject a therapeutically effective amount of a compound selected from the group consisting of ribozymes, cyclosporine, tetracycline, cyclospor ...

[0079] 2. The method of embodiment 1, wherein said CTLA-4-containing protein comprises the human CTLA-4 extracellular domain.

[0080] 3. The method of embodiment 1 or 2, wherein the CTLA-4 containing protein is a fusion protein.

[0081] 4. The method of embodiment 3, wherein the fusion protein comprises a human CTLA-4 extracellular domain and a human immunoglobulin Fc domain.

[0082] 5. The method of embodiment 4, wherein the Fc domain is a modified Fc domain comprising an immunoglobulin hinge region, a CH2 region and a CH3 region.

[0083] 6. The method of embodiment 4 or 5, wherein the human immunoglobulin Fc domain is a human IgG1 Fc domain.

[0084] 7. The method of any one of embodiments 1 to 6, wherein the CTLA-4 containing protein is glycosylated.

[0085] 8. The CTLA-4 containing protein comprises a monomer having the following amino acid sequence:

[0086] [ka] The method of any one of embodiments 1 to 7, comprising:

[0087] 9. The method of embodiment 8, wherein the CTLA-4 containing protein comprises a homodimer of two monomers, each of which comprises the amino acid sequence of SEQ ID NO:1.

[0088] 10. The method of embodiment 1, wherein said CTLA-4 containing protein is abatacept.

[0089] 11. The method according to any one of embodiments 1 to 10, wherein said IL-2 protein is a human IL-2 protein.

[0090] 12. The method of embodiment 11, wherein said human IL-2 protein comprises a serine at the amino acid position corresponding to native mature human IL-2 amino acid residue 125.

[0091] 13. The method of embodiment 11 or 12, wherein said human IL-2 protein lacks an N-terminal alanine amino acid.

[0092] 14. The human IL-2 protein has the following amino acid sequence:

[0093] [ka] The method of any one of embodiments 11 to 13, comprising:

[0094] 15. The method of any one of embodiments 1-14, wherein the IL-2 protein is not glycosylated.

[0095] 16. The method of embodiment 11, wherein said IL-2 protein is aldesleukin.

[0096] 17. A method for treating a neurodegenerative or neuroinflammatory disease or disorder in a subject in need thereof, comprising administering to the subject i) abatacept; and ii) Aldesleukin wherein said method comprises administering to said subject a therapeutically effective amount of a compound selected from the group consisting of ribozymes, cyclosporine, tetracycline, cyclospor ...

[0097] 18. The method of embodiment 17, wherein abatacept is administered by injection or infusion.

[0098] 19. The method of embodiment 18, wherein abatacept is administered subcutaneously.

[0099] 20. The method of embodiment 18, wherein abatacept is administered intravenously.

[0100] 21. The method of embodiment 17, wherein aldesleukin is administered by injection or infusion.

[0101] 22. The method of embodiment 21, wherein aldesleukin is administered subcutaneously.

[0102] 23. The method of embodiment 21, wherein aldesleukin is administered intravenously.

[0103] 24. The method of embodiment 17, wherein abatacept and aldesleukin are administered subcutaneously.

[0104] 25. The method of embodiment 17, wherein abatacept and aldesleukin are administered intravenously.

[0105] 26. The method of any one of embodiments 17-25, wherein abatacept is administered once every two weeks.

[0106] 27. The method of embodiment 26, wherein abatacept is administered subcutaneously once every two weeks.

[0107] 28. The method of embodiment 26 or 27, wherein abatacept is administered once every two weeks for 15 weeks.

[0108] 29. The method of any one of embodiments 17-28, wherein aldesleukin is administered once a day for three consecutive days.

[0109] 30. The method of embodiment 29, wherein aldesleukin is administered subcutaneously once daily for three consecutive days.

[0110] 31.a) abatacept is administered once every 2 weeks; and b) aldesleukin is administered once daily for 3 consecutive days starting from the day abatacept is administered; A method according to any one of embodiments 17 to 25.

[0111] 32. The method of embodiment 31, wherein abatacept and aldesleukin are administered subcutaneously.

[0112] 33.a) Abatacept was administered once every 2 weeks for 15 weeks; b) aldesleukin administration begins in week 3; and c) Once aldesleukin is initiated, it will be administered once daily for 3 consecutive days beginning on the day abatacept is administered. A method according to any one of embodiments 17 to 25.

[0113] 34. The method of embodiment 33, wherein abatacept and aldesleukin are administered subcutaneously.

[0114] 35. The method of any one of embodiments 17-34, wherein abatacept is administered in an amount ranging from 50 mg to 125 mg.

[0115] 36. The method of embodiment 35, wherein abatacept is administered in an amount of 50 mg.

[0116] 37. The method of embodiment 36, wherein abatacept is administered subcutaneously in a volume of 0.4 mL.

[0117] 38. The method of embodiment 35, wherein abatacept is administered in an amount of 87.5 mg.

[0118] 39. The method of embodiment 38, wherein abatacept is administered subcutaneously in a volume of 0.7 mL.

[0119] 40. The method of embodiment 35, wherein abatacept is administered in an amount of 125 mg.

[0120] 41. The method of embodiment 40, wherein abatacept is administered subcutaneously in a volume of 1.0 mL.

[0121] 42. The method of any one of embodiments 17-41, wherein aldesleukin is administered in an amount ranging from 500,000 units to 3,000,000 units.

[0122] 43. The method of embodiment 42, wherein aldesleukin is administered in an amount ranging from 500,000 units to 2,000,000 units.

[0123] 44. The method of embodiment 43, wherein aldesleukin is administered in an amount of 1,000,000 units.

[0124] 45. The method of any one of embodiments 42-44, wherein aldesleukin is administered subcutaneously.

[0125] 46. ​​A method of treating a neurodegenerative or neuroinflammatory disease or disorder in a subject in need thereof, comprising a dosing cycle beginning on day 1, i) abatacept; and ii) Aldesleukin wherein the method comprises administering to a subject a formulation comprising:

[0126] 47. The method of embodiment 46, wherein the formulation is administered by injection or infusion.

[0127] 48. The method of embodiment 46, wherein the formulation is administered subcutaneously.

[0128] 49. The method of embodiment 46, wherein the formulation is administered intravenously.

[0129] 50. The method of any one of embodiments 46-49, wherein the dosing cycle comprises administering the formulation to the subject 1 to 10 times.

[0130] 51. The method of any one of embodiments 46-49, wherein the dosing cycle comprises a single administration of the formulation to the subject on day 1 of the dosing cycle.

[0131] 52. The method of any one of embodiments 46-49, wherein the dosing cycle comprises administering the formulation to the subject daily for two consecutive days, beginning on day 1 of the dosing cycle.

[0132] 53. The method of any one of embodiments 46-49, wherein the dosing cycle comprises administering the formulation to the subject daily for three consecutive days, beginning on day 1 of the dosing cycle.

[0133] 54. The method of any one of embodiments 46-49, wherein the dosing cycle comprises administering the formulation to the subject daily for 4 consecutive days, beginning on day 1 of the dosing cycle.

[0134] 55. The method of any one of embodiments 46-49, wherein the dosing cycle comprises administering the formulation to the subject daily for 5 consecutive days beginning on day 1 of the dosing cycle.

[0135] 56. The method of any one of embodiments 46-55, wherein the dosing cycle is repeated 1 to 12 times.

[0136] 57. The method of any one of embodiments 46-55, wherein the dosing cycle is repeated six times.

[0137] 58. The method of embodiment 56 or 57, wherein each repeat dosing cycle begins 10 to 28 days after day 1 of the previous dosing cycle.

[0138] 59. The method of any one of embodiments 56-58, wherein each repeat dosing cycle begins 14 days after day 1 of the previous dosing cycle.

[0139] 60. The method of any one of embodiments 46-49, wherein a first dosing cycle comprises administering the formulation to the subject daily for three consecutive days beginning on day 1 of the dosing cycle, and wherein the first dosing cycle is repeated six times, with each repeated dosing cycle beginning 14 days after day 1 of the previous dosing cycle.

[0140] 61. The dosing cycle comprises about 5 mg to about 125 mg of abatacept and about 3x10 4 ~about 3x10 7 The method of any one of embodiments 46 to 49, comprising administering to a subject a formulation comprising a unit of aldesleukin.

[0141] 62. The dosing cycle comprises about 8.75 mg to about 87.5 mg of abatacept and about 3x10 4 ~about 3x10 7 The method of any one of embodiments 46 to 49, comprising administering to a subject a formulation comprising a unit of aldesleukin.

[0142] 63. The dosing cycle comprises about 29.17 mg of abatacept and about 1x10 5 The method of any one of embodiments 46 to 49, comprising administering to a subject a formulation comprising a unit of aldesleukin.

[0143] 64. The dosing cycle comprises about 29.17 mg of abatacept and about 1x10 6 The method of any one of embodiments 46 to 49, comprising administering to a subject a formulation comprising a unit of aldesleukin.

[0144] 65. The dosing cycle comprises about 29.17 mg of abatacept and about 1x10 7 The method of any one of embodiments 46 to 49, comprising administering to a subject a formulation comprising a unit of aldesleukin.

[0145] 66. The dosing cycle comprises about 5 mg to about 50 mg of abatacept and about 3x10 4 ~about 3x10 7 The method of any one of embodiments 46 to 49, comprising administering to a subject a formulation comprising a unit of aldesleukin.

[0146] 67. The dosing cycle comprises about 16.67 mg of abatacept and about 1x10 5 The method of any one of embodiments 46 to 49, comprising administering to a subject a formulation comprising a unit of aldesleukin.

[0147] 68. The dosing cycle comprises about 16.67 mg of abatacept and about 1x10 6 The method of any one of embodiments 46 to 49, comprising administering to a subject a formulation comprising a unit of aldesleukin.

[0148] 69. The dosing cycle comprises about 16.67 mg of abatacept and about 1x10 7 The method of any one of embodiments 46 to 49, comprising administering to a subject a formulation comprising a unit of aldesleukin.

[0149] 70. The dosing cycle comprises about 12.5 mg to about 125 mg of abatacept and about 3x10 4 ~about 3x10 7 The method of any one of embodiments 46 to 49, comprising administering to a subject a formulation comprising a unit of aldesleukin.

[0150] 71. The dosing cycle comprises about 41.67 mg of abatacept and about 1x10 5 The method of any one of embodiments 46 to 49, comprising administering to a subject a formulation comprising a unit of aldesleukin.

[0151] 72. The dosing cycle comprises about 41.67 mg of abatacept and about 1x10 6 The method of any one of embodiments 46 to 49, comprising administering to a subject a formulation comprising a unit of aldesleukin.

[0152] 73. The dosing cycle comprises about 41.67 mg of abatacept and about 1x10 7 The method of any one of embodiments 46 to 49, comprising administering to a subject a formulation comprising a unit of aldesleukin.

[0153] 74. The dosing cycle comprises administering the formulation to the subject daily for three consecutive days beginning on day 1 of the dosing cycle, the formulation comprising about 29.17 mg of abatacept and about 1x10 6 The method of any one of embodiments 46 to 49, comprising administering to said patient a dose of 100 mg of aldesleukin.

[0154] 75. The method of embodiment 74, wherein the dosing cycle is repeated six times, with each repeated dosing cycle beginning 14 days after day 1 of the previous dosing cycle.

[0155] 76. The method of embodiment 75, wherein the dosing cycle comprises 1 to 10 administrations of an abatacept / aldesleukin formulation as shown in Table 1A.

[0156] 77. Abatacept 50mg total per dosing cycle and 3x10 6 The method of any one of embodiments 46 to 49, wherein units of aldesleukin are administered to the subject.

[0157] 78. The method of embodiment 77, wherein the dosing cycle comprises 1 to 10 administrations of an abatacept / aldesleukin formulation as shown in Table 1B.

[0158] 79. Abatacept 50mg total per dosing cycle and 3x10 7 The method of any one of embodiments 46 to 49, wherein units of aldesleukin are administered to the subject.

[0159] 80. The method of embodiment 79, wherein the dosing cycle comprises 1 to 10 administrations of an abatacept / aldesleukin formulation as set forth in Table 1C.

[0160] 81. Abatacept 3x10 with a total of 87.5mg per dosing cycle 5 The method of any one of embodiments 46 to 49, wherein units of aldesleukin are administered to the subject.

[0161] 82. The method of embodiment 81, wherein the dosing cycle comprises 1 to 10 administrations of an abatacept / aldesleukin formulation as shown in Table 2A.

[0162] 83. Abatacept 3x10 with a total of 87.5mg per dosing cycle 6 The method of any one of embodiments 46 to 49, wherein units of aldesleukin are administered to the subject.

[0163] 84. The method of embodiment 83, wherein the dosing cycle comprises 1 to 10 administrations of an abatacept / aldesleukin formulation as shown in Table 2B.

[0164] 85. Abatacept 3x10 with a total of 87.5mg per dosing cycle 7 The method of any one of embodiments 46 to 49, wherein units of aldesleukin are administered to the subject.

[0165] 86. The method of embodiment 85, wherein the dosing cycle comprises 1 to 10 administrations of an abatacept / aldesleukin formulation as shown in Table 2C.

[0166] 87. Abatacept 125mg total per dosing cycle and 3x10 5 The method of any one of embodiments 46 to 49, wherein units of aldesleukin are administered to the subject.

[0167] 88. The method of embodiment 87, wherein the dosing cycle comprises 1 to 10 administrations of an abatacept / aldesleukin formulation as shown in Table 3A.

[0168] 89. Abatacept 125mg total per dosing cycle and 3x10 6The method of any one of embodiments 46 to 49, wherein units of aldesleukin are administered to the subject.

[0169] 90. The method of embodiment 89, wherein the dosing cycle comprises 1 to 10 administrations of an abatacept / aldesleukin formulation as shown in Table 3B.

[0170] 91. Abatacept 125mg total per dosing cycle and 3x10 7 The method of any one of embodiments 46 to 49, wherein units of aldesleukin are administered to the subject.

[0171] 92. The method of embodiment 91, wherein the dosing cycle comprises 1 to 10 administrations of an abatacept / aldesleukin formulation as shown in Table 3C.

[0172] 93. The method of any one of embodiments 46-92, wherein the dosing cycle is repeated six times, with each repeated dosing cycle beginning 14 days after day 1 of the previous dosing cycle.

[0173] 94. The method of any one of embodiments 46-92, wherein the formulation is administered by injection or infusion.

[0174] 95. The method of any one of embodiments 46-92, wherein the formulation is administered subcutaneously.

[0175] 96. The method of any one of embodiments 46-92, wherein the formulation is administered intravenously.

[0176] 97. The method of any one of embodiments 46-96, further comprising administering to the subject an abatacept formulation 14 days prior to day 1 of the first dosing cycle, wherein the abatacept formulation comprises abatacept.

[0177] 98. The method of embodiment 97, wherein the abatacept formulation contains 50 mg to 125 mg of abatacept.

[0178] 99. The method of embodiment 97, wherein the abatacept formulation contains 87.5 mg of abatacept.

[0179] 100. The method of any one of embodiments 97-99, wherein the abatacept formulation is administered by injection or infusion.

[0180] 101. The method of any one of embodiments 97-99, wherein the abatacept formulation is administered subcutaneously.

[0181] 102. The method of any one of embodiments 97-99, wherein the abatacept formulation is administered intravenously.

[0182] 103. The method of any one of embodiments 97-99, wherein the neurodegenerative disease or disorder is amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, multiple sclerosis, frontotemporal dementia or Huntington's disease.

[0183] 104. The method of embodiment 103, wherein the neurodegenerative disease or disorder is Alzheimer's disease.

[0184] 105. The method of any one of embodiments 1-104, 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.

[0185] 106. The method of any one of embodiments 1 to 105, wherein the method further comprises implementing a cognitive rehabilitation program, a neurostimulation technique, or a combination thereof.

[0186] 107. The method of embodiment 106, wherein the cognitive rehabilitation program is a computer-implemented cognitive rehabilitation program.

[0187] 108. The method of embodiment 105 or 106, wherein the neurostimulation technique is an invasive brain stimulation (IBS) technique.

[0188] 109. The method of embodiment 105 or 106, wherein the neurostimulation technique is a non-invasive brain stimulation (NIBS) technique.

[0189] 110. The method of embodiment 108, wherein the IBS technique is selected from the group consisting of deep brain stimulation (DBS) and invasive vagus nerve stimulation (VNS).

[0190] 111. The method of embodiment 109, 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 therapy (ECT), magnetic seizure therapy (MST), cranial electrical stimulation therapy (CES), and non-invasive VNS.

[0191] 112. A kit comprising, in separate containers, i) one or more doses of a formulation containing 50 to 125 mg of abatacept, and ii) one or more doses of a formulation containing 500,000 to 3,000,000 units of aldesleukin.

[0192] 113. The kit according to embodiment 112, wherein the kit comprises one or more doses of a formulation containing 50 mg of abatacept.

[0193] 114. The kit of embodiment 112, wherein the kit comprises one or more doses of a formulation containing 87.5 mg of abatacept.

[0194] 115. The kit according to embodiment 112, wherein the kit comprises one or more doses of a formulation containing 125 mg of abatacept.

[0195] 116. The kit according to any one of embodiments 112-115, wherein the kit comprises one or more doses of a formulation of aldesleukin at 500,000 to 2,000,000 units.

[0196] 117. The kit according to any one of embodiments 112-116, wherein the kit comprises one or more doses of a formulation of 1,000,000 units of aldesleukin.

[0197] 118. The kit according to any one of embodiments 112-117, wherein one or more doses of abatacept are present in lyophilized form.

[0198] 119. The kit of embodiment 118, wherein the one or more doses of abatacept are present as a lyophilized powder or lyophilized cake.

[0199] 120. The kit according to any one of embodiments 112-119, wherein one or more doses of aldesleukin are present in lyophilized form.

[0200] 121. The kit of embodiment 120, wherein one or more doses of aldesleukin are present as a lyophilized powder or lyophilized cake.

[0201] 122. The kit according to any one of embodiments 112-121, wherein the formulation of one or more doses of abatacept is suitable for subcutaneous administration.

[0202] 123. The kit according to any one of embodiments 112-121, wherein the formulation of one or more doses of abatacept is suitable for intravenous administration.

[0203] 124. The kit of any one of embodiments 112-123, wherein the formulation of one or more doses of aldesleukin is suitable for subcutaneous administration.

[0204] 125. The kit according to any one of embodiments 112-123, wherein the formulation of one or more doses of aldesleukin is suitable for intravenous administration.

[0205] A pharmaceutical composition comprising an abatacept / aldesleukin dose of 126.1 or greater.

[0206] 127. Abatacept / Aldesleukin Doses of 5mg to 125mg of abatacept and 3x10 4 ~3x10 7 127. The pharmaceutical composition of embodiment 126, comprising units of aldesleukin.

[0207] 128. Abatacept / aldesleukin: The dose is about 8.75 to about 87.5 mg of abatacept and about 3x10 4 ~about 3x10 7 127. The pharmaceutical composition of embodiment 126, comprising units of aldesleukin.

[0208] 129. The abatacept / aldesleukin dose is approximately 29.17 mg of abatacept and approximately 1x10 5 127. The pharmaceutical composition of embodiment 126, comprising units of aldesleukin.

[0209] 130. Abatacept / aldesleukin dose is approximately 29.17 mg of abatacept and approximately 1x10 6 127. The pharmaceutical composition of embodiment 126, comprising units of aldesleukin.

[0210] 131. The abatacept / aldesleukin dose is approximately 29.17 mg of abatacept and approximately 1x10 7 127. The pharmaceutical composition of embodiment 126, comprising units of aldesleukin.

[0211] 132. Abatacept / Aldesleukin: The dose is about 5 mg to about 50 mg of abatacept and about 3x10 4 ~about 3x10 7 127. The pharmaceutical composition of embodiment 126, comprising units of aldesleukin.

[0212] 133. The abatacept / aldesleukin dose is approximately 16.67 mg of abatacept and approximately 1 x 10 5 127. The pharmaceutical composition of embodiment 126, comprising units of aldesleukin.

[0213] 134. The abatacept / aldesleukin dose is approximately 16.67 mg of abatacept and approximately 1x10 6 127. The pharmaceutical composition of embodiment 126, comprising units of aldesleukin.

[0214] 135. The abatacept / aldesleukin dose is approximately 16.67 mg of abatacept and approximately 1 x 10 7 127. The pharmaceutical composition of embodiment 126, comprising units of aldesleukin.

[0215] 136. Abatacept / aldesleukin: The dose is about 12.5 mg to about 125 mg of abatacept and about 3x10 4 ~about 3x10 7 127. The pharmaceutical composition of embodiment 126, comprising units of aldesleukin.

[0216] 137. The abatacept / aldesleukin dose is approximately 41.67 mg of abatacept and approximately 1x10 5 127. The pharmaceutical composition of embodiment 126, comprising units of aldesleukin.

[0217] 138. The abatacept / aldesleukin dose is approximately 41.67 mg of abatacept and approximately 1x10 6 127. The pharmaceutical composition of embodiment 126, comprising units of aldesleukin.

[0218] 139. The abatacept / aldesleukin dose is approximately 41.67 mg of abatacept and approximately 1x10 7 127. The pharmaceutical composition of embodiment 126, comprising units of aldesleukin.

[0219] 140. The pharmaceutical composition according to embodiment 126, wherein the pharmaceutical composition comprises one or more abatacept / aldesleukin doses as shown in Table 4.

[0220] 141. The pharmaceutical composition according to any one of embodiments 126 to 140, wherein the pharmaceutical composition is in lyophilized form.

[0221] 142. The pharmaceutical composition according to embodiment 141, wherein the pharmaceutical composition is present as a lyophilized powder or a lyophilized cake.

[0222] 143. The pharmaceutical composition according to any one of embodiments 126-140, wherein the pharmaceutical composition is a solution.

[0223] 144. The pharmaceutical composition according to embodiment 143, wherein the pharmaceutical composition is in the form of an aqueous solution.

[0224] 145. The pharmaceutical composition of embodiment 143 or 144, wherein the 1 or more abatacept / aldesleukin doses are present in a concentration of 1 abatacept / aldesleukin dose / 0.4 ml.

[0225] 145. The pharmaceutical composition of embodiment 143 or 144, wherein 146.1 or more abatacept / aldesleukin doses are present in a concentration of 1 abatacept / aldesleukin dose / 0.7 ml.

[0226] 145. The pharmaceutical composition of embodiment 143 or 144, wherein the 147.1 or more abatacept / aldesleukin doses are present in a concentration of 1 abatacept / aldesleukin dose / 1.0 ml.

[0227] 145. The pharmaceutical composition of embodiment 143 or 144, wherein 148.1 or more abatacept / aldesleukin doses are present in a concentration of 1 abatacept / aldesleukin dose / 1.5 ml.

[0228] 145. The pharmaceutical composition of embodiment 143 or 144, wherein the 149.1 or more abatacept / aldesleukin doses are present in a concentration of 1 abatacept / aldesleukin dose / 2.0 ml.

[0229] 150. The pharmaceutical composition according to any one of embodiments 126 to 149, wherein the pharmaceutical composition is suitable for subcutaneous administration.

[0230] 151. The pharmaceutical composition according to any one of embodiments 126-149, wherein the pharmaceutical composition is suitable for intravenous administration. [Brief description of the drawings]

[0231] (4. BRIEF DESCRIPTION OF THE DRAWINGS) [Figure 1] Figure 1: Dose-dependent suppression of M1 IL-6 expression in proinflammatory M1 macrophages by increasing doses of CTLA4 IgG (abatacept).

[0232] [Diagram 2] Figure 2: Dose-dependent inhibition of Tresp proliferation by increasing doses of CTLA4 IgG (abatacept).

[0233] [Diagram 3] Figure 3: Dose-dependent enhanced suppressive function of increasing doses of CTLA4 IgG (abatacept) on Tresp proliferation of IL-2-induced, in vivo expanded Tregs isolated from Alzheimer's disease patients.

[0234] [Figure 4] Figure 4: Dose-dependent augmentation of Treg suppression by increasing amounts of CTLA4 IgG (abatacept) on M1 IL6 protein expressed in IL-2-induced, in vivo expanded (isolated from Alzheimer's disease patients) Treg:M1 co-cultures.

[0235] [Diagram 5] Figure 5: Effect of Treg suppression on the percentage of M1-IL6 protein expression when Tregs isolated from Alzheimer's disease patients were co-cultured with M1s and IL-2 or CTLA4 IgG (abatacept), or their combination was added.

[0236] [Figure 6] Figure 6: Effect of IL-2 and abatacept treatment in restoring Treg function in patient AD-01.

[0237] [Figure 7] Figure 7: Effect of IL-2 and abatacept treatment in restoring Treg function in patient AD-02.

[0238] [Figure 8] Figure 8: Effect of IL-2 and abatacept treatment on cognitive improvement (MMSE score) in patient AD-01 and patient AD-02.

[0239] [Figure 9] Figure 9: Effect of IL-2 monotherapy on MMSE scores in patients with AD (n=8) and effect of IL-2 and abatacept treatment on MMSE scores in patients with AD (n=3). "Screening" refers to measurements taken before the start of the dosing regimen.

[0240] [Figure 10] Figure 10: Effect of IL-2 monotherapy on Treg suppressive function in AD patients (n=8; left graph) and effect of IL-2 and abatacept treatment on Treg suppressive function in AD patients (n=3; right graph). F / U=follow-up, post-treatment. Baseline and SC are measurements taken just before the start of the dosing regimen. For the IL-2 and abatacept graphs, the D8 measurement (showing a change of about 19% above the SC) was taken after the first abatacept monotherapy dose.

[0241] [Figure 11] Figure 11: Effect of IL-2 and abatacept treatment on Treg suppressive function in ALS patients.

[0242] [Figure 12] Figure 12: Effect of IL-2 and abatacept treatment on the percentage of cells expressing CD4+CD25+FOXP3+ in ALS patients.

[0243] [Figure 13] Figure 13: Effect of IL-2 and abatacept treatment on the percentage of cells expressing CD8+ in ALS patients.

[0244] [Figure 14]Figure 14: ALSFRS-R scores in ALS patients before and during treatment with IL-2 and abatacept.

[0245] [Figure 15] Figure 15: Maximum inspiratory pressure (MIP) values ​​in ALS patients before and during (shaded) treatment with IL-2 and abatacept. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0246] (5. Detailed Description) In one aspect, provided herein is a method of treating a disease or disorder, e.g., a neurodegenerative or neuroinflammatory disease or disorder, e.g., Alzheimer's disease, comprising administering to a subject in need of treatment i) a CTLA-4 containing protein, and ii) an IL-2 protein, whereby one or more symptoms associated with the disease or disorder are alleviated. In one embodiment, the CTLA-4 containing protein is abatacept. In one embodiment, the IL-2 protein is aldesleukin. In one embodiment, the CTLA-4 containing protein is abatacept and the IL-2 protein is aldesleukin.

[0247] In some embodiments, the CTLA-4 containing protein and the IL-2 protein are administered separately to the subject. In some embodiments, the CTLA-4 containing protein is abatacept, and the abatacept and the IL-2 protein are administered separately to the subject. In some embodiments, the IL-2 protein is aldesleukin, and the aldesleukin and the CTLA-4 containing protein are administered separately to the subject. In some embodiments, the CTLA-4 containing protein is abatacept, the IL-2 protein is aldesleukin, and the abatacept and aldesleukin are administered separately to the subject.

[0248] In some embodiments, the CTLA-4 containing protein and the IL-2 protein are administered to the subject together in a single formulation. In some embodiments, the CTLA-4 containing protein is abatacept, and the abatacept and the IL-2 protein are administered to the subject together in a single formulation. In some embodiments, the IL-2 protein is aldesleukin, and the aldesleukin and the CTLA-4 containing protein are administered to the subject together in a single formulation. In some embodiments, the CTLA-4 containing protein is abatacept, the IL-2 protein is aldesleukin, and the abatacept and aldesleukin are administered to the subject together in a single formulation.

[0249] Also provided herein are pharmaceutical compositions comprising a CTLA-4-containing protein and one or more doses of an IL-2 protein (a "CTLA-4-containing protein / IL-2 protein dose"). In certain embodiments, provided herein are pharmaceutical compositions comprising abatacept and one or more doses of aldesleukin (an "abatacept / aldesleukin dose").

[0250] In another aspect, a kit is provided herein that includes, in separate containers, i) one or more doses of a formulation comprising 50-125 mg of abatacept, and ii) one or more doses of a formulation comprising 500,000-3,000,000 units of aldesleukin. In an embodiment, the kit includes one or more doses of a formulation comprising 50 mg of abatacept, 87.5 mg of abatacept, or 125 mg of abatacept. In a specific embodiment, the one or more doses of abatacept are present in lyophilized form, e.g., as a lyophilized powder or lyophilized cake. In an embodiment, the one or more doses of abatacept formulation are suitable for subcutaneous or intravenous administration. In an embodiment, the kit includes one or more doses of a formulation comprising 500,000-2,000,000 units of aldesleukin, or 1,000,000 units of aldesleukin. In a specific embodiment, the one or more doses of aldesleukin are present in lyophilized form, for example, as a lyophilized powder or lyophilized cake. In some embodiments, the formulation of the one or more doses of aldesleukin is suitable for subcutaneous or intravenous administration.

[0251] Recitation of ranges of values ​​herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise stated herein, and each separate value is incorporated herein as if each separate value were individually recited herein.

[0252] Unless specifically stated or clear from the context, as used herein, the terms "a," "an," and "the" are understood to be in the singular or plural and mean "one or more."

[0253] The terms "including," "including," and the like are intended to convey inclusion without limitation, unless specifically indicated otherwise.

[0254] The terms "or" and "and" can be used interchangeably and can be understood to mean "and / or."

[0255] Description of any aspect or embodiment of the invention using terms such as "comprising," "having," "including," or "containing" herein in reference to an element or elements is intended to provide support for similar aspects or embodiments of the invention that "consist," "consist essentially of," or "substantially comprise" that particular element or elements, unless otherwise indicated or clearly contradicted by context (e.g., a composition described herein as comprising a particular element should be understood to also describe a composition consisting of that element, unless otherwise indicated or clearly contradicted by context).

[0256] The terms "about" and "approximately" used herein are interchangeable and should generally be understood to refer to a range of numbers around a given number, as well as all numbers within the range of numbers listed (e.g., "about 5 to 15" means "about 5 to about 15" unless otherwise specified). Furthermore, all numerical ranges herein should be understood to include each whole integer within the range. In particular, unless otherwise stated, the term means within plus or minus 10% of the given value or range. When an integer is required, the term means within plus or minus 10% of the given value or range, rounded up or down to the nearest integer.

[0257] 5.1 CTLA-4-Containing Proteins The methods and compositions presented herein include or utilize a CTLA-4 containing protein, eg, a human CTLA-4 containing protein.

[0258] The CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) protein is known. See, for example, UniProtKB identifier P16410.

[0259] In some embodiments, the CTLA-4 containing protein is a human CTLA-4 containing protein. In some embodiments, the CTLA-4 containing protein comprises a CD80 and / or CD86 binding portion of CTLA-4. In some embodiments, the CTLA-4 containing protein comprises a human CTLA-4 extracellular domain. In certain embodiments, the CTLA-4 containing protein has the following sequence: [ka] For example, in certain embodiments, the CTLA-4 containing protein comprises the underlined portion of SEQ ID NO:4. In other embodiments, the CTLA-4 containing protein comprises at least 80%, 85%, 90%, 95%, 98%, 99% of the underlined portion of SEQ ID NO:4. In other embodiments, the CTLA-4 containing protein comprises at least 80%, 85%, 90%, 95%, 98%, 99% of the bolded and underlined portion of SEQ ID NO:4. In certain embodiments, for example, the CTLA-4 containing protein can comprise the amino acid sequence of SEQ ID NO:4, the underlined portion of SEQ ID NO:4, or a sequence that is at least 90%, 95%, 98%, or 99% identical to the bolded and underlined portions of SEQ ID NO:4.

[0260] To determine the percent identity of two amino acid sequences, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced into the sequence of the first amino acid sequence for optimal alignment with the second amino acid sequence). The amino acid residues at corresponding amino acid positions are then compared. If a position in the first sequence is occupied by the same amino acid residue as the corresponding position in the second sequence, the molecules are identical at that position. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences (i.e., % identity = number of identical overlapping positions / total number of positions x 100%). In one embodiment, the two sequences are the same length. In some embodiments, the percent identity is determined over the entire length of the amino acid sequence.

[0261] The determination of percent identity between two sequences (e.g., amino acid sequences) can also be accomplished using a mathematical algorithm. A preferred, non-limiting example of a mathematical algorithm utilized for comparing two sequences includes the algorithm of Karlin and Altschul, 1990, Proc. Natl. Acad. Sci. USA 87:2264 2268, modified as in Karlin and Altschul, 1993, Proc. Natl. Acad. Sci. USA 90:5873 5877. Such an algorithm is incorporated into the XBLAST program of Altschul et al., 1990, J. Mol. Biol. 215:403. BLAST protein searches can be performed, for example, using the XBLAST program parameters set to score 50, word length=3 to obtain amino acid sequences homologous to the protein molecules described herein. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et al., 1997, Nucleic Acids Res. 25:3389 3402. Alternatively, PSI BLAST can be used to perform an iterated search that detects distant relationships between molecules (see above). When utilizing BLAST, Gapped BLAST, and PSI Blast programs, the default parameters of the respective programs (e.g., XBLAST) can be used (see, e.g., the National Center for Biotechnology Information (NCBI) on the worldwide web, ncbi.nlm.nih.gov). Another preferred, non-limiting example of a mathematical algorithm utilized for the comparison of sequences is the algorithm of Myers and Miller, 1988, CABIOS 4:11 17. Such an algorithm is incorporated in the ALIGN program (version 2.0), which is part of the GCG sequence alignment software package.When utilizing the ALIGN program for comparing amino acid sequences, a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4 can be used.

[0262] The percent identity between two sequences can be determined using techniques similar to those described above, with or without allowing gaps. In calculating percent identity, typically only exact matches are counted.

[0263] In some embodiments, the CTLA-4 containing protein is a monomer, hi some embodiments, the CTLA-4 containing protein is a dimer.

[0264] In certain embodiments, the CTLA-4 containing protein is a fusion protein, e.g., a fusion protein comprising a human CTLA-4 extracellular domain, such as those described herein, and a human immunoglobulin Fc domain, e.g., a modified Fc domain comprising an immunoglobulin hinge region, CH2 region, and CH3. In certain embodiments, the human immunoglobulin Fc domain is an Ig domain, e.g., a human IgG1 Fc domain. In some embodiments, the CTLA-4 containing protein is glycosylated.

[0265] In one embodiment, the CTLA-4 containing protein comprises a monomer having the following amino acid sequence: [ka] In a specific embodiment, the CTLA-4 containing protein comprises a homodimer of two monomers, each monomer comprising the amino acid sequence of SEQ ID NO:1.

[0266] In a particular embodiment, the CTLA-4 containing protein is abatacept.

[0267] In one embodiment, the CTLA-4 containing protein comprises a monomer having the following amino acid sequence: [ka] In a specific embodiment, the CTLA-4 containing protein comprises a homodimer of two monomers, each monomer comprising the amino acid sequence of SEQ ID NO:2.

[0268] In a particular embodiment, the CTLA-4 containing protein is belatacept.

[0269] In some embodiments, the CTLA-4 containing protein is glycosylated.

[0270] 5.2 IL-2 Protein The methods and compositions presented herein include or utilize an IL-2 protein, for example, a human IL-2 protein.

[0271] The IL-2 protein is well known, see, for example, UniProtKB identifier Q0GK43.

[0272] In some embodiments, the IL-2 protein is a human IL-2 protein. For example, in some embodiments, the IL-2 protein has the following native mature human IL-2 amino acid sequence: [ka] is or is derived from

[0273] In certain embodiments, the IL-2 protein contains one or more mutations with respect to a naturally occurring mature human IL-2 polypeptide. For example, in certain embodiments, the human IL-2 protein lacks an N-terminal alanine amino acid. In certain embodiments, the human IL-2 protein contains a mutation at an amino acid position corresponding to naturally occurring mature human IL-2 amino acid residue 125 (underlined in the sequence above). For example, in certain embodiments, the IL-2 protein contains a serine at an amino acid position corresponding to naturally occurring mature human IL-2 amino acid residue 125. In certain embodiments, the human IL-2 protein lacks an N-terminal alanine amino acid and contains a serine at an amino acid position corresponding to naturally occurring mature human IL-2 amino acid residue 125.

[0274] In a specific embodiment, the IL-2 protein is aglycosylated.

[0275] In a particular embodiment, the human IL-2 protein lacks the N-terminal alanine amino acid, contains a serine at the amino acid position corresponding to native mature human IL-2 amino acid residue 125, and is not glycosylated.

[0276] In one embodiment, the IL-2 protein is aldesleukin (des-alanyl-1, serine-125 human interleukin-2; trade name Proleukin), which is well known.

[0277] In one embodiment, the human IL-2 protein has the following amino acid sequence: [ka] Includes.

[0278] 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 the IL-2 receptor (IL-2R) alpha subunit (CD25) relative to that of naturally occurring 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 the IL-2 receptor beta subunit (CD122) relative to that of naturally occurring 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 the IL-2 receptor gamma subunit (CD132) relative to that of wild-type 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 the IL-2 receptor beta and gamma subunits relative to that of naturally occurring mature IL-2 protein. In certain embodiments, the IL-2 protein contains one or more modifications, e.g., mutations, compared to that of mature human IL-2, and exhibits reduced binding to the IL-2 receptor alpha and beta subunits relative to that of the naturally occurring mature IL-2 protein. In certain embodiments, the IL-2 protein contains one or more modifications, e.g., mutations, compared to that of mature human IL-2, and exhibits reduced binding to the IL-2 receptor beta subunit, but not reduced binding to the IL-2 receptor subunit alpha relative to that of the naturally occurring mature IL-2 protein. In certain embodiments, the IL-2 protein contains one or more modifications, e.g., mutations, compared to that of mature human IL-2, and exhibits reduced binding to the IL-2 receptor alpha, beta, and gamma subunits relative to that of the naturally occurring mature IL-2 protein.

[0279] 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, e.g., by assessing STAT5 phosphorylation. See, e.g., Ghelani et al. (2020) Front. Immunol., incorporated herein in its entirety. 11 Please see :1106.

[0280] In certain embodiments, the IL-2 protein contains 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, e.g., 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, supra (2020).

[0281] In some embodiments, the IL protein is an IL-2 mutein (i.e., an IL-2 protein that contains one or more mutations relative to the native mature IL-2 protein) that includes an amino acid sequence corresponding to native mature human IL-2, which may include a substitution or deletion at one or more amino acid positions, e.g., A1 (e.g., 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); H1 6 (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, Q2 2F); 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 (e.g., I 92F); K97 (e.g., K97Q); M104 (e.g., M104A, M104T, M104V); D109 (e.g., D109C or a substitution with a non-natural amino acid having 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).

[0282] In one embodiment, the human IL-2 protein has the following amino acid sequence: [ka] Includes.

[0283] 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 further comprises a D20A and H16E mutation; a D20A and M104T mutation; an H16E and E61Q mutation; a V91K, D20A and M104V mutation; a D20G mutation; a D20W mutation; an F42Y mutation; an N88K mutation; or a D20A, H16R and E61Q mutation.

[0284] In some embodiments, the IL protein is an IL-2 mutein that includes an amino acid sequence corresponding to native mature human IL-2 and further includes a D20, N88, and / or Q126 mutation. For example, in certain embodiments, the IL-2 protein can include a D20H mutation, an N88R, N88I, or N88G mutation, and / or a Q126D mutation. See, e.g., U.S. Patent No. 6,955,807.

[0285] In some embodiments, the IL-2 protein is an IL-2Ra / IL-2Rb biased IL-2 protein. For example, in one embodiment, the IL-12 is STK-012 (Emmerich, J. et al. Cancer Res 2021;81(13_Suppl):Abstract nr 1744).

[0286] In certain embodiments, the IL-2 protein is fused or conjugated to one or more additional moieties. In some embodiments, the IL protein is fused or conjugated to one or more polymers, for example, one or more polymers having a weight average molecular weight of about 250 Daltons to about 50,000 Daltons. In some embodiments, the IL-2 protein is pegylated. See, for example, WO202114636. In certain 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 WO2021140416. In some embodiments, the IL-2 protein is the IL-2 clinical candidate BPT-143 (Bright Peak).

[0287] 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 a non-natural amino acid. In some embodiments, the water soluble polymer comprises polyethylene glycol (PEG), polypropylene glycol (PPG), copolymers of ethylene glycol and propylene glycol, poly(oxyethylated polyols), poly(olefinic alcohols), poly(vinylpyrrolidone), poly(hydroxyalkyl methacrylamides), poly(hydroxyalkyl methacrylates), polysaccharides, poly(a-hydroxy acids), poly(vinyl alcohols), polyphosphazenes, polyoxazolines (POZ), poly(N-acryloylmorpholines), poly[oligo(ethylene glycol)methyl methacrylate] (POEGMA), or combinations thereof. In a specific embodiment, the water soluble polymer is PEG and has a weight average molecular weight of about 100 Daltons to about 150,000 Daltons.

[0288] In some embodiments, the IL-2 protein is conjugated to one or more polyethylene glycol (PEG) polymers, e.g., 1-7 PEG polymers, e.g., branched PEGs, via releasable linkages. In certain embodiments, the PEG polymers are branched polymers each having a weight average molecular weight of about 20,000 Daltons to 85,000 Daltons. In some embodiments, the releasable branched PEGs are attached at amino groups of lysines on the IL-2 protein. In some embodiments, there are multiple conjugates that are mixtures of mono-, di-, and tri-PEGylated conjugates. In some embodiments, the IL-2 protein is a conjugate of IL-2 protein as described in U.S. Pat. Nos. 9,861,705, 10,960,079, or PCT Publication WO2012065086. In some embodiments, the IL-2 protein is the clinical candidate NKTR-214.

[0289] 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, e.g., a human Fc domain, e.g., a human IgG Fc domain. In certain 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 indirectly attached to the IL-2 protein, e.g., via a linker, e.g., via a GSSSS-containing linker, e.g., a GSSS, (GSSSS)2, (GSSSS)3, or (GSSSS)4-containing linker.

[0290] In certain embodiments, the IL protein comprises an amino acid sequence corresponding to native mature human IL-2 and further comprises: i) mutations at one or more of L53 (e.g., L53I), L56 (e.g., L56I), L80 (e.g., L80I), and L118 (e.g., L118I); and, optionally, mutations at V69 (e.g., V69A), Q74 (e.g., Q74P), N88 (e.g., N88D), and C125 (e.g., C125D). (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, for example an N-terminal human IgG1 Fc domain.

[0291] In some embodiments, the IL-2 protein comprises i) an amino acid sequence corresponding to native mature human IL-2 and further comprises one or more of the following 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., For example, an IL-2 mutein comprising a substitution at: 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, fused or conjugated to an antibody or antigen-binding fragment that binds MAdCAM, OAT1, OCT2, FXYD2, TSPAN7, DPP6, HEPACAM2, TMEM27, or GPR119.

[0292] In some embodiments, the IL-2 protein or IL-2 mutein, e.g., an IL-2 mutein fused or conjugated to one or more additional moieties, e.g., an antibody, an antigen-binding fragment of an antibody, or an Fc domain, is as described in U.S. Pat. Nos. 10,174,091, 10,174,092, 10,946,068, 11,091,526, or 11,091,527, or PCT Publication Nos. WO2019112852 or WO2019112854.

[0293] In some embodiments, the IL-2 protein is PT101 / MK-6194 (Pandion Therapeutics / Merck & Co).

[0294] In some embodiments, the IL-2 protein is an IL-2 mutein conjugated to an antibody or fragment thereof described in PCT Publication WO2020247843.

[0295] In some embodiments, the IL-2 protein is the IL-2 clinical candidate AB248.

[0296] In some embodiments, the IL-2 protein is ANV419 (Anaveon).

[0297] In certain embodiments, an IL-2 protein comprises one or more non-standard or unnatural amino acids. For example, in certain embodiments, an IL-2 protein may comprise an amino acid sequence corresponding to the mature human IL-2 protein and may further comprise one or more amino acids other than the 20 standard amino acids found in most proteins.

[0298] 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 a norleucine substitution at position 23, 39, or 46.

[0299] 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 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 analog or comprises an aromatic side chain. In some embodiments, the unnatural amino acid is N6-[(2-azidoethoxy)carbonyl]-l-lysine.

[0300] 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 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 analog 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, such as those described in U.S. Patent No. 10,610,571 or PCT Publication WO2019028419 or WO2019028425; PCT Publication WO19165453; U.S. Patent No. 11,077,195 or PCT Publication WO2020163532; PCT Publication WO2021030706; PCT Publication WO2021050554; or PCT Publication WO2021263026. In some embodiments, the IL-2 protein is THOR-707 (Sanofi).

[0301] In some embodiments, the IL-2 protein is an IL-2 mimetic (e.g., a novel protein that mimics the activity of IL-2). In some embodiments, the IL-2 protein is an IL-2 mimetic described in PCT Publication WO2021081193 or PCT Publication WO2021188374. In some embodiments, the IL-2 mimetic induces heterodimerization of two IL-2 cell membrane receptors. In some embodiments, the IL-2 mimetic is neoleukin-2 / 15. In some embodiments, the IL-2 protein is the IL-2 clinical candidate NL-201.

[0302] (5.3 Treatment) Provided herein is a method of treating a disease or disorder, comprising administering to a subject in need of treatment i) a CTLA-4 containing protein, and ii) an IL-2 protein, whereby one or more symptoms associated with the disease or disorder are alleviated. In one embodiment, the CTLA-4 containing protein is abatacept. In one embodiment, the IL-2 protein is aldesleukin. In one embodiment, the CTLA-4 containing protein is abatacept and the IL-2 protein is aldesleukin.

[0303] In some embodiments, the CTLA-4 containing protein and the IL-2 protein are administered separately to the subject. In some embodiments, the CTLA-4 containing protein is abatacept, and the abatacept and the IL-2 protein are administered separately to the subject. In some embodiments, the IL-2 protein is aldesleukin, and the aldesleukin and the CTLA-4 containing protein are administered separately to the subject. In some embodiments, the CTLA-4 containing protein is abatacept, the IL-2 protein is aldesleukin, and the abatacept and aldesleukin are administered separately to the subject.

[0304] In some embodiments, the CTLA-4 containing protein and the IL-2 protein are administered to the subject together in a single formulation. In some embodiments, the CTLA-4 containing protein is abatacept, and the abatacept and the IL-2 protein are administered to the subject together in a single formulation. In some embodiments, the IL-2 protein is aldesleukin, and the aldesleukin and the CTLA-4 containing protein are administered to the subject together in a single formulation. In some embodiments, the CTLA-4 containing protein is abatacept, the IL-2 protein is aldesleukin, and the abatacept and aldesleukin are administered to the subject together in a single formulation.

[0305] In some embodiments, the disease or disorder is associated with Treg dysfunction and the subject is diagnosed with or suspected of having a disorder associated with Treg dysfunction. In some embodiments, the disease or disorder is associated with Treg deficiency and the subject is diagnosed with or 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 suspected of having a condition driven by a T cell response.

[0306] In some embodiments, the disease is a neurodegenerative disease and the subject is diagnosed with or suspected of having a neurodegenerative disease, hi some embodiments, the subject is diagnosed with or suspected of having Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, or frontotemporal dementia.

[0307] In some embodiments, the disorder is one that would benefit from downregulation of the immune system, and the subject is diagnosed with or suspected of having a disorder that would benefit from downregulation of the immune system.

[0308] In some embodiments, the disease is an autoimmune disease and the subject is diagnosed with or suspected of having an autoimmune disease. The autoimmune disease can be, for example, systemic sclerosis (scleroderma), polymyositis, ulcerative colitis, inflammatory bowel disease, Crohn's disease, celiac disease, multiple sclerosis (MS), rheumatoid arthritis (RA), type I diabetes, psoriasis, dermatomyositis, systemic lupus erythematosus, cutaneous lupus, myasthenia gravis, autoimmune nephropathy, autoimmune hemolytic anemia, autoimmune cytopenia, autoimmune hepatitis, autoimmune uveitis, alopecia, thyroiditis, or pemphigus.

[0309] In one embodiment, the disease is moderately to severely active RA. In one embodiment, the disease is moderately to severely active RA and the subject is an adult. In one embodiment, the disease is polyarticular juvenile idiopathic arthritis (pJIA). In a particular embodiment, the disease is pJIA and the subject is 2 years of age or older, for example, 6 years of age or older. In one embodiment, the disease is psoriatic arthritis. In a particular embodiment, the disease is psoriatic arthritis and the subject is an adult.

[0310] In some embodiments, the disease or disorder is heart failure or ischemic cardiomyopathy, and the subject has been diagnosed with or is suspected of having heart failure or ischemic cardiomyopathy. In some embodiments, the disease is graft-versus-host disease, and the subject has been diagnosed with or is suspected of having graft-versus-host disease, for example, after receiving an organ transplant (such as a kidney or liver transplant) or after receiving a stem cell transplant (such as a hematopoietic stem cell transplant).

[0311] 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. Neuroinflammation can be associated with, for example, 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.

[0312] In some embodiments, the disease or disorder is carditis, and the subject has been diagnosed with or is suspected of having carditis, e.g., carditis associated with atherosclerosis, myocardial infarction with heart failure, or ischemic cardiomyopathy.

[0313] In some embodiments, the disease or disorder is chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and the subject has been diagnosed with or is suspected of having CIDP. In some embodiments, the disease or disorder is acute inflammatory demyelinating polyneuropathy (AIDP) and the subject has been diagnosed with or is suspected of having AIDP. In some embodiments, the disease or disorder is Guillain-Barre syndrome (GBS) and the subject has been diagnosed with or is suspected of having GBS.

[0314] In some embodiments, the subject has had a stroke.

[0315] In some embodiments, the subject being treated has been diagnosed with or is suspected of having cancer, eg, a hematological cancer.

[0316] In some embodiments, the subject being treated is diagnosed with or suspected of having asthma.

[0317] In some embodiments, the subject being treated has been diagnosed with or is suspected of having eczema.

[0318] In some embodiments, the subject being treated has been diagnosed with or is suspected of having a disorder associated with overactivation of the immune system.

[0319] In some embodiments, the subject being treated is diagnosed with or suspected of having a tregopathy, which may be caused by loss-of-function mutations in the FOXP3, CD25, cytotoxic T-lymphocyte-associated antigen 4 (CTLA4), LPS-responsive beige-like anchor protein (LRBA), or BTB domain and CNC homolog 2 (BACH2) genes, or gain-of-function mutations in signal transducer and activator of transcription 3 (STAT3).

[0320] In one aspect, there is provided a method of treating a disease or disorder, e.g., a disease or disorder described herein, e.g., a neurodegenerative or neuroinflammatory disease or disorder, in a subject in need thereof, comprising administering to the subject i) a CTLA-4 containing protein; and ii) IL-2 protein Provided herein is a method for alleviating one or more symptoms associated with a neurodegenerative or neuroinflammatory disease or disorder in a treated subject, comprising administering to said subject a CTLA-4 containing protein. In one embodiment, the CTLA-4 containing protein is abatacept. In one embodiment, the IL-2 protein is aldesleukin. In one embodiment, the CTLA-4 containing protein is abatacept and the IL-2 protein is aldesleukin.

[0321] In some embodiments, the CTLA-4 containing protein is administered by injection or infusion. In certain embodiments, the CTLA-4 containing protein is administered subcutaneously. In certain embodiments, the CTLA-4 containing protein is administered intravenously. In some 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. In some embodiments, the CTLA-4 containing protein and the IL-2 protein are administered by injection or infusion. In certain embodiments, the CTLA-4 containing protein and the IL-2 protein are administered subcutaneously. In certain embodiments, the CTLA-4 containing protein and the IL-2 protein are administered intravenously.

[0322] In some embodiments, the CTLA-4 containing protein comprises a human CTLA-4 extracellular domain. In certain embodiments, the CTLA-4 containing protein is a fusion protein, e.g., a fusion protein comprising a human CTLA-4 extracellular domain and a human immunoglobulin Fc domain, e.g., a modified Fc domain comprising an immunoglobulin hinge region, a CH2 region, and a CH3. In certain embodiments, the human immunoglobulin Fc domain is a human IgG1 Fc domain. In some embodiments, the CTLA-4 containing protein is glycosylated.

[0323] In one embodiment, the CTLA-4 containing protein comprises a monomer having the following amino acid sequence: [ka] In a specific embodiment, the CTLA-4 containing protein comprises a homodimer of two monomers, each monomer comprising the amino acid sequence of SEQ ID NO:1.

[0324] In a particular embodiment, the CTLA-4 containing protein is abatacept.

[0325] 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 naturally occurring 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 lacks an N-terminal alanine amino acid and comprises a serine at the amino acid position corresponding to naturally occurring mature human IL-2 amino acid residue 125.

[0326] In one embodiment, the human IL-2 protein has the following amino acid sequence: [ka] Includes.

[0327] In a specific embodiment, the IL-2 protein is non-glycosylated, hi some embodiments, the IL-2 protein is aldesleukin.

[0328] In one embodiment, the human IL-2 protein has the following amino acid sequence: [ka] Includes.

[0329] In some embodiments, according to the methods provided herein, the CTLA-4 containing protein is administered to the subject once every two weeks. In some embodiments, the CTLA-4 containing protein is administered intravenously to the subject once every two weeks. In some embodiments, the CTLA-4 containing protein is administered subcutaneously to the subject once every two weeks. In some embodiments, the CTLA-4 containing protein is administered to the subject once every two weeks for 10-20 weeks. For example, in some embodiments, the CTLA-4 containing protein is administered to the subject once every two weeks for 12 weeks, 15 weeks, or 18 weeks. In some embodiments, the CTLA-4 containing protein is abatacept.

[0330] In some embodiments, according to the methods provided herein, the CTLA-4 containing protein is administered to the subject once a week. In some embodiments, the CTLA-4 containing protein is administered intravenously to the subject once a week. In some embodiments, the CTLA-4 containing protein is administered subcutaneously to the subject once a week. In some embodiments, the CTLA-4 containing protein is administered to the subject once a week for 10-20 weeks. For example, in some embodiments, the CTLA-4 containing protein is administered to the subject once a week for 12 weeks, 15 weeks, or 18 weeks. In some embodiments, the CTLA-4 containing protein is abatacept.

[0331] In some embodiments, according to the methods provided herein, the CTLA-4 containing protein is administered to the subject once a day for 2-5 consecutive days. For example, in some embodiments, the CTLA-4 containing protein is administered to the subject once a day for 2, 3, 4, or 5 consecutive days. In some embodiments, the CTLA-4 containing protein is administered to the subject once a day for 3 consecutive days. In some embodiments, the CTLA-4 containing protein is administered intravenously to the subject once a day for 2-5 consecutive days. In some embodiments, the CTLA-4 containing protein is administered subcutaneously to the subject once a day for 2-5 consecutive days. For example, in some embodiments, the CTLA-4 containing protein is administered subcutaneously to the subject once a day for 2, 3, 4, or 5 consecutive days. In some embodiments, the CTLA-4 containing protein is administered subcutaneously to the subject once a day for 3 consecutive days. In some embodiments, the IL-2 protein is administered to the subject once a day for 2-5 consecutive days. For example, in some embodiments, the IL-2 protein is administered to the subject once per day for 2, 3, 4, or 5 consecutive days. In some embodiments, the IL-2 protein is administered to the subject once per day for 3 consecutive days. In some embodiments, the IL-2 protein is administered intravenously to the subject once per day for 2-5 consecutive days. In some embodiments, the IL-2 protein is administered subcutaneously to the subject once per day for 2-5 consecutive days. For example, in some embodiments, the IL-2 protein is administered subcutaneously to the subject once per day for 2, 3, 4, or 5 consecutive days. In some embodiments, the IL-2 protein is administered subcutaneously to the subject once per day for 3 consecutive days. In some embodiments, the CTLA-4 containing protein is abatacept. In some embodiments, the IL-2 protein is aldesleukin.

[0332] In some embodiments, according to the methods provided herein, the CTLA-4 containing protein is administered to the subject one or more times during a dosing cycle, e.g., 1-10 times during a dosing cycle, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 times during a dosing cycle. In some embodiments, the CTLA-4 containing protein is administered to the subject as a single dose on day 1 of the dosing cycle. In some embodiments, the CTLA-4 containing protein is administered to the subject daily for a series of consecutive days starting from day 1 of the dosing cycle. In some embodiments, the CTLA-4 containing protein is administered to the subject daily for two consecutive days starting from day 1 of the dosing cycle. In some embodiments, the CTLA-4 containing protein is administered to the subject daily for three consecutive days starting from day 1 of the dosing cycle. In some embodiments, the CTLA-4 containing protein is administered to the subject daily for four consecutive days starting from day 1 of the dosing cycle. In some embodiments, the CTLA-4 containing protein is administered to the subject daily for five consecutive days starting from day 1 of the dosing cycle. In some embodiments, the CTLA-4 containing protein is administered to the subject for a series of non-consecutive days beginning on day 1 of a dosing cycle, e.g., for a series of 2, 3, 4, 5, 6, 7, 8, 9, or 10 non-consecutive days, independently separated by 1, 2, 3, 4, or 5 days, beginning on day 1 of a dosing cycle. In some embodiments, the CTLA-4 containing protein is abatacept.

[0333] In some embodiments, according to the methods provided herein, the IL-2 protein is administered to the subject one or more times during a dosing cycle, e.g., 1-10 times during a dosing cycle, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 times during a dosing cycle. In some embodiments, the IL-2 protein is administered to the subject daily for a series of consecutive days starting from day 1 of the dosing cycle. In some embodiments, the IL-2 protein is administered to the subject daily for two consecutive days starting from day 1 of the dosing cycle. In some embodiments, the IL-2 protein is administered to the subject daily for three consecutive days starting from day 1 of the dosing cycle. In some embodiments, the IL-2 protein is administered to the subject daily for four consecutive days starting from day 1 of the dosing cycle. In some embodiments, the IL-2 protein is administered to the subject daily for five consecutive days starting from day 1 of the dosing cycle. In some embodiments, the IL-2 protein is administered to the subject for a series of non-consecutive days beginning with day 1 of the dosing cycle, e.g., for a series of 2, 3, 4, 5, 6, 7, 8, 9, or 10 non-consecutive days independently separated by 1, 2, 3, 4, or 5 days beginning with day 1 of the dosing cycle. In some embodiments, the IL-2 protein is aldesleukin.

[0334] In some embodiments, according to the methods provided herein, the dosing cycle is 1-6 weeks. In some embodiments, according to the methods provided herein, the dosing cycle is 2-6 weeks. In some embodiments, the dosing cycle is 1 week. In some embodiments, the dosing cycle is 2 weeks. In some embodiments, the dosing cycle is 3 weeks. In some embodiments, the dosing cycle is 4 weeks. In some embodiments, the dosing cycle is 5 weeks. In some embodiments, the dosing cycle is 6 weeks. In some embodiments, the dosing cycle is repeated 1-12 times. In some embodiments, the dosing cycle is repeated 10 times. In some embodiments, the dosing cycle is repeated 8 times. In some embodiments, the dosing cycle is repeated 6 times. In some embodiments, each repeated dosing cycle begins 10-28 days after day 1 of the previous dosing cycle. For example, in some embodiments, each repeated dosing cycle begins 14 days after day 1 of the previous dosing cycle. In some embodiments, each repeated dosing cycle begins 2-6 weeks after day 1 of the previous dosing cycle. In some embodiments, each repeated dosing cycle begins 2 weeks after day 1 of the previous dosing cycle. In some embodiments, each repeated dosing cycle begins 3 weeks after day 1 of the previous dosing cycle. In some embodiments, each repeated dosing cycle begins 4 weeks after day 1 of the previous dosing cycle. In some embodiments, each repeated dosing cycle begins 5 weeks after day 1 of the previous dosing cycle. In some embodiments, each repeated dosing cycle begins 6 weeks after day 1 of the previous dosing cycle. In some embodiments, the CTLA-4 containing protein is administered to the subject daily for 3 consecutive days starting from day 1 of the first dosing cycle. In some embodiments, the IL-2 protein is administered to the subject daily for 3 consecutive days starting from day 1 of the first dosing cycle. In some embodiments, the IL-2 protein is administered to the subject daily for 3 consecutive days starting from day 1 of the second dosing cycle. In some embodiments, the initial dosing cycle is repeated six times, with each repeated dosing cycle beginning 14 days after day 1 of the previous dosing cycle.In some embodiments, the CTLA-4 containing protein is abatacept. In some embodiments, the IL-2 protein is aldesleukin.

[0335] In some embodiments, the CTLA4-containing protein is administered to the subject weekly. In certain embodiments, the CTLA4-containing protein is administered to the subject weekly on day 1 of each week (in other words, if the first administration of the CTLA4-containing protein is administered to the subject on day 1, subsequent administrations of the CTLA4-containing protein occur on days 8, 15, 22, etc.). In some embodiments, the CTLA-4-containing protein is abatacept.

[0336] In specific embodiments, the CTLA4 containing protein is administered to the subject every week and the IL-2 protein is administered to the subject every two weeks. For example, in some embodiments, the CTLA4 containing protein is administered to the subject every week starting from week 1, and the IL-2 protein is administered to the subject on week 2, week 4, week 6, etc. For example, in some embodiments, the CTLA4 containing protein is administered to the subject every week starting from week 1, and the IL-2 protein is administered to the subject on week 3, week 5, week 7, etc. In some embodiments, the CTLA-4 containing protein is abatacept. In some embodiments, the IL-2 protein is aldesleukin.

[0337] In one embodiment, the CTLA4-containing protein is administered to the subject weekly on the first day of each week (in other words, if the first administration of the CTLA4-containing protein is administered to the subject on day 1, then subsequent administrations of the CTLA4-containing protein occur on days 8, 15, 22, etc.), and the IL-2 protein is administered to the subject on the first day of every other week beginning with week 2, or on the first day of every other week (in other words, on days 8, 22, 36, etc.). In one embodiment, the IL-2 protein is administered to the subject on day 1 of the week of IL-2 protein administration for a series of consecutive days, e.g., daily for 2 consecutive days, daily for 3 consecutive days, daily for 4 consecutive days, or daily for 5 consecutive days. In one embodiment, the IL-2 protein is administered to the subject on day 1 of the week of IL-2 protein administration for a series of non-consecutive days, such as 2, 3, 4, 5, 6, or 7 non-consecutive days, independently separated by 1, 2, 3, 4, or 5 days. In some embodiments, the CTLA-4 containing protein is abatacept. In some embodiments, the IL-2 protein is aldesleukin.

[0338] In one embodiment, the CTLA4-containing protein is administered to the subject weekly on day 1 of week 1 (in other words, if the first administration of the CTLA4-containing protein is administered to the subject on day 1, then subsequent administrations of the CTLA4-containing protein occur on days 8, 15, 22, etc.), and the IL-2 protein is administered to the subject on day 1 of every other week beginning with week 3, or on day 1 of every other week (in other words, on days 15, 29, 53, etc.). In one embodiment, the IL-2 protein is administered to the subject on day 1 of the week of IL-2 protein administration for a series of consecutive days, e.g., daily for 2 consecutive days, daily for 3 consecutive days, daily for 4 consecutive days, or daily for 5 consecutive days. In one embodiment, the IL-2 protein is administered to the subject on day 1 of the week of IL-2 protein administration for a series of non-consecutive days, such as 2, 3, 4, 5, 6, or 7 non-consecutive days, independently separated by 1, 2, 3, 4, or 5 days. In some embodiments, the CTLA-4 containing protein is abatacept. In some embodiments, the IL-2 protein is aldesleukin.

[0339] In some embodiments, according to the methods provided herein, the CTLA4-containing protein is administered to the subject weekly in an amount ranging from 20 to 50 mg per week, e.g., as described in any of the embodiments provided herein. In an embodiment, according to the methods provided herein, the CTLA4-containing protein is administered to the subject weekly in an amount ranging from 20 mg per week, e.g., as described in any of the embodiments provided herein. In an embodiment, according to the methods provided herein, the CTLA4-containing protein is administered to the subject weekly in an amount ranging from 25 mg per week, e.g., as described in any of the embodiments provided herein. In an embodiment, according to the methods provided herein, the CTLA4-containing protein is administered to the subject weekly in an amount ranging from 30 mg per week, e.g., as described in any of the embodiments provided herein. In an embodiment, according to the methods provided herein, the CTLA4-containing protein is administered to the subject weekly in an amount ranging from 35 mg per week, e.g., as described in any of the embodiments provided herein. In some embodiments, according to the methods provided herein, a CTLA4-containing protein is administered to a subject weekly in an amount ranging from 40 mg per week, e.g., as described in any of the embodiments provided herein. In some embodiments, according to the methods provided herein, a CTLA4-containing protein is administered to a subject weekly in an amount ranging from 45 mg per week, e.g., as described in any of the embodiments provided herein. In some embodiments, according to the methods provided herein, a CTLA4-containing protein is administered to a subject weekly in an amount ranging from 50 mg per week, e.g., as described in any of the embodiments provided herein. In some embodiments, the CTLA4-containing protein is abatacept. In some embodiments, the IL-2 protein, e.g., aldesleukin, administered in combination with the method comprising weekly administration of a CTLA4-containing protein, e.g., abatacept, is administered in an amount ranging from 10,000 to 3,000,000 units.In some such embodiments, the IL-2 protein, e.g., aldesleukin, is administered in an amount ranging from 500,000 to 3,000,000 units. In some such embodiments, the IL-2 protein, e.g., aldesleukin, is administered in an amount ranging from 500,000 to 2,000,000 units. In some embodiments, the IL-2 protein, e.g., aldesleukin, is administered in an amount of 1,000,000 units.

[0340] In one aspect, there is provided a method of treating a disease or disorder, e.g., a disease or disorder described herein, e.g., a neurodegenerative or neuroinflammatory disease or disorder, in a subject in need thereof, comprising administering to the subject: i) abatacept; and ii) Aldesleukin and alleviating one or more symptoms associated with a neurodegenerative or neuroinflammatory disease or disorder in a treated subject.

[0341] In some embodiments, abatacept is administered by injection or infusion. In certain embodiments, abatacept is administered subcutaneously. In certain embodiments, abatacept is administered intravenously. In some embodiments, aldesleukin is administered by injection or infusion. In certain embodiments, aldesleukin is administered subcutaneously. In certain embodiments, aldesleukin is administered intravenously. In some embodiments, abatacept and aldesleukin are administered by injection or infusion. In certain specific embodiments, abatacept and aldesleukin are administered subcutaneously. In certain embodiments, abatacept and aldesleukin are administered intravenously.

[0342] In some embodiments, the CTLA-4 containing protein, e.g., abatacept, is administered to the subject once every two weeks. In certain embodiments, the CTLA-4 containing protein, e.g., abatacept, is administered subcutaneously to the subject once every two weeks. In some embodiments, the CTLA-4 containing protein, e.g., abatacept, is administered to the subject once every two weeks for 15 weeks. In certain embodiments, the CTLA-4 containing protein, e.g., abatacept, is administered subcutaneously to the subject once every two weeks for 15 weeks.

[0343] In some embodiments, the IL-2 protein, e.g., aldesleukin, is administered to a subject once per day for three consecutive days. In certain embodiments, the IL-2 protein, e.g., aldesleukin, is administered subcutaneously to a subject once per day for three consecutive days.

[0344] In one embodiment, the CTLA-4 containing protein, e.g., abatacept, is administered to the subject once every two weeks and the IL-2 protein, e.g., aldesleukin, is administered to the subject once per day for three consecutive days. In one embodiment, the CTLA-4 containing protein, e.g., abatacept, is administered subcutaneously to the subject once every two weeks and the IL-2 protein, e.g., aldesleukin, is administered subcutaneously to the subject once per day for three consecutive days.

[0345] In one embodiment, a CTLA-4 containing protein, e.g., abatacept, is administered to a subject once every two weeks and an IL-2 protein, e.g., aldesleukin, is administered to a subject once per day for three consecutive days beginning on the day that the CTLA-4 containing protein, e.g., abatacept, is administered to the subject. In one embodiment, a CTLA-4 containing protein, e.g., abatacept, is administered subcutaneously to a subject once every two weeks and an IL-2 protein, e.g., aldesleukin, is administered subcutaneously to a subject once per day for three consecutive days beginning on the day that the CTLA-4 containing protein, e.g., abatacept, is administered to a subject.

[0346] In one embodiment, a CTLA-4 containing protein, e.g., abatacept, is administered to a subject once every two weeks for 15 weeks, and an IL-2 protein, e.g., aldesleukin, is administered to the subject beginning in week 3, and the IL-2 protein is administered to the subject once per day for three consecutive days beginning on the day the CTLA-4 containing protein, e.g., abatacept, is administered to the subject subcutaneously once every two weeks for 15 weeks, and an IL-2 protein, e.g., aldesleukin, is administered to the subject beginning in week 3, and the IL-2 protein is administered to the subject subcutaneously once per day for three consecutive days beginning on the day the CTLA-4 containing protein, e.g., abatacept, is administered to the subject.

[0347] In some embodiments, about 5 mg to about 200 mg, about 10 mg to about 200 mg, about 15 mg to about 200 mg, about 20 mg to about 200 mg, about 25 mg to about 200 mg, about 50 mg to about 200 mg, about 50 mg to about 175 mg, about 50 mg to about 150 mg, or about 50 mg to about 125 mg of a CTLA-4-containing protein, such as abatacept, is administered to the subject. In certain embodiments, the CTLA-4-containing protein, such as abatacept, is administered subcutaneously to the subject.

[0348] In certain embodiments, about 50 mg of the CTLA-4 containing protein, e.g., abatacept, is administered to the subject. In a specific embodiment, about 50 mg of the CTLA-4 containing protein, e.g., abatacept, is administered to the subject in a volume of 0.4 mL. In certain embodiments, the CTLA-4 containing protein, e.g., abatacept, is administered subcutaneously to the subject.

[0349] In certain embodiments, about 87.5 mg of CTLA-4 containing protein, e.g., abatacept, is administered to the subject. In a specific embodiment, about 87.5 mg of CTLA-4 containing protein, e.g., abatacept, is administered to the subject in a volume of 0.7 mL. In certain embodiments, the CTLA-4 containing protein, e.g., abatacept, is administered subcutaneously to the subject.

[0350] In certain embodiments, about 125 mg of CTLA-4 containing protein, e.g., abatacept, is administered to the subject. In a specific embodiment, about 125 mg of CTLA-4 containing protein, e.g., abatacept, is administered to the subject in a volume of 1.0 mL. In certain embodiments, the CTLA-4 containing protein, e.g., abatacept, is administered subcutaneously to the subject.

[0351] In certain embodiments, about 1 x 10 4 ~ approx. 1x10 7 , about 5x10 4 ~ approx. 1x10 7 , Approx. 1x10 5 ~ approx. 1x10 7 , about 5x10 5 ~ approx. 1x10 7 , 5x10 5 ~about 5x10 6 , 5x10 5 ~about 4x10 6 , 5x10 5 ~about 3x10 6 , 5x10 5 ~about 2x10 6 , about 5x10 5 ~ approx. 1x10 6 Units of an IL-2 protein, such as aldesleukin, are administered to the subject. In certain embodiments, the IL-2 protein, such as aldesleukin, is administered subcutaneously to the subject.

[0352] In a specific embodiment, about 500,000 units to 3,000,000 units of an IL-2 protein, e.g., aldesleukin, are administered to the subject, e.g., subcutaneously. In a specific embodiment, about 500,000 units to 2,000,000 units of an IL-2 protein, e.g., aldesleukin, are administered to the subject, e.g., subcutaneously. In a specific embodiment, about 500,000 units to 1,000,000 units of an IL-2 protein, e.g., aldesleukin, are administered to the subject, e.g., subcutaneously.

[0353] In some embodiments, according to the methods provided herein, abatacept is administered in an amount ranging from 20 to 200 mg. In some embodiments, abatacept is administered in an amount ranging from 25 to 200 mg. In some embodiments, abatacept is administered in an amount ranging from 50 to 200 mg. In some embodiments, abatacept is administered in an amount ranging from 50 to 175 mg. In some embodiments, abatacept is administered in an amount ranging from 50 to 150 mg. In some embodiments, abatacept is administered in an amount ranging from 50 to 125 mg. In some embodiments, abatacept is administered in a 50 mg amount. In some embodiments, abatacept is administered in an 87.5 mg amount. In some embodiments, abatacept is administered in a 125 mg amount. In some embodiments, abatacept is administered subcutaneously in a volume of 0.1 to 2.0 mL. In some embodiments, abatacept is administered subcutaneously in a 0.4 mL volume. In some embodiments, abatacept is administered subcutaneously in a 0.7 mL volume. In some embodiments, abatacept is administered subcutaneously in a 1.0 mL volume. In some embodiments, abatacept is administered subcutaneously in a 50 mg amount in a 0.4 mL volume. In some embodiments, abatacept is administered subcutaneously in a 87.5 mg amount in a 0.7 mL volume. In some embodiments, abatacept is administered subcutaneously in a 125 mg amount in a 1.0 mL volume. In some embodiments, aldesleukin is administered in an amount ranging from 10,000 to 3,000,000 units. In some embodiments, aldesleukin is administered in an amount ranging from 500,000 to 3,000,000 units. In some embodiments, aldesleukin is administered in an amount ranging from 500,000 to 2,000,000 units. In some embodiments, aldesleukin is administered in an amount of 1,000,000 units. In some embodiments, aldesleukin is administered subcutaneously.

[0354] In some embodiments, according to the methods provided herein, abatacept is administered to the subject in an amount ranging from 20-50 mg per dose cycle for a plurality of dose cycles. In some embodiments, only abatacept is administered to the subject in the absence of IL-2 during one dose cycle of the plurality of dose cycles. In some embodiments, abatacept is administered in combination with IL-2 during one dose cycle of the plurality of dose cycles. In some embodiments, the plurality of dose cycles includes (i) a dose cycle in which only abatacept is administered to the subject in the absence of IL-2 during each dose cycle; and (ii) a dose cycle in which abatacept is administered in combination with IL-2 during each dose cycle. In one embodiment, the multiple dosage cycles include (i) dosage cycles in which only abatacept is administered to the subject in the absence of IL-2 in each dosage cycle; and (ii) dosage cycles in which abatacept is administered in combination with IL-2 in each dosage cycle, where the dosage cycles in (i) and (ii) are alternated in the multiple dosage cycles (e.g., a dosage cycle in which only abatacept is administered is followed by a dosage cycle in which abatacept is administered in combination with IL-2, which in turn is a dosage cycle in which abatacept is administered alone is followed by a dosage cycle in which abatacept is administered in combination with IL-2. Each dosage cycle in the multiple dosage cycles can be, for example, one week long. In one embodiment, the IL-2 protein is aldesleukin.

[0355] In one embodiment, according to the methods provided herein, abatacept is administered to a subject in an amount ranging from 20-50 mg per dosing cycle, e.g., 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, or 50 mg per dosing cycle, for multiple dosing cycles, wherein the multiple dosing cycles are administered according to the following dosing schedule: Cycle 1: abatacept alone in the absence of IL-2; Cycle 2: abatacept alone in the absence of IL-2; Cycle 3: abatacept in combination with IL-2; Cycle 4: abatacept alone in the absence of IL-2; wherein dosing cycles 3 and 4 are repeated for subsequent cycles, e.g., for a total of 6, 8, 10, 12, 16, 18, 20, or more cycles. In one embodiment, the IL-2 protein is aldesleukin.

[0356] In some embodiments, according to the methods provided herein, abatacept is administered to a subject once every two weeks. In some embodiments, abatacept is administered intravenously to a subject once every two weeks. In some embodiments, abatacept is administered subcutaneously to a subject once every two weeks. In some embodiments, abatacept is administered to a subject once every two weeks for 10-20 weeks. For example, in some embodiments, abatacept is administered to a subject once every two weeks for 12 weeks, 15 weeks, or 18 weeks. In some embodiments, abatacept is administered to a subject once every two weeks for 15 weeks. In some embodiments, abatacept is administered to a subject once daily for 2-5 consecutive days. For example, in some embodiments, abatacept is administered to a subject once daily for 2, 3, 4, or 5 consecutive days. In some embodiments, abatacept is administered to a subject once daily for 3 consecutive days. In some embodiments, abatacept is administered intravenously to a subject once daily for 2-5 consecutive days. In some embodiments, abatacept is administered subcutaneously to a subject once daily for 2-5 consecutive days. For example, in some embodiments, abatacept is administered subcutaneously to a subject once daily for 2, 3, 4, or 5 consecutive days. In some embodiments, abatacept is administered subcutaneously to a subject once daily for 3 consecutive days.

[0357] In some embodiments, according to the methods provided herein, aldesleukin is administered to a subject once a day for 2-5 consecutive days. For example, in some embodiments, aldesleukin is administered to a subject once a day for 2, 3, 4, or 5 consecutive days. In some embodiments, aldesleukin is administered to a subject once a day for 3 consecutive days. In some embodiments, aldesleukin is administered intravenously to a subject once a day for 2-5 consecutive days. In some embodiments, aldesleukin is administered subcutaneously to a subject once a day for 2-5 consecutive days. For example, in some embodiments, aldesleukin is administered subcutaneously to a subject once a day for 2, 3, 4, or 5 consecutive days. In some embodiments, aldesleukin is administered subcutaneously to a subject once a day for 3 consecutive days.

[0358] In some embodiments, according to the methods provided herein, abatacept is administered once every two weeks, and aldesleukin is administered once a day for 2-5 consecutive days, e.g., 3 consecutive days, from the day abatacept is administered. In some embodiments, abatacept and aldesleukin are administered subcutaneously. In some embodiments, abatacept is administered once every two weeks for 10-20 weeks, e.g., 15 weeks, with aldesleukin administration beginning in the third week; once aldesleukin administration begins, aldesleukin is administered once a day for 2-5 consecutive days, e.g., 3 consecutive days, from the day abatacept is administered. In some embodiments, abatacept and aldesleukin are administered subcutaneously.

[0359] In some embodiments, according to the methods provided herein, abatacept is administered to the subject one or more times during a dosing cycle, e.g., 1-10 times during a dosing cycle, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times during a dosing cycle. In some embodiments, abatacept is administered to the subject as a single dose on day 1 of the dosing cycle. In some embodiments, abatacept is administered to the subject daily for a series of consecutive days starting from day 1 of the dosing cycle. In some embodiments, abatacept is administered to the subject daily for two consecutive days starting from day 1 of the dosing cycle. In some embodiments, abatacept is administered to the subject daily for three consecutive days starting from day 1 of the dosing cycle. In some embodiments, abatacept is administered to the subject daily for four consecutive days starting from day 1 of the dosing cycle. In some embodiments, abatacept is administered to the subject daily for five consecutive days starting from day 1 of the dosing cycle. In some embodiments, abatacept is administered to the subject for a series of non-consecutive days starting from day 1 of a dosing cycle, e.g., a series of non-consecutive days, such as 2, 3, 4, 5, 6, 7, 8, 9 or 10 non-consecutive days independently separated by 1, 2, 3, 4 or 5 days.

[0360] In some embodiments, according to the methods provided herein, aldesleukin is administered to a subject one or more times during a dosing cycle, e.g., 1-10 times during a dosing cycle, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times during a dosing cycle. In some embodiments, aldesleukin is administered to a subject daily for a series of consecutive days starting from day 1 of a dosing cycle. In some embodiments, aldesleukin is administered to a subject daily for 2 consecutive days starting from day 1 of a dosing cycle. In some embodiments, aldesleukin is administered to a subject daily for 3 consecutive days starting from day 1 of a dosing cycle. In some embodiments, aldesleukin is administered to a subject daily for 4 consecutive days starting from day 1 of a dosing cycle. In some embodiments, aldesleukin is administered to a subject daily for 5 consecutive days starting from day 1 of a dosing cycle. In some embodiments, aldesleukin is administered to the subject for a series of non-consecutive days starting from day 1 of a dosing cycle, e.g., 2, 3, 4, 5, 6, 7, 8, 9 or 10 non-consecutive days independently separated by 1, 2, 3, 4 or 5 days.

[0361] In some embodiments, according to the methods provided herein, abatacept is administered to the subject as a single dose on day 1 of a dosing cycle. In some embodiments, abatacept is administered to the subject daily for 2-5 consecutive days, e.g., 3 consecutive days, starting from day 1 of the first dosing cycle. In some embodiments, aldesleukin is administered to the subject daily for 3 consecutive days starting from day 1 of the first dosing cycle. In some embodiments, aldesleukin is administered to the subject daily for 3 consecutive days starting from day 1 of the first dosing cycle. In some embodiments, aldesleukin is administered to the subject daily for 3 consecutive days starting from day 1 of the second dosing cycle. In some embodiments, the first dosing cycle is repeated 6 times, with each repeated dosing cycle beginning 14 days after day 1 of the previous dosing cycle.

[0362] In some embodiments, according to the methods provided herein, the dosing cycle is 2-6 weeks. In some embodiments, the dosing cycle is 2 weeks. In some embodiments, the dosing cycle is 3 weeks. In some embodiments, the dosing cycle is 4 weeks. In some embodiments, the dosing cycle is 5 weeks. In some embodiments, the dosing cycle is 6 weeks. In some embodiments, the dosing cycle is repeated 1-12 times. In some embodiments, the dosing cycle is repeated 10 times. In some embodiments, the dosing cycle is repeated 8 times. In some embodiments, the dosing cycle is repeated 6 times. In some embodiments, each repeat dosing cycle begins 10-28 days after day 1 of the previous dosing cycle. For example, in some embodiments, each repeat dosing cycle begins 14 days after day 1 of the previous dosing cycle. In some embodiments, each repeat dosing cycle begins 2-6 weeks after day 1 of the previous dosing cycle. In some embodiments, each repeat dosing cycle begins 2 weeks after day 1 of the previous dosing cycle. In some embodiments, each repeating dosing cycle begins 3 weeks after day 1 of the previous dosing cycle. In some embodiments, each repeating dosing cycle begins 4 weeks after day 1 of the previous dosing cycle. In some embodiments, each repeating dosing cycle begins 5 weeks after day 1 of the previous dosing cycle. In some embodiments, each repeating dosing cycle begins 6 weeks after day 1 of the previous dosing cycle.

[0363] In one aspect, a method of treating a disease or disorder, e.g., a disease or disorder described herein, e.g., a neurodegenerative or neuroinflammatory disease or disorder, in a subject in need thereof, comprising a dosing cycle beginning on day 1: i) a CTLA-4 containing protein; and ii) IL-2 protein Provided herein is a method for alleviating one or more symptoms associated with a neurodegenerative or neuroinflammatory disease or disorder in a treated subject, comprising administering to the subject a formulation comprising: The formulation is administered to the subject one or more times during a dosing cycle. The dosing cycle can be repeated one or more times. There can be a period between the completion of one dosing cycle and the start of the next dosing cycle. In one embodiment, the CTLA-4 containing protein is abatacept.

[0364] In one embodiment, the IL-2 protein is aldesleukin.In one embodiment, the CTLA-4 containing protein is abatacept and the IL-2 protein is aldesleukin.

[0365] For ease of description, the formulation may be referred to herein as a "CTLA-4-containing protein / IL-2 protein formulation" or an "IL-2 protein / CTLA-4 containing protein formulation." When the CTLA-4 containing protein is abatacept and the IL-2 protein is aldesleukin, the formulation may be referred to herein as an "abatacept / aldesleukin formulation" or an "aldesleukin / abatacept formulation."

[0366] In some embodiments, the formulation is administered to the subject by injection or infusion. In a specific embodiment, the formulation is administered to the subject subcutaneously. In a specific embodiment, the formulation is administered to the subject intravenously.

[0367] In certain embodiments of such methods, a dosing cycle comprises administering the formulation to the subject 1 to 10 times.

[0368] In a specific embodiment of the method described herein, the dosing cycle comprises administering the formulation to the subject on day 1 of the dosing cycle in a single dose. In a specific embodiment of such a method, the dosing cycle comprises administering the formulation to the subject daily for 2 consecutive days starting from day 1 of the dosing cycle. In a specific embodiment of such a method, the dosing cycle comprises administering the formulation to the subject daily for 3 consecutive days starting from day 1 of the dosing cycle. In a specific embodiment of such a method, the dosing cycle comprises administering the formulation to the subject daily for 4 consecutive days starting from day 1 of the dosing cycle. In a specific embodiment of such a method, the dosing cycle comprises administering the formulation to the subject daily for 5 consecutive days starting from day 1 of the dosing cycle.

[0369] In specific embodiments of the methods described herein, a dosing cycle comprises administering the formulation to a subject daily for at least two non-consecutive days. In one non-limiting embodiment, for example, the formulation is first administered to a subject on day 1, and then administered to a subject on day 3, 4, 5, 6, or 7 of a dosing cycle.

[0370] In certain embodiments of the methods described herein, the dosing cycle is repeated 1-12 times. In a specific embodiment, the dosing cycle is repeated 6 times. In certain embodiments, each repeating dosing cycle begins 10-28 days after day 1 of the previous dosing cycle. In certain embodiments, each repeating dosing cycle begins 10-28 days after completion of the previous dosing cycle. In a specific embodiment, each repeating dosing cycle begins 14 days after day 1 of the previous dosing cycle. In certain embodiments, each repeating dosing cycle begins 14 days after completion of the previous dosing cycle.

[0371] In certain embodiments of the methods described herein, a first dosing cycle comprises administering the formulation to a subject daily for three consecutive days beginning on day 1 of the dosing cycle, and the first dosing cycle is repeated six times, with each repeat dosing cycle beginning 14 days after day 1 of the previous dosing cycle.

[0372] In certain embodiments of the methods described herein, a dosing cycle comprises about 5 mg to about 125 mg of a CTLA-4-containing protein and about 3x10 4 ~about 3x10 7 In one embodiment of the methods described herein, a dosing cycle comprises administering to a subject a CTLA-4-containing protein / IL-2 protein formulation comprising about 5 mg to about 125 mg of abatacept and about 3x10 units of IL-2 protein. 4 ~about 3x10 7 The method includes administering to the subject an abatacept / aldesleukin formulation containing units of aldesleukin.

[0373] In certain embodiments of the methods described herein, a dosing cycle comprises about 8.75 mg to about 87.5 mg of abatacept and about 3x10 4 ~about 3x10 7 The method includes administering to the subject a formulation containing a unit of aldesleukin.

[0374] In certain embodiments of the methods described herein, a dosing cycle comprises about 29.17 mg of abatacept and about 1x10 5 In some embodiments of the methods described herein, a dosing cycle includes administering to a subject a formulation containing about 29.17 mg of abatacept and about 1x10 units of aldesleukin. 6 In some embodiments of the methods described herein, a dosing cycle includes administering to a subject a formulation containing about 29.17 mg of abatacept and about 1x10 units of aldesleukin. 7 The method includes administering to the subject a formulation containing a unit of aldesleukin.

[0375] In certain embodiments of the methods described herein, a dosing cycle comprises about 5 mg to about 50 mg of abatacept and about 3x10 4 ~about 3x10 7 The method includes administering to the subject a formulation containing a unit of aldesleukin.

[0376] In certain embodiments of the methods described herein, a dosing cycle comprises about 16.67 mg of abatacept and about 1x105 In some embodiments of the methods described herein, a dosing cycle includes administering to a subject a formulation containing about 16.67 mg of abatacept and about 1x10 units of aldesleukin. 6 In some embodiments of the methods described herein, a dosing cycle includes administering to a subject a formulation containing about 16.67 mg of abatacept and about 1x10 units of aldesleukin. 7 The method includes administering to the subject a formulation containing a unit of aldesleukin.

[0377] In certain embodiments of the methods described herein, a dosing cycle comprises about 12.5 mg to about 125 mg of abatacept and about 3x10 4 ~about 3x10 7 The method includes administering to the subject a formulation containing a unit of aldesleukin.

[0378] In one embodiment of the methods described herein, a dosing cycle comprises about 41.67 mg of abatacept and about 1x10 5 In some embodiments of the methods described herein, a dosing cycle comprises administering to a subject a formulation containing about 41.67 mg of abatacept and about 1x10 units of aldesleukin. 6 In some embodiments of the methods described herein, a dosing cycle comprises administering to a subject a formulation containing about 41.67 mg of abatacept and about 1x10 units of aldesleukin. 7 The method includes administering to the subject a formulation containing a unit of aldesleukin.

[0379] In certain embodiments of the methods described herein, a dosing cycle comprises administering the formulation to a subject daily for three consecutive days beginning on day 1 of the dosing cycle, the formulation comprising about 29.17 mg of abatacept and about 1x10 6 In a specific embodiment, the dosing cycle is repeated six times, with each repeated dosing cycle beginning 14 days after day 1 of the previous dosing cycle.

[0380] In some embodiments of the methods described herein, a total of 50 mg of abatacept and 3x10 5 In one embodiment of the methods described herein, a total of 50 mg of abatacept and 3x10 units of aldesleukin are administered to the subject in one or more doses of the abatacept / aldesleukin formulation per dosing cycle. 5 A unit of aldesleukin is administered to a subject in between 1 and 10 administrations of an abatacept / aldesleukin formulation. In certain embodiments, a dosing cycle comprises between 1 and 10 administrations of an abatacept / aldesleukin formulation as shown in Table 1A.

[0381] In some embodiments of the methods described herein, a total of 50 mg of abatacept and 3x10 6 In one embodiment of the methods described herein, a total of 50 mg of abatacept and 3x10 units of aldesleukin are administered to the subject in one or more doses of the abatacept / aldesleukin formulation per dosing cycle. 6 A unit of aldesleukin is administered to a subject in between 1 and 10 administrations of an abatacept / aldesleukin formulation. In certain embodiments, a dosing cycle comprises between 1 and 10 administrations of an abatacept / aldesleukin formulation as shown in Table 1B.

[0382] In some embodiments of the methods described herein, a total of 50 mg of abatacept and 3x10 7 In one embodiment of the methods described herein, a total of 50 mg of abatacept and 3x10 units of aldesleukin are administered to the subject in one or more doses of the abatacept / aldesleukin formulation per dosing cycle. 7 A unit of aldesleukin is administered to a subject in between 1 and 10 administrations of an abatacept / aldesleukin formulation. In certain embodiments, a dosing cycle comprises between 1 and 10 administrations of an abatacept / aldesleukin formulation as shown in Table 1C.

[0383] In one embodiment of the methods described herein, a total of 87.5 mg of abatacept and 3x10 5 In one embodiment of the methods described herein, a total of 87.5 mg of abatacept and 3x10 units of aldesleukin are administered to the subject in one or more doses of the abatacept / aldesleukin formulation per dosing cycle. 5 A unit of aldesleukin is administered to a subject in between 1 and 10 administrations of an abatacept / aldesleukin formulation. In certain embodiments, a dosing cycle comprises between 1 and 10 administrations of an abatacept / aldesleukin formulation as shown in Table 2A.

[0384] In one embodiment of the methods described herein, a total of 87.5 mg of abatacept and 3x10 6 In one embodiment of the methods described herein, a total of 87.5 mg of abatacept and 3x10 units of aldesleukin are administered to the subject in one or more doses of the abatacept / aldesleukin formulation per dosing cycle. 6 A unit of aldesleukin is administered to a subject in between 1 and 10 administrations of an abatacept / aldesleukin formulation. In certain embodiments, a dosing cycle comprises between 1 and 10 administrations of an abatacept / aldesleukin formulation as shown in Table 2B.

[0385] In one embodiment of the methods described herein, a total of 87.5 mg of abatacept and 3x10 7 In one embodiment of the methods described herein, a total of 87.5 mg of abatacept and 3x10 units of aldesleukin are administered to the subject in one or more doses of the abatacept / aldesleukin formulation per dosing cycle. 7 A unit of aldesleukin is administered to a subject in between 1 and 10 administrations of an abatacept / aldesleukin formulation. In certain embodiments, a dosing cycle comprises between 1 and 10 administrations of an abatacept / aldesleukin formulation as shown in Table 2C.

[0386] In one embodiment of the methods described herein, a total of 125 mg of abatacept and 3x10 5 In one embodiment of the methods described herein, a total of 125 mg of abatacept and 3x10 units of aldesleukin are administered to the subject in one or more doses of the abatacept / aldesleukin formulation per dosing cycle. 5 A unit of aldesleukin is administered to a subject in between 1 and 10 administrations of an abatacept / aldesleukin formulation. In certain embodiments, a dosing cycle comprises between 1 and 10 administrations of an abatacept / aldesleukin formulation as shown in Table 3A.

[0387] In one embodiment of the methods described herein, a total of 125 mg of abatacept and 3x10 6 In one embodiment of the methods described herein, a total of 125 mg of abatacept and 3x10 units of aldesleukin are administered to the subject in one or more doses of the abatacept / aldesleukin formulation per dosing cycle. 6 A unit of aldesleukin is administered to a subject in one or more administrations of an abatacept / aldesleukin formulation. In certain embodiments, a dosing cycle comprises 1 to 10 administrations of an abatacept / aldesleukin formulation as shown in Table 3B.

[0388] In one embodiment of the methods described herein, a total of 125 mg of abatacept and 3x10 7 In one embodiment of the methods described herein, a total of 125 mg of abatacept and 3x10 units of aldesleukin are administered to the subject in one or more doses of the abatacept / aldesleukin formulation per dosing cycle. 7 A unit of aldesleukin is administered to a subject in one or more administrations of an abatacept / aldesleukin formulation. In certain embodiments, a dosing cycle comprises 1 to 10 administrations of an abatacept / aldesleukin formulation as shown in Table 3C.

[0389] Table 1 (50 mg of abatacept / dosage cycle. A=3x105 Units of aldesleukin / dosage cycle; B=3x10 6 Units of aldesleukin / dosage cycle; C=3x10 7 Units of aldesleukin / dosage cycle; #dosage cycles = number of administrations of the formulation (number of doses) per dosing cycle [Table 1]

[0390] Table 2 (87.5 mg of abatacept / dosage cycle. A=3x10 5 Units of aldesleukin / dosage cycle; B=3x10 6 Units of aldesleukin / dosage cycle; C=3x10 7 Units of aldesleukin / dosage cycle; #dosage cycles = number of administrations of the formulation (number of doses) per dosing cycle [Table 2]

[0391] Table 3 (125 mg of abatacept / dosage cycle. A=3x10 5 Units of aldesleukin / dosage cycle; B=3x10 6 Units of aldesleukin / dosage cycle; C=3x10 7 Units of aldesleukin / dosage cycle; #dosage cycles = number of administrations of the formulation (number of doses) per dosing cycle [Table 3]

[0392] In certain embodiments, the methods described herein further comprise administering to the subject a CTLA-4 containing protein formulation, e.g., an abatacept formulation, prior to the first administration of a CTLA-4 containing / IL-2 protein formulation, e.g., an abatacept / aldesleukin formulation, to the subject. In certain embodiments, the methods described herein further comprise administering to the subject a CTLA-4 containing protein formulation, e.g., an abatacept formulation, 14 days prior to day 1 of the first dosing cycle, i.e., 14 days prior to the first administration of a CTLA-4 containing / IL-2 protein formulation, e.g., an abatacept / aldesleukin formulation, to the subject.

[0393] In a specific embodiment, the CTLA-4-containing protein formulation contains 50 mg to 125 mg of CTLA-4-containing protein, for example, 50 mg of CTLA-4-containing protein, 87.5 mg of CTLA-4-containing protein, or 125 mg of CTLA-4-containing protein. In a specific embodiment, the abatacept formulation contains 50 mg to 125 mg of abatacept, for example, 50 mg of abatacept, 87.5 mg of abatacept, or 125 mg of abatacept. In an embodiment, the CTLA-4-containing protein formulation, for example, the abatacept formulation, is administered to the subject by injection or infusion. In an embodiment, the CTLA-4-containing protein formulation, for example, the abatacept formulation, is administered to the subject subcutaneously or intravenously.

[0394] In some embodiments, according to the methods provided herein, a dosing cycle comprises administering the formulation to a subject 1-10 times. In some embodiments, a dosing cycle comprises administering a single dose of the formulation to a subject on day 1 of the dosing cycle. In some embodiments, a dosing cycle comprises administering the formulation to a subject daily for 2 consecutive days starting from day 1 of the dosing cycle. In some embodiments, a dosing cycle comprises administering the formulation to a subject daily for 3 consecutive days starting from day 1 of the dosing cycle. In some embodiments, a dosing cycle comprises administering the formulation to a subject daily for 4 consecutive days starting from day 1 of the dosing cycle. In some embodiments, a dosing cycle comprises administering the formulation to a subject daily for 5 consecutive days starting from day 1 of the dosing cycle. In some embodiments, a dosing cycle comprises administering the formulation to a subject daily for 6 consecutive days starting from day 1 of the dosing cycle. In some embodiments, a dosing cycle comprises administering the formulation to a subject daily for 7 consecutive days starting from day 1 of the dosing cycle. In some embodiments, the dosing cycle is repeated six times, with each repeating dosing cycle beginning 14 days after day 1 of the previous dosing cycle. In some embodiments, the first dosing cycle comprises administering the formulation to the subject daily for 2-5 consecutive days, e.g., 3 consecutive days, beginning on day 1 of the dosing cycle, and the first dosing cycle is repeated six times, with each repeating dosing cycle beginning 14 days after day 1 of the previous dosing cycle.

[0395] In some embodiments, according to the methods provided herein, the method further comprises administering to the subject an abatacept formulation 14 days prior to day 1 of the first dosing cycle, the abatacept formulation comprising abatacept. In some embodiments, the abatacept formulation comprises 50 mg to 125 mg of abatacept. In some embodiments, the abatacept formulation comprises 87.5 mg of abatacept. In some embodiments, the abatacept is administered subcutaneously in a volume of 0.1 to 2.0 mL. In some embodiments, the abatacept is administered subcutaneously in a volume of 0.4 mL. In some embodiments, the abatacept is administered subcutaneously in a volume of 0.7 mL. In some embodiments, the abatacept is administered subcutaneously in a volume of 1.0 mL. In some embodiments, the abatacept is administered subcutaneously in an amount of 50 mg in a volume of 0.4 mL. In some embodiments, the abatacept formulation is administered by injection or infusion. In some embodiments, the abatacept formulation is administered subcutaneously. In some embodiments, the abatacept formulation is administered intravenously. In some embodiments, the abatacept is administered subcutaneously in an amount of 87.5 mg in a volume of 0.7 mL. In some embodiments, the abatacept is administered subcutaneously in an amount of 125 mg in a volume of 1.0 mL.

[0396] In certain embodiments, the methods of treatment provided herein comprise administering to a subject in need of treatment a pharmaceutical composition described herein.

[0397] In some embodiments, the subject is diagnosed with or suspected of having a disorder associated with Treg dysfunction. In some embodiments, the subject is diagnosed with or suspected of having a disorder associated with Treg deficiency. In some embodiments, the subject is diagnosed with or suspected of having a condition driven by a T cell response.

[0398] In some embodiments, the subject is diagnosed with or suspected of having a neurodegenerative disease, hi some embodiments, the subject is diagnosed with or suspected of having Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, or frontotemporal dementia.

[0399] In some embodiments, the subject is diagnosed with or suspected of having a disorder that would benefit from downregulation of the immune system.

[0400] In some embodiments, the subject is diagnosed with or suspected of having an autoimmune disease, which may be, for example, systemic sclerosis (scleroderma), polymyositis, ulcerative colitis, inflammatory bowel disease, Crohn's disease, celiac disease, multiple sclerosis (MS), rheumatoid arthritis (RA), type I diabetes, psoriasis, dermatomyositis, systemic lupus erythematosus, cutaneous lupus, myasthenia gravis, autoimmune nephropathy, autoimmune hemolytic anemia, autoimmune cytopenia, autoimmune hepatitis, autoimmune uveitis, alopecia, thyroiditis, or pemphigus.

[0401] In some embodiments, the subject is diagnosed with or suspected of having heart failure or ischemic cardiomyopathy. In some embodiments, the subject is diagnosed with or suspected of having graft-versus-host disease, for example, after receiving an organ transplant (such as a kidney or liver transplant) or after receiving a stem cell transplant (such as a hematopoietic stem cell transplant).

[0402] In some embodiments, the subject is diagnosed with or suspected of having neuroinflammation, which may be associated with, for example, 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.

[0403] In some embodiments, the subject has been diagnosed with or is suspected of having carditis, eg, carditis associated with atherosclerosis, myocardial infarction with heart failure, ischemic cardiomyopathy.

[0404] In some embodiments, the subject is diagnosed with or suspected of having chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). In some embodiments, the subject is diagnosed with or suspected of having acute inflammatory demyelinating polyneuropathy (AIDP). In some embodiments, the subject is diagnosed with or suspected of having Guillain-Barre syndrome (GBS).

[0405] In some embodiments, the subject has had a stroke.

[0406] In some embodiments, the subject has been diagnosed with or is suspected of having cancer, eg, a hematological cancer.

[0407] In some embodiments, the subject is diagnosed with or suspected of having asthma.

[0408] In some embodiments, the subject has been diagnosed with or is suspected of having eczema.

[0409] In some embodiments, the subject is diagnosed with or suspected of having a disorder associated with overactivation of the immune system.

[0410] In some embodiments, the subject is diagnosed with or suspected of having a tregopathy, which may be caused by loss-of-function mutations in the FOXP3, CD25, cytotoxic T-lymphocyte-associated antigen 4 (CTLA4), LPS-responsive beige-like anchor protein (LRBA), or BTB domain and CNC homolog 2 (BACH2) genes, or gain-of-function mutations in signal transducer and activator of transcription 3 (STAT3).

[0411] (5.3.1 Method for assessing therapeutic efficacy) The efficacy of the therapeutic methods provided herein can be assessed by monitoring the clinical signs and symptoms of the disease being treated.

[0412] The efficacy of the treatment methods described herein can be measured 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, about 120 weeks, about 140 weeks, about 160 weeks, about 180 weeks, about 190 weeks, about 210 weeks, about 220 weeks, about 230 weeks, about 240 weeks, about 250 weeks, about 260 weeks, about 270 weeks, about 280 weeks, about 290 weeks, about 300 weeks, about 310 weeks, about 320 weeks, about 330 weeks, about 340 weeks, about 350 weeks, about 360 weeks, about 370 weeks, about 380 weeks, about 390 weeks, about 400 weeks, about 410 weeks, about 420 weeks, about 430 weeks, about 440 weeks, about 450 weeks, about 460 weeks, about 470 weeks, about 480 weeks, about 490 weeks, about 520 weeks, about 560 weeks, about 520 weeks, about 560 weeks, about 540 weeks, about 560 weeks, about 580 weeks, about 590 weeks, about 600 weeks, about 600 weeks, about 610 weeks, about 620 weeks, about 630 weeks, about 640 weeks, about 650 weeks, about 660 weeks, about 670 weeks The evaluation may be performed at about weeks, 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 years, 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.

[0413] In some embodiments, the therapeutic methods provided herein result in a change in Mini Mental State Examination (MMSE) score compared to baseline. In the context of evaluating the efficacy of a therapeutic method, the term "baseline" refers to a measurement taken before treatment. The MMSE score measures overall Alzheimer's disease symptoms. In some embodiments, an increase in the MMSE score compared to baseline in a subject treated according to the methods provided herein indicates an improvement in symptoms. In other embodiments, the MMSE score remains unchanged compared to baseline in a subject treated according to the methods provided herein.

[0414] In some embodiments, the treatment methods provided herein result in a change in Appel ALS score compared to baseline. In the context of evaluating the efficacy of a treatment method, the term "baseline" refers to a measurement taken before treatment. The Appel ALS score measures the overall progression of a disorder or functional change. In some embodiments, a decrease in the Appel ALS score compared to baseline in a subject treated according to the methods provided herein indicates an improvement in symptoms. In other embodiments, the Appel ALS score remains unchanged compared to baseline in a subject treated according to the methods provided herein.

[0415] In some embodiments, the treatment methods provided herein result 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 impairment or functional changes. In some embodiments, an increase in the ALSFRS-R score compared to baseline in a subject treated according to the methods provided herein indicates an improvement in symptoms. In other embodiments, the Appel ALSFRS-R score remains unchanged compared to baseline in a subject treated according to the methods provided herein.

[0416] In some embodiments, the treatment methods provided herein cause changes in forced vital capacity (FVC; the strength of the muscle used with exhalation) compared to baseline, with the highest number being the strongest measurement.In some embodiments, FVC increases in the subject treated according to the methods provided herein compared to baseline.In other embodiments, FVC does not change in the subject treated according to the methods provided herein compared to baseline.

[0417] In some embodiments, the treatment methods provided herein cause a change in maximum inspiratory pressure (MIP; the strength of the muscle used with inspiration) compared to baseline, with the highest number being the strongest measurement.In some embodiments, MIP increases in subjects treated according to the methods provided herein compared to baseline.In other embodiments, MIP does not change in subjects treated according to the methods provided herein compared to baseline.

[0418] In some embodiments, the treatment methods provided herein result in a change in the Neuropsychiatric Inventory Questionnaire (NPI-Q) compared to baseline. The NPI-Q provides an assessment of symptom severity and distress for each reported symptom, with total severity and distress scores reflecting the sum of the individual domain scores. In some embodiments, the NPI-Q score is reduced compared to baseline in subjects treated according to the methods provided herein. In other embodiments, the NPI-Q score is unchanged compared to baseline in subjects treated according to the methods provided herein.

[0419] In some embodiments, the methods of treatment provided herein reduce the frequency of GI symptoms, anaphylaxis, or seizures compared to baseline.

[0420] In some embodiments, the treatment methods provided herein result in a change in 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 are decreased in subjects treated according to the methods provided herein compared to baseline. In other embodiments, the levels of CSF amyloid and / or CSF tau protein are unchanged in subjects treated according to the methods provided herein compared to baseline.

[0421] In some embodiments, the treatment methods provided herein result in a change in the Clinical Dementia Rating (CDR) compared to baseline. The CDR assesses memory, orientation, judgment and problem solving, community problems, home and hobbies, and personal care, followed by a global rating ranging from 0-no impairment to 3-severe impairment. In some embodiments, the CDR is reduced compared to baseline in subjects treated according to the methods provided herein. In other embodiments, the CDR is unchanged compared to baseline in subjects treated according to the methods provided herein.

[0422] In some embodiments, the treatment methods provided herein result in a change in Alzheimer's Disease Assessment Scale (ADAS)-cog13 score compared to baseline. ADAS-cog tests cognitive ability, with an upper limit of 85 (low performance) and a lower limit of zero (best performance). In some embodiments, the ADAS-cog13 score is reduced in subjects treated according to the methods provided herein compared to baseline. In other embodiments, the ADAS-cog13 score is unchanged in subjects treated according to the methods provided herein.

[0423] (5.4 Composition) In one aspect, provided herein is a pharmaceutical composition comprising a CTLA-4 containing protein and one or more doses of an IL-2 protein (a "CTLA-4 containing protein / IL-2 protein dose"). In certain embodiments, provided herein is a pharmaceutical composition comprising abatacept and one or more doses of aldesleukin (an "abatacept / aldesleukin dose").

[0424] In one embodiment, a pharmaceutical composition comprising one or more abatacept / aldesleukin doses is provided herein, the abatacept / aldesleukin dose being between 5 mg and 125 mg of abatacept and 3x10 4 ~3x10 7 Contains units of aldesleukin.

[0425] In certain embodiments, pharmaceutical compositions comprising one or more abatacept / aldesleukin doses are provided herein, the abatacept / aldesleukin dose being 8.75-87.5 mg of abatacept and 3x10 4 ~3x10 7 In a specific embodiment, a pharmaceutical composition is provided herein that includes one or more abatacept / aldesleukin doses, the abatacept / aldesleukin doses being 29.17 mg abatacept and 1x10 5 Units of Aldesleukin, 1x10 6 Units of Aldesleukin or 1x107 In a specific embodiment, a pharmaceutical composition is provided herein that includes one or more abatacept / aldesleukin doses, the abatacept / aldesleukin doses being 29.17 mg abatacept and 1x10 6 Contains units of aldesleukin.

[0426] In certain embodiments, pharmaceutical compositions comprising one or more abatacept / aldesleukin doses are provided herein, the abatacept / aldesleukin doses being between 5 mg and 50 mg of abatacept and 3x10 4 ~3x10 7 In a specific embodiment, a pharmaceutical composition is provided herein that includes one or more abatacept / aldesleukin doses, the abatacept / aldesleukin doses being 16.67 mg abatacept and 1x10 5 Units of Aldesleukin, 1x10 6 Units of Aldesleukin or 1x10 7 In a specific embodiment, a pharmaceutical composition is provided herein that includes one or more abatacept / aldesleukin doses, the abatacept / aldesleukin doses being 16.67 mg abatacept and 1x10 6 Contains units of aldesleukin.

[0427] In certain embodiments, pharmaceutical compositions comprising one or more abatacept / aldesleukin doses are provided herein, the abatacept / aldesleukin doses being 12.5 mg to 125 mg of abatacept and 3x10 4 ~3x10 7 In a specific embodiment, a pharmaceutical composition is provided herein that includes one or more abatacept / aldesleukin doses, the abatacept / aldesleukin doses being 41.67 mg abatacept and 1x10 5 Units of Aldesleukin, 1x10 6 Units of Aldesleukin or 1x10 7In a specific embodiment, a pharmaceutical composition is provided herein that includes one or more abatacept / aldesleukin doses, the abatacept / aldesleukin doses being 41.67 mg abatacept and 1x10 6 Contains units of aldesleukin.

[0428] In certain embodiments, the pharmaceutical compositions provided herein comprise one or more abatacept / aldesleukin doses as shown in Table 4. The shaded numbers correspond to the amount of abatacept (mg) per dose, and the unshaded numbers correspond to the amount of aldesleukin (units) per dose. Each pair of shaded (top) and unshaded (bottom) values ​​corresponds to the amount of abatacept and aldesleukin in a particular dose. For example, in the top left of the table, 50 (shaded, top) and 3x10 5 (Unshaded, bottom) 50mg abatacept / 3x10 5 This refers to the unit dose of aldesleukin.

[0429] Table 4. Abatacept / Aldesleukin Dosage [Table 4]

[0430] In one embodiment, provided herein is a pharmaceutical composition comprising a CTLA-4-containing protein and an IL-2 protein in a mass ratio of 270:1 to 680:1 (CTLA4-containing protein:Il-2 protein). In some embodiments, provided herein is a pharmaceutical composition comprising a CTLA-4-containing protein and an IL-2 protein in a mass ratio of 450:1 to 500:1 (CTLA4-containing protein:Il-2 protein). In one embodiment, the mass ratio is 450:1, 455:1, 460:1, 465:1, 470:1, 475:1, 477:1, 480:1, 485:1, 490:1, 495:1, or 500:1 (CTLA4-containing protein:Il-2 protein). In one embodiment, the mass ratio is 480:1 (CTLA4-containing protein:Il-2 protein).

[0431] In some embodiments, provided herein are pharmaceutical compositions comprising abatacept and aldesleukin in a mass ratio of 270:1 to 680:1 (abatacept:aldesleukin). In some embodiments, provided herein are pharmaceutical compositions comprising abatacept and aldesleukin in a mass ratio of 450:1 to 500:1 (abatacept:aldesleukin). In some embodiments, the mass ratio is 450:1, 455:1, 460:1, 465:1, 470:1, 475:1, 477:1, 480:1, 485:1, 490:1, 495:1, or 500:1 (abatacept:aldesleukin). In some embodiments, the mass ratio is 480:1 (abatacept:aldesleukin). It will be understood that the standard quantitative measure of IL-2 is the International Unit (IU), which is based not on protein mass but on activity in biological assays such as those established by the World Health Organization's First International Standard for Interleukin-2 (human). In practice, however, where the manufacture of IL-2 products is standardized, conversion between drug mass and units is routinely possible. For example, for proleukin products, the conversion is 18x10 6 One IU is equivalent to 1.1 mg of protein.

[0432] In certain embodiments, a pharmaceutical composition comprising one or more CTLA4-containing protein / IL-2 protein doses described herein is in lyophilized form, e.g., as a lyophilized powder or lyophilized cake. In certain embodiments, a pharmaceutical composition comprising one or more abatacept / aldesleukin doses described herein is in lyophilized form, e.g., as a lyophilized powder or lyophilized cake.

[0433] In certain embodiments, the pharmaceutical composition comprising one or more CTLA4-containing protein / IL-2 protein doses described herein is a solution, e.g., an aqueous solution. In specific embodiments, the one or more CTLA4-containing protein / IL-2 protein doses are present in the pharmaceutical composition at a concentration of 1 CTLA4-containing protein / IL-2 protein dose / 0.4 ml, 1 CTLA4-containing protein / IL-2 protein dose / 0.7 ml, 1 CTLA4-containing protein / IL-2 protein dose / 1.0 ml, 1 CTLA4-containing protein / IL-2 protein dose / 1.5 ml, or 1 CTLA4-containing protein / IL-2 protein dose / 2.0 ml.

[0434] In certain embodiments, the pharmaceutical composition comprising one or more abatacept / aldesleukin doses described herein is a solution, e.g., an aqueous solution. In specific embodiments, the one or more abatacept / aldesleukin doses are present in the pharmaceutical composition in a concentration of 1 abatacept / aldesleukin dose / 0.4 ml, 1 abatacept / aldesleukin dose / 0.7 ml, 1 abatacept / aldesleukin dose / 1.0 ml, 1 abatacept / aldesleukin dose / 1.5 ml, or 1 abatacept / aldesleukin dose / 2.0 ml.

[0435] In some embodiments, pharmaceutical compositions comprising one or more CTLA4 containing protein / IL-2 protein doses described herein are suitable for subcutaneous administration. In some embodiments, pharmaceutical compositions comprising one or more CTLA4 containing protein / IL-2 protein doses described herein are suitable for intravenous administration.

[0436] In some embodiments, pharmaceutical compositions comprising one or more abatacept / aldesleukin doses described herein are suitable for subcutaneous administration. In some embodiments, pharmaceutical compositions comprising one or more abatacept / aldesleukin doses described herein are suitable for intravenous administration.

[0437] In some embodiments, provided herein are pharmaceutical compositions comprising: i) a therapeutically effective amount of a CTLA4-containing protein; ii) a therapeutically effective amount of an IL-2 protein; and iii) one or more inactive ingredients, including a pharma- ceutical acceptable salt, excipient, or carrier. In some embodiments, the therapeutically effective amount of the CTLA4-containing protein is in the range of 25-200 mg, e.g., 25-200 mg, 50-200 mg, 50-175 mg, 50-150 mg, or 50-125 mg. In some embodiments, the therapeutically effective amount of the CTLA4-containing protein is 50 mg. In some embodiments, the therapeutically effective amount of the CTLA4-containing protein is 87.5 mg. In some embodiments, the therapeutically effective amount of the CTLA4-containing protein is 125 mg. In some embodiments, the therapeutically effective amount of the IL-2 protein is in the range of 10,000-3,000,000 units, e.g., 500,000-3,000,000 units, or 500,000-2,000,000 units. In some embodiments, the therapeutically effective amount of IL-2 protein is 1,000,000 units. In some embodiments, the therapeutically effective amount of IL-2 protein is 2,000,000 units. In some embodiments, the therapeutically effective amount of IL-2 protein is 3,000,000 units. In some embodiments, the therapeutically effective amount of IL-2 protein is 4,000,000 units. In some embodiments, the therapeutically effective amount of IL-2 protein is 5,000,000 units.

[0438] In some embodiments, provided herein are pharmaceutical compositions that include one or more inactive ingredients, including i) a therapeutically effective amount of abatacept, ii) a therapeutically effective amount of aldesleukin; and iii) a pharma- ceutical acceptable salt, excipient, or carrier. In some embodiments, the therapeutically effective amount of abatacept is in the range of 25-200 mg, e.g., 25-200 mg, 50-200 mg, 50-175 mg, 50-150 mg, or 50-125 mg. In some embodiments, the therapeutically effective amount of abatacept is 50 mg. In some embodiments, the therapeutically effective amount of abatacept is 87.5 mg. In some embodiments, the therapeutically effective amount of abatacept is 125 mg. In some embodiments, the therapeutically effective amount of aldesleukin is in the range of 10,000-3,000,000 units, e.g., 500,000-3,000,000 units, or 500,000-2,000,000 units. In some embodiments, the therapeutically effective amount of aldesleukin is 1,000,000 units. In some embodiments, the therapeutically effective amount of aldesleukin is 2,000,000 units. In some embodiments, the therapeutically effective amount of aldesleukin is 3,000,000 units. In some embodiments, the therapeutically effective amount of aldesleukin is 4,000,000 units. In some embodiments, the therapeutically effective amount of aldesleukin is 5,000,000 units.

[0439] An effective amount, e.g., an effective amount of abatacept or aldesleukin, refers to an amount sufficient to produce a desired result. An effective amount can refer, for example, to the amount in a dose, e.g., the amount of abatacept or aldesleukin, administered to a subject as part of a dosing regimen that produces a desired result. Such a dosing regimen can include administration of a single dose or administration of two or more doses, e.g., multiple doses. Such a dosing regimen can include, for example, a single dosing cycle or two or more dosing cycles, each of which can include administration of a single dose or administration of two or more doses, e.g., multiple doses.

[0440] In some embodiments, the one or more inactive ingredients included in the pharmaceutical composition provided herein include a pharma- ceutically acceptable salt, excipient, or carrier selected from the group consisting of sodium chloride, sodium dodecyl sulfate, monobasic sodium phosphate, dibasic sodium phosphate, maltose, mannitol, poloxamer, or sucrose. In some embodiments, the pharmaceutical composition is a lyophilized powder. In some embodiments, the pharmaceutical composition is a solution. For example, in some embodiments, the solution is an aqueous solution.

[0441] In certain embodiments, the CTLA4-containing protein / IL-2 protein pharmaceutical compositions, such as the abatacept / aldesleukin pharmaceutical compositions provided herein, are suitable for self-administration (e.g., dermal administration) by a subject using, for example, a pre-filled syringe, an injection device (e.g., the INJECT-EASE™ or GENJECT™ device), an infusion pump (e.g., the Accu-Chek™ infusion pump), an injector pen (e.g., the GENPEN™ injector pen), a needleless device (e.g., the MEDDECTOR™ or BIOJECTOR™ needleless device), or an autoinjector (e.g., the ClickJect™ autoinjector).

[0442] In some embodiments, the pharmaceutical composition of CTLA4 containing protein / IL-2 protein, e.g., abatacept / aldesleukin, is administered using an autoinjector, which may be, for example, 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). Those skilled in the art will appreciate that in some embodiments, when using an autoinjector, the subject may activate drug delivery without actuating a push button (e.g., simply by applying pressure to the injection site). In some embodiments, the autoinjector used to administer the pharmaceutical composition disclosed herein may be a device that replaces in whole or in part the activities involved in drug delivery from a standard syringe. By way of non-limiting example, these activities may include removing the protective syringe cap, inserting the needle into the patient's skin, injecting the drug, removing the needle, shielding the needle, and preventing the device from being reused.

[0443] In some embodiments, the self-administration device, e.g., an injection device (e.g., an autoinjector, an autoinjector pen, etc.), is mechanical. In some embodiments, the injection device (e.g., an autoinjector, an autoinjector pen, etc.), is electronic. Such an injection device may be provided separately from the pharmaceutical composition 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 a cassette or cartridge.

[0444] In some embodiments, a device suitable for self-administration, e.g., subcutaneous administration, of a pharmaceutical composition disclosed herein is provided in a disposable container (e.g., a disposable vial, ampoule, syringe, or autoinjector). In some embodiments, the disposable container can be easily disposed of. In some embodiments, an injection device suitable for self-administration, e.g., subcutaneous administration, of a pharmaceutical composition disclosed herein can be provided pre-filled with the pharmaceutical composition held in a reservoir within the device, and the entire device can be discarded once the reservoir is emptied of the pharmaceutical composition.

[0445] In some embodiments, devices suitable for self-administration, e.g., subcutaneous administration, of the pharmaceutical compositions disclosed herein are reusable. As a non-limiting example, in some embodiments, a reusable autoinjector delivery device can utilize a replaceable cartridge containing the pharmaceutical composition, and once the pharmaceutical composition in 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 containing the pharmaceutical composition.

[0446] In certain embodiments, any pen and / or autoinjector injection device known in the art can be used for subcutaneous delivery of the pharmaceutical compositions disclosed herein.

[0447] (5.5 Additional Therapy) In some embodiments, a subject treated according to the methods of treatment described herein further receives one or more additional therapies or multiple additional therapies known in the art for treating diseases, such as neurodegenerative and neuroinflammatory diseases.

[0448] In some embodiments, a subject treated according to the methods described herein receives one or more additional therapies for the treatment of Alzheimer's disease. Additional therapies for the treatment of Alzheimer's disease may include an acetylcholinesterase inhibitor (e.g., donepezil (Aricept®), galantamine (Razadyne®), or rivastigmine (Exelon®)) or an NMDA receptor antagonist (e.g., memantine (Acatinol®, Axula®, Ebixa® / Abixa®, MemoX®, and Namenda®). Additional therapies may include anti-inflammatory agents (e.g., nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, indomethacin, and sulindac sulfide), neuronal death-associated protein kinase (DAPK) inhibitors such as derivatives of 3-aminopyridazine, cyclooxygenase (COX-1 and 2) inhibitors, or antioxidants such as vitamins C and E.

[0449] In some embodiments, a subject treated according to the methods described herein receives one or more additional therapies for the treatment of ALS. Additional therapies for the treatment of ALS can include riluzole (Rilutek®) or riluzole (Rilutek®).

[0450] In some embodiments, a subject treated according to the methods described herein receives one or more additional therapies, which may include, but are not limited to, the following:

[0451] (a) TNF-alpha inhibitors (e.g., infliximab, adalimumab (Humira®), etanercept, golimumab, or certolizumab);

[0452] (b) an IL-6 inhibitor (e.g., siltuximab, tocilizumab, olokizumab, ersilimomab, clazakizumab, or sirukumab);

[0453] (c) an IL-23 inhibitor (e.g., tildrakizumab, guselkumab, or risankizumab);

[0454] (d) an IL-17 inhibitor (e.g., secukinumab, ixekizumab, or brodalumab);

[0455] (e) IL-12 / IL-23 subunit p40 inhibitors (e.g., ustekinumab or briakinumab);

[0456] (f) an IL-1 inhibitor (e.g., anakinra (Kineret®), canakinumab, or rilonacept);

[0457] (g) C3-targeted complement inhibitors (e.g., pegcetacoplan);

[0458] (h) C5-targeted complement inhibitors (e.g., ravulizumab or eculizumab);

[0459] (i) a JAK inhibitor (e.g., baricitinib, tofacitinib, or upadacitinib);

[0460] (j) anti-CD40 CD40L (e.g., tolarizumab, dapirorizumab pegol, or ruplizumab); or

[0461] (k) CD14 inhibitors (e.g., IC14).

[0462] In some embodiments, the subject treated according to the therapeutic methods described herein further receives Treg cell therapy, e.g., as described in WO 2021 / 113685 A2, which is incorporated herein in its entirety for all purposes.

[0463] In some embodiments, subjects treated according to the therapeutic methods described herein are further administered extracellular vesicles (EVs) derived from ex vivo expanded human Tregs as a therapy ("Treg EV therapy"). Treg EV therapy is described, for example, in International Application PCT / US2022 / 017990, filed February 25, 2022, which is incorporated herein in its entirety for all purposes.

[0464] In one aspect, a method of treating a disease or disorder, e.g., a disease or disorder described herein, e.g., a neurodegenerative or neuroinflammatory disease or disorder, in a subject in need thereof, comprising administering to the subject i) IL-2 proteins (e.g., aldesleukin); and ii) Add-on therapy and alleviating one or more symptoms associated with a neurodegenerative or neuroinflammatory disease or disorder in a treated subject, wherein the additional therapy is selected from the group consisting of: (a) a TNF-alpha inhibitor (e.g., infliximab, adalimumab (Humira®), etanercept, golimumab, or certolizumab); (b) an IL-6 inhibitor (e.g., siltuximab, tocilizumab, olokizumab, ersilimomab, clazakizumab, or sirukumab); (c) an IL-23 inhibitor (e.g., tildrakizumab, guselkumab, or risankizumab); (d) a IL-23 inhibitor (e.g., tildrakizumab, guselkumab, or risankizumab); (e) IL-17 inhibitors (e.g., secukinumab, ixekizumab, or brodalumab); (e) IL-12 / IL-23 subunit p40 inhibitors (e.g., ustekinumab or briakinumab); (f) IL-1 inhibitors (e.g., anakinra (Kineret®), canakinumab, or rilonacept); (g) C3-targeted complement inhibitors (e.g., pegcetacoplan); (h) C5-targeted complement inhibitors (e.g., ravulizumab or eculizumab); (i) JAK inhibitors (e.g., baricitinib, tofacitinib, or upadacitinib); (j) anti-CD40 Presented herein are methods including: (k) CD40L (e.g., toralizumab, dapirolizumab pegol, or ruplizumab); (l) Treg cell therapy, e.g., as described in WO 2021 / 113685 A2; or (m) Treg EV therapy, e.g., as described in International Application PCT / US2022 / 017990, filed February 25, 2022.

[0465] (5.6 Additional Therapeutic Interventions) In some embodiments, the methods disclosed herein can be employed in conjunction with one or more additional therapeutic interventions known in the art to treat diseases such as neurodegenerative and neuroinflammatory diseases, e.g., ALS or Alzheimer's disease. By way of non-limiting example, in some embodiments, the additional therapeutic interventions can include cognitive rehabilitation programs, neurostimulation techniques, or a combination thereof.

[0466] Any cognitive rehabilitation program known in the art can be used in conjunction with the methods disclosed herein. Cognitive training, stimulation, and rehabilitation methods and software delivered via digital devices are used in the art to improve cognitive function in subjects with neurodegenerative and neuroinflammatory diseases, such as 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 is a program such as FesKits (Gaitan 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; 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).

[0467] In some embodiments, the neurostimulation technique is non-invasive brain stimulation (NIBS). In some embodiments, the neurostimulation technique is invasive brain stimulation (IBS). Any neurostimulation technique 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 stimulation (tACS), electroconvulsive therapy (ECT), magnetic seizure therapy (MST), cranial electrical stimulation therapy (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 the use of an implant and vagus nerve stimulator (e.g., NeuroCybernetic Prosthesis, Cyberonics, Houston TX). See, e.g., Sjogren, MJ et al., J Clin Psychiatry. (2002) 63(11):972-80. In some embodiments, any method known in the art of using vagus nerve stimulation to enhance cognition in a subject (e.g., by programming a pulse generator to deliver an electrical signal using parameters known in the art) may be used.

[0468] (5.7 kit) In one embodiment, a kit is provided herein that includes, in separate containers, i) one or more doses of a formulation comprising 50-125 mg of abatacept, and ii) one or more doses of a formulation comprising 500,000-3,000,000 units of aldesleukin. In some embodiments, the kit includes one or more doses of a formulation comprising 50 mg of abatacept, 87.5 mg of abatacept, or 125 mg of abatacept. In specific embodiments, the one or more doses of abatacept are present in lyophilized form, e.g., as a lyophilized powder or lyophilized cake. In some embodiments, the one or more doses of abatacept formulation are suitable for subcutaneous or intravenous administration. In some embodiments, the kit includes one or more doses of a formulation comprising 500,000-2,000,000 units of aldesleukin, or 1,000,000 units of aldesleukin. In a specific embodiment, the one or more doses of aldesleukin are present in lyophilized form, for example, as a lyophilized powder or lyophilized cake. In some embodiments, the formulation of the one or more doses of aldesleukin is suitable for subcutaneous or intravenous administration.

[0469] In some embodiments, provided herein is a kit comprising, in separate containers, i) one or more doses of a formulation comprising an amount of abatacept in the range of 20-200 mg, and ii) one or more doses of a formulation comprising an amount of aldesleukin in the range of 10,000-3,000,000 Units. In some embodiments, the abatacept formulation comprises an amount of abatacept in the range of 25-200 mg, e.g., 25-200 mg, 50-200 mg, 50-175 mg, 50-150 mg, or 50-125 mg. In some embodiments, the abatacept formulation comprises 50 mg of abatacept. In some embodiments, the abatacept formulation comprises 87.5 mg of abatacept. In some embodiments, the abatacept formulation comprises 125 mg of abatacept. In some embodiments, the aldesleukin formulation comprises an amount of aldesleukin ranging from 10,000 to 3,000,000 Units, e.g., an amount of aldesleukin ranging from 500,000 to 3,000,000 Units or 500,000 to 2,000,000 Units. In some embodiments, the aldesleukin formulation comprises 1,000,000 Units of aldesleukin. For example, in some embodiments, the kits provided herein comprise, in separate containers, i) one or more doses of a formulation comprising 87.5 mg of abatacept, and ii) one or more doses of a formulation comprising 1,000,000 Units of aldesleukin.

[0470] In some embodiments, according to the kits provided herein, the abatacept formulation is an intravenous formulation. In some embodiments, the intravenous abatacept formulation is a lyophilized powder. In some embodiments, the intravenous abatacept formulation further comprises monobasic sodium phosphate. In some embodiments, the intravenous abatacept formulation further comprises sodium chloride. In some embodiments, the intravenous abatacept formulation further comprises maltose. In some embodiments, the intravenous abatacept formulation has a pH in the range of 7.2 to 7.8 when reconstituted with 3.5 mL of USP Sterile Water for Injection.

[0471] In some embodiments, according to the kits provided herein, the abatacept formulation is a subcutaneous formulation. In some embodiments, the subcutaneous abatacept formulation is a solution having a pH ranging from 6.8 to 7.4. In some embodiments, the subcutaneous abatacept formulation further comprises sodium phosphate dibasic. In some embodiments, the subcutaneous abatacept formulation further comprises sodium phosphate monobasic. In some embodiments, the subcutaneous abatacept formulation further comprises a poloxamer. In some embodiments, the subcutaneous abatacept formulation further comprises sucrose. In some embodiments, the subcutaneous abatacept formulation further comprises sterile water for injection, USP. In some embodiments, the volume of the abatacept formulation is 0.1 to 2.0 mL. For example, in some embodiments, the volume of the abatacept formulation is 0.4 mL, 0.7 mL, or 1.0 mL.

[0472] In some embodiments, according to the kits provided herein, the aldesleukin formulation is a subcutaneous formulation. In some embodiments, the aldesleukin formulation is a lyophilized powder. In some embodiments, the aldesleukin formulation further comprises dibasic sodium phosphate. In some embodiments, the aldesleukin formulation further comprises monobasic sodium phosphate. In some embodiments, the aldesleukin formulation further comprises sodium dodecyl sulfate. In some embodiments, the aldesleukin formulation further comprises mannitol. In some embodiments, the aldesleukin formulation, when reconstituted with USP Sterile Water for Injection, has a concentration of 18,000,000 units per mL and a pH in the range of 7.2 to 7.8.

[0473] In some embodiments, the kits provided herein include instructions for use, additional reagents (e.g., sterile water or saline for diluting the compositions), or components such as tubes, containers or syringes for collecting a biological sample, processing the biological sample, and / or reagents for quantifying the amount of one or more surface markers in a sample (e.g., detection reagents such as antibodies).

[0474] In some embodiments, the kit comprises one or more containers containing an abatacept formulation and an aldesleukin formulation for use in the methods provided herein. The one or more containers holding the abatacept formulation may be a single-use or multi-use vial. The one or more containers holding the aldesleukin formulation may be a single-use or multi-use vial. In some embodiments, the product or kit may further comprise a third container containing a suitable diluent. In some embodiments, the kit comprises instructions for use (e.g., dilution and / or administration) of the abatacept formulation and / or the aldesleukin formulation provided herein.

[0475] In some embodiments, the kits provided herein include multiple doses or dosage units of one or more medicaments along 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 separately from the pharmaceutical compositions or pre-filled with the pharmaceutical compositions. In some embodiments, the kits provided herein include one or more doses of the pharmaceutical compositions and / or formulations in separate containers. In some embodiments, the containers are enclosed in the injection device or can be inserted into the injection device (e.g., a disposable dose cassette or cartridge that can be inserted into an autoinjector device for administration).

[0476] In one aspect, provided herein is a kit comprising a pharmaceutical composition comprising, in one container, one or more doses of a CTLA-4-containing protein, e.g., abatacept, and an IL-2 protein, e.g., aldesleukin (a "CTLA-4-containing protein / IL-2 protein dose"). In some embodiments, the kit further comprises instructions for use, additional reagents (e.g., sterile water or saline for dilution of the composition), or components such as tubes, containers, or syringes for collection of a biological sample, processing of the biological sample, reagents for quantifying 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)). EXAMPLES

[0477] 6. Working Examples 6.1 Example 1: In Vitro Results of Combination of CTLA4 IgG (Abatacept) and Interleukin-2 (Il-2) The experiments described in this Example demonstrate that the combination of CTLA4 IgG (abatacept) and IL-2 synergistically enhances the suppressive function of Tregs.

[0478] 6.1.1 Effect of Increasing Doses of CTLA4 IgG (Abatacept) on M1 IL6 Protein Expression CTLA4 IgG (abatacept) or its isotype control was added to induced pluripotent stem cell (iPSC)-derived proinflammatory macrophages (M1) in vitro, and changes in proinflammatory IL-6 protein expression were assayed by enzyme-linked immunoassay (ELISA). Abatacept dose-dependently reduced M1 IL6 protein expression, whereas the isotype control had no statistically significant effect on IL-6 expression. The results are summarized in Figure 1.

[0479] 6.1.2 Effect of ascending doses of abatacept on T-responder proliferation T-response cells (Tresp) were isolated from the blood of Alzheimer's patients not receiving IL-2 therapy and plated in 96-well plates at a density of 50,000 cells per plate. CTLA4 IgG (abatacept) or its isotype control was added to the Tresp of Alzheimer's patients. After 5 days of culture, Tresp proliferation was assayed via thymidine incorporation. Abatacept dose-dependently reduced Tresp proliferation, whereas the isotype control had no statistically significant effect on Tresp proliferation. The results are summarized in Figure 2.

[0480] 6.1.3 Effect of increasing doses of abatacept on the ability of IL-2-induced in vivo expanded Alzheimer's disease Tregs to suppress Tresp proliferation Patients with Alzheimer's disease were given IL-2 (1x10 6 Units of aldesleukin) were administered over a 5-day course to expand Tregs in vivo. On day 8, IL-2-induced in vivo expanded Tregs were isolated from patient blood samples. A 5-day course of IL-2 therapy increased the number of Tregs in the blood up to 2-fold as measured by flow cytometry. The ability of IL-2-induced in vivo expanded Tregs to suppress Tresp proliferation was assayed in vitro via thymidine incorporation. Addition of abatacept to IL-2-induced in vivo expanded Tregs enhanced the ability of Tregs to suppress Tresp proliferation in a dose-dependent manner. The results are summarized in Figure 3.

[0481] 6.1.4 Effect of increasing doses of abatacept on the ability of IL-2-induced in vivo expanded Alzheimer's disease Tregs to suppress M1 IL6 production To expand Tregs in vivo, Alzheimer's disease patients were given a 5-day course of IL-2 by subcutaneous injection. On day 8, IL-2-induced in vivo expanded Tregs were isolated from patient blood samples and co-cultured with iPSC-derived pro-inflammatory M1 macrophages in vitro for 24 h. Media was collected to assess cytokine protein levels by ELISA and assay the ability of Tregs to suppress pro-inflammatory M1 macrophage function. Addition of abatacept to IL-2-induced in vivo expanded Treg:M1 co-cultures synergistically enhanced the ability of Tregs to suppress M1 IL6 protein expression in a dose-dependent manner. The results are summarized in Figure 4. Synergistic enhancement is supported, for example, by the fact that addition of abatacept alone to the co-culture actually worsens suppressive function, whereas addition of IL-2 plus abatacept substantially enhances Treg suppressive function, as described in the next section and summarized in Figure 5.

[0482] (6.1.5 Effects of abatacept and IL-2 on the suppressive function of Alzheimer's disease Tregs) Tregs were isolated from Alzheimer's disease patients not receiving IL-2 therapy as described above and co-cultured with pro-inflammatory (M1) macrophages. Addition of IL-2 and abatacept to the Treg:M1 co-cultures synergistically enhanced the ability of Tregs to suppress pro-inflammatory M1 function as measured by IL-6 expression, whereas addition of abatacept alone actually reduced IL-6 expression. The results are summarized in Figure 5.

[0483] 6.2 Example 2: Phase I Clinical Trial Using Abatacept and Interleukin-2 (Il-2) in Patients with Alzheimer's Disease (AD) The purpose of this study is to evaluate the effect of low-dose abatacept followed by IL-2 in patients with AD. In particular, this is a Phase I, open-label study to evaluate the safety and tolerability of abatacept followed by low-dose subcutaneous IL-2. Briefly, patients will receive low-dose abatacept followed by IL-2 for a total of 4 months. Changes in inflammatory markers will be measured during the study period.

[0484] (6.2.1. Main purpose) To evaluate the safety and tolerability in AD patients of abatacept administered according to the dosages described in this protocol followed by IL-2.

[0485] (6.2.2. Secondary Objectives) To investigate the immunomodulatory effects of abatacept followed by IL-2 administration in AD patients by comparing pre-, mid- and post-treatment: (a) monitoring changes in Treg numbers and immune phenotype; (b) monitoring changes in the suppressive activity of CD4+CD25+FoxP3+ Tregs on T effector proliferation; (c) monitoring changes in the levels of cytokines secreted by PBMCs throughout the course of the study; and (d) measuring disease progression throughout the course of the clinical trial.

[0486] (6.2.3 Test Design) This is a Phase I, open-label, uncontrolled study to evaluate the safety of abatacept followed by subcutaneous IL-2.

[0487] Four AD patients with mild clinical dementia (MMSE of 12-25) will receive fixed low-dose abatacept followed by IL-2 treatment for a total of 4 months.

[0488] In addition to assessing the safety and toxicity of low-dose abatacept followed by IL-2 administration in treating the progression of AD, the goal of this Phase I study is to evaluate the magnitude of enhancement of Treg suppressive function in subjects. The measurement to assess enhancement of Treg suppression is the area under the curve (AUC).

[0489] On day 1 of week 1, patients receive a fixed dose of subcutaneous abatacept (87.5 mg / 0.7 mL). Two weeks later (day 1 of week 3 (D1)), patients receive a second dose of subcutaneous abatacept (87.5 mg / 0.7 mL). In addition, patients receive subcutaneous IL-2 (1x10 6100 mg / kg / day) to the patient for 3 days (Days 1-3 of Week 3 (D1-3)). If this treatment regimen is tolerated, the patient will receive six more similar treatment courses of abatacept and IL-2 every 2 weeks.

[0490] Alternative treatment strategies may be employed. For example, on a 5-day dosing schedule, on day 1 of week 1, the patient receives a fixed dose of subcutaneous abatacept (87.5 mg / 0.7 mL). Two weeks later (day 1 of week 3 (D1)), the patient receives a second dose of subcutaneous abatacept (87.5 mg / 0.7 mL). In addition, subcutaneous IL-2 (1x10 6 units / day) to the patient for 5 days (Days 1-5 of Week 3 (D1-5)) and the patient receives 6 similar treatment courses of abatacept and IL-2 every 2 weeks. In another alternative, on a 7-day dosing schedule, on Day 1 of Week 1, the patient receives a fixed dose of subcutaneous abatacept (87.5 mg / 0.7 mL). Two weeks later (Day 1 of Week 3 (D1)), the patient receives a second dose of subcutaneous abatacept (87.5 mg / 0.7 mL). In addition, the patient receives 1x10 6 units / day) will be administered to the patient for 7 days (days 1 to 7 (D1–7) of week 3), and the patient will receive six similar treatment courses of abatacept and IL-2 every 2 weeks.

[0491] In another alternative, on a 5-day dosing schedule, on day 1 of week 1, the patient is administered a fixed dose of subcutaneous abatacept (125 mg / 0.7 mL). Two weeks later (day 1 (D1) of week 3), the patient is administered a second dose of subcutaneous abatacept (125 mg / 0.7 mL). In addition, the patient is administered subcutaneous IL-2 (1x10 6 units / day) is administered to the patient for 5 days (Days 1-5 of Week 3 (D1-5)) and the patient receives six similar treatment courses of abatacept and IL-2 every 2 weeks. See Table 5. Table 5: Abatacept / IL-2 Dosing Schedule [Table 5]

[0492] (6.2.4 Drug Information) Interleukin 2 The recombinant human IL-2 used is Proleukin (aldesleukin). Currently, the approved dose of Proleukin (aldesleukin) is 600,000 international units / kg (0.037 mg / kg). This study used a fixed dose of subcutaneous IL-2 (1x10 6 units) is administered to the patient.

[0493] Proleukin (aldesleukin) is a highly purified protein made for injection with a molecular weight of approximately 15,300 daltons. Its chemical name is des-alanyl-1, serine-125 human interleukin-2. Proleukin differs from native IL-2 in the following ways: a) it is derived from E. coli and is therefore not glycosylated; b) it lacks an N-terminal alanine - the codon for this amino acid was removed during the genetic engineering procedure; c) it has had the serine at amino acid position 125 replaced by a cysteine ​​by site-specific manipulation during the genetic engineering procedure; and d) its aggregation state is likely different from native IL-2.

[0494] Proleukin is supplied as a sterile, white to off-white, lyophilized cake in single-use vials intended for intravenous (IV) or subcutaneous administration. Vials of lyophilized Proleukin for injection should be protected from light.

[0495] When reconstituted with 1.2 mL of USP Sterile Water for Injection (SWFI), each mL contains 18 million IU (1.1 mg) Proleukin, 50 mg mannitol, and 0.18 mg sodium dodecyl sulfate, buffered to pH 7.5 (range 7.2-7.8) with approximately 0.17 mg sodium phosphate monobasic and 0.89 mg sodium phosphate dibasic.

[0496] Under sterile conditions in a laminar flow hood, a vial of Proleukin is reconstituted with 1.2 mL of SWFI and the sample is further diluted in D5W (dextrose 5% in water) to a concentration of 200 µg / mL and stored in Becton-Dickinson (BD) plastic syringes at 2 °C to 8 °C (36 °F to 46 °F). Under these conditions, stability and sterility are maintained for up to 14 days. After delivery of the diluted syringes to study participants, the syringes should also be stored in the home refrigerator (2 °C to 8 °C) before use.

[0497] The vial of reconstituted IL-2 solution is further diluted with an appropriate amount of D5W to obtain a subcutaneous dose of 1 million units per dose (subcutaneous doses should not exceed 2 mL).

[0498] The biological potency of Proleukin was determined by lymphocyte proliferation bioassay and is expressed in International Units (IU) established by the World Health Organization's first international standard for human IL-2. The relationship between potency and protein mass is as follows: 18 million (18 x 106) IU Proleukin = 1.1 mg protein.

[0499] Abatacept Abatacept is an FDA-approved drug marketed as Orencia, indicated as monotherapy or in combination with other anti-inflammatory drugs to regulate inflammation in autoimmune disorders.

[0500] The Orencia (abatacept) dose for this study is a fixed dose of 87.5 mg / 0.7 mL. The dosing in this study is consistent with the currently approved and commercially available Orencia label, which describes the following approved injectable doses: 50 mg / 0.4 mL, 87.5 mg / 0.7 mL, and 125 mg / mL clear to slightly opalescent, colorless to pale yellow solution in a single-dose prefilled glass syringe.

[0501] Abatacept is a recombinant soluble fusion protein containing the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) linked to a modified Fc (hinge, CH2, and CH3 domains) portion of human immunoglobulin G1.

[0502] 6.2.5 Duration of Treatment Proleukin This study will utilize 3-day cycles of Proleukin for 15 weeks with rest periods every other week. The approved duration of Proleukin is 5-day cycles with rest periods for a total of 19 days of treatment. The longer total treatment duration in this study is supported by previous Phase I studies and preclinical evidence of acceptable tolerability.

[0503] Orencia The study proposes weekly dosing of Orencia with a break every other week for a total of 16 weeks. An approved Orencia treatment period will be administered with either a loading dose or fixed dose, followed by therapy with a dosing schedule that varies by indication. The treatment period utilized in this study will be paired with IL-2 administration and will not require ongoing therapy.

[0504] 6.2.6 Patient Assessment (6.2.6.1 Before starting therapy) The following pretreatment assessments are completed prior to the first abatacept / IL-2 injection:

[0505] (a) Baseline history and physical examination;

[0506] (b) vital signs, weight;

[0507] (c) pulse oximetry;

[0508] (d) Laboratory: Complete blood count, PT / PTT, chemistry, liver function tests, thyroid function tests, QuantiFERON;

[0509] (e) baseline ECG; and

[0510] (f) Baseline research labs: Treg, Th1, and Treg suppression.

[0511] (6.2.6.2 During therapy) The following data will be obtained on day 1 and every 2 weeks while receiving the abatacept / IL-2 infusion:

[0512] (a) a physical examination; and

[0513] (b) Vital signs, weight, and pulse oximetry.

[0514] The following laboratory results will be obtained every 2 weeks during abatacept / IL-2 therapy: complete blood count, chemistry, and liver function tests.

[0515] The following laboratory results will be obtained on day 1 and every two weeks during abatacept / IL-2 therapy: Research labs (Treg analysis): Treg, Th1, and Treg suppression.

[0516] (6.2.6.3 Post-therapy) Upon completion of the IL-2 treatment cycle, treated patients will undergo the following surveys at Weeks 17 and 24:

[0517] (a) Physical examination;

[0518] (b) vital signs, weight, and pulse oximetry; and

[0519] (c) Laboratory: complete blood count, chemistry, liver function tests, thyroid function tests, Treg analysis.

[0520] 6.2.6.4 Disease-specific evaluation Cognitive status assessments, including the MMSE, will be performed at baseline and at weeks 5, 9, 13, 17, and 24 of the trial.

[0521] Cognitive status assessments, including ADAS-Cog and CDR-SB, will be performed at baseline and at weeks 13 and 24.

[0522] (6.2.6.5 Immune reconstitution analysis) Depending on patient samples and reagent availability, immune reconstitution test results, including immunophenotypic and functional assays, will be obtained serially at the following time points before, during and after treatment:

[0523] Approximately 1-2 tablespoons (15-30 ml) of patient blood will be collected, if possible, at the baseline visit and on day 1 (before abatacept treatment) of each treatment cycle during therapy, then at weeks 17 and 24.

[0524] If the patient's hemoglobin is less than 8.0 g / dL at any assessment time, the amount of blood taken for assessment will be reduced and may be obtained over two or more venipunctures, if necessary.

[0525] 6.2.6.6 Management of Hypotension Interrupt IL-2 for grade 3 or greater hypotension. Adequate hydration fluids should be administered to maintain blood pressure. If this process fails, patients are managed according to guidelines in the intensive care unit.

[0526] 6.2.6.7 Management of respiratory distress / dyspnea The patient is given supplemental oxygen and appropriate imaging studies are performed. If this is ineffective, the patient is managed in the intensive care unit.

[0527] (6.2.6.8 Infection control) Patients who develop a new infection while receiving abatacept should be closely monitored and receive standard treatment. If a patient develops a severe infection, abatacept should be discontinued. Before treating patients with abatacept, patients will be screened for tuberculosis. If a patient tests positive for tuberculosis, they should be treated according to standard medical practice and removed from the study.

[0528] 6.2.6.9 Changes in Therapy Abatacept / IL-2 therapy is administered to patients with the following: hypotension unresponsive to fluids, dyspnea, or oxygen saturation less than 90% on 2 liters of supplemental oxygen; sudden mental status changes; grade 3 ventricular or supraventricular arrhythmias; evidence of myocarditis or ischemia; bilirubin or creatinine >5 mg / dL; evidence of sepsis; or any other grade 3 or 4 intolerable toxicity. Treatment may be resumed at a 50% reduced dose for all toxicities that return to grade 1 or less within 72 hours, except for grade 3 or 4 ventricular arrhythmias, myocardial infarction, intubation, sepsis, coma, dialysis, or any toxicity considered life-threatening.

[0529] 6.2.7 Selection Criteria for Initial Study Enrollment Patients are eligible for initial enrollment into this study if they meet the following criteria:

[0530] (a) diagnosis of probable Alzheimer's disease according to the National Institute on Aging-Alzheimer's Disease Association (NIA-AA) criteria 13 ;

[0531] (b) Male or female, aged 60–86 years;

[0532] (c) MMSE of 12–25;

[0533] (d) total bilirubin less than or equal to 1.5 mg / dL;

[0534] (e) alanine aminotransferase level (ALT) less than 5 times normal, albumin greater than or equal to 3.0 gm / dL;

[0535] (f) serum creatinine less than 1.5 mg / dL;

[0536] (g) speaking English;

[0537] (h) A family member or caregiver who is expected to be consistently available to administer both the investigational drugs abatacept and IL-2 and to attend study visits throughout the study; and

[0538] (i) For AD patients with limited decision-making capacity, a legally authorized representative (LAD) must be present and give consent based on the patient's best interests.

[0539] 6.2.8 Exclusion Criteria for Initial Study Enrollment A patient is ineligible to participate if any of the following apply:

[0540] (a) Severe active bacterial, fungal or viral infection, active or latent tuberculosis;

[0541] (b) Severe pulmonary dysfunction: FEV1 and FVC <40% of predicted (or 3 SD below normal) at baseline if pulmonary function tests are clinically indicated; history of intubation >72 hours;

[0542] (c) severe cardiac dysfunction defined as a left ventricular ejection fraction less than 40% if echocardiography is medically indicated to clarify ongoing symptoms or EKG findings; history of uncontrolled cardiac arrhythmias; history of cardiac tamponade; unstable angina or MI within the past 3 months;

[0543] (d) hypersensitivity or allergy to IL-2 or abatacept;

[0544] (e) history of intestinal ischemia / perforation or GI bleeding requiring surgery;

[0545] (f) a history of resistant seizures, coma or toxic psychosis lasting more than 48 hours;

[0546] (g) 100,000 / mm 3 less than 30% hematocrit (HCT);

[0547] (h) A history of cancer within the past 5 years (other than basal cell or squamous cell carcinoma of the skin); or

[0548] (i) Hx of immunosuppressive therapy, including IL-2 administration, in the past 90 days.

[0549] (6.2.9 Concomitant medications) Antibiotics, antifungals, antivirals, G / GM-CSF, and immune serum globulin will be authorized and administered per standard operating procedures outlined. Nutritional support including tube feeding and / or total parenteral nutrition will also be authorized. Tylenol will be required for fever and appropriate clinical response to fever will be implemented per standard operating procedures.

[0550] (6.2.10 Excluded Drugs) The biological response modifiers interferon and TNFα blockers should not be given in combination with the IL-2 / abatacept treatment regimen. Continuous use of steroids should not be used in combination with IL-2.

[0551] (6.2.11. Subject Withdrawal) (6.2.11.1 Subject Withdrawal Criteria) Criteria for subject withdrawal include:

[0552] (a) Patients who develop irreversible, life-threatening, or non-hematologic grade 3 or 4 toxicity considered primarily related to abatacept or IL-2;

[0553] (b) severe, life-threatening infection;

[0554] (c) intubation;

[0555] (d) coma;

[0556] (e) severe cardiac dysfunction, including evidence of ischemia, cardiac arrest, reduction in left ventricular systolic function (LVSF) to less than 25%, or life-threatening cardiac arrhythmias;

[0557] (f) Severe pulmonary impairment or severe pulmonary failure requiring more than 2 liters of oxygen to maintain oxygen saturation greater than 90%;

[0558] (g) creatinine greater than 5 mg / dL or severe renal impairment with renal dialysis; or

[0559] (h) Severe hepatic dysfunction with direct bilirubin greater than 5 mg / dL or hepatic failure.

[0560] 6.3 Example 3: Phase I Study Using a Combination of Abatacept and Interleukin-2 (IL-2) Followed by Low-Dose IL-2 in Two Alzheimer's Disease (AD) Patients It has previously been documented that Treg immune phenotype and function are impaired in AD patients, but dysfunctional AD Tregs can be normalized by expanding Tregs in vitro in the presence of IL-2 (Faridar et al., Brain Commun. 2.2 (2020): fca 112).

[0561] The in vitro data described in Example 1 demonstrated a synergistic effect of IL-2 and abatacept in remodeling immunological pathways in Alzheimer's disease, with the addition of abatacept to IL-2-treated Tregs substantially improving the immunoregulatory function of the cells. To evaluate this finding in a clinical setting, two patients who initially received 4 months of low-dose IL-2 monotherapy were subsequently administered abatacept / IL-2 combination therapy.

[0562] In particular, two AD patients received subcutaneous low-dose IL-2 (1x10 6 The patients were treated with 100 mg / kg / day (1 unit / day) for 4 months. Patients were administered low-dose IL-2 for 5 days (days 1-5 (D1-5) of weeks 1, 5, 9, and 13) as shown in Table 6. Tregs were isolated from the patients and co-cultured with T-responders (Tresp) at a 1:1 ratio. IL-2 monotherapy enhanced Treg immunosuppressive function against T-responder (Tresp) proliferation (1:1 Treg:Tresp ratio) (see, e.g., Figures 6 and 7, "4 months of IL-2 monotherapy"). Table 6: IL-2 administration schedule [Table 6]

[0563] Following the 3-day dosing protocol described in Table 5, two patients who initially received monotherapy were administered abatacept alone, followed by low-dose IL-2 and 87.5 mg of abatacept after a period of approximately 10 months following the end of 4 months of low-dose IL-2 monotherapy (see, e.g., Figures 6 and 7, "Abatacept Alone" and "Abatacept + IL-2 Treatment," respectively).

[0564] Treg suppressive function against Tresp proliferation was monitored as a surrogate biomarker of response to treatment. As discussed below, IL-2 + abatacept treatment had a synergistic effect in restoring Treg immunosuppressive function. Furthermore, as also discussed below, restoration of Treg immunoregulatory function enhanced cognitive function in enrolled AD patients.

[0565] 6.3.1 Effect of IL-2 and Abatacept Treatment on Recovery of Tregs and Cognitive Function in Patients with AD Two Alzheimer's disease patients received a 4-month course of low-dose IL-2 monotherapy by subcutaneous injection to expand Tregs in vivo, as described above. IL-2 administration selectively expanded the peripheral Treg population and enhanced its immunosuppressive function. As described in section 6.3 above, the two AD patients were later administered abatacept alone and a combination of low-dose IL-2 and 87.5 mg abatacept according to the 3-day administration protocol described in Table 5. See, e.g., Figures 6-8.

[0566] Figure 6 shows that patient AD-01 showed a 53.5% increase in Treg suppression at the fourth IL-2 monotherapy cycle, but then showed a rapid decline in Treg suppression. The patient also exhibited a concomitant decline in cognitive function as measured by the MMSE shown in Figure 8. When patient AD-01 was treated with abatacept and IL-2 combination, Treg suppressive function against Tresp proliferation increased to 85.2%, exceeding the levels observed in response to IL-2 (53.5%) or abatacept alone (27.3%) (Figure 6). Patient AD-01 also showed improvement in cognitive function (Figure 8).

[0567] Similarly, as shown in Figure 7, patient AD-02 showed a 27% increase in Treg suppression at day 98 of IL-2 monotherapy treatment, followed by a dramatic decrease in Treg suppression by day 280. Patient AD-02 exhibited a concomitant decline in cognitive function as measured by MMSE (Figure 8). At the initiation of abatacept / IL-2 combination treatment, the patient showed a 60.5% increase in Treg suppressive function against Tresp proliferation after the second abatacept / IL-2 dose, exceeding the levels observed in response to IL-2 (27.3%) or abatacept alone (13%) (Figure 7), and further exhibited a concomitant increase in cognitive function as measured by MMSE (Figure 8).

[0568] 6.3.2 Comparison of MMSE scores and Treg suppression for IL-2 monotherapy versus IL-2 plus abatacept in additional AD patients In addition to the two Alzheimer's disease patients described in the previous section, another six Alzheimer's disease patients received a four-month course of low-dose IL-2 monotherapy by subcutaneous injection (leading to a total of eight AD patients). Cognitive status in the eight AD patients was assessed with the MMSE test at baseline and two weeks after the last cycle of IL-2 immunotherapy (monotherapy) (Figure 9, left panel). Treg suppressive function was also assessed in the eight AD patients, as shown in Figure 10 (left panel).

[0569] Three patients (patients AD-01, AD02 above, and a third patient who had not previously received IL-2 monotherapy) were administered abatacept alone and the combination of low-dose IL-2 and 87.5 mg abatacept according to the 3-day dosing protocol described in section 6.3 above and in Table 5. Cognitive status was monitored along with MMSE changes at baseline and 2 weeks after the last cycle of IL-2 and abatacept immunotherapy, as shown in Figure 9 (right panel). Treg suppressive function in these three patients was assessed, as shown in Figure 10 (right panel).

[0570] The results are presented in FIG. 9 and demonstrate the beneficial effect of IL-2 / abatacept combination therapy on cognition compared to IL-2 alone. In particular, the results show that administration of IL-2 / abatacept resulted in a 15.7% improvement in MMSE score at 2 weeks post-treatment compared to pre-treatment screening, whereas IL-2 administration alone only increased by 3.3%. This corresponds to a 4.75-fold incremental percentage improvement in MMSE score with IL-2 / abatacept versus IL-2 alone. The results presented in FIG. 10 show the percentage change in Treg suppressive function over the study period above the pre-treatment baseline. The results show an increase in Treg suppressive function in AD patients treated with IL-2 / abatacept compared to patients treated with IL-2 alone, demonstrating the synergistic effect of the combination therapy on Treg suppressive function. Furthermore, the data demonstrate that IL-2 / abatacept treatment was much more successful in maintaining Treg suppressive function post-treatment than IL-2 treatment alone, which showed a greater decline in Treg suppressive function over the same post-treatment period.

[0571] 6.4 Example 4: Phase I Clinical Trial Using a Combination of Abatacept and Interleukin-2 (Il-2) in Patients with Alzheimer's Disease The purpose of this study is to evaluate the effect of IL-2 and low-dose abatacept in patients with AD. In particular, this is a phase I, open-label study evaluating the safety and tolerability of IL-2 and low-dose abatacept administered subcutaneously in a single formulation. Changes in inflammatory markers will be measured over the course of the study.

[0572] (6.4.1. Main purpose) To evaluate the safety and tolerability in patients with AD of IL-2 and low-dose abatacept administered in a single formulation according to the dosages described in this protocol.

[0573] (6.4.2. Secondary Objectives) To investigate the immunomodulatory effects of IL-2 and low-dose abatacept administered as a single formulation in AD patients by comparing pre-, mid- and post-treatment: (a) monitoring changes in Treg numbers and immune phenotype; (b) monitoring changes in the suppressive activity of CD4+CD25+FoxP3+ Tregs on T effector proliferation; (c) monitoring changes in the levels of cytokines secreted by PBMCs throughout the course of the study; and (d) measuring disease progression throughout the course of the clinical trial.

[0574] (6.4.3 Test Design) This is a Phase I, open-label, uncontrolled study evaluating the safety of administering IL-2 and low-dose abatacept subcutaneously as a single formulation.

[0575] AD patients with mild clinical dementia (MMSE of 12-25) will receive fixed low-dose IL-2 and abatacept treatment for a total of 4 months, with IL-2 and abatacept administered in a single formulation.

[0576] In addition to assessing the safety and toxicity of administration in treating the progression of AD, the goal of this Phase I study is to assess the magnitude of enhanced Treg suppressive function in subjects. The measurement to assess enhanced Treg suppression is the area under the curve (AUC).

[0577] 1x10 per day delivered subcutaneously in a single formulation 6 The patient is administered a combination of 1x10 units of IL-2 (Proleukin; Aldesleukin) and 29.17 mg of abatacept for 3 days (Days 1-3; D1-3) in the first week. If this treatment regimen is tolerated, the patient is administered a combination of IL-2 and abatacept subcutaneously every 2 weeks for a further similar course of treatment for the next 15 weeks. Alternative treatment strategies may be employed. For example, 1x10 units of IL-2 per day delivered subcutaneously in a single formulation. 6In another alternative example, the patient is administered 1x10 units of IL-2 (proleukin; aldesleukin) and 17.5 mg of abatacept per day for 5 days (Days 1-5; D1-5) in the first week, followed by a subcutaneous IL-2 and abatacept combination every 2 weeks for a further similar course of treatment for the next 15 weeks. 6 Patients will be administered a combination of 100 mg of IL-2 (Proleukin; Aldesleukin) and 12.5 mg of abatacept for 7 days (Days 1-7; D1-7) in the first week, and then every 2 weeks for a further similar course of treatment for the next 15 weeks with a combination of IL-2 and abatacept administered subcutaneously. See Table 7. Table 7: Dosing schedule for abatacept / IL-2 combination [Table 7]

[0578] Patient evaluation criteria, inclusion and exclusion criteria, as well as information regarding concomitant and excluded medications and subject withdrawals, are the same for this study as those presented in Example 1.

[0579] 6.5 Example 5: Stability of IL-2 / Abatacept Combination Formulations This example demonstrates that aqueous formulations containing IL-2 and abatacept are stable at room temperature under standard test conditions (STC) for up to 24 hours.

[0580] IL-2 (Proleukin (Aldesleukin), Clinigen, 1.3 mg / vial, lyophilized) was reconstituted with 1.2 mL of water to 1.1 mg / mL and mixed with abatacept (Orencia, Bristol Myers Squibb, 87.5 mg / 0.7 mL, PFS (prefilled syringe) to obtain a 480:1 mass ratio combination formulation of IL-2 / abatacept (101 mg / mL abatacept and 0.21 mg / mL IL-2). The solution was held under STC with samples taken at baseline, 3 hours, 6 hours, and 24 hours and evaluated by UV spectroscopy (A280 / 340), light obscuration (HIAC), and dynamic light scattering (DLS).

[0581] For UV spectroscopy, samples of the combination formulation were diluted 135-fold with saline and the absorbance at 280 nm and 340 nm was measured on a Thermo Scientific Evolution 220 UV / Vis spectrophotometer (sample volume 0.45 mL). The aggregation index (AI) was determined as AI=100×(A340) / (A280-A340). The results are shown in Table 8 and show that the concentration changes are within the variability of the method. These results indicate that the concentration (mg / mL) of the IL-2 / abatacept solution is stable at room temperature for 24 hours (the last time point tested). Table 8: Absorbance of IL-2 / Abatacept co-formulations [Table 8]

[0582] Undiluted samples (0.05 mL) were added in triplicate to wells of a Thermo Scientific flat-bottom clear 96-well plate and light scattering was measured at A280 and A340 in a BioTeck Synergy HTX multimode reader. The results are shown in Table 9. The results show that light scattering is stable at room temperature for at least 24 hours (the last time point tested), indicating that the IL-2 / abatacept combination formulation is stable and not prone to forming aggregates and particles for at least 24 hours at room temperature. Table 9: Light scattering of IL-2 / Abatacept co-formulations [Table 9]

[0583] The HIAC results of the samples from the BioTeck Synergy HTX multimode reader for subvisible particles are shown in Table 10. These results show that the subvisible particle counts >2 μm and >5 μm were stable for at least 24 hours (the last time point tested), and the subvisible particle counts >10 μm and >25 μm were stable for 24 hours, meeting EU and USP requirements. Table 10: IL-2 / Abatacept Coformulation-Subvisible Particles [Table 10]

[0584] The DLS results are summarized in Table 11. The DLS results showed that the particle size in the IL-2 / abatacept combination formulation was stable for 24 hours. Most of the particles were in the main peak. The PDI was high. This is likely due to the diversity of particle size distribution beyond the main peak. Table 11: IL-2 / Abatacept Coformulation - Particle Size by DLS [Table 11]

[0585] 6.6 Example 6: Phase I Clinical Trial Using Abatacept and Interleukin-2 (IL-2) in Patients with Amyotrophic Lateral Sclerosis (ALS) The purpose of this study is to evaluate the effect of low-dose abatacept followed by IL-2 administration in ALS patients. In particular, this Phase 1 study aims to determine whether combination therapy of subcutaneous IL-2 and abatacept (ORENCIA®) ​​is safe and well tolerated in ALS patients and whether the therapy enhances the number and suppressive function of Tregs in vivo.

[0586] (6.6.1. Main purpose) To evaluate the safety and tolerability in ALS patients of abatacept administered according to the dosages described in this protocol followed by IL-2.

[0587] (6.6.2. Secondary Objectives) To investigate the immunomodulatory effects of IL-2 following abatacept administered to ALS patients by comparing (a) the number of Tregs; (b) the suppressive activity of Tregs on T effector proliferation; (c) the levels of cytokines secreted by PBMCs throughout the course of the study; and (d) disease progression as determined by Appel ALS Rating Scale (AALS) and ALS Functional Rating Scale-Revised (ALSFRS-R) scores, as well as clinical outcome measures of ALS including forced vital capacity (FVC) and maximum inspiratory pressure (MIP), before, during, and after treatment.

[0588] (6.6.3 Test Design) This is a Phase I, open-label, uncontrolled study to evaluate the safety of abatacept followed by subcutaneous IL-2. In addition to evaluating the safety and toxicity of low-dose abatacept followed by IL-2 in the treatment of ALS progression, the goal of this Phase I study is to evaluate the magnitude of Treg population enhancement in subjects.

[0589] The ALS patient receives fixed low dose abatacept and IL-2 treatment for a total of 4 months. Specifically, the patient receives a fixed dose of subcutaneous abatacept (125 mg / mL) on day 1 of week 1. Two weeks later (day 1 of week 3), the patient receives a second dose of subcutaneous abatacept (125 mg / mL). Additionally, the patient receives subcutaneous IL-2 (1x10 6 units / day) for 5 days (days 2-5 of week 3). If this treatment regimen is tolerated, the patient will receive six more similar treatment courses of abatacept and IL-2 every 2 weeks. See Table 12 below for the dosing schedule. Table 12: Abatacept / IL-2 Dosing Schedule [Table 12]

[0590] (6.6.4 Drug Information) The recombinant human IL-2 used is Proleukin (aldesleukin). The abatacept used is that in the Orencia product. See section 6.2.4 above.

[0591] 6.6.5 Patient Assessment (6.6.5.1 Before starting therapy) The following pre-treatment evaluations are completed prior to the first abatacept / IL-2 injection: (a) baseline history and physical exam; (b) vital signs, weight; (c) pulse oximetry; (d) safety labs: complete blood count, PT / PTT, chemistry, liver function tests, thyroid function tests, QuantiFERON; (e) baseline ECG; and (f) research labs: immune biomarkers and Treg function and flow assays.

[0592] (6.6.5.2 During therapy) The following data: vital signs, weight, pulse oximetry will be obtained on day 1 and every 2 weeks while the abatacept / IL-2 is being infused.

[0593] During abatacept / IL-2 therapy, obtain results of the following laboratory tests every 2 weeks: complete blood count, chemistry, and liver function tests.

[0594] During abatacept / IL-2 therapy, the following laboratory tests will be obtained twice every 2 weeks (days 1 and 8 of each treatment cycle): Immune biomarkers: plasma, serum and messenger RNA results.

[0595] During abatacept / IL-2 therapy, the following laboratory tests will be obtained on days 1, 8, 22, 50, 78 and 106: Treg function and flow assay results.

[0596] (6.6.5.3 Post-therapy) Upon completion of the IL-2 treatment cycle, treated patients will undergo the following investigations at weeks 17 and 24: (a) physical examination; (b) vital signs, weight, and pulse oximetry; and (c) laboratories: complete blood count, chemistry, liver function tests, thyroid function tests, immune biomarkers, and Treg function and flow assays (week 24 only).

[0597] 6.6.5.4 Disease-specific evaluation Measures of disease progression, including the Appel ALS Rating Scale (AALS), ALS Functional Rating Scale-Revised (ALSFRS-R), forced vital capacity (FVC), and mean inspiratory pressure (MIP), will be performed at screening, baseline (week 1), and weeks 5, 9, 13, 17, and 24 of the study.

[0598] 6.6.5.5 Analysis of Immune Reconstitution Depending on patient samples and reagent availability, immune reconstitution test results, including immunophenotypic and functional assays, will be obtained serially at the following time points: before, during and after treatment.

[0599] Approximately 2-5 tablespoons (30-75 cc) of patient blood, if possible, will be collected at the baseline visit and on days 1 and 8 of each treatment cycle (twice every other week), then at weeks 17 and 24 during therapy.

[0600] If the patient's hemoglobin is less than 8.0 g / dL at any assessment time, the amount of blood taken for assessment will be reduced and may be obtained over two or more venipunctures, if necessary.

[0601] Management of hypotension, management of respiratory distress / dyspnea, management of infection, and modification of therapy are as described in Example 2 above.

[0602] (6.6.6 Registration Selection Criteria) Subjects are eligible for initial enrollment into this study if they meet the following criteria:

[0603] (a) You have provided informed consent that complies with state and local patient privacy regulations and is authorized to use your Protected Health Information (PHI).

[0604] (b) ALS fulfilling the El Escorial criteria for possible ALS, probable ALS, laboratory-supported probable ALS, or definite ALS.

[0605] (c) At least 18 years of age.

[0606] (d) Total bilirubin less than or equal to 1.5 mg / dL.

[0607] (e) Alanine aminotransferase level (ALT) less than 5 times normal, albumin greater than 3.0 gm / dL.

[0608] (f) Serum creatinine less than 1.5 mg / dL.

[0609] (g) be able to comply with all study procedures, including delivery of study medication;

[0610] (h) A family member or caregiver who is expected to be consistently able to administer both study medications, abatacept and IL-2, if the participant is unable to do so.

[0611] (i) Have been on a stable riluzole regimen for at least 30 days at screening and, if not taking riluzole at study entry, be willing to refrain from initiating the medication for the duration of the study.

[0612] (j) Patients taking edaravone must be willing to refrain from taking edaravone on the same day that they receive an abatacept injection during the study period. If not taking edaravone at the time of study enrollment, they must be willing to refrain from starting the medication during the study period.

[0613] (k) Having a forced vital capacity (FVC) of 50% or greater than predicted for age, height, and sex at screening, or receiving treatment with noninvasive ventilation if the FVC is less than 50% predicted for age, height, and sex at screening.

[0614] (6.6.7. Exclusion Criteria for Registration) Patients were ineligible to participate if any of the following were true at screening:

[0615] (a) Severe active bacterial, fungal or viral infection, active or latent tuberculosis.

[0616] (b) Tracheotomy.

[0617] (c) severe cardiac dysfunction defined as a left ventricular ejection fraction less than 40% if echocardiography is medically indicated to clarify ongoing symptoms or EKG findings; history of uncontrolled cardiac arrhythmias; history of cardiac tamponade; unstable angina or MI within the past 3 months;

[0618] (d) Hypersensitivity or allergy to IL-2 or abatacept.

[0619] (e) History of intestinal ischemia / perforation or GI bleeding requiring surgery.

[0620] (f) History of resistant seizures, coma or toxic psychosis lasting more than 48 hours.

[0621] (g) Platelets less than 100,000 / mm3; hematocrit less than 30%.

[0622] (h) History of cancer within the past 5 years (excluding basal cell or squamous cell carcinoma of the skin).

[0623] (i) Hx of immunomodulatory therapy, including IL-2 or abatacept administration, in the past 90 days.

[0624] (j) Treatment with another investigational drug, biological agent, or device within 30 days or 5 half-lives of screening, whichever is longer.

[0625] (k) Females who are breastfeeding, known to be pregnant, planning to become pregnant during the study, or unwilling to use effective contraception during the study and for 90 days after treatment.

[0626] (l) Males of reproductive potential who are unwilling to use effective contraception during the study and for 90 days after treatment.

[0627] 6.7 Example 7: Interim Results of an Ongoing Phase I Clinical Trial Using Abatacept and Interleukin-2 (Il-2) in Patients with Amyotrophic Lateral Sclerosis (ALS) The Phase I clinical trial described in Example 6 above involves a total of 4 months of abatacept and IL-2 treatment. To date, subjects enrolled in the trial have been on the treatment regimen for at least 3 weeks, and the trial is ongoing. In this example, we provide interim results (i.e., results available to date, as the trial is ongoing) from four ALS patients enrolled in the trial.

[0628] Table 13 below provides the demographics and baseline characteristics of the enrolled subjects. Table 13: Demographics and baseline characteristics of enrolled subjects [Table 13]

[0629] Figures 11-13 show Treg suppressive function (Figure 11), CD4+CD25+FOXP3+Treg cell surface phenotype (Figure 12) and CD8+ cell surface phenotype (Figure 13) from each of these subjects. Abatacept alone was administered on day 1, immediately following baseline measurements. In Figures 11-13, "Week 1" refers to measurements taken one week after abatacept administration alone. As explained above, abatacept / IL-2 combination treatment was initiated two weeks after abatacept administration alone and continued every two weeks thereafter for the course of treatment. In Figures 11-13, "Week 3" refers to measurements taken one week after the first abatacept / IL-2 administration and "Week 7" refers to measurements taken one week after the third abatacept / IL-2 administration.

[0630] Figure 11 shows Treg suppressive function in Tregs from each subject. As shown, after the introduction of abatacept / IL-2 dual dosing, an improvement in Treg suppressive function was observed in each subject relative to their baseline values.

[0631] The percentage of cells expressing the CD4+CD25+FOXP3+ Treg phenotype in the subjects is shown in Figure 12. As the figure shows, as the treatment regimen progressed, the percentage of cells exhibiting such a Treg phenotype increased relative to baseline in each of the four subjects.

[0632] The percentage of Tregs expressing a CD8+ cytotoxic pro-inflammatory phenotype is shown in Figure 13. As the figure shows, the percentage of cells exhibiting such a phenotype either remained stable or improved (decreased) relative to baseline in each of the four subjects by week 3 (i.e., one week after the first abatacept / IL-2 dose). Interestingly, an improvement (decrease) in the percentage of CD8+ cells is observed in both subjects (subjects 2 and 4) who progressed to week 7 of the treatment regimen (one week after the third abatacept / IL-2 dose).

[0633] Disease progression was monitored by ALSFRS-R scores in four subjects undergoing abatacept / IL-2 treatment (Figure 14). The ALSFRS-R is a widely accepted and validated outcome measure of activity limitation for ALS patients. It contains 12 items rated on a scale of 0 to 4 (4 = normal function, 0 = complete loss of function). The 12 items are categorized into four domains: bulbar, fine motor, total motor, and respiratory. Each point reduction in the ALSFRS-R represents a loss of ability to perform basic activities of daily living. Thus, ALS progression is reflected by a decline in the ALSFRS-R score over time.

[0634] As shown in FIG. 14, each subject had progressed at different rates prior to enrollment in the study ("Pre-Treatment (Screening)"). After enrollment, ALSFRS-R was measured at baseline (immediately prior to administration of the abatacept-only dose) and then every 4 weeks during the study ("Week 4" and "Week 8"). Overall, as shown in FIG. 14, disease progression, as assessed by ALSFRS-R scoring, has stabilized since the initiation of abatacept / IL-2 treatment in four subjects.

[0635] Disease progression was also monitored by maximum inspiratory pressure (MIP) in four subjects undergoing abatacept / IL-2 treatment (Figure 15). Maximum inspiratory pressure (MIP) is a measure of the strength of the inspiratory muscles, primarily the diaphragm, and allows for the assessment of ventilatory failure, restrictive lung disease and respiratory muscle strength. A decline in MIP is associated with progressive clinical deterioration in patients with various conditions, including ALS. Figure 15 shows MIP values ​​before and after the initiation of treatment with IL-2 and abatacept in four subjects enrolled in a Phase I clinical trial. As shown in Figure 15, overall, disease progression as assessed by MIP has been stable since the initiation of abatacept / IL-2 treatment in four subjects.

[0636] All publications, patents, and patent applications cited in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

[0637] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those skilled in the art in light of the teachings of the invention that certain changes and modifications can be made thereto without departing from the spirit or scope of the appended claims.

[0638] The present invention should not be limited in scope by the specific embodiments described herein. Indeed, various modifications of the present invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and accompanying figures. Such modifications are intended to be included within the scope of the appended claims.

Claims

1. A pharmaceutical composition comprising (i) a CTLA-4 containing protein and (ii) an IL-2 protein for the therapeutic and / or prophylactic treatment of one or more symptoms associated with a neurodegenerative or neuroinflammatory disease or disorder in a subject.

2. The CTLA-4 containing protein comprises a monomer having the following amino acid sequence: 【Chemistry 1】 2. The pharmaceutical composition of claim 1, comprising:

3. The pharmaceutical composition of claim 1, wherein the CTLA-4 containing protein comprises a homodimer of two monomers, each of which comprises the amino acid sequence of SEQ ID NO:

1.

4. 2. The pharmaceutical composition of claim 1, wherein the CTLA-4 containing protein is abatacept.

5. The IL-2 protein has the following amino acid sequence: 【Chemistry 2】 The pharmaceutical composition according to any one of claims 1 to 4, comprising:

6. The pharmaceutical composition of claim 5, wherein the IL-2 protein is non-glycosylated.

7. 2. The pharmaceutical composition of claim 1, wherein the IL-2 protein is aldesleukin.

8. A pharmaceutical composition comprising abatacept for the therapeutic and / or prophylactic treatment of one or more symptoms associated with a neurodegenerative or neuroinflammatory disease or disorder in a subject, wherein the pharmaceutical composition is used in combination with aldesleukin.

9. A pharmaceutical composition comprising aldesleukin, used in combination with abatacept, for the therapeutic and / or prophylactic treatment of one or more symptoms associated with a neurodegenerative or neuroinflammatory disease or disorder in a subject.

10. 10. The pharmaceutical composition of claim 8 or 9, wherein the abatacept is administered by injection or infusion.

11. 11. The pharmaceutical composition of claim 10, wherein the abatacept is administered subcutaneously or intravenously.

12. 10. The pharmaceutical composition of claim 8 or 9, wherein the aldesleukin is administered by injection or infusion.

13. 13. The pharmaceutical composition of claim 12, wherein the aldesleukin is administered subcutaneously or intravenously.

14. 10. The pharmaceutical composition of claim 8 or 9, wherein the abatacept and the aldesleukin are administered subcutaneously.

15. The pharmaceutical composition of any one of claims 8 to 14, wherein the abatacept is administered once every two weeks.

16. The pharmaceutical composition of any one of claims 8 to 14, wherein the aldesleukin is administered once a day for 3 to 5 consecutive days.

17. a) the abatacept is administered once every two weeks; and b) the aldesleukin is administered once a day for 3 to 5 consecutive days starting from the day the abatacept is administered; The pharmaceutical composition according to any one of claims 8 to 14.

18. 10. The pharmaceutical composition of claim 8 or 9, wherein the abatacept is administered in an amount ranging from 50 mg to 125 mg.

19. 20. The pharmaceutical composition of claim 18, wherein the abatacept is administered in an amount of 125 mg.

20. 10. The pharmaceutical composition of claim 8 or 9, wherein the aldesleukin is administered in an amount ranging from 500,000 units to 3,000,000 units.

21. 21. The pharmaceutical composition of claim 20, wherein the aldesleukin is administered in an amount of 1,000,000 units.

22. 19. The pharmaceutical composition of claim 18, wherein the aldesleukin is administered in an amount ranging from 500,000 units to 3,000,000 units.

23. 23. The pharmaceutical composition of claim 22, wherein the aldesleukin is administered in an amount of 1,000,000 units.

24. 1. A pharmaceutical composition for the therapeutic and / or prophylactic treatment of one or more symptoms associated with a neurodegenerative or neuroinflammatory disease or disorder in a subject, comprising abatacept and aldesleukin, The pharmaceutical composition, wherein the pharmaceutical composition is for use in a dosing cycle beginning on day 1.

25. The dosing cycle comprises about 5 mg to about 125 mg of abatacept and about 3x10 4 ~Approx. 3x10 7 25. The pharmaceutical composition of claim 24, comprising administering to the subject the pharmaceutical composition comprising a unit of aldesleukin.

26. 26. The pharmaceutical composition of claim 25, wherein the pharmaceutical composition comprises 50 mg to 125 mg of abatacept.

27. 27. The pharmaceutical composition of claim 26, wherein the pharmaceutical composition comprises 125 mg of abatacept.

28. 28. The pharmaceutical composition according to any one of claims 1 to 27, wherein the neurodegenerative disease or disorder is amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, multiple sclerosis, frontotemporal dementia or Huntington's disease.

29. 29. The pharmaceutical composition of claim 28, wherein the neurodegenerative disease or disorder is amyotrophic lateral sclerosis.

30. 28. The pharmaceutical composition of any one of claims 1 to 27, 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.

31. A kit comprising, in separate containers: i) one or more doses of a formulation comprising 50-125 mg of abatacept; and ii) one or more doses of a formulation comprising 500,000-3,000,000 units of aldesleukin.

32. 32. The kit of claim 31, wherein the kit comprises one or more doses of a formulation containing 125 mg of abatacept.

33. 32. The kit of claim 31, wherein the kit comprises one or more doses of a formulation of aldesleukin between 500,000 and 2,000,000 units.

34. 34. The kit of claim 33, wherein the kit comprises one or more doses of a 1,000,000 unit formulation of aldesleukin.

35. A pharmaceutical composition comprising one or more abatacept / aldesleukin doses.

36. The abatacept / aldesleukin dose is 5mg to 125mg of abatacept and 3x10 4 ~3x10 7 36. The pharmaceutical composition of claim 35, comprising units of aldesleukin.

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