CN117337189A - Methods and compositions for treating diseases - Google Patents

Methods and compositions for treating diseases Download PDF

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Publication number
CN117337189A
CN117337189A CN202280034612.5A CN202280034612A CN117337189A CN 117337189 A CN117337189 A CN 117337189A CN 202280034612 A CN202280034612 A CN 202280034612A CN 117337189 A CN117337189 A CN 117337189A
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China
Prior art keywords
aldesleukin
subject
formulation
dosing cycle
abacavir
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CN202280034612.5A
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Chinese (zh)
Inventor
斯坦利·赫什·阿佩尔
阿里雷扎·法里达尔
霍华德·伯曼
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Koya Treatment Co
Methodist Hospital
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Koya Treatment Co
Methodist Hospital
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Application filed by Koya Treatment Co, Methodist Hospital filed Critical Koya Treatment Co
Priority claimed from PCT/US2022/019748 external-priority patent/WO2022192536A1/en
Publication of CN117337189A publication Critical patent/CN117337189A/en
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Abstract

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

Description

Methods and compositions for treating diseases
Cross Reference to Related Applications
The present application claims the benefit of U.S. provisional application Ser. No. 63/159,919 filed on day 3 and 11 of 2021, U.S. provisional application Ser. No. 63/225,846 filed on day 7 and 26 of 2021, and U.S. provisional application Ser. No. 63/310,839 filed on day 2 and 16 of 2022, each of which are incorporated herein by reference in their entirety.
Reference to an electronically submitted sequence Listing
The present application incorporates by reference the sequence listing entitled "14678-014-228_SEQ_LISTIN G.txt" filed herewith as a text file created at 2022, 3, 9 and having a size of 12,142 bytes.
1. Technical field
The present disclosure provides methods for treating diseases such as neurodegenerative and neuroinflammatory diseases, e.g., alzheimer's disease, comprising administering CTLA-4-containing proteins, e.g., abatacept, and IL-2 proteins, e.g., aldeslukin, separately or in a single formulation to a subject. Also provided herein are pharmaceutical compositions comprising a CTLA-4-containing protein, such as abapple, and an IL-2 protein, such as aldesleukin.
2. Background art
Inflammatory and neuroinflammatory mechanisms lead to a variety of destructive diseases including neurodegenerative diseases such as Amyotrophic Lateral Sclerosis (ALS), alzheimer's disease, and Parkinson's disease. Neurodegenerative diseases such as these can present a significant health and economic burden that is only further exacerbated over time.
Currently, there is no disease-modifying treatment for such diseases. Anti-inflammatory treatments have been used for decades in an attempt to ameliorate a variety of neurodegenerative diseases. However, little progress has been made in single drug/target approaches.
More and more studies point to the involvement of the immune system in the etiology of diseases such as this, and to immune cell dysfunction as a major mediator of disease pathogenesis. The complex signaling mechanisms and built-in redundancy of the immune system and its components may help explain the ineffectiveness of such single drug/single target anti-inflammatory approaches.
Recently, regulatory T cell (Treg) cell therapies have shown tremendous promise, which may represent a more comprehensive approach to inhibiting immune system dysfunction leading to disease. For example, clinical trials involving the administration of expanded autologous tregs to ALS patients report that Treg therapy slows the rate of progression in early and late stages of disease, and that Treg suppression function is associated with the slowing of disease progression (Thonhoff, j.r. et al, 2018, neurology-Neuroim munology Neuroinflammation (4)).
Nevertheless, there remains a need to develop additional therapies that can inhibit and/or promote the components of the inflammatory immune system.
3. Summary of the invention
In one aspect, provided herein is 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 the method reduces one or more symptoms associated with a neurodegenerative or neuroinflammatory disease or disorder in the subject being treated. In certain embodiments, the CTLA-4-containing protein is abacavir. In certain embodiments, the IL-2 protein is an aldesleukin. In certain embodiments, the CTLA-4-containing protein is Abauprine and the IL-2 protein is aldesleukin.
In certain embodiments, the CTLA-4-containing protein is administered by injection or infusion. In particular embodiments, the CTLA-4-containing protein is administered subcutaneously. In particular embodiments, the CTLA-4-containing protein is administered intravenously. In certain embodiments, the IL-2 protein is administered by injection or infusion. In certain embodiments, the IL-2 protein is administered subcutaneously. In certain embodiments, the IL-2 protein is administered intravenously. In certain embodiments, the CTLA-4-containing protein and IL-2 protein are administered by injection or infusion. In particular embodiments, the CTLA-4-containing protein and the IL-2 protein are administered subcutaneously. In particular embodiments, the CTLA-4-containing protein and the IL-2 protein are administered intravenously.
In certain embodiments, the CTLA-4-containing protein comprises a human CTLA-4 extracellular domain. In particular 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 CH 3). In a particular embodiment, the human immunoglobulin Fc domain is a human IgG1 Fc domain. In certain embodiments, the CTLA-4-containing protein is glycosylated.
In certain embodiments, the CTLA-4-containing protein comprises the following amino acid sequence monomers:
MHVAQPAVVLASSRGIASFVCEYASPGKATEVRVTVLRQADSQVTEVCAATYMMGNELTFLDDSICTGTSSGNQVNLTIQGLRAMDTGLYICKVELMYPPPYYLGIGNGTQIYVIDPEPCPDSDQEPKSSDKTHTSPPSPAPELLGGSSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLS PGK (SEQ ID NO: 1). 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.
In a particular embodiment, the CTLA-4-containing protein is abacavir.
In certain embodiments, the CTLA-4-containing protein comprises the following amino acid sequence monomers:
MHVAQPAVVLASSRGIASFVCEYASPGKYTEVRVTVLRQADSQVTEVCAATYMMGNELTFLDDSICTGTSSGNQVNLTIQGLRAMDTGLYICKVELMYPPPYYEGIGNGTQIYVIDPEPCPDSDQEPKSSDKTHTSPPSPAPELLGGSSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 2). 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.
In a particular embodiment, the CTLA-4-containing protein is beraprost (belatacept).
In certain embodiments, the IL-2 protein is a human IL-2 protein. In certain embodiments, the human IL-2 protein comprises serine at an amino acid position corresponding to amino acid residue 125 of naturally occurring mature human IL-2. 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 serine at an amino acid position corresponding to naturally occurring human IL-2 amino acid residue 125.
In certain embodiments, the human IL-2 protein comprises the following amino acid sequence:
PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT(SEQID NO:3)。
in specific embodiments, the IL-2 protein is not glycosylated. In certain embodiments, the IL-2 protein is an aldesleukin.
In certain embodiments, the human IL-2 protein comprises the following amino acid sequence:
PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT(SEQID NO:6)。
in one aspect, provided herein is a method of treating a neurodegenerative or neuroinflammatory disease or disorder in a subject in need thereof, comprising administering to the subject:
i) Abacavir; and
ii) aldesleukin;
wherein the method reduces one or more symptoms associated with a neurodegenerative or neuroinflammatory disease or disorder in the subject being treated.
In certain embodiments, the abacavir is administered by injection or infusion. In certain embodiments, the abasic is administered subcutaneously. In particular embodiments, the abacavir is administered intravenously. In certain embodiments, the aldesleukin is administered by injection or infusion. In particular embodiments, the aldesleukin is administered subcutaneously. In particular embodiments, the aldesleukin is administered intravenously. In certain embodiments, the aturprine and the aldehydic interleukins are administered by injection or infusion. In particular embodiments, the aturprine and the aldesleukin are administered subcutaneously. In particular embodiments, the aturprine and the aldesleukin are administered intravenously.
In certain embodiments, the CTLA-4-containing protein, such as abamectin, is administered to the subject during 2 months, 3 months, 4 months, 5 months, 6 months, 1 year, 2 years, 5 years, 10 years, or more.
In certain embodiments, the CTLA-4-containing protein, such as abacavir, is administered to the subject once every two weeks. In certain embodiments, the CTLA-4-containing protein, such as abacavir, is administered subcutaneously to a subject once every two weeks. In certain embodiments, a CTLA-4-containing protein, e.g., abasic, is administered to a subject once every two weeks for 15 weeks, sixteen weeks, 4 months, 5 months, 6 months, 1 year, 2 years, 5 years, 10 years, or more. In particular embodiments, the CTLA-4-containing protein, e.g., abasic, is administered subcutaneously to the subject once every two weeks for 15 weeks, sixteen 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, such as abacavir, is administered to the subject once every three weeks. In certain embodiments, the CTLA-4-containing protein, such as abacavir, is administered subcutaneously to a subject once every three weeks. In certain embodiments, a CTLA-4-containing protein, e.g., abasic, is administered to a subject once every three weeks for 15 weeks, sixteen weeks, 4 months, 5 months, 6 months, 1 year, 2 years, 5 years, 10 years, or more. In particular embodiments, the CTLA-4-containing protein, e.g., abasic, is administered subcutaneously to the subject once every three weeks for 15 weeks, sixteen 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, such as abacavir, is administered to the subject once every four weeks. In certain embodiments, the CTLA-4-containing protein, such as abacavir, is administered subcutaneously to a subject once every four weeks. In certain embodiments, the CTLA-4-containing protein, e.g., abasic, is administered to the subject once every four weeks for 15 weeks, sixteen weeks, 4 months, 5 months, 6 months, 1 year, 2 years, 5 years, 10 years, or more. In particular embodiments, the CTLA-4-containing protein, e.g., abasic, is administered subcutaneously to the subject once every four weeks for 15 weeks, sixteen weeks, 4 months, 5 months, 6 months, 1 year, 2 years, 5 years, 10 years, or more.
In certain embodiments, the IL-2 protein, e.g., aldesleukin, is administered to the subject once daily for three consecutive days. In a particular embodiment, the IL-2 protein, e.g., aldesleukin, is administered subcutaneously to the subject once daily for three consecutive days.
In certain embodiments, a protein comprising CTLA-4, such as abacavir, is administered to a subject once every two weeks, and an IL-2 protein, such as aldesleukin, is administered to the subject once daily for three consecutive days. In certain embodiments, a protein comprising CTLA-4, such as abacavir, is administered subcutaneously to a subject once every two weeks, and an IL-2 protein, such as aldesleukin, is administered subcutaneously to a subject once daily for three consecutive days.
In certain embodiments, the CTLA-4-containing protein, such as abacavir, is administered to the subject once every two weeks, and the IL-2 protein, such as aldesleukin, is administered to the subject once daily for three consecutive days starting on the day of administration of the CTLA-4-containing protein, such as abacavir. In certain embodiments, the CTLA-4-containing protein, such as albazedox, is administered to the subject subcutaneously once every two weeks, and the IL-2 protein, such as aldesleukin, is administered to the subject once daily for three consecutive days starting on the day of administration of the CTLA-4-containing protein, such as albazedox, to the subject.
In certain embodiments, the CTLA-4-containing protein, e.g., abacavir, is administered to the subject once every two weeks for fifteen weeks, sixteen 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 daily for three consecutive days starting on the day of administration of the CTLA-4-containing protein, e.g., abacavir, to the subject. In certain embodiments, the first administration of a protein comprising CTLA-4 to a subject is performed without administration of IL-2 protein. For example, in certain embodiments, the subject is administered an IL-2 protein, such as aldesleukin, from the third week, and the subject is administered the IL-2 protein daily for three consecutive days, starting on the day of administration of the CTLA-4-containing protein, such as abafop, to the subject. In certain embodiments, a CTLA-4-containing protein, such as abacavir, is administered subcutaneously to a subject once every two weeks for fifteen weeks, sixteen 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 daily for three consecutive days starting on the day of administration of the CTLA-4-containing protein, such as abacavir. In certain embodiments, the first administration of a protein comprising CTLA-4 to a subject is performed without administration of the TL-2 protein. For example, in certain embodiments, the IL-2 protein, e.g., aldesleukin, is administered to the subject from the third week, and the IL-2 protein is administered to the subject subcutaneously three days a day, starting on the day of administration of the CTLA-4 containing protein, e.g., abafop, to the subject.
In certain embodiments, a protein containing CTLA-4, such as abacavir, is administered to a subject once every three weeks, and an IL-2 protein, such as aldesleukin, is administered to the subject once daily for three consecutive days. In certain embodiments, a protein comprising CTLA-4, such as abacavir, is administered subcutaneously to a subject once every three weeks, and an IL-2 protein, such as aldesleukin, is administered subcutaneously to a subject once daily for three consecutive days.
In certain embodiments, the CTLA-4-containing protein, such as abacavir, is administered to the subject once every three weeks, and the IL-2 protein, such as aldesleukin, is administered to the subject once daily for three consecutive days starting with the day of administration of the CTLA-4-containing protein, such as abacavir. In certain embodiments, the CTLA-4-containing protein, such as albazedox, is administered to the subject subcutaneously once every three weeks, and the IL-2 protein, such as aldesleukin, is administered to the subject subcutaneously once daily for three consecutive days starting on the day of administration of the CTLA-4-containing protein, such as albazedox, to the subject.
In certain embodiments, the CTLA-4-containing protein, e.g., abacavir, is administered to the subject once every three weeks for fifteen weeks, sixteen 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 daily for three consecutive days starting on the day of administration of the CTLA-4-containing protein, e.g., abacavir, to the subject. In certain embodiments, a CTLA-4-containing protein, such as abacavir, is administered subcutaneously to a subject once every three weeks for fifteen weeks, sixteen 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 daily for three consecutive days starting on the day of administration of the CTLA-4-containing protein, such as abacavir. In certain embodiments, the first administration of a protein comprising CTLA-4 to a subject is performed without administration of IL-2 protein.
In certain embodiments, the CTLA-4-containing protein, such as abacavir, is administered to the subject once every three weeks, and the IL-2 protein, such as aldesleukin, is administered to the subject once daily for three consecutive days starting with the day of administration of the CTLA-4-containing protein, such as abacavir. In certain embodiments, the CTLA-4-containing protein, such as albazedox, is administered to the subject subcutaneously once every three weeks, and the IL-2 protein, such as aldesleukin, is administered to the subject subcutaneously once daily for three consecutive days starting on the day of administration of the CTLA-4-containing protein, such as albazedox, to the subject.
In certain embodiments, the CTLA-4-containing protein, e.g., abacavir, is administered to the subject once every four weeks for fifteen weeks, sixteen 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 daily for three consecutive days starting on the day of administration of the CTLA-4-containing protein, e.g., abacavir, to the subject. In certain embodiments, a protein containing CTLA-4, e.g., abacavir, is administered subcutaneously to a subject once every four weeks for fifteen weeks, sixteen 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 daily for three consecutive days starting on the day of administration of the protein containing CTLA-4, e.g., abacavir. In certain embodiments, the first administration of a protein comprising CTLA-4 to a subject is performed without administration of IL-2 protein.
In certain embodiments, about 5mg to about 200mg, about 10mg to about 200mg, about 15mg to about 200mg, about 20mg to about 200mg, about 25mg to about 200mg, about 50mg to about 175mg, about 50mg to about 150mg, or about 50mg to about 125mg of a protein containing CTLA-4, such as abacavir, is administered to a subject. In certain embodiments, a protein comprising CTLA-4, such as abacavir, is administered subcutaneously to a subject.
In a particular embodiment, about 50mg of a protein containing CTLA-4, such as abacavir, is administered to a subject. In a specific embodiment, about 50mg of CTLA-4-containing protein, such as abacavir, is administered to a subject in a volume of 0.4 mL. In certain embodiments, a protein comprising CTLA-4, such as abacavir, is administered subcutaneously to a subject.
In a particular embodiment, about 87.5mg of a protein containing CTLA-4, such as abacavir, is administered to a subject. In a specific embodiment, about 87.5mg of a protein containing CTLA-4, such as abacavir, is administered to a subject in a volume of 0.7 mL. In certain embodiments, a protein comprising CTLA-4, such as abacavir, is administered subcutaneously to a subject.
In a particular embodiment, about 125mg of a protein containing CTLA-4, such as abacavir, is administered to a subject. In a specific embodiment, a volume of 1.0mL of about 125mg CTLA-4-containing protein, such as abacavir, is administered to a subject. In certain embodiments, a protein comprising CTLA-4, such as abacavir, is administered subcutaneously to a subject.
In particular embodiments, about 1x10 is administered to a subject 4 Up to about 1x10 7 About 5x10 4 Up to about 1x10 7 About 1x10 5 Up to about 1x10 7 About 5x10 5 Up to about 1x10 7 、5x10 5 Up to about 5x10 6 、5x10 5 Up to about 4x10 6 、5x10 5 Up to about 3x10 6 、5x10 5 Up to about 2x10 6 About 5x10 5 Up to about 1x10 6 A unit of IL-2 protein, such as aldesleukin. In certain embodiments, the IL-2 protein, e.g., aldesleukin, is administered subcutaneously to the subject.
In specific embodiments, the IL-2 protein, e.g., aldesleukin, is administered to the subject, e.g., subcutaneously, in an amount of about 500,000 units to about 3,000,000 units. In specific embodiments, the IL-2 protein, e.g., aldesleukin, is administered to the subject, e.g., subcutaneously from about 500,000 units to about 2,000,000 units. In specific embodiments, the IL-2 protein, e.g., aldesleukin, is administered to the subject, e.g., subcutaneously from about 500,000 units to about 1,000,000 units.
In one aspect, provided herein is a method of treating a neurodegenerative or neuroinflammatory disease or disorder in a subject in need thereof, wherein the method comprises administering to the subject a formulation comprising:
i) A CTLA-4-containing protein; and
ii) IL-2 protein;
wherein the method reduces one or more symptoms associated with a neurodegenerative or neuroinflammatory disease or disorder in the subject being treated. The formulation is administered to the subject one or more times. In certain embodiments, the formulation is administered to the subject during 2 months, 3 months, 4 months, 5 months, 6 months, 1 year, 2 years, 5 years, 10 years, or more. In certain embodiments, the CTLA-4-containing protein is abacavir. In certain embodiments, the CTLA-4-containing protein is beraprost. In certain embodiments, the IL-2 protein is an aldesleukin. In certain embodiments, the CTLA-4-containing protein is Abauprine and the IL-2 protein is aldesleukin.
In one aspect, provided herein is a method of treating a neurodegenerative or neuroinflammatory disease or disorder in a subject in need thereof, comprising starting on day 1 and comprising administering to the subject a dosing cycle comprising:
i) A CTLA-4-containing protein; and
ii) IL-2 protein; wherein the method reduces one or more symptoms associated with a neurodegenerative or neuroinflammatory disease or disorder in the subject being treated. The formulation may be administered to the subject one or more times during the dosing cycle.
The method may include one or more administration cycles. In certain embodiments, the method comprises more than one dosing cycle and each dosing cycle is the same. In certain embodiments, the method comprises more than one dosing cycle and at least one dosing cycle is different from the others. The administration cycle may be repeated one or more times. There may be a period of time between the completion of one dosing cycle and the start of the next dosing cycle.
In certain embodiments, the CTLA-4-containing protein is abacavir. In certain embodiments, the CTLA-4-containing protein is beraprost. In certain embodiments, the IL-2 protein is an aldesleukin. In certain embodiments, the CTLA-4-containing protein is Abauprine and the IL-2 protein is aldesleukin.
For ease of description, the formulation may be referred to herein as a "CTLA-4 containing protein/IL-2 protein formulation" or "IL-2 protein/CTLA-4 containing protein formulation". In the case where the CTLA-4-containing protein is abacavir and the IL-2 protein is aldesleukin, the formulation may be referred to herein as an "abasic/aldesleukin formulation" or an "aldesleukin/abasic formulation. "
In certain embodiments, a protein/IL-2 protein formulation containing CTLA-4, e.g., an abasic plain/aldesleukin formulation, is administered to a subject by injection or infusion. In particular embodiments, a protein/IL-2 protein formulation containing CTLA-4, e.g., an abasic/aldesleukin formulation, is administered subcutaneously to a subject. In particular embodiments, a protein/IL-2 protein formulation comprising CTLA-4, e.g., an abasic/aldesleukin formulation, is administered intravenously to a subject.
In certain embodiments of such methods, the dosing cycle comprises administering a protein/IL-2 protein formulation comprising CTLA-4, e.g., an abasic plain/aldesleukin formulation, 1-10 times to the subject.
In particular embodiments of the methods described herein, the dosing cycle comprises a single administration of a protein/IL-2 protein formulation comprising CTLA-4, e.g., an abasic/aldesleukin formulation, to a subject on day 1 of the dosing cycle. In particular embodiments of such methods, the dosing cycle comprises daily administration of a protein/IL-2 protein formulation comprising CTLA-4, such as an abasic/aldesleukin formulation, to the subject for two consecutive days starting on day 1 of the dosing cycle. In particular embodiments of such methods, the dosing cycle comprises daily administration of a protein/IL-2 protein formulation comprising CTLA-4, such as an abasic plain/aldesleukin formulation, to the subject for three consecutive days starting on day 1 of the dosing cycle. In particular embodiments of such methods, the dosing cycle comprises daily administration of a protein/IL-2 protein formulation comprising CTLA-4, such as an abasic plain/aldesleukin formulation, to the subject for four consecutive days starting on day 1 of the dosing cycle. In particular embodiments of such methods, the dosing cycle comprises daily administration of a protein/IL-2 protein formulation comprising CTLA-4, such as an abasic plain/aldesleukin formulation, to the subject for five consecutive days starting on day 1 of the dosing cycle. In particular embodiments of such methods, the dosing cycle comprises daily administration of a protein/IL-2 protein formulation comprising CTLA-4, such as an abasic plain/aldesleukin formulation, to the subject for six consecutive days starting on day 1 of the dosing cycle. In particular embodiments of such methods, the dosing cycle comprises daily administration of a protein/IL-2 protein formulation comprising CTLA-4, such as an abasic plain/aldehydic interleukin formulation, to the subject for seven consecutive days starting on day 1 of the dosing cycle.
In particular embodiments of the methods described herein, the dosing cycle comprises daily administration of a protein/IL-2 protein formulation comprising CTLA-4, e.g., an Abamezepine/Aldi interleukin formulation, to a subject for at least two discrete days. In one non-limiting embodiment, for example, a protein/IL-2 protein formulation containing CTLA-4, such as an abasic/aldesleukin formulation, is administered to a subject for the first time on day 1 of the dosing cycle, followed by administration to the subject on day 3, day 4, day 5, day 6, or day 7.
In certain embodiments of the methods described herein, the method comprises 2-13 dosing cycles. In certain embodiments of the methods described herein, the dosing cycle is repeated 1-12 times. In a specific embodiment, the method comprises 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 particular 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.
In certain embodiments of the methods described herein, the first dosing cycle comprises administering a protein/IL-2 protein formulation comprising CTLA-4, e.g., an abasic/aldesleukin formulation, to the subject daily for three consecutive days beginning on day 1 of the dosing cycle, and the first dosing cycle is repeated 6 times, wherein each repeated dosing cycle begins 14 days after day 1 of the previous dosing cycle.
In certain embodiments of the methods described herein, the dosing cycle comprises administering to the subject a CTLA-4-containing protein/IL-2 protein formulation comprising about 5mg to about 125mg of the CTLA-4-containing protein and about 3X10 4 Up to about 3x10 7 A unit of IL-2 protein. In certain embodiments of the methods described herein, the dosing cycle comprises administering to the subject an abamectin/aldesleukin formulation comprising about 5mg to about 125mg abamectin and about 3x10 4 Up to about 3x10 7 Units of aldesleukin.
In certain embodiments of the methods described herein, the dosing cycle comprises administering to the subject a formulation comprising about 8.75mg to about 87.5mg abamectin and about 3x10 4 Up to about 3x10 7 Units of aldesleukin.
In certain embodiments of the methods described herein, the dosing cycle comprises administering to the subject a formulation comprising about 29.17mg of abasic and about 1x10 5 Units of aldesleukin. In certain embodiments of the methods described herein, the dosing cycle comprises administering to the subject a formulation comprising about 29.17mg of abasic and about 1x10 6 Units of aldesleukin. In certain embodiments of the methods described herein, the dosing cycle comprises administering to the subject a formulation comprising about 29.17mg of abasic and about 1x10 7 Units of aldesleukin.
In certain embodiments of the methods described herein, the dosing cycle comprises administering to the subject a formulation comprising about 5mg to about 50mg of abasic and about 3x10 4 Up to about 3x10 7 Units of aldesleukin.
Certain of the methods described hereinIn some embodiments, the dosing cycle comprises administering to the subject a formulation comprising about 16.67mg of abamectin and about 1x10 5 Units of aldesleukin. In certain embodiments of the methods described herein, the dosing cycle comprises administering to the subject a formulation comprising about 16.67mg of abasic and about 1x10 6 Units of aldesleukin. In certain embodiments of the methods described herein, the dosing cycle comprises administering to the subject a formulation comprising about 16.67mg of abasic and about 1x10 7 Units of aldesleukin.
In certain embodiments of the methods described herein, the dosing cycle comprises administering to the subject a formulation comprising about 12.5mg to about 125mg of abamectin and about 3x10 4 Up to about 3x10 7 Units of aldesleukin.
In certain embodiments of the methods described herein, the dosing cycle comprises administering to the subject a formulation comprising about 41.67mg of abasic and about 1x10 5 Units of aldesleukin. In certain embodiments of the methods described herein, the dosing cycle comprises administering to the subject a formulation comprising about 41.67mg of abasic and about 1x10 6 Units of aldesleukin. In certain embodiments of the methods described herein, the dosing cycle comprises administering to the subject a formulation comprising about 41.67mg of abasic and about 1x10 7 Units of aldesleukin.
In certain embodiments of the methods described herein, the dosing cycle comprises daily administration of a formulation to a subject for three consecutive days starting on day 1 of the dosing cycle, wherein the formulation comprises about 29.17mg of abamectin and about 1x10 6 Units of aldesleukin. In a specific embodiment, the dosing cycle is repeated 6 times, wherein each repeated dosing cycle begins 14 days after day 1 of the previous dosing cycle.
In certain embodiments of the methods described herein, the dosing cycle continues during 2 months, 3 months, 4 months, 5 months, 6 months, 1 year, 2 years, 5 years, 10 years, or longer, e.g., the dosing cycle repeats during 2 months, 3 months, 4 months, 5 months, 6 months, 1 year, 2 years, 5 years, 10 years, or longer.
In certain embodiments, the methods described herein further comprise administering a protein formulation comprising CTLA-4, such as an abamectin formulation, to the subject prior to first administering the protein/IL-2 protein formulation comprising CTLA-4, such as an abamectin formulation, to the subject. In certain embodiments, the methods described herein further comprise administering a protein formulation comprising CTLA-4, e.g., an abacavir 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 the protein/IL-2 protein formulation comprising CTLA-4, e.g., an abamectin formulation, to the subject.
In particular embodiments, the CTLA-4-containing protein formulation comprises 50mg to 125mg of the CTLA-4-containing protein, e.g., 50mg of the CTLA-4-containing protein, 87.5mg of the CTLA-4-containing protein, or 125mg of the CTLA-4-containing protein. In specific embodiments, the abacavir formulation comprises 50mg to 125mg of abacavir, e.g., 50mg of abacavir, 87.5mg of abacavir, or 125mg of abacavir. In certain embodiments, a protein formulation containing CTLA-4, such as an abacavir formulation, is administered to a subject by injection or infusion. In certain embodiments, a protein formulation containing CTLA-4, e.g., an abapple formulation, is administered to a subject subcutaneously or intravenously.
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.
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 polyneuropathy, chronic inflammatory demyelinating polyneuropathy, guillain-Barre syndrome, transverse myelitis, optic neuromyelitis, epilepsy, traumatic brain injury, spinal cord injury, encephalitis, central nervous system vasculitis, sarcoidosis, autoimmune or post-infection encephalitis, or chronic meningitis.
In certain embodiments of the methods described herein, the method further comprises performing an additional therapeutic intervention, wherein the additional therapeutic intervention comprises a cognitive rehabilitation program, a neural stimulation technique, or a combination thereof. In certain embodiments, the cognitive rehabilitation program is a computer-implemented cognitive rehabilitation program. In certain embodiments, the neural stimulation technique is an Invasive Brain Stimulation (IBS) technique. In some embodiments, the neural stimulation 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 Vagal 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 (tcacs), electroconvulsive therapy (ECT), magnetic epileptic therapy (MST), craniocerebral Electrical Stimulation (CES), and non-invasive VNS.
In one aspect, provided herein is a kit comprising i) one or more doses of a formulation comprising 50 to 125mg of albazedox, and ii) one or more doses of a formulation comprising 500,000 to 3,000,000 units of albazedox in separate containers. In certain embodiments, the kit comprises one or more doses of a formulation comprising 50mg of abacavir, 87.5mg of abacavir, or 125mg of abacavir. In particular embodiments, one or more doses of abamectin are present in lyophilized form, for example in the form of a lyophilized powder or cake. In certain embodiments, one or more doses of the formulation of abacavir are suitable for subcutaneous or intravenous administration. In certain embodiments, the kit comprises one or more doses of a formulation comprising 500,000 to 2,000,000 units of aldesleukin or 1,000,000 units of aldesleukin. In particular embodiments, one or more doses of the aldesleukin are present in lyophilized form, for example in lyophilized powder or cake form. In certain embodiments, one or more doses of the formulation of aldesleukin are suitable for subcutaneous or intravenous administration.
In one aspect, provided herein is a pharmaceutical composition comprising one or more doses of a protein comprising CTLA-4 and an IL-2 protein ("CTLA-4-containing protein/IL-2 protein dose"). In certain embodiments, provided herein is a pharmaceutical composition comprising one or more doses of albazedox and aldesleukin ("albazedox dose").
In certain embodiments, provided herein is a pharmaceutical composition comprising one or more abamectin/aldesleukin doses, wherein one abamectin/aldesleukin dose comprises 5mg to 125mg of abamectin and 3x10 4 Up to 3x10 7 Units of aldesleukin.
In a particular embodiment, provided herein is a pharmaceutical composition comprising one or more abasic/aldesleukin doses, wherein one abasic/aldesleukin dose comprises 8.75 to 87.5mg of abasic and 3x10 4 Up to 3x10 7 Units of aldesleukin. In a specific embodiment, provided herein is a pharmaceutical composition comprising one or more abamectin/aldesleukin doses, wherein one abamectin/aldesleukin dose comprises 29.17mg abamectin and 1x10 5 Unit of Aldi interleukin, 1x10 6 Unit of Aldi-interleukin or 1x10 7 Units of aldesleukin. In a specific embodiment, provided herein is a pharmaceutical composition comprising one or more abamectin/aldesleukin doses, wherein one abamectin/aldesleukin dose comprises 29.17mg abamectin and 1x10 6 Units of aldesleukin.
In a particular embodiment, provided herein is a pharmaceutical composition comprising one or more abasic/aldesleukin doses, wherein one abasic/aldesleukin dose comprises 5mg to 50mg of abasic and 3x10 4 Up to 3x10 7 Unit AldiInterleukins. In a specific embodiment, provided herein is a pharmaceutical composition comprising one or more abamectin/aldesleukin doses, wherein one abamectin/aldesleukin dose comprises 16.67mg abamectin and 1x10 5 Unit of Aldi interleukin, 1x10 6 Unit of Aldi-interleukin or 1x10 7 Units of aldesleukin. In a specific embodiment, provided herein is a pharmaceutical composition comprising one or more abamectin/aldesleukin doses, wherein one abamectin/aldesleukin dose comprises 16.67mg abamectin and 1x10 6 Units of aldesleukin.
In a particular embodiment, provided herein is a pharmaceutical composition comprising one or more abasic/aldesleukin doses, wherein one abasic/aldesleukin dose comprises 12.5mg to 125mg of abasic and 3x10 4 Up to 3x10 7 Units of aldesleukin. In a specific embodiment, provided herein is a pharmaceutical composition comprising one or more abamectin/aldesleukin doses, wherein one abamectin/aldesleukin dose comprises 41.67mg abamectin and 1x10 5 Unit of Aldi interleukin, 1x10 6 Unit of Aldi-interleukin or 1x10 7 Units of aldesleukin. In a specific embodiment, provided herein is a pharmaceutical composition comprising one or more abamectin/aldesleukin doses, wherein one abamectin/aldesleukin dose comprises 41.67mg abamectin and 1x10 6 Units of aldesleukin.
In certain embodiments, provided herein is a pharmaceutical composition comprising one or more of the abasic/aldesleukin doses as shown in table 4.
In certain embodiments, the pharmaceutical composition comprising one or more of the abamectin/aldesleukin doses described herein is present in lyophilized form, for example, in the form of a lyophilized powder or a lyophilized cake.
In certain embodiments, the pharmaceutical composition comprising one or more of the abasic/aldesleukin doses described herein is a solution, e.g., an aqueous solution. In particular embodiments, one or more of the abamectin/aldesleukin doses are present in the pharmaceutical composition at a concentration of 1 abamectin/aldesleukin dose/0.4 ml, 1 abamectin/aldesleukin dose/0.7 ml, 1 abamectin/aldesleukin dose/1.0 ml, 1 abamectin/aldesleukin dose/1.5 ml or 1 abamectin/aldesleukin dose/2.0 ml.
In certain embodiments, provided herein is a pharmaceutical composition comprising one or more of the abasic/aldesleukin doses described herein suitable for subcutaneous administration. In certain embodiments, provided herein is a pharmaceutical composition comprising one or more abasic/aldesleukin doses suitable for intravenous administration.
Further illustrative embodiments are as follows:
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 the method reduces one or more symptoms associated with a neurodegenerative or neuroinflammatory disease or disorder in the subject being treated.
2. The method of embodiment 1, wherein the CTLA-4-containing protein comprises a human CTLA-4 extracellular domain.
3. The method of embodiment 1 or 2, wherein the CTLA-4-containing protein is a fusion protein.
4. The method of embodiment 3, wherein the fusion protein comprises a human CTLA-4 extracellular domain and a human immunoglobulin Fc domain.
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 CH 3.
6. The method of embodiment 4 or 5, wherein the human immunoglobulin Fc domain is a human IgG1 Fc domain.
7. The method of any one of embodiments 1-6, wherein the CTLA-4-containing protein is glycosylated.
8. The method of any one of embodiments 1-7, wherein the CTLA-4-containing protein comprises the following amino acid sequence monomers:
MHVAQPAVVLASSRGIASFVCEYASPGKATEVRVTVLRQADSQVTEVCAATYMMGNELTFLDDSICTGTSSGNQVNLTIQGLRAMDTGLYICKVELMYPPPYYLGIGNGTQIYVIDPEPCPDSDQEPKSSDKTHTSPPSPAPELLGGSSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:1)。
9. The method of embodiment 8, wherein the CTLA-4-containing protein comprises a homodimer of two monomers, each monomer comprising the amino acid sequence of SEQ ID No. 1.
10. The method of embodiment 1, wherein the CTLA-4-containing protein is abacavir.
11. The method of any one of embodiments 1-10, wherein the IL-2 protein is a human IL-2 protein.
12. The method of embodiment 11, wherein the human IL-2 protein comprises serine at an amino acid position corresponding to amino acid residue 125 of naturally occurring mature human IL-2.
13. The method of embodiment 11 or 12, wherein the human IL-2 protein lacks an N-terminal alanine amino acid.
14. The method of any one of embodiments 11-13, wherein the human IL-2 protein comprises the amino acid sequence of seq id no:
PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT(SEQ ID NO:3)。
15. the method of any one of embodiments 1-14, wherein the IL-2 protein is not glycosylated.
16. The method of embodiment 11, wherein the IL-2 protein is an aldesleukin.
17. A method of treating a neurodegenerative or neuroinflammatory disease or disorder in a subject in need thereof, comprising administering to the subject:
i) Abacavir; and
ii) aldesleukin;
wherein the method reduces one or more symptoms associated with a neurodegenerative or neuroinflammatory disease or disorder in the subject being treated.
18. The method of embodiment 17, wherein the abacavir is administered by injection or infusion.
19. The method of claim 18, wherein the abamectin is administered subcutaneously.
20. The method of claim 18, wherein the abacavir is administered intravenously.
21. The method of embodiment 17, wherein the aldesleukin is administered by injection or infusion.
22. The method of claim 21, wherein the aldesleukin is administered subcutaneously.
23. The method of claim 21, wherein the aldesleukin is administered intravenously.
24. The method of embodiment 17, wherein the abacavir and the aldesleukin are administered subcutaneously.
25. The method of embodiment 17, wherein the abacavir and the aldesleukin are administered intravenously.
26. The method of any one of embodiments 17-25, wherein the abacavir is administered once every two weeks.
27. The method of embodiment 26, wherein the abacavir is administered subcutaneously once every two weeks.
28. The method of embodiment 26 or 27, wherein the abacavir is administered once every two weeks for 15 weeks.
29. The method of any one of embodiments 17-28, wherein the aldesleukin is administered once daily for three consecutive days.
30. The method of embodiment 29, wherein the aldesleukin is administered subcutaneously once daily for three consecutive days.
31. The method of any one of embodiments 17-25, wherein:
a) Administering said abacavir once every two weeks; and is also provided with
b) The aldehydic interleukin is administered once daily for three consecutive days, starting on the day of administration of the abacavir.
32. The method of embodiment 31, wherein the abacavir and the aldesleukin are administered subcutaneously.
33. The method of any one of embodiments 17-25, wherein:
a) Administering said abacavir once every two weeks for fifteen weeks;
b) The administration of aldesleukin starting from the third week; and is also provided with
c) Once the administration of the aldesleukin is started, the aldesleukin is administered once daily for three consecutive days starting from the day of administration of the abacavir.
34. The method of embodiment 33, wherein the abacavir and the aldesleukin are administered subcutaneously.
35. The method of any one of embodiments 17-34, wherein the abacavir is administered in an amount ranging from 50mg to 125 mg.
36. The method of embodiment 35, wherein the abacavir is administered in an amount of 50 mg.
37. The method of embodiment 36, wherein the abacavir is administered subcutaneously in a volume of 0.4 mL.
38. The method of embodiment 35, wherein the abacavir is administered in an amount of 87.5 mg.
39. The method of embodiment 38, wherein the abacavir is administered subcutaneously in a volume of 0.7 mL.
40. The method of embodiment 35, wherein the abacavir is administered in an amount of 125 mg.
41. The method of embodiment 40, wherein the abacavir is administered subcutaneously in a volume of 1.0 mL.
42. The method of any one of embodiments 17-41, wherein the aldesleukin is administered in an amount ranging from 500,000 units to 3,000,000 units.
43. The method of embodiment 42, wherein the aldesleukin is administered in an amount in the range of 500,000 units to 2,000,000 units.
44. The method of embodiment 43, wherein the aldesleukin is administered in an amount of 1,000,000 units.
45. The method of any one of embodiments 42-44, wherein the aldesleukin is administered subcutaneously.
46. A method of treating a neurodegenerative or neuroinflammatory disease or disorder in a subject in need thereof, comprising starting on day 1 and comprising administering to the subject a dosing cycle comprising a formulation of:
i) Abacavir; and
ii) aldesleukin;
wherein the method reduces one or more symptoms associated with a neurodegenerative or neuroinflammatory disease or disorder in the subject being treated.
47. The method of embodiment 46, wherein the formulation is administered by injection or infusion.
48. The method of embodiment 46, wherein the formulation is administered subcutaneously.
49. The method of embodiment 46, wherein the formulation is administered intravenously.
50. The method of any one of embodiments 46-49, wherein the dosing cycle comprises administering the formulation to the subject 1-10 times.
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.
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 starting on day 1 of the dosing cycle.
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 starting on day 1 of the dosing cycle.
54. The method of any one of embodiments 46-49, wherein the dosing cycle comprises administering the formulation to the subject daily for four consecutive days starting on day 1 of the dosing cycle.
55. The method of any one of embodiments 46-49, wherein the dosing cycle comprises administering the formulation to the subject daily for five consecutive days starting on day 1 of the dosing cycle.
56. The method of any one of embodiments 46-55, wherein the administration cycle is repeated 1-12 times.
57. The method of any one of embodiments 46-55, wherein the dosing cycle is repeated 6 times.
58. The method of embodiment 56 or 57, wherein each repeated dosing cycle begins 10-28 days after day 1 of the previous dosing cycle.
59. The method of any of embodiments 56-58, wherein each repeated dosing cycle begins 14 days after day 1 of the previous dosing cycle.
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 the first dosing cycle is repeated 6 times, wherein each repeated dosing cycle begins 14 days after day 1 of the previous dosing cycle.
61. The method of any one of embodiments 46-49, wherein the dosing cycle comprises administering to the subject a formulation comprising about 5mg to about 125mg abamectin and about 3x10 4 Up to about 3x10 7 Units of aldesleukin.
62. The method of any one of embodiments 46-49, wherein the dosing cycle comprises administering to the subjectWith a formulation comprising about 8.75mg to about 87.5mg abasic and about 3x10 4 Up to about 3x10 7 Units of aldesleukin.
63. The method of any one of embodiments 46-49, wherein the dosing cycle comprises administering to the subject a formulation comprising about 29.17mg abamectin and about 1x10 5 Units of aldesleukin.
64. The method of any one of embodiments 46-49, wherein the dosing cycle comprises administering to the subject a formulation comprising about 29.17mg abamectin and about 1x10 6 Units of aldesleukin.
65. The method of any one of embodiments 46-49, wherein the dosing cycle comprises administering to the subject a formulation comprising about 29.17mg abamectin and about 1x10 7 Units of aldesleukin.
66. The method of any one of embodiments 46-49, wherein the dosing cycle comprises administering to the subject a formulation comprising about 5mg to about 50mg abamectin and about 3x10 4 Up to about 3x10 7 Units of aldesleukin.
67. The method of any one of embodiments 46-49, wherein the dosing cycle comprises administering to the subject a formulation comprising about 16.67mg of abamectin and about 1x10 5 Units of aldesleukin.
68. The method of any one of embodiments 46-49, wherein the dosing cycle comprises administering to the subject a formulation comprising about 16.67mg of abamectin and about 1x10 6 Units of aldesleukin.
69. The method of any one of embodiments 46-49, wherein the dosing cycle comprises administering to the subject a formulation comprising about 16.67mg of abamectin and about 1x10 7 Units of aldesleukin.
70. The method of any one of embodiments 46-49, wherein the dosing cycle comprises administering to the subject a formulation comprising about 12.5mg to about 125mg of abacavirPrime about 3x10 4 Up to about 3x10 7 Units of aldesleukin.
71. The method of any one of embodiments 46-49, wherein the dosing cycle comprises administering to the subject a formulation comprising about 41.67mg of abamectin and about 1x10 5 Units of aldesleukin.
72. The method of any one of embodiments 46-49, wherein the dosing cycle comprises administering to the subject a formulation comprising about 41.67mg of abamectin and about 1x10 6 Units of aldesleukin.
73. The method of any one of embodiments 46-49, wherein the dosing cycle comprises administering to the subject a formulation comprising about 41.67mg of abamectin and about 1x10 7 Units of aldesleukin.
74. The method of any one of embodiments 46-49, wherein the dosing cycle comprises daily administration of the formulation to the subject for three consecutive days starting on day 1 of the dosing cycle, wherein the formulation comprises about 29.17mg of abamectin and about 1x10 6 Units of aldesleukin.
75. The method of embodiment 74, wherein the dosing cycle is repeated 6 times, wherein each repeated dosing cycle begins 14 days after day 1 of the previous dosing cycle.
76. The method of embodiment 75, wherein the dosing cycle comprises 1-10 administrations of an abamectin/aldesleukin formulation as shown in table 1A.
77. The method of any one of embodiments 46-49, wherein a total of 50mg of abacavir and 3x10 are administered to the subject per dosing cycle 6 Units of aldesleukin.
78. The method of embodiment 77, wherein the dosing cycle comprises 1-10 administrations of an abamectin/aldesleukin formulation as shown in table 1B.
79. The method of any one of embodiments 46-49, wherein a total of 50mg of abacavir and 3x10 are administered to the subject per dosing cycle 7 Unit AInterleukin.
80. The method of embodiment 79, wherein the dosing cycle comprises 1-10 administrations of an abamectin/aldesleukin formulation as shown in table 1C.
81. The method of any one of embodiments 46-49, wherein a total of 87.5mg of abacavir and 3x10 are administered to the subject per dosing cycle 5 Units of aldesleukin.
82. The method of embodiment 81, wherein the dosing cycle comprises 1-10 administrations of an abamectin/aldesleukin formulation as shown in table 2A.
83. The method of any one of embodiments 46-49, wherein a total of 87.5mg of abacavir and 3x10 are administered to the subject per dosing cycle 6 Units of aldesleukin.
84. The method of embodiment 83, wherein the dosing cycle comprises 1-10 administrations of an abamectin/aldesleukin formulation as shown in table 2B.
85. The method of any one of embodiments 46-49, wherein a total of 87.5mg of abacavir and 3x10 are administered to the subject per dosing cycle 7 Units of aldesleukin.
86. The method of embodiment 85, wherein the dosing cycle comprises 1-10 administrations of an abamectin/aldesleukin formulation as shown in table 2C.
87. The method of any one of embodiments 46-49, wherein a total of 125mg of abacavir and 3x10 are administered to the subject per dosing cycle 5 Units of aldesleukin.
88. The method of embodiment 87, wherein the dosing cycle comprises 1-10 administrations of an abamectin/aldesleukin formulation as shown in table 3A.
89. The method of any one of embodiments 46-49, wherein a total of 125mg of abacavir and 3x10 are administered to the subject per dosing cycle 6 Units of aldesleukin.
90. The method of embodiment 89, wherein the dosing cycle comprises 1-10 administrations of an abamectin/aldesleukin formulation as shown in table 3B.
91. The method of any one of embodiments 46-49, wherein a total of 125mg of abacavir and 3x10 are administered to the subject per dosing cycle 7 Units of aldesleukin.
92. The method of embodiment 91, wherein the dosing cycle comprises 1-10 administrations of an abamectin/aldesleukin formulation as shown in table 3C.
93. The method of any one of embodiments 46-92, wherein the dosing cycle is repeated 6 times, wherein each repeated dosing cycle begins 14 days after day 1 of the previous dosing cycle.
94. The method of any of embodiments 46-92, wherein the formulation is administered by injection or infusion.
95. The method of any of embodiments 46-92, wherein the formulation is administered subcutaneously.
96. The method of any of embodiments 46-92, wherein the formulation is administered intravenously.
97. The method of any one of embodiments 46-96, further comprising administering to the subject an abacavir formulation 14 days prior to day 1 of the first dosing cycle, wherein the abacavir formulation comprises abamectin.
98. The method of embodiment 97, wherein the abacavir formulation comprises 50mg to 125mg of abacavir.
99. The method of embodiment 97, wherein the abacavir formulation comprises 87.5mg of abamectin.
100. The method of any one of embodiments 97-99, wherein the abacavir formulation is administered by injection or infusion.
101. The method of any one of embodiments 97-99, wherein the abacavir formulation is administered subcutaneously.
102. The method of any one of embodiments 97-99, wherein the abacavir formulation is administered intravenously.
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.
104. The method of embodiment 103, wherein the neurodegenerative disease or disorder is alzheimer's disease.
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 polyneuropathy, chronic inflammatory demyelinating polyneuropathy, guillain-barre syndrome, transverse myelitis, optic neuromyelitis, epilepsy, traumatic brain injury, spinal cord injury, encephalitis, central nervous system vasculitis, sarcoidosis, autoimmune or post-infection encephalitis, or chronic meningitis.
106. The method of any of embodiments 1-105, wherein the method further comprises performing a cognitive rehabilitation procedure, a neural stimulation technique, or a combination thereof.
107. The method of embodiment 106, wherein the cognitive rehabilitation program is a computer-implemented cognitive rehabilitation program.
108. The method of embodiment 105 or 106, wherein the neural stimulation technique is an Invasive Brain Stimulation (IBS) technique.
109. The method of embodiment 105 or 106, wherein the neural stimulation technique is a non-invasive brain stimulation (NIBS) technique.
110. The method of embodiment 108, wherein the IBS technique is selected from the group consisting of: deep Brain Stimulation (DBS) and invasive Vagal Nerve Stimulation (VNS).
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 (tcacs), electroconvulsive therapy (ECT), magnetic epileptic therapy (MST), craniocerebral Electrical Stimulation (CES), and non-invasive VNS.
112. A kit comprising i) one or more doses of a formulation comprising 50 to 125mg of albazedox, and ii) one or more doses of a formulation comprising 500,000 to 3,000,000 units of albazedox in separate containers.
113. The kit of embodiment 112, wherein the kit comprises one or more doses of a formulation comprising 50mg of abacavir.
114. The kit of embodiment 112, wherein the kit comprises one or more doses of a formulation comprising 87.5mg of abacavir.
115. The kit of embodiment 112, wherein the kit comprises one or more doses of a formulation comprising 125mg of abacavir.
116. The kit of any one of embodiments 112-115, wherein the kit comprises one or more doses of a formulation comprising 500,000 to 2,000,000 units of aldesleukin.
117. The kit of any one of embodiments 112-116, wherein the kit comprises one or more doses of a formulation comprising 1,000,000 units of aldesleukin.
118. The kit of any one of embodiments 112-117, wherein the one or more doses of abacavir are present in lyophilized form.
119. The kit of embodiment 118, wherein the one or more doses of abacavir are in the form of a lyophilized powder or a lyophilized cake.
120. The kit of any one of embodiments 112-119, wherein the one or more doses of aldesleukin are present in lyophilized form.
121. The kit of embodiment 120, wherein the one or more doses of aldesleukin are present in the form of a lyophilized powder or a lyophilized cake.
122. The kit of any one of embodiments 112-121, wherein one or more doses of the formulation of abacavir are suitable for subcutaneous administration.
123. The kit of any one of embodiments 112-121, wherein one or more doses of the formulation of abacavir are suitable for intravenous administration.
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.
125. The kit of any one of embodiments 112-123, wherein the formulation of one or more doses of aldesleukin is suitable for intravenous administration.
126. A pharmaceutical composition comprising one or more abasic pro/aldesleukin doses.
127. The pharmaceutical composition of embodiment 126, wherein the dose of abasic prine/aldesleukin comprises 5mg to 125mg of abasic prine and 3x10 4 Up to 3x10 7 Units of aldesleukin.
128. The pharmaceutical composition of embodiment 126, wherein the dose of abasic prine/aldesleukin comprises 8.75mg to about 87.5mg of abasic prine and 3x10 4 Up to 3x10 7 Units of aldesleukin.
129. The pharmaceutical composition of embodiment 126, wherein the dose of abamectin/aldesleukin comprises about 29.17mg abamectin and about 1x10 5 Units of aldesleukin.
130. The pharmaceutical composition of embodiment 126, wherein the dose of abasic prine/aldesleukin comprises about 29.17mg of abasic prine and 1x10 6 Units of aldesleukin.
131. The pharmaceutical composition of embodiment 126, wherein the dose of abamectin/aldesleukin comprises about 29.17mg abamectin and about 1x10 7 Units of aldesleukin.
132. The pharmaceutical composition of embodiment 126, wherein the abamectin/aldesleukin dose comprises about 5mg to about 50mg abamectin and about 3x10 4 Up to about 3x10 7 Units of aldesleukin.
133. The pharmaceutical composition of embodiment 126, wherein the dose of abamectin/aldesleukin comprises about 16.67mg abamectin and about 1x10 5 Units of aldesleukin.
134. The pharmaceutical combination according to embodiment 126A compound wherein the abamectin/aldesleukin dose comprises about 16.67mg abamectin and about 1x10 6 Units of aldesleukin.
135. The pharmaceutical composition of embodiment 126, wherein the dose of abamectin/aldesleukin comprises about 16.67mg abamectin and about 1x10 7 Units of aldesleukin.
136. The pharmaceutical composition of embodiment 126, wherein the dose of abamectin/aldesleukin comprises about 12.5mg to about 125mg abamectin and about 3x10 4 Up to about 3x10 7 Units of aldesleukin.
137. The pharmaceutical composition of embodiment 126, wherein the dose of abamectin/aldesleukin comprises about 41.67mg abamectin and about 1x10 5 Units of aldesleukin.
138. The pharmaceutical composition of embodiment 126, wherein the dose of abamectin/aldesleukin comprises about 41.67mg abamectin and about 1x10 6 Units of aldesleukin.
139. The pharmaceutical composition of embodiment 126, wherein the dose of abamectin/aldesleukin comprises about 41.67mg abamectin and about 1x10 7 Units of aldesleukin.
140. The pharmaceutical composition of embodiment 126, wherein the pharmaceutical composition comprises one or more of the abasic/aldesleukin doses as shown in table 4.
141. The pharmaceutical composition of any one of embodiments 126-140, wherein the pharmaceutical composition is in lyophilized form.
142. The pharmaceutical composition of embodiment 141, wherein the pharmaceutical composition is in the form of a lyophilized powder or a lyophilized cake.
143. The pharmaceutical composition of any one of embodiments 126-140, wherein the pharmaceutical composition is a solution.
144. The pharmaceutical composition of embodiment 143, wherein the pharmaceutical composition is in the form of an aqueous solution.
145. The pharmaceutical composition of embodiment 143 or 144, wherein the one or more abasic/aldesleukin doses are present at a concentration of 1 abasic/aldesleukin dose/0.4 ml.
146. The pharmaceutical composition of embodiment 143 or 144, wherein the one or more abasic/aldesleukin doses are present at a concentration of 1 abasic/aldesleukin dose/0.7 ml.
147. The pharmaceutical composition of embodiment 143 or 144, wherein the one or more abasic/aldesleukin doses are present at a concentration of 1 abasic/aldesleukin dose/1.0 ml.
148. The pharmaceutical composition of embodiment 143 or 144, wherein the one or more abasic/aldesleukin doses are present at a concentration of 1 abasic/aldesleukin dose/1.5 ml.
149. The pharmaceutical composition of embodiment 143 or 144, wherein the one or more abasic/aldesleukin doses are present at a concentration of 1 abasic/aldesleukin dose/2.0 ml.
150. The pharmaceutical composition of any one of embodiments 126-149, wherein the pharmaceutical composition is suitable for subcutaneous administration.
151. The pharmaceutical composition of any one of embodiments 126-149, wherein the pharmaceutical composition is suitable for intravenous administration.
4. Description of the drawings
Fig. 1: dose-dependent inhibition of M1 IL-6 expression in pro-inflammatory M1 macrophages with increasing amounts of CTLA4 IgG (abasic).
Fig. 2: dose-dependent inhibition of Tresp proliferation with increasing amounts of CTLA4 IgG (abasic).
Fig. 3: as CTLA4 IgG (aba-cit) amount increases, tregs have an increased dose-dependent inhibitory function on IL-2-induced in vivo expanded Tresp expansion of tregs isolated from alzheimer's patients.
Fig. 4: dose-dependent enhanced Treg inhibition of M1 IL6 protein expression of IL-2-induced in vivo expanded Treg (isolated from alzheimer's patients) with increasing amounts of CTLA4 IgG (aba-cit).
Fig. 5: effect on Treg inhibition of the percentage of M1-IL6 protein expression of co-cultures of Treg and M1 isolated from alzheimer's patients after addition of IL-2 or CTLA4 IgG (abasip) or a combination thereof.
Fig. 6: IL-2 and Abelip treatment play a role in restoring Treg function in patients with AD-01.
Fig. 7: IL-2 and Abelip treatment play a role in restoring Treg function in patients with AD-02.
Fig. 8: effect of IL-2 and abacavir treatment on cognitive improvement (MMSE score) in patients AD-01 and AD-02.
Fig. 9: effect of IL-2 monotherapy on MMSE score of AD patients (n=8), and effect of IL-2 and abanpu treatment on MMSE score of AD patients (n=3). "screening" refers to measurements taken prior to the initiation of a dosing regimen.
Fig. 10: effect of IL-2 monotherapy on Treg inhibition function in AD patients (n=8; left panel), and effect of IL-2 and abatopiramate treatment on Treg inhibition function in AD patients (n=3; right panel). F/U = follow-up, post-treatment. Baseline and SC are measurements taken prior to initiation of the dosing regimen. For IL-2 gabexapu, D8 measurements (showing approximately 19% change compared to SC) were made after the initial abamectin-only dose.
Fig. 11: IL-2 and Abelip treat effects on the Treg suppression function in ALS patients.
Fig. 12: effect of IL-2 and abanpu treatment on the percentage of cells expressing cd4+cd25+foxp3+ in ALS patients.
Fig. 13: effect of IL-2 and abapple treatment on the percentage of cells expressing cd8+ in ALS patients.
Fig. 14: ALSFRS-R scores for ALS patients prior to and during treatment with IL-2 and Abelip.
Fig. 15: maximum Inspiratory Pressure (MIP) values of ALS patients before and during treatment with IL-2 and abafpu (shading).
5. Detailed description of the preferred embodiments
In one aspect, provided herein are methods 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, wherein the methods reduce one or more symptoms associated with the disease or disorder. In certain embodiments, the CTLA-4-containing protein is abacavir. In certain embodiments, the IL-2 protein is an aldesleukin. In certain embodiments, the CTLA-4-containing protein is Abauprine and the IL-2 protein is aldesleukin.
In certain embodiments, the CTLA-4-containing protein and the IL-2 protein are administered to the subject separately. In certain embodiments, the CTLA-4-containing protein is abamectin, and the abamectin and IL-2 proteins are administered to the subject separately. In certain embodiments, the IL-2 protein is an aldesleukin, and the aldesleukin and the CTLA-4-containing protein are administered to the subject separately. In certain embodiments, the CTLA-4-containing protein is abacavir and the IL-2 protein is aldesleukin, and the abacavir and aldesleukin are administered to the subject separately.
In certain embodiments, the CTLA-4-containing protein and the IL-2 protein are administered together to the subject in a single formulation. In certain embodiments, the CTLA-4-containing protein is abamectin, and the abamectin and IL-2 proteins are administered together to the subject in a single formulation. In certain embodiments, the IL-2 protein is an aldesleukin, and the aldesleukin and the CTLA-4-containing protein are administered together in a single formulation to the subject. In certain embodiments, the CTLA-4-containing protein is abacavir and the IL-2 protein is aldesleukin, and the abacavir and aldesleukin are administered together to the subject in a single formulation.
Also provided herein are pharmaceutical compositions comprising one or more doses of a CTLA-4-containing protein and an IL-2 protein ("CTLA-4-containing protein/IL-2 protein dose"). In certain embodiments, provided herein is a pharmaceutical composition comprising one or more doses of albazedox and aldesleukin ("albazedox dose").
In another aspect, provided herein is a kit comprising i) one or more doses of a formulation comprising 50 to 125mg of albazedox, and ii) one or more doses of a formulation comprising 500,000 to 3,000,000 units of albazedox in separate containers. In certain embodiments, the kit comprises one or more doses of a formulation comprising 50mg of abacavir, 87.5mg of abacavir, or 125mg of abacavir. In particular embodiments, one or more doses of abamectin are present in lyophilized form, for example in the form of a lyophilized powder or cake. In certain embodiments, one or more doses of the formulation of abacavir are suitable for subcutaneous or intravenous administration. In certain embodiments, the kit comprises one or more doses of a formulation comprising 500,000 to 2,000,000 units of aldesleukin or 1,000,000 units of aldesleukin. In particular embodiments, one or more doses of the aldesleukin are present in lyophilized form, for example in lyophilized powder or cake form. In certain embodiments, one or more doses of the formulation of aldesleukin are suitable for subcutaneous or intravenous administration.
Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein.
The terms "a" and "an" and "the" as used herein are to be understood as singular or plural and mean "one or more" unless explicitly stated or apparent from the context.
The terms "comprising," "such as," and the like are intended to be inclusive and not limiting unless expressly stated otherwise.
The terms "or" and "are used interchangeably and may be understood to mean" and/or ".
The description herein of any aspect or embodiment of the invention using terms such as "comprising," "having," "including," or "containing" with reference to one or more elements is intended to provide support for "consisting of," "consisting essentially of," or "consisting essentially of" similar aspects or embodiments of the invention, unless otherwise indicated herein or clearly contradicted by context (e.g., a composition described herein as comprising the particular element is to be understood as also describing a composition consisting of the element, unless otherwise indicated herein or clearly contradicted by context).
The terms "about" and "approximately" as used herein are interchangeable and should generally be understood to refer to a range of numbers around a given number, as well as all numbers within the recited range of numbers (e.g., "about 5 to 15" means "about 5 to about 15"). Furthermore, all numerical ranges herein should be understood to include each and every integer within the range. In particular, unless otherwise indicated, these terms are intended to be within plus or minus 10% of a given value or range. Where integers are required, the term means within plus or minus 10% of a given value or range, rounded up or down to the nearest integer.
5.1 CTLA-4 containing proteins
The methods and compositions provided herein comprise or utilize CTLA-4-containing proteins, e.g., human CTLA-4-containing proteins.
CTLA-4 (cytotoxic T lymphocyte-associated protein 4) proteins are well known. See, e.g., uniProtKB identifier P16410.
In certain embodiments, the CTLA-4-containing protein is a human CTLA-4-containing protein. In certain embodiments, the CTLA-4-containing protein comprises a CD80 and/or CD86 binding portion of CTLA-4. In certain embodiments, the CTLA-4-containing protein comprises a human CTLA-4 extracellular domain. In particular embodiments, the CTLA-4-containing protein comprises an extracellular domain of the sequence:
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 bold and underlined portions of SEQ ID NO. 4. In particular embodiments, for example, a protein comprising CTLA-4 can comprise a sequence at least 90%, 95%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:4, the underlined portion of SEQ ID NO:4, or the bold and underlined portions of SEQ ID NO:4
To determine the percent identity of two amino acid sequences, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in the sequence of a first amino acid sequence for optimal alignment with a second amino acid sequence). The amino acid residues at the corresponding amino acid positions are then compared. When a position in the first sequence is occupied by the same amino acid residue as the corresponding position in the second sequence, then the molecules are identical at that position. The percent identity between 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 X100%). In one embodiment, the two sequences have the same length. In a certain embodiment, the percent identity is determined over the entire length of the amino acid sequence.
The percent identity between two sequences (e.g., amino acid sequences) can also be determined using a mathematical algorithm. Non-limiting examples of mathematical algorithms for comparing two sequences are as modified from Karlin and Altschul,1993, proc.Natl. Acad.Sci.U.S. A.90:58735877, karlin and Altschul,1990, proc.Natl. Acad.Sci.U.S. A.87:22642268. 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 using the XBLAST program parameter set, e.g., score 50, word length=3, to obtain amino acid sequences homologous to protein molecules described herein. To obtain a gap alignment for comparison purposes, gapped BLAST may be utilized as described in Altschul et al, 1997,Nucleic Acids Res.25:3389 3402. Alternatively, PSI BLAST can be used to conduct iterative searches to detect near-far relationships between molecules (supra). When using BLAST, gapped BLAST, and PSI BLAST programs, default parameters for the corresponding program (e.g., XBLAST) can be used (see, e.g., national Center for Biotechnology Information (NCBI), world Wide Web NCBI. N lm. Nih. Gov). Another preferred non-limiting example of a mathematical algorithm for comparing sequences is the algorithm of Myers and Miller,1988,CABIOS 4:11 17. Such an algorithm is incorporated into the ALIGN program (version 2.0) which is part of the GCG sequence alignment software package. When amino acid sequences are compared using the ALIGN program, PAM120 weight residue table, gap length penalty 12, and gap penalty 4 can be used.
The percent identity between two sequences can be determined using techniques similar to those described above, with or without gaps being allowed. In calculating the percent identity, only exact matches are typically calculated.
In certain embodiments, the CTLA-4-containing protein is a monomer. In certain embodiments, the CTLA-4-containing protein is a dimer.
In particular 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, a CH2 region, and a CH 3). In a particular embodiment, the human immunoglobulin Fc domain is an Ig domain, such as a human IgG1 Fc domain. In certain embodiments, the CTLA-4-containing protein is glycosylated.
In certain embodiments, the CTLA-4-containing protein comprises the following amino acid sequence monomers:
MHVAQPAVVLASSRGIASFVCEYASPGKATEVRVTVLRQADSQVTEVCAATYMMGNELTFLDDSICTGTSSGNQVNLTIQGLRAMDTGLYICKVELMYPPPYYLGIGNGTQIYVIDPEPCPDSDQEPKSSDKTHTSPPSPAPELLGGSSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1). 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.
In a particular embodiment, the CTLA-4-containing protein is abacavir.
In certain embodiments, the CTLA-4-containing protein comprises the following amino acid sequence monomers:
MHVAQPAVVLASSRGIASFVCEYASPGKYTEVRVTVLRQADSQVTEVCAATYMMGNELTFLDDSICTGTSSGNQVNLTIQGLRAMDTGLYICKVELMYPPPYYEGIGNGTQIYVIDPEPCPDSDQEPKSSDKTHTSPPSPAPELLGGSSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 2). 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.
In a particular embodiment, the CTLA-4-containing protein is beraprost.
In certain embodiments, the CTLA-4-containing protein is glycosylated.
5.2IL-2 proteins
The methods and compositions provided herein comprise or utilize IL-2 proteins, e.g., human IL-2 proteins.
IL-2 proteins are well known. See, e.g., uniProtKB identifier Q0GK43.
In certain embodiments, the IL-2 protein is a human IL-2 protein. For example, in certain embodiments, the IL-2 protein is or is derived from the following naturally occurring human IL-2 amino acid sequence:
APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT(SEQ ID NO:5)。
In certain embodiments, the IL-2 protein contains one or more mutations relative 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 particular embodiments, the human IL-2 protein comprises a mutation (underlined in the sequence set forth above) at an amino acid position corresponding to amino acid residue 125 of naturally occurring mature human IL-2. For example, in certain embodiments, the IL-2 protein contains serine at an amino acid position corresponding to amino acid residue 125 of naturally occurring mature human IL-2. In certain embodiments, the human IL-2 protein lacks an N-terminal alanine amino acid and comprises serine at an amino acid position corresponding to naturally occurring human IL-2 amino acid residue 125.
In specific embodiments, the IL-2 protein is not glycosylated.
In certain embodiments, the human IL-2 protein lacks an N-terminal alanine amino acid, comprises serine at an amino acid position corresponding to naturally occurring human IL-2 amino acid residue 125, and is not glycosylated.
In certain embodiments, the IL-2 protein is the well-known aldesleukin (des-alanyl-1, serine-125 human interleukin-2; trade name PROLEUKIN).
In certain embodiments, the human IL-2 protein comprises the following amino acid sequence:
PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFK FYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNI NVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT(SEQ ID NO:6)。
in certain embodiments, the IL-2 protein comprises one or more modifications, e.g., mutations, as compared to mature human IL-2 and exhibits reduced binding to the IL-2 receptor (IL-2R) alpha subunit (CD 25) relative to the native mature IL-2 protein. In certain embodiments, the IL-2 protein comprises one or more modifications, e.g., mutations, as compared to mature human IL-2 and exhibits reduced binding to the IL-2 receptor beta subunit (CD 122) relative to the native IL-2 protein. In certain embodiments, the IL-2 protein comprises one or more modifications, e.g., mutations, as compared to mature human IL-2, and has reduced binding to the gamma subunit of the IL-2 receptor (CD 132) relative to wild-type IL-2 protein. In certain embodiments, the IL-2 protein comprises one or more modifications, such as mutations, as compared to mature human IL-2 and exhibits reduced binding to the beta and gamma subunits of the IL-2 receptor relative to the native mature IL-2 protein. In certain embodiments, the IL-2 protein comprises one or more modifications, such as mutations, as compared to mature human IL-2 and exhibits reduced binding to the alpha and beta subunits of the IL-2 receptor relative to the native mature IL-2 protein. In certain embodiments, the IL-2 protein comprises one or more modifications, e.g., mutations, as compared to 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 the native mature IL-2 protein. In certain embodiments, the IL-2 protein comprises one or more modifications, such as mutations, as compared to mature human IL-2 and exhibits reduced binding to the alpha, beta, and gamma subunits of the IL-2 receptor relative to the native mature IL-2 protein.
In certain embodiments, the IL-2 protein comprises one or more modifications, e.g., mutations, as compared to mature human IL-2 and exhibits reduced IL-2 receptor-mediated signaling activity relative to the native mature IL-2 protein. IL-2 receptor mediated signaling activity can be measured using conventional well-known techniques, such as by assessment of STAT5 phosphorylation. See, e.g., ghenani et al (2020) front.111106, which is incorporated herein in its entirety.
In certain embodiments, the IL-2 protein comprises one or more modifications, e.g., mutations, as compared to mature human IL-2, and exhibits selectivity (e.g., preferential activation) for T regulatory (Treg) cells, e.g., relative to natural killer cells and/or T effector cells, as assessed, e.g., by Treg cell proliferation assays, treg-mediated inhibition functions, and/or lineage and/or phenotypic marker expression. Such assays are well known. See, e.g., ghenani (2020), supra.
In some embodiments, the IL-protein is an IL-2 mutein (i.e., an IL-2 protein comprising one or more mutations relative to the native mature IL-2 protein) comprising an amino acid sequence corresponding to native mature human IL-2, said amino acid sequence further comprising a substitution or deletion at one or more amino acid positions, such as A1 (deletion); p2 (e.g., deletion); t3 (e.g., T3C, T3A, T3G, T3Q, T3E, T3N, T3D, T3R, T3K, T3P or deletion); s4 (e.g., a deletion); s5 (e.g., deletion); s6 (e.g., deletion); h16 (e.g., H16E, H R), L18 (e.g., L18R, L18G, L18M, L18F, L18E, L18H, L18W, L K, L18Q, L18S, L18V, L18I, L Y, L18H, L18D, L T); d20 (e.g., D20A, D20G, D20H, D20W); q22 (e.g., Q22F, Q22E, Q22G, Q22A, Q22L, Q22M, Q22F, Q22W, Q22K, Q22S, Q22I, Q22Y, Q22H, Q22R, Q N, Q22D, Q22T, Q F); k35 (e.g., K35E); r38 (e.g., R38A, R G); m39 (e.g., M39L, M39V); f42 (e.g., F42A, F42L, F42Y); y45 is, for example, Y45A); h55 (e.g., H55Y); c58 (e.g., a deletion); e61 (e.g., E61Q); e62 (e.g., E62A); i86 (e.g., I86V); n88 (e.g., N88I, N88G, N88D, N88K, N88R); i89 (e.g., I89V); v91 (e.g., V91D, V91K); i92 (I92F); k97 (e.g, K97Q); m104 (e.g., M104A, M104T, M V); d109 (e.g., D109C or substitution with an unnatural amino acid with an activated side chain); t113 (e.g., T113N); c125 (e.g., C125A, C125S); q126 (e.g., Q126H, Q126M, Q K, Q C, Q126D, Q126E, Q G, Q126I, Q R, Q38126S, Q T); or S130 (e.g., S130T, S130G, S R).
In certain embodiments, the human IL-2 protein comprises the following amino acid sequence:
PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFK FYMPKKATELKHLQLEEELKPLEEVLNLAQSKNFHLRPRDLISNIN VIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT(SEQ ID NO:3)。
in some embodiments, the IL-protein is an IL-2 mutein comprising an amino acid sequence corresponding to naturally occurring mature human IL-2 and said amino acid sequence further comprising D20A and H16E mutations; D20A and M104T mutations; H16E and E61Q mutations; V91K, D a and M104V mutations; D20G mutation; D20W mutation; F42Y mutation; an N88K mutation; or D20A, H R and E61Q mutations.
In some embodiments, the IL-protein is an IL-2 mutein comprising an amino acid sequence corresponding to naturally occurring mature human IL-2 and said amino acid sequence further comprising D20, N88 and/or Q126 mutations. For example, in certain embodiments, an IL-2 protein may comprise a D20H mutation, an N88R, N88I or N88G mutation, and/or a Q126D mutation. See, for example, US6955807.
In some embodiments, the IL-2 protein is an IL-2Ra/IL-2Rb biased IL-2 protein. For example, in certain embodiments, IL-12 is STK-012 (Emmerich, J. Et al Cancer Res 2021;81 (13_supplement): abstract nr 1744).
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, e.g., one or more polymers having a weight average molecular weight of about 250 daltons to about 50,000 daltons. In some embodiments, 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 a specific embodiment, the pegylated tyrosine residue is Y45 or F42Y. In some embodiments, the IL-2 protein is a modified IL-2 polypeptide, as described in PCT publication No. WO 2021140416. In some embodiments, the IL-2 protein is the clinical candidate for IL-2 BPT-143 (Bright Peak).
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 an unnatural amino acid. In some embodiments, the water-soluble polymer includes polyethylene glycol (PEG), poly (propylene glycol) (PPG), a copolymer of ethylene glycol and propylene glycol, poly (oxyethylated polyol), poly (enol), poly (vinylpyrrolidone), poly (hydroxyalkyl methacrylamide), poly (hydroxyalkyl methacrylate), polysaccharide, poly (α -hydroxy acid), poly (vinyl alcohol), polyphosphazene, polyoxazoline (POZ), poly (N-acrylomorpholine), poly [ oligo (ethylene glycol) methyl methacrylate ] (POEGMA), or a combination 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.
In some embodiments, the IL-2 protein is conjugated to one or more polyethylene glycol (PEG) polymers, e.g., to one to seven PEG polymers, e.g., branched PEG, via releasable bonds. In particular 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 PEG is attached at the amino group of a lysine of an IL-2 protein. In some embodiments, there are a variety of conjugates that are mixtures of mono-, di-and trimerized ethylene glycol conjugates. In some embodiments, the IL-2 protein is a conjugate of an IL-2 protein, as described in U.S. Pat. No. 9,861,705, 10,960,079 or PCT publication No. WO 2012065086. In some embodiments, the IL-2 protein is a clinical candidate for NKTR-214.
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 an intact 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 IgG Fc domain. In particular embodiments, the IL-2 protein comprises an N-terminal or C-terminal human Fc domain fusion or conjugate, such as a human IgG Fc domain. In some embodiments, such moieties are directly linked to the IL-2 protein. In other embodiments, such moieties are indirectly linked to the IL-2 protein, e.g., through a linker containing GSSSS, e.g., containing GSSS, (GSSSS) 2 、(GSSSS) 3 Or (GSSSS) 4 Is a joint of a metal wire.
In a specific embodiment, the IL-protein is an IL-2 mutein comprising an amino acid sequence corresponding to naturally occurring mature human IL-2 and further comprising: 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 one or more of V69 (e.g., V69A), Q74 (e.g., Q74P), N88 (e.g., N88D), and C125 (e.g., C125S), e.g., L53I, N88D, V69A, Q P and C125S mutations; L56I, N88D, V69A, Q P and C125S mutations; the L80I, N88D, V69A, Q P and C125S mutations; or L118I, N88D, V69A, Q P and C125S mutations; and ii) optionally an Fc domain, e.g. a human IgG1Fc domain, e.g. an N-terminal human IgG1Fc domain.
In some embodiments, the IL-2 protein is an IL-2 mutein comprising: i) An amino acid sequence corresponding to naturally occurring mature human IL-2, said amino acid sequence further comprising substitution at one or more positions: e15 (e.g., E15Q); h16 (e.g., H16N); q22 (e.g., Q22E); n29 (e.g., N29S); y31 (e.g., Y31S, Y H); k35 (e.g., K35R); t37 (e.g., T37A); k48 (e.g., K48E); v69 (e.g., V69A); n71 (e.g., N71R); q74 (e.g., Q74P); d84 (e.g., D84N); n88 (e.g., N88D, N88R); e95 (e.g., E95Q); c125 (e.g., C125A, C125S); or Q126 (e.g., Q126E); and ii) optionally fused or conjugated to an antibody or antigen binding fragment that binds to MAdCAM, OAT1, OCT2, FXYD2, TSPAN7, DPP6, HEPACAM2, TMEM27 or GPR 119.
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, antigen binding fragment of an antibody, or Fc domain) is as described in U.S. patent nos. 10,174,091, 10,174,092, 10,946,068, 11,091,526, or 11,091,527 or PCT publication nos. WO2019112852 or WO 2019112854.
In some embodiments, the IL-2 protein is PT101/MK-6194 (Pandion Therapeutics/Merck & Co).
In some embodiments, the IL-2 protein is an IL-2 mutein conjugated to an antibody or fragment thereof, as described in PCT publication No. WO 2020247843.
In some embodiments, the IL-2 protein is an IL-2 clinical candidate AB248.
In some embodiments, the IL-2 protein is ANV419 (Anaveon).
In certain embodiments, the IL-2 protein comprises one or more non-standard or unnatural amino acids. For example, in particular embodiments, an IL-2 protein may comprise an amino acid sequence corresponding to a mature human IL-2 protein, and may further comprise one or more amino acids other than the standard twenty amino acids found in most proteins.
For example, in some embodiments, the IL-protein is an IL-2 mutein comprising a homoserine (Hse) substitution at any 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.
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 that corresponds to native mature human IL-2, which substitution is 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 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 that corresponds to native mature human IL-2, which substitution is 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, e.g., U.S. Pat. No. 10,610,571 or PCT publication No. WO2019028419 or WO2019028425; PCT publication No. WO19165453; U.S. patent No. 11,077,195 or PCT publication No. WO2020163532; PCT publication No. WO2021030706; PCT publication No. WO2021050554; or PCT publication No. WO 2021263026. In some embodiments, the IL-2 protein is THOR-707 (Sanofi).
In some embodiments, the IL-2 protein is an IL-2 mimetic (e.g., a slave protein that mimics IL-2 activity). In some embodiments, the IL-2 protein is an IL-2 mimetic as described in PCT publication No. WO2021081193 or PCT publication No. WO 2021188374. 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 IL-2 clinical candidate NL-201.
5.3 methods of treatment
Provided herein are methods 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, wherein the methods alleviate one or more symptoms associated with the disease or disorder. In certain embodiments, the CTLA-4-containing protein is abacavir. In certain embodiments, the IL-2 protein is an aldesleukin. In certain embodiments, the CTLA-4-containing protein is Abauprine and the IL-2 protein is aldesleukin.
In certain embodiments, the CTLA-4-containing protein and the IL-2 protein are administered to the subject separately. In certain embodiments, the CTLA-4-containing protein is abamectin, and the abamectin and IL-2 proteins are administered to the subject separately. In certain embodiments, the IL-2 protein is an aldesleukin, and the aldesleukin and the CTLA-4-containing protein are administered to the subject separately. In certain embodiments, the CTLA-4-containing protein is abacavir and the IL-2 protein is aldesleukin, and the abacavir and aldesleukin are administered to the subject separately.
In certain embodiments, the CTLA-4-containing protein and the IL-2 protein are administered together to the subject in a single formulation. In certain embodiments, the CTLA-4-containing protein is abamectin, and the abamectin and IL-2 proteins are administered together to the subject in a single formulation. In certain embodiments, the IL-2 protein is an aldesleukin, and the aldesleukin and the CTLA-4-containing protein are administered together in a single formulation to the subject. In certain embodiments, the CTLA-4-containing protein is abacavir and the IL-2 protein is aldesleukin, and the abacavir and aldesleukin are administered together to the subject in a single formulation.
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 disorder driven by a T cell response and the subject is diagnosed with or suspected of having a disorder driven by a T cell response.
In some embodiments, the disease is a neurodegenerative disease and the subject is diagnosed with or suspected of having a neurodegenerative disease. In 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.
In some embodiments, the disorder is a disorder that would benefit from down-regulation of the immune system, and the subject is diagnosed with or suspected of having a disorder that would benefit from down-regulation of the immune system.
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 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 kidney disease, autoimmune hemolytic anemia, autoimmune cytopenia, autoimmune hepatitis, autoimmune uveitis, alopecia, thyroiditis, or pemphigus.
In certain embodiments, the disease is moderate to severe active RA. In certain embodiments, the disease is moderate to severe active RA and the subject is an adult. In certain embodiments, the disease is polyarthritis essential to young (pJIA). In particular embodiments, the disease is pJIA and the subject is 2 years old or older, e.g., 6 years old or older. In certain embodiments, the disease is psoriatic arthritis. In a particular embodiment, the disease is psoriatic arthritis and the subject is an adult.
In some embodiments, the disease or disorder is heart failure or ischemic cardiomyopathy, and the subject is diagnosed with or suspected of having heart failure or ischemic cardiomyopathy. In some embodiments, the disease is graft-versus-host disease, and the subject is diagnosed with or suspected of having graft-versus-host disease, e.g., after undergoing an organ transplant (such as a kidney transplant or a liver transplant), or after receiving a stem cell transplant (such as a hematopoietic stem cell transplant).
In some embodiments, the disease or disorder is or is associated with neuroinflammation, and the subject is diagnosed with or suspected of suffering from neuroinflammation. The neuroinflammation may be associated, for example, with: stroke, acute Disseminated Encephalomyelitis (ADEM), acute optic neuritis, transverse myelitis, optic Neuromyelitis (NMO), epilepsy, traumatic brain injury, spinal cord injury, encephalitis, central Nervous System (CNS) vasculitis, neuromyelitis, autoimmune or post-infection encephalitis, or chronic meningitis.
In some embodiments, the disease or disorder is cardiac inflammation, and the subject is diagnosed with or suspected of suffering from cardiac inflammation, e.g., cardiac inflammation associated with atherosclerosis, myocardial infarction, ischemic cardiomyopathy, heart failure.
In some embodiments, the disease or disorder is Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), and the subject is diagnosed with or suspected of having CIDP. In some embodiments, the disease or disorder is Acute Inflammatory Demyelinating Polyneuropathy (AIDP), and the subject is diagnosed with or suspected of having AIDP. In some embodiments, the disease or disorder is guillain-barre syndrome (GBS), and the subject is diagnosed with or suspected of having GBS.
In some embodiments, the subject has suffered a stroke.
In some embodiments, the subject being treated is diagnosed with or suspected of having cancer, e.g., a hematological cancer.
In some embodiments, the subject being treated is diagnosed with or suspected of having asthma.
In some embodiments, the subject being treated is diagnosed with or suspected of having eczema.
In some embodiments, the subject being treated is diagnosed with or suspected of having a disorder associated with excessive activation of the immune system.
In some embodiments, the subject being treated is diagnosed with or suspected of having Treg disease. Treg disease may be caused by: FOXP3, CD25, cytotoxic T lymphocyte-associated antigen 4 (CTLA 4), LPS-reactive beige-like dockerin (LRBA), or BTB domain and CNC homolog 2 (BACH 2) gene loss-of-function mutations, or signal transducer and transcriptional activator 3 (STAT 3) function gain-of-function mutations.
In one aspect, provided herein is a method of treating a disease or disorder, such as 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;
wherein the method reduces one or more symptoms associated with a neurodegenerative or neuroinflammatory disease or disorder in the subject being treated. In certain embodiments, the CTLA-4-containing protein is abacavir. In certain embodiments, the IL-2 protein is an aldesleukin. In certain embodiments, the CTLA-4-containing protein is Abauprine and the IL-2 protein is aldesleukin.
In certain embodiments, the CTLA-4-containing protein is administered by injection or infusion. In particular embodiments, the CTLA-4-containing protein is administered subcutaneously. In particular embodiments, the CTLA-4-containing protein is administered intravenously. In certain embodiments, the IL-2 protein is administered by injection or infusion. In certain embodiments, the IL-2 protein is administered subcutaneously. In certain embodiments, the IL-2 protein is administered intravenously. In certain embodiments, the CTLA-4-containing protein and IL-2 protein are administered by injection or infusion. In particular embodiments, the CTLA-4-containing protein and the IL-2 protein are administered subcutaneously. In particular embodiments, the CTLA-4-containing protein and the IL-2 protein are administered intravenously.
In certain embodiments, the CTLA-4-containing protein comprises a human CTLA-4 extracellular domain. In particular 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 CH 3). In a particular embodiment, the human immunoglobulin Fc domain is a human IgG1 Fc domain. In certain embodiments, the CTLA-4-containing protein is glycosylated.
In certain embodiments, the CTLA-4-containing protein comprises the following amino acid sequence monomers:
MHVAQPAVVLASSRGIASFVCEYASPGKATEVRVTVLRQADSQVTEVCAATYMMGNELTFLDDSICTGTSSGNQVNLTIQGLRAMDTGLYICKVELMYPPPYYLGIGNGTQIYVIDPEPCPDSDQEPKSSDKTHTSPPSPAPELLGGSSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 1). 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.
In a particular embodiment, the CTLA-4-containing protein is abacavir.
In certain embodiments, the IL-2 protein is a human IL-2 protein. In certain embodiments, the human IL-2 protein comprises serine at an amino acid position corresponding to amino acid residue 125 of naturally occurring mature human IL-2. 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 serine at an amino acid position corresponding to naturally occurring human IL-2 amino acid residue 125.
In certain embodiments, the human IL-2 protein comprises the following amino acid sequence:
PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFK FYMPKKATELKHLQLEEELKPLEEVLNLAQSKNFHLRPRDLISNIN VIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT(SEQ ID NO:3)。
in specific embodiments, the IL-2 protein is not glycosylated. In certain embodiments, the IL-2 protein is an aldesleukin.
In certain embodiments, the human IL-2 protein comprises the following amino acid sequence:
PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFK FYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNI NVIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT(SEQ ID NO:6)。
in some embodiments, a protein comprising CTLA-4 is administered to a subject once every two weeks according to the methods provided herein. 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, for 15 weeks, or for 18 weeks. In some embodiments, the CTLA-4-containing protein is abacavir.
In some embodiments, a protein comprising CTLA-4 is administered to a subject once weekly according to the methods provided herein. In some embodiments, the protein comprising CTLA-4 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, for 15 weeks, or for 18 weeks. In some embodiments, the CTLA-4-containing protein is abacavir.
In some embodiments, a protein comprising CTLA-4 is administered to a subject once daily for 2-5 consecutive days according to the methods provided herein. For example, in some embodiments, the CTLA-4-containing protein is administered to the subject once daily for 2, 3, 4, or 5 consecutive days. In some embodiments, the CTLA-4-containing protein is administered to the subject once daily for three consecutive days. In some embodiments, the protein comprising CTLA-4 is administered intravenously to the subject once daily for 2-5 consecutive days. In some embodiments, the CTLA-4-containing protein is administered subcutaneously to the subject once daily for 2-5 consecutive days. For example, in some embodiments, the CTLA-4-containing protein is administered subcutaneously to the subject once daily for 2, 3, 4, or 5 consecutive days. In some embodiments, the CTLA-4-containing protein is administered to the subject subcutaneously once daily for three consecutive days. In some embodiments, the IL-2 protein is administered to the subject once daily for 2-5 consecutive days. For example, in some embodiments, the IL-2 protein is administered to the subject once daily for 2, 3, 4, or 5 consecutive days. In some embodiments, the IL-2 protein is administered to the subject once daily for three consecutive days. In some embodiments, the IL-2 protein is administered intravenously to the subject once daily for 2-5 consecutive days. In some embodiments, the IL-2 protein is administered to the subject subcutaneously once daily for 2-5 days. For example, in some embodiments, the IL-2 protein is administered to the subject subcutaneously once daily for 2, 3, 4, or 5 consecutive days. In some embodiments, the IL-2 protein is administered to the subject subcutaneously once daily for three consecutive days. In some embodiments, the CTLA-4-containing protein is abacavir. In some embodiments, the IL-2 protein is an aldesleukin.
In some embodiments, a CTLA-4-containing protein is administered to a subject one or more times during a dosing cycle, e.g., 1-10 times during a dosing cycle, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times during a dosing cycle, according to the methods provided herein. In some embodiments, the CTLA-4-containing protein is administered to the subject as a single administration 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 days starting on 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 on 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 on 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 on 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 on day 1 of the dosing cycle. In some embodiments, the CTLA-4-containing protein is administered to the subject from day 1 of the dosing cycle over a series of discrete days, e.g., from day 1 of the dosing cycle over a series of discrete days, such as 2, 3, 4, 5, 6, 7, 8, 9, or 10 discrete days, that are independently spaced 1, 2, 3, 4, or 5 days apart. In some embodiments, the CTLA-4-containing protein is abacavir.
In some embodiments, according to the methods provided herein, an IL-2 protein is administered to a subject one or more times during a dosing cycle, e.g., 1-10 times during a dosing cycle, such as 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 days starting on day 1 of the dosing cycle. In some embodiments, the IL-2 protein is administered to the subject daily for two consecutive days, starting on day 1 of the dosing cycle. In some embodiments, the IL-2 protein is administered to the subject daily for three consecutive days, starting on day 1 of the dosing cycle. In some embodiments, the IL-2 protein is administered to the subject daily for four consecutive days, starting on day 1 of the dosing cycle. In some embodiments, the IL-2 protein is administered to the subject daily for five consecutive days, starting on day 1 of the dosing cycle. In some embodiments, the IL-2 protein is administered to the subject from day 1 of the dosing cycle over a series of discrete days, e.g., from day 1 of the dosing cycle over a series of discrete days, such as 2, 3, 4, 5, 6, 7, 8, 9, or 10 discrete days, that are independently spaced 1, 2, 3, 4, or 5 days apart. In some embodiments, the IL-2 protein is an aldesleukin.
In some embodiments, the dosing period is 1-6 weeks according to the methods provided herein. In some embodiments, the dosing period is 2-6 weeks according to the methods provided herein. In some embodiments, the dosing period is 1 week. In some embodiments, the dosing period is 2 weeks. In some embodiments, the dosing period is 3 weeks. In some embodiments, the dosing period is 4 weeks. In some embodiments, the dosing period is 5 weeks. In some embodiments, the dosing period 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 three consecutive days starting on day 1 of the first dosing cycle. In some embodiments, the IL-2 protein is administered to the subject daily for three consecutive days, starting on day 1 of the first dosing cycle. In some embodiments, the IL-2 protein is administered to the subject daily for three consecutive days, starting on day 1 of the second dosing cycle. In some embodiments, the first dosing cycle is repeated 6 times, wherein each repeated dosing cycle begins 14 days after day 1 of the previous dosing cycle. In some embodiments, the CTLA-4-containing protein is abacavir. In some embodiments, the IL-2 protein is an aldesleukin.
In some embodiments, the CTLA 4-containing protein is administered to the subject weekly. In certain embodiments, the CTLA 4-containing protein is administered to the subject weekly on day 1 of each week (in other words, if the first administration of CTLA 4-containing protein is administered to the subject on day 1, then subsequent administrations of CTLA 4-containing protein occur on day 8, day 15, day 22, etc.). In some embodiments, the CTLA-4-containing protein is abacavir.
In specific embodiments, the CTLA 4-containing protein is administered to the subject weekly, and the IL-2 protein is administered to the subject every two weeks. For example, in certain embodiments, a protein comprising CTLA4 is administered to a subject weekly starting at week 1, and IL-2 protein is administered to the subject at week 2, week 4, week 6, etc. For example, in certain embodiments, a protein comprising CTLA4 is administered to a subject weekly starting at week 1, and IL-2 protein is administered to the subject at week 3, week 5, week 7, etc. In some embodiments, the CTLA-4-containing protein is abacavir. In some embodiments, the IL-2 protein is an aldesleukin.
In certain embodiments, the CTLA 4-containing protein is administered to the subject weekly on day 1 of each week (in other words, if the first administration of CTLA 4-containing protein is administered to the subject on day 1, then subsequent administrations of CTLA 4-containing protein occur on day 8, day 15, day 22, etc.), and the IL-2 protein is administered to the subject starting on day 2, on day 1 of every other week, or starting on day 1 of every other week (in other words, day 8, day 22, day 36, etc.). In certain embodiments, the IL-2 protein is administered to the subject on day 1 of the week of IL-2 protein administration, for example, every two consecutive days, every three consecutive days, every four consecutive days, or every five consecutive days. In certain embodiments, the IL-2 protein is administered to the subject on day 1 of the week of IL-2 protein administration on a series of discrete days, such as 2, 3, 4, 5, 6, or 7 discrete days, that are independently spaced 1, 2, 3, 4, or 5 days apart. In some embodiments, the CTLA-4-containing protein is abacavir. In some embodiments, the IL-2 protein is an aldesleukin.
In certain embodiments, the CTLA 4-containing protein is administered to the subject weekly on day 1 of week 1 (in other words, if the first administration of CTLA 4-containing protein is administered to the subject on day 1, then subsequent administrations of CTLA 4-containing protein occur on day 8, day 15, day 22, etc.), and the IL-2 protein is administered to the subject starting on day 3, on day 1 of every other week, or starting on day 1 of every other week (in other words, day 15, day 29, day 53, etc.). In certain embodiments, the IL-2 protein is administered to the subject on day 1 of the week of IL-2 protein administration, for example, every two consecutive days, every three consecutive days, every four consecutive days, or every five consecutive days. In certain embodiments, the IL-2 protein is administered to the subject on day 1 of the week of IL-2 protein administration on a series of discrete days, such as 2, 3, 4, 5, 6, or 7 discrete days, that are independently spaced 1, 2, 3, 4, or 5 days apart. In some embodiments, the CTLA-4-containing protein is abacavir. In some embodiments, the IL-2 protein is an aldesleukin.
In some embodiments, a CTLA 4-containing protein is administered to a subject weekly in an amount ranging from 20-50mg weekly according to the methods provided herein, e.g., as described in any of the embodiments presented herein. In certain embodiments, a CTLA 4-containing protein is administered weekly to a subject in an amount ranging from 20mg weekly according to the methods provided herein, e.g., as described in any of the embodiments presented herein. In certain embodiments, a CTLA 4-containing protein is administered to a subject weekly in an amount ranging from 25mg weekly according to the methods provided herein, e.g., as described in any of the embodiments presented herein. In certain embodiments, a CTLA 4-containing protein is administered to a subject weekly in an amount ranging from 30mg weekly according to the methods provided herein, e.g., as described in any of the embodiments presented herein. In certain embodiments, a CTLA 4-containing protein is administered weekly to a subject in an amount ranging from 35mg weekly according to the methods provided herein, e.g., as described in any of the embodiments presented herein. In certain embodiments, a CTLA 4-containing protein is administered weekly to a subject in an amount ranging from 40mg weekly according to the methods provided herein, e.g., as described in any of the embodiments presented herein. In certain embodiments, a CTLA 4-containing protein is administered weekly to a subject in an amount ranging from 45mg weekly according to the methods provided herein, e.g., as described in any of the embodiments presented herein. In certain embodiments, a CTLA 4-containing protein is administered weekly to a subject in an amount ranging from 50mg weekly according to the methods provided herein, e.g., as described in any of the embodiments presented herein. In certain embodiments, the CTLA 4-containing protein is abacavir. In some embodiments, the IL-2 protein, e.g., aldesleukin, is administered in an amount within the range of 10,000-3,000,000 units in combination with a method comprising weekly administration of a protein comprising CTLA4, e.g., abafop. In some such embodiments, the IL-2 protein, e.g., aldesleukin, is administered in an amount within the range of 500,000-3,000,000 units. In some such embodiments, the IL-2 protein, e.g., aldesleukin, is administered in an amount within the range of 500,000-2,000,000 units. In some embodiments, the IL-2 protein, such as aldesleukin, is administered in an amount of 1,000,000 units.
In one aspect, provided herein is a method of treating a disease or disorder, such as 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) Abacavir; and
ii) aldesleukin;
wherein the method reduces one or more symptoms associated with a neurodegenerative or neuroinflammatory disease or disorder in the subject being treated.
In certain embodiments, the abacavir is administered by injection or infusion. In certain embodiments, the abasic is administered subcutaneously. In particular embodiments, the abacavir is administered intravenously. In certain embodiments, the aldesleukin is administered by injection or infusion. In particular embodiments, the aldesleukin is administered subcutaneously. In particular embodiments, the aldesleukin is administered intravenously. In certain embodiments, the aturprine and the aldehydic interleukins are administered by injection or infusion. In particular embodiments, the aturprine and the aldesleukin are administered subcutaneously. In particular embodiments, the aturprine and the aldesleukin are administered intravenously.
In certain embodiments, the CTLA-4-containing protein, such as abacavir, is administered to the subject once every two weeks. In certain embodiments, the CTLA-4-containing protein, such as abacavir, is administered subcutaneously to a subject once every two weeks. In certain embodiments, the CTLA-4-containing protein, e.g., abasic, is administered to the subject once every two weeks for 15 weeks. In certain embodiments, the CTLA-4-containing protein, e.g., abasic, is administered subcutaneously to the subject once every two weeks for 15 weeks.
In certain embodiments, the IL-2 protein, e.g., aldesleukin, is administered to the subject once daily for three consecutive days. In a particular embodiment, the IL-2 protein, e.g., aldesleukin, is administered subcutaneously to the subject once daily for three consecutive days.
In certain embodiments, a protein comprising CTLA-4, such as abacavir, is administered to a subject once every two weeks, and an IL-2 protein, such as aldesleukin, is administered to the subject once daily for three consecutive days. In certain embodiments, a protein comprising CTLA-4, such as abacavir, is administered subcutaneously to a subject once every two weeks, and an IL-2 protein, such as aldesleukin, is administered subcutaneously to a subject once daily for three consecutive days.
In certain embodiments, the CTLA-4-containing protein, such as abacavir, is administered to the subject once every two weeks, and the IL-2 protein, such as aldesleukin, is administered to the subject once daily for three consecutive days starting on the day of administration of the CTLA-4-containing protein, such as abacavir. In certain embodiments, the CTLA-4-containing protein, such as albazedox, is administered to the subject subcutaneously once every two weeks, and the IL-2 protein, such as aldesleukin, is administered to the subject once daily for three consecutive days starting on the day of administration of the CTLA-4-containing protein, such as albazedox, to the subject.
In certain embodiments, the CTLA-4-containing protein, e.g., abacavir, is administered to the subject once every two weeks for fifteen weeks, and the IL-2 protein, e.g., aldesleukin, is administered to the subject starting at the third week, and the IL-2 protein is administered to the subject once daily for three consecutive days starting at the day of administration of the CTLA-4-containing protein, e.g., abacavir, to the subject. In certain embodiments, the CTLA-4-containing protein, e.g., abacavir, is administered subcutaneously to the subject once every two weeks for fifteen weeks, and the IL-2 protein, e.g., aldesleukin, is administered to the subject starting from the third week, and the IL-2 protein is administered subcutaneously to the subject once daily for three consecutive days starting from the day of administration of the CTLA-4-containing protein, e.g., abacavir.
In certain embodiments, about 5mg to about 200mg, about 10mg to about 200mg, about 15mg to about 200mg, about 20mg to about 200mg, about 25mg to about 200mg, about 50mg to about 175mg, about 50mg to about 150mg, or about 50mg to about 125mg of a protein containing CTLA-4, such as abacavir, is administered to a subject. In certain embodiments, a protein comprising CTLA-4, such as abacavir, is administered subcutaneously to a subject.
In a particular embodiment, about 50mg of a protein containing CTLA-4, such as abacavir, is administered to a subject. In a specific embodiment, about 50mg of CTLA-4-containing protein, such as abacavir, is administered to a subject in a volume of 0.4 mL. In certain embodiments, a protein comprising CTLA-4, such as abacavir, is administered subcutaneously to a subject.
In a particular embodiment, about 87.5mg of a protein containing CTLA-4, such as abacavir, is administered to a subject. In a specific embodiment, about 87.5mg of a protein containing CTLA-4, such as abacavir, is administered to a subject in a volume of 0.7 mL. In certain embodiments, a protein comprising CTLA-4, such as abacavir, is administered subcutaneously to a subject.
In a particular embodiment, about 125mg of a protein containing CTLA-4, such as abacavir, is administered to a subject. In a specific embodiment, a volume of 1.0mL of about 125mg CTLA-4-containing protein, such as abacavir, is administered to a subject. In certain embodiments, a protein comprising CTLA-4, such as abacavir, is administered subcutaneously to a subject.
In particular embodiments, about 1x10 is administered to a subject 4 Up to about 1x10 7 About 5x10 4 Up to about 1x10 7 About 1x10 5 Up to about 1x10 7 About 5x10 5 Up to about 1x10 7 、5x10 5 Up to about 5x10 6 、5x10 5 Up to about 4x10 6 、5x10 5 Up to about 3x10 6 、5x10 5 Up to about 2x10 6、 About 5x10 5 Up to about 1x10 6 A unit of IL-2 protein, such as aldesleukin. In certain embodiments, the IL-2 protein, e.g., aldesleukin, is administered subcutaneously to the subject.
In specific embodiments, the IL-2 protein, e.g., aldesleukin, is administered to the subject, e.g., subcutaneously, in an amount of about 500,000 units to about 3,000,000 units. In specific embodiments, the IL-2 protein, e.g., aldesleukin, is administered to the subject, e.g., subcutaneously from about 500,000 units to about 2,000,000 units. In specific embodiments, the IL-2 protein, e.g., aldesleukin, is administered to the subject, e.g., subcutaneously from about 500,000 units to about 1,000,000 units.
In some embodiments, the abamectin is administered in an amount in the range of 20-200mg according to the methods provided herein. In some embodiments, abamectin is administered in an amount in the range of 25-200 mg. In some embodiments, abamectin is administered in an amount in the range of 50-200 mg. In some embodiments, abamectin is administered in an amount in the range of 50-175 mg. In some embodiments, abamectin is administered in an amount in the range of 50-150 mg. In some embodiments, abamectin is administered in an amount in the range of 50-125 mg. In some embodiments, abamectin is administered in an amount of 50 mg. In some embodiments, abamectin is administered in an amount of 87.5 mg. In some embodiments, abamectin is administered in an amount of 125 mg. In some embodiments, abamectin is administered subcutaneously in a volume of 0.1-2.0 mL. In some embodiments, the abacavir is administered subcutaneously in a volume of 0.4 mL. In some embodiments, the abacavir is administered subcutaneously in a volume of 0.7 mL. In some embodiments, the abacavir is administered subcutaneously in a volume of 1.0 mL. In some embodiments, the abacavir is administered subcutaneously in an amount of 50mg in a volume of 0.4 mL. In some embodiments, the abacavir is administered subcutaneously in an amount of 87.5mg in a volume of 0.7 mL. In some embodiments, the abacavir is administered subcutaneously in an amount of 125mg in a volume of 1.0 mL. In some embodiments, the aldesleukin is administered in an amount within the range of 10,000-3,000,000 units. In some embodiments, the aldesleukin is administered in an amount within the range of 500,000-3,000,000 units. In some embodiments, the aldesleukin is administered in an amount within the range of 500,000-2,000,000 units. In some embodiments, the aldesleukin is administered in an amount of 1,000,000 units. In some embodiments, the aldesleukin is administered subcutaneously.
In some embodiments, according to the methods provided herein, the abacavir is administered to the subject in an amount in the range of 20-50mg per dosing cycle. In some embodiments, the abacavir alone is administered to the subject in the absence of IL-2 during one of a plurality of dosing cycles. In some embodiments, abasic is administered in combination with IL-2 during one of a plurality of dosing cycles. In some embodiments, the plurality of dosing cycles comprises (i) a dosing cycle wherein in each dosing cycle, the abacavir alone is administered to the subject in the absence of IL-2; and (ii) a dosing cycle wherein abamectin is administered in combination with IL-2 in each dosing cycle. In certain embodiments, the plurality of dosing cycles comprises (i) a dosing cycle wherein in each dosing cycle, the abacavir alone is administered to the subject in the absence of IL-2; and (ii) a dosing cycle in which abamectin is administered in combination with IL-2 in each dosing cycle, wherein the dosing cycles in (i) and (ii) alternate in multiple dosing cycles (e.g., a dosing cycle in which abamectin alone is administered followed by a dosing cycle in which abamectin is administered in combination with IL-2, followed by a dosing cycle in which abamectin alone is administered, followed by a dosing cycle in which abamectin is administered in combination with IL-2). Each of the plurality of dosing cycles may be, for example, 1 week. In certain embodiments, the IL-2 protein is an aldesleukin.
In certain embodiments, according to the methods provided herein, the abapple is administered to the subject in a plurality of dosing cycles, each dosing cycle ranging from 20-50mg, e.g., in an amount of 20mg, 25mg, 30mg, 35mg, 40mg, 45mg, or 50mg per dosing cycle, wherein the plurality of dosing cycles comprises a 1 week dosing cycle according to the following regimen:
cycle 1: abacavir alone, in the absence of IL-2;
cycle 2: abacavir alone, in the absence of IL-2;
cycle 3: combination of abamectin and IL-2;
cycle 4: abacavir alone, in the absence of IL-2;
wherein administration cycles 3 and 4 are repeated in subsequent cycles, e.g. 6, 8, 10, 12, 16, 18, 20 or more cycles in total. In certain embodiments, the IL-2 protein is an aldesleukin.
In some embodiments, the subject is administered abacavir once every two weeks according to the methods provided herein. In some embodiments, the subject is administered the abacavir intravenously once every two weeks. In some embodiments, the subject is subcutaneously administered abacavir once every two weeks. In some embodiments, the subject is administered abamectin once every two weeks for 10-20 weeks. For example, in some embodiments, the subject is administered abapple once every two weeks for 12 weeks, for 15 weeks, or for 18 weeks. In some embodiments, the abamectin is administered once every two weeks for 15 weeks. In some embodiments, the subject is administered abacavir once daily for 2-5 consecutive days. For example, in some embodiments, the subject is administered abacavir once daily for 2, 3, 4, or 5 consecutive days. In some embodiments, the subject is administered abacavir once daily for three consecutive days. In some embodiments, the subject is administered the abacavir intravenously once daily for 2-5 consecutive days. In some embodiments, the subject is subcutaneously administered abacavir once daily for 2-5 days. For example, in some embodiments, the subject is subcutaneously administered abacavir once daily for 2, 3, 4, or 5 consecutive days. In some embodiments, the subject is subcutaneously administered abacavir once daily for three consecutive days.
In some embodiments, the aldesleukin is administered to the subject once daily for 2-5 consecutive days according to the methods provided herein. For example, in some embodiments, the aldesleukin is administered to the subject once daily for 2, 3, 4, or 5 consecutive days. In some embodiments, the aldesleukin is administered to the subject once daily for three consecutive days. In some embodiments, the aldesleukin is administered intravenously to the subject once daily for 2-5 consecutive days. In some embodiments, the aldesleukin is administered to the subject subcutaneously once daily for 2-5 consecutive days. For example, in some embodiments, the aldesleukin is administered to the subject subcutaneously once daily for 2, 3, 4, or 5 consecutive days. In some embodiments, the aldesleukin is administered to the subject subcutaneously once daily for three consecutive days.
In some embodiments, the abamectin is administered once every two weeks according to the methods provided herein, and the aclidinium is administered once daily for 2-5 days, such as three consecutive days, starting from the day of administration of aclarubicin. In some embodiments, the aturprine and the aldesleukin are administered subcutaneously. In some embodiments, the abamectin is administered once every two weeks for 10-20 weeks, such as fifteen weeks, beginning with the third week of aldesleukin administration; and once the administration of the aldesleukin begins, the aldesleukin is administered once a day for 2-5 consecutive days, such as three consecutive days, starting from the day of administration of the abarelix. In some embodiments, the aturprine and the aldesleukin are administered subcutaneously.
In some embodiments, according to the methods provided herein, abamectin is administered to the subject one or more times during the dosing period, e.g., 1-10 times during the dosing period, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times during the dosing period. In some embodiments, the abacavir is administered to the subject as a single administration on day 1 of the dosing cycle. In some embodiments, the subject is administered abacavir daily for a continuous series of days starting on day 1 of the dosing cycle. In some embodiments, the subject is administered abacavir daily for two consecutive days starting on day 1 of the dosing cycle. In some embodiments, the subject is administered abacavir daily for three consecutive days starting on day 1 of the dosing cycle. In some embodiments, the subject is administered abacavir daily four consecutive days starting on day 1 of the dosing cycle. In some embodiments, the subject is administered abacavir daily for five consecutive days starting on day 1 of the dosing cycle. In some embodiments, the subject is administered the abacavir over a series of discrete days starting on day 1 of the dosing cycle, e.g., the subject is administered the abacavir over a series of discrete days, such as 2, 3, 4, 5, 6, 7, 8, 9, or 10 discrete days, starting on day 1 of the dosing cycle, the discrete days being independently spaced 1, 2, 3, 4, or 5 days apart.
In some embodiments, the aldesleukin is administered to the subject one or more times during the dosing period, e.g., 1-10 times during the dosing period, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times during the dosing period, according to the methods provided herein. In some embodiments, the aldesleukin is administered to the subject daily for a continuous series of days starting on day 1 of the dosing cycle. In some embodiments, the aldesleukin is administered to the subject daily for two consecutive days, starting on day 1 of the dosing cycle. In some embodiments, the aldesleukin is administered to the subject daily for three consecutive days, starting on day 1 of the dosing cycle. In some embodiments, the aldesleukin is administered to the subject daily for four consecutive days, beginning on day 1 of the dosing cycle. In some embodiments, the aldesleukin is administered to the subject daily for five consecutive days, starting on day 1 of the dosing cycle. In some embodiments, the aldesleukin is administered to the subject over a series of discrete days starting on day 1 of the dosing cycle, e.g., from day 1 of the dosing cycle, the aldesleukin is administered to the subject over a series of discrete days, such as 2, 3, 4, 5, 6, 7, 8, 9, or 10 discrete days, that are independently spaced 1, 2, 3, 4, or 5 days apart.
In some embodiments, the method provided herein comprises administering to the subject abacavir as a single administration on day 1 of the dosing cycle. In some embodiments, the subject is administered the abapple daily for 2-5 days, such as three days in succession, starting on day 1 of the first dosing cycle. In some embodiments, the aldehydic interleukin is administered to the subject daily for three consecutive days, starting on day 1 of the first dosing cycle. In some embodiments, the aldehydic interleukin is administered to the subject daily for three consecutive days, starting on day 1 of the first dosing cycle. In some embodiments, the aldehydic interleukin is administered to the subject daily for three consecutive days, starting on day 1 of the second dosing cycle. In some embodiments, the first dosing cycle is repeated 6 times, wherein each repeated dosing cycle begins 14 days after day 1 of the previous dosing cycle.
In some embodiments, the dosing period is 2-6 weeks according to the methods provided herein. In some embodiments, the dosing period is 2 weeks. In some embodiments, the dosing period is 3 weeks. In some embodiments, the dosing period is 4 weeks. In some embodiments, the dosing period is 5 weeks. In some embodiments, the dosing period 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 one aspect, provided herein is a method of treating a disease or disorder, such as a disease or disorder described herein, e.g., a neurodegenerative or neuroinflammatory disease or disorder, in a subject in need thereof, comprising starting on day 1 and comprising administering to the subject a dosing cycle comprising a formulation of:
i) A CTLA-4-containing protein; and
ii) IL-2 protein;
wherein the method reduces one or more symptoms associated with a neurodegenerative or neuroinflammatory disease or disorder in the subject being treated. The formulation is administered to the subject one or more times during the dosing cycle. The administration cycle may be repeated one or more times. There may be a period of time between the completion of one dosing cycle and the start of the next dosing cycle. In certain embodiments, the CTLA-4-containing protein is abacavir.
In certain embodiments, the IL-2 protein is an aldesleukin. In certain embodiments, the CTLA-4-containing protein is Abauprine and the IL-2 protein is aldesleukin.
For ease of description, the formulation may be referred to herein as a "CTLA-4 containing protein/IL-2 protein formulation" or "IL-2 protein/CTLA-4 containing protein formulation". In the case where the CTLA-4-containing protein is abacavir and the IL-2 protein is aldesleukin, the formulation may be referred to herein as an "abasic/aldesleukin formulation" or an "aldesleukin/abasic formulation. "
In certain embodiments, the formulation is administered to the subject by injection or infusion. In particular embodiments, the formulation is administered to the subject subcutaneously. In particular embodiments, the formulation is administered to the subject intravenously.
In certain embodiments of such methods, the dosing cycle comprises administering the formulation to the subject 1-10 times.
In particular embodiments of the methods described herein, the dosing cycle comprises a single administration of the formulation to the subject on day 1 of the dosing cycle. In particular embodiments of such methods, the dosing cycle comprises administering the formulation to the subject daily, beginning on day 1 of the dosing cycle, for two consecutive days. In particular embodiments of such methods, the dosing cycle comprises administering the formulation to the subject daily for three consecutive days, starting on day 1 of the dosing cycle. In particular embodiments of such methods, the dosing cycle comprises administering the formulation to the subject daily, starting on day 1 of the dosing cycle, four consecutive days. In particular embodiments of such methods, the dosing cycle comprises administering the formulation to the subject daily for five consecutive days, starting on day 1 of the dosing cycle.
In particular embodiments of the methods described herein, the dosing cycle comprises at least two discrete days of daily administration of the formulation to the subject. In one non-limiting embodiment, for example, the formulation is administered to the subject for the first time on day 1 of the dosing cycle, followed by administration to the subject on day 3, day 4, day 5, day 6, or day 7.
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 repeated dosing cycle begins 10-28 days after day 1 of the previous dosing cycle. In certain embodiments, each repeated dosing cycle begins 10-28 days after completion of the previous dosing cycle. In a specific embodiment, each repeated dosing cycle begins 14 days after day 1 of the previous dosing cycle. In certain embodiments, each repeated dosing cycle begins 14 days after completion of the previous dosing cycle.
In certain embodiments of the methods described herein, the first dosing cycle comprises administering the formulation to the subject daily starting on day 1 of the dosing cycle for three consecutive days, and the first dosing cycle is repeated 6 times, wherein each repeated dosing cycle starts 14 days after day 1 of the previous dosing cycle.
In certain embodiments of the methods described herein, the dosing cycle comprises administering to the subject a CTLA-4-containing protein/IL-2 protein formulation comprising about 5mg to about 125mg of the CTLA-4-containing protein and about 3X10 4 Up to about 3x10 7 A unit of IL-2 protein. In certain embodiments of the methods described herein, the dosing cycle comprises administering to the subject an abamectin/aldesleukin formulation comprising about 5mg to about 125mg abamectin and about 3x10 4 Up to about 3x10 7 Units of aldesleukin.
In certain embodiments of the methods described herein, the dosing cycle comprises administering to the subject a formulation comprising about 8.75mg to about 87.5mg abamectin and about 3x10 4 Up to about 3x10 7 Units of aldesleukin.
In certain embodiments of the methods described herein, the dosing cycle comprises administering to the subject a formulation comprising about 29.17mg of abasic and about 1x10 5 Units of aldesleukin. In certain embodiments of the methods described herein, the dosing cycle comprises administering to the subject a formulation comprising about 29.17mg of abasic and about 1x10 6 Units of aldesleukin. In certain embodiments of the methods described herein, the dosing cycle comprises administering to the subject a formulation that The agent comprises about 29.17mg of abasic and about 1x10 7 Units of aldesleukin.
In certain embodiments of the methods described herein, the dosing cycle comprises administering to the subject a formulation comprising about 5mg to about 50mg of abasic and about 3x10 4 Up to about 3x10 7 Units of aldesleukin.
In certain embodiments of the methods described herein, the dosing cycle comprises administering to the subject a formulation comprising about 16.67mg of abasic and about 1x10 5 Units of aldesleukin. In certain embodiments of the methods described herein, the dosing cycle comprises administering to the subject a formulation comprising about 16.67mg of abasic and about 1x10 6 Units of aldesleukin. In certain embodiments of the methods described herein, the dosing cycle comprises administering to the subject a formulation comprising about 16.67mg of abasic and about 1x10 7 Units of aldesleukin.
In certain embodiments of the methods described herein, the dosing cycle comprises administering to the subject a formulation comprising about 12.5mg to about 125mg of abamectin and about 3x10 4 Up to about 3x10 7 Units of aldesleukin.
In certain embodiments of the methods described herein, the dosing cycle comprises administering to the subject a formulation comprising about 41.67mg of abasic and about 1x10 5 Units of aldesleukin. In certain embodiments of the methods described herein, the dosing cycle comprises administering to the subject a formulation comprising about 41.67mg of abasic and about 1x10 6 Units of aldesleukin. In certain embodiments of the methods described herein, the dosing cycle comprises administering to the subject a formulation comprising about 41.67mg of abasic and about 1x10 7 Units of aldesleukin.
In certain embodiments of the methods described herein, the dosing cycle comprises daily administration of a formulation to a subject for three consecutive days starting on day 1 of the dosing cycle, wherein the formulation comprises about 29.17mg of abamectin and about 1x10 6 Units of aldesleukin. In particular embodiments, the feed isThe dosing cycle was repeated 6 times, with each repeated dosing cycle beginning 14 days after day 1 of the previous dosing cycle.
In certain embodiments of the methods described herein, a total of 50mg of abarelip and 3x10 are administered to the subject per dosing cycle by one or more administrations of the abarelip/aldesleukin formulation 5 Units of aldesleukin. In certain embodiments of the methods described herein, a total of 50mg of albazedox and 3x10 are administered to the subject per dosing cycle by 1-10 administrations of the albazedox formulation 5 Units of aldesleukin. In a particular embodiment, the dosing cycle comprises 1-10 administrations of an abasic/aldesleukin formulation as shown in table 1A.
In certain embodiments of the methods described herein, a total of 50mg of abarelip and 3x10 are administered to the subject per dosing cycle by one or more administrations of the abarelip/aldesleukin formulation 6 Units of aldesleukin. In certain embodiments of the methods described herein, a total of 50mg of albazedox and 3x10 are administered to the subject per dosing cycle by 1-10 administrations of the albazedox formulation 6 Units of aldesleukin. In a particular embodiment, the dosing cycle comprises 1-10 administrations of an abasic/aldesleukin formulation as shown in table 1B.
In certain embodiments of the methods described herein, a total of 50mg of abarelip and 3x10 are administered to the subject per dosing cycle by one or more administrations of the abarelip/aldesleukin formulation 7 Units of aldesleukin. In certain embodiments of the methods described herein, a total of 50mg of albazedox and 3x10 are administered to the subject per dosing cycle by 1-10 administrations of the albazedox formulation 7 Units of aldesleukin. In a particular embodiment, the dosing cycle comprises 1-10 administrations of an abasic/aldesleukin formulation as shown in table 1C.
In certain embodiments of the methods described herein, a total of 87.5mg of abamectin is administered to the subject per dosing cycle by one or more administrations of the abamectin/aldesleukin formulationSipran and 3x10 5 Units of aldesleukin. In certain embodiments of the methods described herein, a total of 87.5mg of albazedox and 3x10 are administered to the subject per dosing cycle by 1-10 administrations of the albazedox formulation 5 Units of aldesleukin. In a particular embodiment, the dosing cycle comprises 1-10 administrations of an abasic/aldesleukin formulation as shown in table 2A.
In certain embodiments of the methods described herein, a total of 87.5mg of abarelip and 3x10 are administered to the subject per dosing cycle by one or more administrations of the abarelip/aldesleukin formulation 6 Units of aldesleukin. In certain embodiments of the methods described herein, a total of 87.5mg of albazedox and 3x10 are administered to the subject per dosing cycle by 1-10 administrations of the albazedox formulation 6 Units of aldesleukin. In a particular embodiment, the dosing cycle comprises 1-10 administrations of an abasic/aldesleukin formulation as shown in table 2B.
In certain embodiments of the methods described herein, a total of 87.5mg of abarelip and 3x10 are administered to the subject per dosing cycle by one or more administrations of the abarelip/aldesleukin formulation 7 Units of aldesleukin. In certain embodiments of the methods described herein, a total of 87.5mg of albazedox and 3x10 are administered to the subject per dosing cycle by 1-10 administrations of the albazedox formulation 7 Units of aldesleukin. In a particular embodiment, the dosing cycle comprises 1-10 administrations of an abasic/aldesleukin formulation as shown in table 2C.
In certain embodiments of the methods described herein, a total of 125mg of abarelip and 3x10 are administered to the subject per dosing cycle by one or more administrations of the abarelip/aldesleukin formulation 5 Units of aldesleukin. In certain embodiments of the methods described herein, a total of 125mg of albazedox and 3x10 are administered to the subject per dosing cycle by 1-10 administrations of the albazedox formulation 5 Units of aldesleukin. In particular embodiments, the feed isThe drug cycle included 1-10 administrations of the abamectin/aldesleukin formulation as shown in table 3A.
In certain embodiments of the methods described herein, a total of 125mg of abarelip and 3x10 are administered to the subject per dosing cycle by one or more administrations of the abarelip/aldesleukin formulation 6 Units of aldesleukin. In certain embodiments of the methods described herein, a total of 125mg of abarelip and 3x10 are administered to the subject per dosing cycle by one or more administrations of the abarelip/aldesleukin formulation 6 Units of aldesleukin. In a particular embodiment, the dosing cycle comprises 1-10 administrations of an abasic/aldesleukin formulation as shown in table 3B.
In certain embodiments of the methods described herein, a total of 125mg of abarelip and 3x10 are administered to the subject per dosing cycle by one or more administrations of the abarelip/aldesleukin formulation 7 Units of aldesleukin. In certain embodiments of the methods described herein, a total of 125mg of abarelip and 3x10 are administered to the subject per dosing cycle by one or more administrations of the abarelip/aldesleukin formulation 7 Units of aldesleukin. In a particular embodiment, the dosing cycle comprises 1-10 administrations of an abasic/aldesleukin formulation as shown in table 3C.
Table 1 (50 mg abacavir/dosing cycle. A=3x10 5 Unit of aldesleukin/dosing cycle; b=3x10 6 Unit of aldesleukin/dosing cycle; c=3x10 7 Unit of aldesleukin/dosing cycle; # dosing cycle = number of administrations (number of doses) of formulation per dosing cycle
Table 2 (87.5 mg abacavir/dosing cycle. A=3x10) 5 Unit of aldesleukin/dosing cycle; b=3x10 6 Unit of aldesleukin/dosing cycle; c=3x10 7 Unit of aldesleukin/dosing cycle; # dosing cycleNumber of administrations (number of doses) of formulation per dosing cycle
Table 3 (125 mg albazedox/dosing cycle. A=3x10) 5 Unit of aldesleukin/dosing cycle; b=3x10 6 Unit of aldesleukin/dosing cycle; c=3x10 7 Unit of aldesleukin/dosing cycle; # dosing cycle = number of administrations (number of doses) of formulation per dosing cycle
In certain embodiments, the methods described herein further comprise administering a protein formulation comprising CTLA-4, such as an abamectin formulation, to the subject prior to first administering the protein/IL-2 protein formulation comprising CTLA-4, such as an abamectin formulation, to the subject. In certain embodiments, the methods described herein further comprise administering a protein formulation comprising CTLA-4, e.g., an abacavir 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 the protein/IL-2 protein formulation comprising CTLA-4, e.g., an abamectin formulation, to the subject.
In particular embodiments, the CTLA-4-containing protein formulation comprises 50mg to 125mg of the CTLA-4-containing protein, e.g., 50mg of the CTLA-4-containing protein, 87.5mg of the CTLA-4-containing protein, or 125mg of the CTLA-4-containing protein. In specific embodiments, the abacavir formulation comprises 50mg to 125mg of abacavir, e.g., 50mg of abacavir, 87.5mg of abacavir, or 125mg of abacavir. In certain embodiments, a protein formulation containing CTLA-4, such as an abacavir formulation, is administered to a subject by injection or infusion. In certain embodiments, a protein formulation containing CTLA-4, e.g., an abapple formulation, is administered to a subject subcutaneously or intravenously.
In some embodiments, according to the methods provided herein, the dosing cycle comprises administering the formulation to the subject 1-10 times. In some embodiments, the dosing cycle comprises a single administration of the formulation to the subject on day 1 of the dosing cycle. In some embodiments, the dosing cycle comprises administering the formulation to the subject daily for two consecutive days starting on day 1 of the dosing cycle. In some embodiments, the dosing cycle comprises administering the formulation to the subject daily for three consecutive days starting on day 1 of the dosing cycle. In some embodiments, the dosing cycle comprises administering the formulation to the subject every four consecutive days, starting on day 1 of the dosing cycle. In some embodiments, the dosing cycle comprises administering the formulation to the subject daily for five consecutive days starting on day 1 of the dosing cycle. In some embodiments, the dosing cycle comprises administering the formulation to the subject daily for six consecutive days, starting on day 1 of the dosing cycle. In some embodiments, the dosing cycle comprises administering the formulation to the subject daily for seven consecutive days starting on day 1 of the dosing cycle. In some embodiments, the dosing cycle is repeated 6 times, wherein each repeated dosing cycle begins 14 days after day 1 of the previous dosing cycle. In some embodiments, the first dosing cycle comprises administering the formulation to the subject from day 1 of the dosing cycle for 2-5 consecutive days, such as three consecutive days, each day, and the first dosing cycle is repeated 6 times, wherein each repeated dosing cycle begins 14 days after day 1 of the previous dosing cycle.
In some embodiments, according to the methods provided herein, the method further comprises administering to the subject an abacavir formulation 14 days before day 1 of the first dosing cycle, wherein the abacavir formulation comprises abamectin. In some embodiments, the abacavir formulation comprises 50mg to 125mg of abacavir. In some embodiments, the abacavir formulation comprises 87.5mg abamectin. In some embodiments, abamectin is administered subcutaneously in a volume of 0.1-2.0 mL. In some embodiments, the abacavir is administered subcutaneously in a volume of 0.4 mL. In some embodiments, the abacavir is administered subcutaneously in a volume of 0.7 mL. In some embodiments, the abacavir is administered subcutaneously in a volume of 1.0 mL. In some embodiments, the abacavir is administered subcutaneously in an amount of 50mg in a volume of 0.4 mL. In some embodiments, the abacavir formulation is administered by injection or infusion. In some embodiments, the abacavir formulation is administered subcutaneously. In some embodiments, the abacavir formulation is administered intravenously. In some embodiments, the abacavir is administered subcutaneously in an amount of 87.5mg in a volume of 0.7 mL. In some embodiments, the abacavir is administered subcutaneously in an amount of 125mg in a volume of 1.0 mL.
In certain aspects, the methods of treatment provided herein comprise administering to a subject in need of treatment a pharmaceutical composition described herein.
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 disorder driven by a T cell response.
In some embodiments, the subject is diagnosed with or suspected of having a neurodegenerative disease. In 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.
In some embodiments, the subject is diagnosed with or suspected of having a disorder that would benefit from down-regulation of the immune system.
In some embodiments, the subject is diagnosed with or suspected of having an autoimmune disease. The autoimmune disease 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 kidney disease, autoimmune hemolytic anemia, autoimmune cytopenia, autoimmune hepatitis, autoimmune uveitis, alopecia, thyroiditis, or pemphigus.
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, e.g., after undergoing an organ transplant (e.g., a kidney transplant or a liver transplant), or after receiving a stem cell transplant (e.g., a hematopoietic stem cell transplant).
In some embodiments, the subject is diagnosed with or suspected of having neuroinflammation. The neuroinflammation may be associated, for example, with: stroke, acute Disseminated Encephalomyelitis (ADEM), acute optic neuritis, transverse myelitis, optic Neuromyelitis (NMO), epilepsy, traumatic brain injury, spinal cord injury, encephalitis, central Nervous System (CNS) vasculitis, neuromyelitis, autoimmune or post-infection encephalitis, or chronic meningitis.
In some embodiments, the subject is diagnosed with or suspected of having cardiac inflammation, e.g., cardiac inflammation associated with atherosclerosis, myocardial infarction, ischemic cardiomyopathy, heart failure.
In some embodiments, the subject is diagnosed with or suspected of having Chronic Inflammatory Demyelinating Polyneuropathy (CIDP). In some embodiments, the subject is diagnosed with or suspected of having an Acute Inflammatory Demyelinating Polyneuropathy (AIDP). In some embodiments, the subject is diagnosed with or suspected of having guillain-barre syndrome (GBS).
In some embodiments, the subject has suffered a stroke.
In some embodiments, the subject is diagnosed with or suspected of having cancer, e.g., leukemia.
In some embodiments, the subject is diagnosed with or suspected of having asthma.
In some embodiments, the subject is diagnosed with or suspected of having eczema.
In some embodiments, the subject is diagnosed with or suspected of having a disorder associated with immune system overactivation.
In some embodiments, the subject is diagnosed with or suspected of having Treg disease. Treg disease may be caused by: FOXP3, CD25, cytotoxic T lymphocyte-associated antigen 4 (CTLA 4), LPS-reactive beige-like dockerin (LRBA), or BTB domain and CNC homolog 2 (BACH 2) gene loss-of-function mutations, or signal transducer and transcriptional activator 3 (STAT 3) function gain-of-function mutations.
5.3.1. Method for determining therapeutic effect
The effect of the methods of treatment provided herein can be assessed by monitoring the clinical signs and symptoms of the disease to be treated.
Efficacy of the methods of treatment described herein can be assessed 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 2-3 months, 3-4 months, 4-5 months, 5-6 months, 6-7 months, 7-8 months, 8-9 months, about 9-10 months, about 10-11 months, about 11-12 months, about 12-18 months, about 18-24 months, about 1-2 years, about 2-3 years, about 3-4 years, about 4-5 years, about 5-6 years, about 6-7 years, about 7-8 years, about 8-9 years, or about 9-9 years after starting treatment according to the methods described herein.
In some embodiments, the methods of treatment provided herein result in a change in a simple mental state examination (MMSE) score from baseline. In the context of assessing the effect of a treatment method, the term "baseline" refers to a measurement prior to treatment. The MMSE score measures overall alzheimer's disease symptoms. In some embodiments, an increase in MMSE score from baseline in a subject treated according to the methods provided herein indicates an improvement in symptoms. In other embodiments, the MMSE score of a subject treated according to the methods provided herein remains unchanged from baseline.
In some embodiments, the methods of treatment provided herein result in a change in the Appel ALS score from baseline. In the context of assessing the effect of a treatment method, the term "baseline" refers to a measurement prior to treatment. The Appel ALS score measures the overall progression of disability or altered function. In some embodiments, a decrease in an Appel ALS score from baseline in a subject treated according to the methods provided herein indicates an improvement in symptoms. In other embodiments, an Appel ALS score of a subject treated according to the methods provided herein remains unchanged from baseline.
In some embodiments, the methods of treatment provided herein result in a change in amyotrophic lateral sclerosis function score scale (ALSFRS-R) score from baseline. ALSFRS-R scores assess progression of disability or functional change. In some embodiments, an increase in ALSFRS-R score compared to baseline for a subject treated according to the methods provided herein indicates an improvement in symptoms. In other embodiments, an Appel ALSFRS-R score of a subject treated according to the methods provided herein remains unchanged from baseline.
In some embodiments, the treatment methods provided herein result in a change in forced vital capacity (FVC; muscle strength used at exhalation) from baseline, where the highest number is the strongest measurement. In some embodiments, FVC in a subject treated according to the methods provided herein is increased compared to baseline. In other embodiments, FVC in a subject treated according to the methods provided herein remains unchanged from baseline.
In some embodiments, the methods of treatment provided herein result in a change in maximum inspiratory pressure (MIP; muscle strength used upon inspiration), where the highest number is the strongest measurement. In some embodiments, the MIP of a subject treated according to the methods provided herein is increased compared to baseline. In other embodiments, MIPs of subjects treated according to the methods provided herein remain unchanged from baseline.
In some embodiments, the methods of treatment provided herein result in a change in neuropsychiatric questionnaire (NPI-Q) from baseline. NPI-Q provides a reported symptom severity and affliction rating for each symptom, as well as a total severity and affliction score reflecting the sum of the scores for each area. In some embodiments, the NPI-Q score of a subject treated according to the methods provided herein is increased compared to baseline. In other embodiments, the NPI-Q score of a subject treated according to the methods provided herein remains unchanged from baseline.
In some embodiments, the methods of treatment provided herein result in a reduced frequency of gastrointestinal symptoms, allergic reactions, or seizures as compared to baseline.
In some embodiments, the methods of treatment provided herein result in a change in CSF amyloid and/or CSF tau protein (CSF-tau) from baseline. In some embodiments, the level of CSF amyloid and/or CSF tau in a subject treated according to the methods provided herein is increased compared to baseline. In other embodiments, the level of CSF amyloid and/or CSF tau in a subject treated according to the methods provided herein remains unchanged from baseline.
In some embodiments, the methods of treatment provided herein result in a change in the clinical dementia scale (CDR) from baseline. CDRs rate memory, targeting, judgment and resolution questions, community transactions, family and hobbies, and personal care, and then generate global ratings ranging from 0 (no damage) to 3 (severe damage). In some embodiments, the CDRs of a subject treated according to the methods provided herein are increased compared to baseline. In other embodiments, the CDRs of a subject treated according to the methods provided herein remain unchanged from baseline.
In some embodiments, the methods of treatment provided herein result in a change in the Alzheimer's Disease Assessment Scale (ADAS) -cog13 score from baseline. ADAS-cog tests for cognitive performance, with an upper limit of 85 (worse performance) and a lower limit of zero (best performance). In some embodiments, the ADAS-cog13 score of a subject treated according to the methods provided herein is increased compared to baseline. In other embodiments, the ADAS-cog13 score of a subject treated according to the methods provided herein remains unchanged.
5.4 compositions
In one aspect, provided herein is a pharmaceutical composition comprising one or more doses of a protein comprising CTLA-4 and an IL-2 protein ("CTLA-4-containing protein/IL-2 protein dose"). In certain embodiments, provided herein is a pharmaceutical composition comprising one or more doses of albazedox and aldesleukin ("albazedox dose").
In certain embodiments, provided herein is a pharmaceutical composition comprising one or more abamectin/aldesleukin doses, wherein one abamectin/aldesleukin dose comprises 5mg to 125mg of abamectin and 3x10 4 Up to 3x10 7 Units of aldesleukin.
In a particular embodiment, provided herein is a pharmaceutical composition comprising one or more abasic/aldesleukin doses, wherein one abasic/aldesleukin dose comprises 8.75 to 87.5mg of abasic and 3x10 4 Up to 3x10 7 Units of aldesleukin. In a specific embodiment, provided herein is a pharmaceutical composition comprising one or more abamectin/aldesleukin doses, wherein one abamectin/aldesleukin dose comprises 29.17mg abamectin and 1x10 5 Unit of Aldi interleukin, 1x10 6 Unit of Aldi-interleukin or 1x10 7 Units of aldesleukin. In a specific embodiment, provided herein is a pharmaceutical composition comprising one or more abamectin/aldesleukin doses, wherein one abamectin/aldesleukin dose comprises 29.17mg abamectin and 1x10 6 Units of aldesleukin.
In a particular embodiment, provided herein is a pharmaceutical composition comprising one or more abasic/aldesleukin doses, wherein one abasic/aldesleukin dose comprises 5mg to 50mg of abasic and 3x10 4 Up to 3x10 7 Units of aldesleukin. In a specific embodimentIn embodiments, provided herein is a pharmaceutical composition comprising one or more abamectin/aldesleukin doses, wherein one abamectin/aldesleukin dose comprises 16.67mg abamectin and 1x10 5 Unit of Aldi interleukin, 1x10 6 Unit of Aldi-interleukin or 1x10 7 Units of aldesleukin. In a specific embodiment, provided herein is a pharmaceutical composition comprising one or more abamectin/aldesleukin doses, wherein one abamectin/aldesleukin dose comprises 16.67mg abamectin and 1x10 6 Units of aldesleukin.
In a particular embodiment, provided herein is a pharmaceutical composition comprising one or more abasic/aldesleukin doses, wherein one abasic/aldesleukin dose comprises 12.5mg to 125mg of abasic and 3x10 4 Up to 3x10 7 Units of aldesleukin. In a specific embodiment, provided herein is a pharmaceutical composition comprising one or more abamectin/aldesleukin doses, wherein one abamectin/aldesleukin dose comprises 41.67mg abamectin and 1x10 5 Unit of Aldi interleukin, 1x10 6 Unit of Aldi-interleukin or 1x10 7 Units of aldesleukin. In a specific embodiment, provided herein is a pharmaceutical composition comprising one or more abamectin/aldesleukin doses, wherein one abamectin/aldesleukin dose comprises 41.67mg abamectin and 1x10 6 Units of aldesleukin.
In certain embodiments, the pharmaceutical compositions provided herein comprise one or more abasic/aldesleukin doses as shown in table 4. The shaded numbers correspond to the amount of albazedox per dose (in mg) and the unshaded numbers correspond to the amount of aldesleukin per dose (in units). Each pair of shaded (top) and unshaded (bottom) values corresponds to the amount of albazedox and aldehydic interleukins in a particular dose. For example, in the upper left of the table, 50 (shaded, top) and 3x10 5 (without yin)Shadow, bottom) means 50mg of Abelip/3 x10 5 Unit dose of aldesleukin.
Table 4 abasic/aldesleukin doses.
50 25 16.67 15 10 8.33 7.14 6.25 5.56 5
3x10 5 1.5x10 5 1x10 5 7.5x10 4 6x10 4 5x10 4 4.3x10 4 3.75x10 4 3.33x10 4 3x10 4
50 25 16.67 15 10 8.33 7.14 6.25 5.56 5
3x10 6 1.5x10 6 1x10 6 7.5x10 5 6x10 5 5x10 5 4.3x10 5 3.75x10 5 3.33x10 5 3x10 5
50 25 16.67 15 10 8.33 7.14 6.25 5.56 5
3x10 7 1.5x10 7 1x10 7 7.5x10 6 6x10 6 5x10 6 4.3x10 6 3.75x10 6 3.33x10 6 3x10 6
87.5 43.75 29.17 21.88 17.5 14.58 12.5 10.94 9.72 8.75
3x10 5 1.5x10 5 1x10 5 7.5x10 4 6x10 4 5x10 4 4.3x10 4 3.75x10 4 3.33x10 4 3x10 4
87.5 43.75 29.17 21.88 17.5 14.58 12.5 10.94 9.72 8.75
3x10 6 1.5x10 6 1x10 6 7.5x10 5 6x10 5 5x10 5 4.3x10 5 3.75x10 5 3.33x10 5 3x10 5
87.5 43.75 29.17 21.88 17.5 14.58 12.5 10.94 9.72 8.75
3x10 7 1.5x10 7 1x10 7 7.5x10 6 6x10 6 5x10 6 4.3x10 6 3.75x10 6 3.33x10 6 3x10 6
125 62.5 41.67 31.25 25 20.83 17.86 15.63 13.89 12.5
3x10 5 1.5x10 5 1x10 5 7.5x10 4 6x10 4 5x10 4 4.3x10 4 3.75x10 4 3.33x10 4 3x10 4
125 62.5 41.67 31.25 25 20.83 17.86 15.63 13.89 12.5
3x10 6 1.5x10 6 1x10 6 7.5x10 5 6x10 5 5x10 5 4.3x10 5 3.75x10 5 3.33x10 5 3x10 5
125 62.5 41.67 31.25 25 20.83 17.86 15.63 13.89 12.5
3x10 7 1.5x10 7 1x10 7 7.5x10 6 6x10 6 5x10 6 4.3x10 6 3.75x10 6 3.33x10 6 3x10 6
In certain embodiments, provided herein is a pharmaceutical composition comprising a CTLA-4-containing protein and an IL-2 protein in a mass ratio of between 270:1 and 680:1 ("CTLA 4-containing protein: IL-2 protein dose"). In some embodiments, provided herein is a pharmaceutical composition comprising a CTLA-4-containing protein and an IL-2 protein ("CTLA 4-containing protein: IL-2 protein dose") in a mass ratio of between 450:1 and 500:1. In certain 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 (CTLA 4-containing protein: il-2 protein). In certain embodiments, the mass ratio is 480:1 (CTLA 4-containing protein: il-2 protein).
In some embodiments, provided herein is a pharmaceutical composition comprising the albazedox and the albeleukin in a mass ratio of between 270:1 and 680:1 (albazedox: albeleukin). In some embodiments, provided herein is a pharmaceutical composition comprising the albazedox and the albeleukin in a mass ratio of between 450:1 and 500:1 (albazedox: albeleukin). In certain 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 (albazem: aldehydic interleukin). In certain embodiments, the mass ratio 480:1 (Abapu: aldesleukin). It should be understood that the standard quantitative measurement of IL-2 is an International Unit (IU) which is not based on the mass of the protein, but rather on activity in a bioassay, such as that established by the first international standard of the world health organization for interleukin-2 (human). However, in practice, when the production of IL-2 products is standardized, a shift between drug quality and unit is often possible. For example, for the PROLEUKIN product, conversion to 18X10 6 IU is equal to 1.1mg protein.
In certain embodiments, the pharmaceutical compositions comprising one or more CTLA 4-containing protein/IL-2 protein doses described herein are present in lyophilized form, e.g., in the form of a lyophilized powder or a lyophilized cake. In certain embodiments, the pharmaceutical composition comprising one or more of the abamectin/aldesleukin doses described herein is present in lyophilized form, for example, in the form of a lyophilized powder or a lyophilized cake.
In certain embodiments, the pharmaceutical composition comprising one or more CTLA 4-containing protein/IL-2 protein doses described herein is a solution, e.g., an aqueous solution. In specific embodiments, one or more CTLA 4-containing protein/IL-2 protein doses are present in the pharmaceutical composition at a concentration of 1 CTLA 4-containing protein/IL-2 protein dose/0.4 ml, 1 CTLA 4-containing protein/IL-2 protein dose/0.7 ml, 1 CTLA 4-containing protein/IL-2 protein dose/1.0 ml, 1 CTLA 4-containing protein/IL-2 protein dose/1.5 ml, or 1 CTLA 4-containing protein/IL-2 protein dose/2.0 ml.
In certain embodiments, the pharmaceutical composition comprising one or more of the abasic/aldesleukin doses described herein is a solution, e.g., an aqueous solution. In particular embodiments, one or more of the abamectin/aldesleukin doses are present in the pharmaceutical composition at a concentration of 1 abamectin/aldesleukin dose/0.4 ml, 1 abamectin/aldesleukin dose/0.7 ml, 1 abamectin/aldesleukin dose/1.0 ml, 1 abamectin/aldesleukin dose/1.5 ml or 1 abamectin/aldesleukin dose/2.0 ml.
In certain embodiments, provided herein is a pharmaceutical composition comprising one or more CTLA 4-containing protein/IL-2 protein doses described herein suitable for subcutaneous administration. In certain embodiments, provided herein is a pharmaceutical composition comprising one or more CTLA 4-containing protein/IL-2 protein doses described herein suitable for intravenous administration.
In certain embodiments, provided herein is a pharmaceutical composition comprising one or more of the abasic/aldesleukin doses described herein suitable for subcutaneous administration. In certain embodiments, provided herein is a pharmaceutical composition comprising one or more abasic/aldesleukin doses suitable for intravenous administration.
In certain embodiments, provided herein is a pharmaceutical composition comprising: i) A therapeutically effective amount of a CTLA 4-containing protein, ii) a therapeutically effective amount of an IL-2 protein; and iii) one or more inactive ingredients comprising a pharmaceutically acceptable salt, excipient or carrier. In some embodiments, the therapeutically effective amount of the CTLA 4-containing protein is in the range of 25-200mg, such as 25-200mg, 50-175mg, 50-150mg, or 50-125 mg. In some embodiments, the therapeutically effective amount of CTLA 4-containing protein is 50mg. In some embodiments, the therapeutically effective amount of CTLA 4-containing protein is 87.5mg. In some embodiments, the therapeutically effective amount of CTLA 4-containing protein is 125mg. In some embodiments, a therapeutically effective amount of an 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.
In certain embodiments, provided herein is a pharmaceutical composition comprising: i) A therapeutically effective amount of abamectin, ii) a therapeutically effective amount of aldesleukin; and iii) one or more inactive ingredients comprising a pharmaceutically acceptable salt, excipient or carrier. In some embodiments, the therapeutically effective amount of abacavir is in the range of 25-200mg, such as 25-200mg, 50-175mg, 50-150mg, or 50-125 mg. In some embodiments, the therapeutically effective amount of abacavir is 50mg. In some embodiments, the therapeutically effective amount of abacavir is 87.5mg. In some embodiments, the therapeutically effective amount of abacavir is 125mg. In some embodiments, a therapeutically effective amount of the 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 the aldesleukin is 1,000,000 units. In some embodiments, the therapeutically effective amount of the aldesleukin is 2,000,000 units. In some embodiments, the therapeutically effective amount of the aldesleukin is 3,000,000 units. In some embodiments, the therapeutically effective amount of the aldesleukin is 4,000,000 units. In some embodiments, the therapeutically effective amount of the aldesleukin is 5,000,000 units.
An effective amount, e.g., an effective amount of albazedox or aldehydic interleukin, refers to an amount sufficient to produce the desired result. An effective amount may, for example, refer to the amount in a dose administered to a subject as part of a dosing regimen that results in a desired result, such as the amount of abacavir or aldesleukin. Such a dosing regimen may include administration of a single dose or administration of more than one dose, e.g., multiple doses. Such dosing regimens may, for example, comprise a single dosing cycle or more than one dosing cycle, each of which may comprise administration of a single dose or administration of more than one dose, for example a plurality of doses.
In some embodiments, the one or more inactive ingredients included in the pharmaceutical compositions provided herein comprise a pharmaceutically acceptable salt, excipient, or carrier selected from the group consisting of: sodium chloride, sodium lauryl sulfate, sodium dihydrogen phosphate, disodium hydrogen 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.
In certain embodiments, a CTLA 4-containing protein/IL-2 protein pharmaceutical composition as provided herein, such as an abasic plague/aldesleukin pharmaceutical composition, is suitable for self-administration (e.g., dermal administration) by a subject, e.g., using a prefilled syringe, injection device (e.g., INJECT-EASE TM Or GENJECT TM Devices), infusion pumps (e.g., accu-Chek TM Infusion pump), injection pen (e.g., GENPEN TM Injection pen), needleless device (e.g., MEDDECTOR TM Or BIOJECTOR TM Needleless device) or an automatic injector (e.g., clickselect) TM An automatic injector).
In some embodiments, the CTLA 4-containing protein/IL-2 protein (e.g., abacavir/aldesleukin) pharmaceutical composition is administered with an auto-injector, which may be, for example, a delivery pen with an automated mechanism. Such an auto-injector may use any automated mechanism 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 auto-injector, the subject may actuate drug delivery without activating the button (e.g., by simply exerting pressure on the injection site). In some embodiments, the auto-injector for administering the pharmaceutical compositions disclosed herein may be a device that completely or partially replaces the activities involved in drug delivery of a standard injector. These activities may include, as non-limiting examples, removing a protective syringe cap, inserting a needle into the patient's skin, injecting a drug, removing a needle, needle capping, and preventing reuse of the device.
In some embodiments, the self-administration device, e.g., an injection device (e.g., an auto-injector, such as an auto-injection pen), is mechanical. In some embodiments, the injection device (e.g., an auto-injector, such as an auto-injection pen) is electronic. Such injection devices may be provided separately from the pharmaceutical composition or pre-filled with the pharmaceutical composition. In some embodiments, the injection device is prefilled. In some embodiments, the device is empty and may be filled using a cartridge or cartridge.
In some embodiments, devices suitable for self-administration (e.g., subcutaneous administration) of the pharmaceutical compositions disclosed herein are provided in disposable containers (e.g., disposable vials, ampoules, syringes, or auto-injectors). In some embodiments, the disposable container may be disposable. In some embodiments, an injection device suitable for self-administration (e.g., subcutaneous administration) of the pharmaceutical composition disclosed herein may be provided that is prefilled with the pharmaceutical composition held in a reservoir within the device, and once the reservoir is empty of the pharmaceutical composition, the entire device may be discarded.
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 auto-injector delivery device may utilize a replaceable cartridge containing a pharmaceutical composition, and once the pharmaceutical composition within the cartridge has been administered and the cartridge is empty or no longer needed, the cartridge may be discarded and replaced with a new cartridge containing the pharmaceutical composition.
In certain embodiments, any pen and/or auto-injector injection device known in the art may be used to subcutaneously deliver the pharmaceutical compositions disclosed herein.
5.5 additional therapies
In some embodiments, a subject treated according to the methods of treatment described herein also receives one or more additional therapies known in the art for treating a disease such as a neurodegenerative disease and a neuroinflammatory disease.
In some embodiments, a subject treated according to the methods described herein receives one or more additional therapies for treating alzheimer's disease. Additional therapies for treating alzheimer's disease may include acetylcholinesterase inhibitors (e.g., donepezil)Galantamine (galantamine)>Or rivastigmine (rivastigmine)>) Or NMDA receptor antagonists (e.g., memantine)And->). Additional therapies may also include anti-inflammatory agents (e.g., non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen (ibuprofen), indomethacin (indomethacin), and sulindac sulfide (sulindac sulfide)), neuronal death-related protein kinase (DAPK) inhibitors such as derivatives of 3-aminopyridazine, cyclooxygenase (COX-1 and-2) inhibitors, or antioxidants such as vitamins C and E. / >
In some embodiments, a subject treated according to the methods described herein receives one or more additional therapies for treating ALS. Additional therapies for treating ALS may include Riluzole (Riluzole)Or riluzole
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:
(a) TNFα inhibitors (e.g., infliximab), adalimumab (adalimumab)Etanercept, golimumab or cetuximabAnti (certolizumab));
(b) IL-6 inhibitors (e.g., siltuximab, tolizumab, olouzumab, ai Ximo mab (elsillimomab), clazakizumab, or cet Lu Kushan-antibody (sirukumab));
(c) IL-23 inhibitors (e.g., tildrakizumab), gulkumab (guselkumab), or risanizumab (risanizumab));
(d) IL-17 inhibitors (e.g., secukinumab (secukinumab), ixekizumab (ixekizumab), or bevacizumab (brodalumab));
(e) IL-12/IL-23 subunit p40 inhibitors (e.g., utekuumab (Utekuumab) or Brukuumab (briakiumab));
(f) IL-1 inhibitors (e.g., anakinra)Kanagamab (canakinumab) or Li Luoxi prilonacept;
(g) C3 targeted complement inhibitors (e.g., pecetacoplan);
(h) C5 targeted complement inhibitors (e.g., lei Fuli bead mab (ravulizumab) or eculizumab (eculizumab));
(i) JAK inhibitors (e.g., barytertinib, tofacitinib, or uppacitinib);
(j) anti-CD 40L (e.g., toralizumab), dapiromant polyethylene glycol (dapirolizumab pegol) or Lu Lizhu mab (ruplizumab)); or (b)
(k) CD14 inhibitors (e.g., IC 14).
In some embodiments, the subject treated according to the methods described herein further receives Treg cell therapy. Treg cell therapies are described, for example, in WO 2021/113685 A2, which is incorporated herein in its entirety for all purposes.
In some embodiments, a subject treated according to the methods described herein further receives Extracellular Vesicles (EVs) derived from ex vivo expanded human tregs as therapy ("Treg EV therapy"). Treg EV therapy is described in International application No. PCT/US2022/017990 filed on 25/2, 2022, for example, which is incorporated herein in its entirety for all purposes.
In one aspect, provided herein is a method of treating a disease or disorder, such as 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) an additional therapy;
wherein the method reduces one or more symptoms associated with a neurodegenerative or neuroinflammatory disease or disorder in the subject being treated, and wherein the additional therapy comprises: (a) TNFα inhibitors (e.g., infliximab, adalimumab)Etanercept, golimumab, or cetuximab); (b) IL-6 inhibitors (e.g., rituximab, tolizumab, olouzumab, ai Ximo mab, claduzumab, or cet Lu Kushan antibody); (c) IL-23 inhibitors (e.g., tiramer, guluroumab, or rasagiline); (d) IL-17 inhibitors (e.g., secukinumab, ickizumab, or bevacizumab); (e) An IL-12/IL-23 subunit p40 inhibitor (e.g., utility mab or plainomab); (f) IL-1 inhibitors (e.g., anakinra->Kanamab or Li Luoxi pri); (g) C3 targeted complement inhibitors (e.g., pecostapram); (h) C5 targeted complement inhibitors (e.g., lei Fuli bead mab or eculizumab); (i) JAK inhibitors (e.g., baroretinib, tofacitinib, or Wu Pati ni); (j) anti-CD 40L (e.g., toltrazumab, dapiromant polyethylene glycol, or Lu Lizhu mab); (k) CD14 inhibitors (e.g., IC 14); (l) Treg cell therapy, for example, as described in WO 2021/113685 A2; or (m) Treg EV therapy, e.g., as submitted on day 25 of 2022, 2 Described in International application No. PCT/US 2022/017990.
5.6 additional therapeutic intervention
In some embodiments, the methods disclosed herein may be used 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. As non-limiting examples, in some embodiments, the additional therapeutic interventions may include cognitive rehabilitation programs, neurostimulation techniques, or combinations thereof.
Any cognitive rehabilitation program known in the art may be used with the methods disclosed herein. The cognitive training, stimulation and rehabilitation methods and software provided by digital devices are used in the art to improve cognitive function in subjects suffering from 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.
In some embodiments, the neural stimulation technique is non-invasive brain stimulation (NIBS). In some embodiments, the neural stimulation technique is Invasive Brain Stimulation (IBS). Any neural stimulation technique known in the art may be used with the methods disclosed herein. As non-limiting examples, IBS includes Deep Brain Stimulation (DBS) and invasive Vagal Nerve Stimulation (VNS), and NIBS includes Transcranial Magnetic Stimulation (TMS), transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tcas), electroconvulsive therapy (ECT), magnetic epileptic therapy (MST), craniocerebral Electrical Stimulation (CES), and/or non-invasive VNS. In some embodiments, the neural stimulation technique is invasive vagal nerve stimulation or non-invasive VNS. As a non-limiting example, in some embodiments, the additional therapeutic intervention is implantation and use of a vagal stimulator (e.g., neuroCybernetic Prosthesis, cyberonics inc., houston TX.). See, e.g., sjogren, MJ et al, J Clin Psychiary (2002) 63 (11): 972-80. In some embodiments, any method known in the art for enhancing cognition in a subject using vagal nerve stimulation may be used (e.g., by programming a pulse generator delivering an electrical signal using parameters known in the art).
5.7 medicine box
In one aspect, provided herein is a kit comprising i) one or more doses of a formulation comprising 50 to 125mg of albazedox, and ii) one or more doses of a formulation comprising 500,000 to 3,000,000 units of albazedox in separate containers. In certain embodiments, the kit comprises one or more doses of a formulation comprising 50mg of abacavir, 87.5mg of abacavir, or 125mg of abacavir. In particular embodiments, one or more doses of abamectin are present in lyophilized form, for example in the form of a lyophilized powder or cake. In certain embodiments, one or more doses of the formulation of abacavir are suitable for subcutaneous or intravenous administration. In certain embodiments, the kit comprises one or more doses of a formulation comprising 500,000 to 2,000,000 units of aldesleukin or 1,000,000 units of aldesleukin. In particular embodiments, one or more doses of the aldesleukin are present in lyophilized form, for example in lyophilized powder or cake form. In certain embodiments, one or more doses of the formulation of aldesleukin are suitable for subcutaneous or intravenous administration.
In certain embodiments, provided herein is a kit comprising i) one or more doses of a formulation comprising an amount in the range of 20-200mg of albazedox, and ii) one or more doses of a formulation comprising an amount in the range of 10,000-3,000,000 units of albazedox in separate containers. In some embodiments, the abacavir formulation comprises an amount of abacavir in the range of 25-200mg, such as 25-200mg, 50-175mg, 50-150mg, or 50-125mg of abacavir. In some embodiments, the abacavir formulation comprises 50mg abamectin. In some embodiments, the abacavir formulation comprises 87.5mg abamectin. In some embodiments, the abacavir formulation comprises 125mg abamectin. In some embodiments, the aldesleukin formulation comprises an amount of aldesleukin within the range of 10,000-3,000,000 units, such as 500,000-3,000,000 units or 500,000-2,000,000 units of aldesleukin. In some embodiments, the aldesleukin formulation comprises 1,000,000 units of aldesleukin. For example, in some embodiments, the kits provided herein comprise i) one or more doses of a formulation comprising 87.5mg of albazedox, and ii) one or more doses of a formulation comprising 1,000,000 units of albazedox in separate containers.
In some embodiments, according to the kits provided herein, the abacavir formulation is an intravenous formulation. In some embodiments, the intravenous abapple formulation is a lyophilized powder. In some embodiments, the intravenous abapple formulation further comprises sodium dihydrogen phosphate. In some embodiments, the intravenous abapple formulation further comprises sodium chloride. In some embodiments, the intravenous abapple formulation further comprises maltose. In some embodiments, the intravenous abacavir formulation has a pH in the range of 7.2-7.8 when reconstituted in 3.5mL sterile injectable water USP.
In some embodiments, according to the kits provided herein, the abacavir formulation is a subcutaneous formulation. In some embodiments, the subcutaneous abamectin formulation is a solution having a pH in the range of 6.8-7.4. In some embodiments, the subcutaneous abamectin formulation further comprises disodium hydrogen phosphate. In some embodiments, the subcutaneous abamectin formulation further comprises sodium phosphate monobasic. In some embodiments, the subcutaneous abamectin formulation further comprises a poloxamer. In some embodiments, the subcutaneous abamectin formulation further comprises sucrose. In some embodiments, the subcutaneous abacavir formulation further comprises sterile water for injection USP. In some embodiments, the volume of the abamectin formulation is 0.1-2.0mL. For example, in some embodiments, the volume of the abacavir formulation is 0.4mL, 0.7mL, or 1.0mL.
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 disodium hydrogen phosphate. In some embodiments, the aldesleukin formulation further comprises sodium dihydrogen 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 has a pH in the range of 7.2-7.8 when reconstituted in sterile water for injection USP at a concentration of 18,000,000 units per 1 ml.
In some embodiments, the kits provided herein comprise instructions for use, additional reagents (e.g., sterile water or saline solution for diluting the composition), or components, such as a tube, container, or syringe for collecting a biological sample, processing a biological sample, and/or reagents (e.g., detection reagents, such as antibodies) for quantifying the amount of one or more surface markers in a sample.
In some embodiments, the kit contains one or more containers containing the abacavir formulation and the aldesleukin formulation for use in the methods provided herein. The one or more containers containing the abamectin formulation may be disposable vials or multiple use vials. The one or more containers containing the aldesleukin formulation can be disposable vials or multiple use vials. In some embodiments, the article of manufacture or kit may further comprise a third container comprising a suitable diluent. In some embodiments, the kit contains instructions for use (e.g., dilution and/or administration) of the abacavir formulation and/or the aldesleukin formulation provided herein.
In some embodiments, kits provided herein comprise a plurality of doses or administration units of one or more drugs and one or more devices for application (e.g., a syringe, an injection pen, and/or an auto-injector). In some embodiments, such devices may be provided separately from the pharmaceutical composition or pre-filled with the pharmaceutical composition. In some embodiments, kits provided herein comprise one or more doses of the pharmaceutical compositions and/or formulations described herein in separate containers. In some embodiments, the container is packaged in an injection device or may be inserted into an injection device (e.g., a disposable dose cartridge or cartridge that may be inserted into an automatic injector device for administration).
In one aspect, provided herein is a kit comprising in one container a pharmaceutical composition comprising one or more doses of a CTLA-4-containing protein, such as abacavir and an IL-2 protein, such as aldesleukin ("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 solution for diluting the composition) or components, such as a tube, container or syringe for collecting a biological sample, processing a 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 reagents for an applicator (e.g., syringe, injection pen, and/or auto-injector).
6. Examples
6.1 example 1: in vitro results of CTLA4 IgG (Abamezept) and Interleukin-2 (Il-2) combinations
The experiments described in this example demonstrate that the combination of CTLA4 IgG (abasic) and IL-2 synergistically enhances the inhibitory function of tregs.
Effect of CTLA4 IgG (abasic) dose escalation on M1 IL6 protein expression
CTLA4 IgG (abacet) or isotype control thereof was added to in vitro Induced Pluripotent Stem Cell (iPSC) -derived pro-inflammatory macrophages (M1) and changes in pro-inflammatory IL-6 protein expression were determined by enzyme-linked immunoassay (ELISA). Abamectin reduces M1 IL6 protein expression in a dose-dependent manner, whereas isotype control has no statistically significant effect on IL-6 expression. The results are summarized in fig. 1.
6.1.2. Effect of increasing abasic dose on proliferation of T responders
T-responsive cells (Tresp) were isolated from the blood of alzheimer's patients not receiving IL-2 therapy and placed in 96-well plates at a density of 50,000 cells per plate. CTLA4 IgG (abasiper) or isotype control thereof was added to Tresp of alzheimer's patients. After 5 days of culture, tresp proliferation was determined by thymidine incorporation. Abamectin reduces Tresp proliferation in a dose-dependent manner, whereas isotype control has no statistically significant effect on Tresp proliferation. The results are summarized in fig. 2.
6.1.3. Effect of increasing dose of abamectin on IL-2-induced in vivo expanded ability of alzheimer's disease tregs to inhibit proliferation of Tresp
Alzheimer's disease patients receive IL-2 (1X 10) for 5 days via subcutaneous injection 6 Unit of aldesleukin) course of therapy to expand tregs in vivo. On day 8, IL-2-induced in vivo expanded tregs were isolated from patient blood samples. The treatment with IL-2 therapy for 5 days increased the number of tregs in the blood by a factor of 2, as measured by flow cytometry. The ability of IL-2-induced in vivo expanded tregs to inhibit Tresp proliferation was determined in vitro by thymidine incorporation. The addition of abamectin to IL-2 induced in vivo expanded tregs enhances the ability of tregs to inhibit Tresp proliferation in a dose dependent manner. The results are summarized in fig. 3.
6.1.4. Effect of increasing dose of abamectin on IL-2-induced in vivo expanded alzheimer's disease Treg ability to inhibit M1 IL6 production
Alzheimer's disease patients receive a 5 day course of IL-2 by subcutaneous injection to expand tregs in vivo. 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 hours. The medium was collected to assess cytokine protein levels by ELISA and to determine the ability of tregs to inhibit the function of proinflammatory M1 macrophages. The addition of abamectin to IL-2 induced in vivo expanded Treg: M1 co-culture synergistically enhances the ability of tregs to inhibit M1 IL6 protein expression in a dose dependent manner. The results are summarized in fig. 4. The enhancements are synergistic, supported for example by the fact that: the addition of abacavir alone to the co-culture actually worsens the inhibitory function, whereas the addition of IL-2 and abacavir resulted in a significant enhancement of Treg inhibitory function, as described in the following section and summarized in fig. 5.
6.1.5. Effect of abasic and IL-2 on Treg inhibition function of alzheimer's disease
Treg was isolated from alzheimer's patients not receiving IL-2 therapy and co-cultured with pro-inflammatory (M1) macrophages, as described above. The addition of IL-2 and abamectin to the Treg: M1 co-culture synergistically enhances the ability of the Treg to inhibit pro-inflammatory M1 function, as measured by IL-6 expression, whereas the addition of abamectin alone actually reduces IL-6 expression. The results are summarized in fig. 5.
6.2 example 2: phase I trial with Abelip and Interleukin-2 (II-2) in Alzheimer's Disease (AD) patients
The purpose of this study was to evaluate the effect of low dose abacavir, followed by IL-2 administration on AD patients. In particular, this is a phase I open-label study for assessing safety and tolerability of abapple, followed by low-dose subcutaneous IL-2 administration. Briefly, patients received low doses of abacavir followed by IL-2 administration for a total of 4 months. Changes in inflammatory markers were measured during the study period.
6.2.1. Main objective
To assess the safety and tolerability of abatopiramate, followed by IL-2 administration in AD patients, administration was performed according to the doses described in this protocol.
6.2.2. Secondary target
To study the immunomodulatory effects of aclarubip, followed by IL-2 in AD patients, pre-treatment, during treatment and post-treatment were compared: (a) monitoring changes in Treg numbers and immunophenotype; (b) Monitoring the change in the inhibitory activity of cd4+cd25+foxp3+ Treg on proliferation of T effectors; (c) Monitoring the change in the level of cytokines secreted by PBMCs throughout the course of the study; and (d) measuring disease progression throughout the course of the test.
6.2.3. Study design
This is a phase I open-label, non-control study for assessing the safety of administration of abacavir, followed by subcutaneous IL-2 administration.
Four AD patients with mild clinical dementia (MMSE between 12-25) received fixed low dose of abacavir followed by IL-2 treatment for a total of 4 months.
In addition to assessing the safety and toxicity of low dose abacavir, followed by IL-2 administration in the treatment of AD progression, the goal of this phase I study was to assess the extent of enhancement of Treg suppression function in subjects. The metric used to evaluate Treg inhibition enhancement was area under the curve (AUC).
The patient received a fixed dose of subcutaneous abacavir (87.5 mg/0.7 mL) on day 1 of week 1. After two weeks (day 1 of week 3 (D1)), the patient received a second dose of subcutaneous abacavir (87.5 mg/0.7 mL). In addition, patients received subcutaneous IL-2 (1X 10 6 Unit/day) for 3 days (days 1-3 of week 3 (D1-3)). If this regimen is tolerable, the patient receives 6 additional courses of similar abasic and IL-2 every two weeks.
Alternative treatment strategies may be employed. For example, in a five day administration schedule, patients received a fixed dose of subcutaneous abacavir (87.5 mg/0.7 mL) on day 1 of week 1. After two weeks (day 1 of week 3 (D1)), the patient received a second dose of subcutaneous abacavir (87.5 mg/0.7 mL). In addition, patients received subcutaneous IL-2 (1X 10 6 Unit/day) for 5 days (days 1-5 of week 3 (D1-5)), wherein the patient received 6 similar treatment courses of abamectin and IL-2 every two weeks. In another alternative example, in a seven day administration schedule, the patient receives a fixed dose of subcutaneous abacavir (87.5 mg/0.7 mL) on day 1 of week 1. After two weeks (day 1 of week 3 (D1)), the patient received a second dose of subcutaneous abacavir (87.5 mg/0.7 mL). In addition, patients received subcutaneous IL-2 (1X 10 6 Unit/day) for 7 days (days 1-7 of week 3 (D1-7)), wherein the patient received 6 similar treatment courses of abamectin and IL-2 every two weeks.
In another alternative example, in a five day administration schedule, the patient receives a fixed dose of subcutaneous abacavir (125 mg/0.7 mL) on day 1 of week 1. After two weeks (day 1 of week 3 (D1)), The patient received a second dose of subcutaneous abacavir (125 mg/0.7 mL). In addition, patients received subcutaneous IL-2 (1X 10 6 Unit/day) for 5 days (days 1-5 of week 3 (D1-5)), wherein the patient received 6 similar treatment courses of abamectin and IL-2 every two weeks. See table 5.
Table 5: albazedox/IL-2 administration schedule
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6.2.4. Drug information
Interleukin 2. The recombinant human IL-2 used was PROLEUKIN (aldesleukin). Currently, the approved dose of PROLEUKIN (aldesleukin) is 600,000 international units/kg (0.037 mg/kg). In this study, patients received subcutaneous IL-2 (1X 10 6 Unit), which is a fixed dose, of about 2.5% of the average labeled single dose infusion.
PROLEUKIN (aldesleukin) is used for injection and is a highly purified protein with a molecular weight of about 15,300 daltons. The chemical name is des-alanyl-1, serine-125 human interleukin-2. PROLEUKIN differs from natural IL-2 as follows: a) It is derived from E.coli and is therefore not glycosylated; b) It has no N-terminal alanine, and the codon of the amino acid is deleted in the genetic engineering process; c) It replaces the cysteine at amino acid position 125 with serine by site-specific manipulation during genetic engineering; d) Its aggregation state may be different from that of natural IL-2.
PROLEUKIN is provided in disposable vials in sterile, white to off-white lyophilized cake form for Intravenous (IV) or subcutaneous administration. The lyophilized PROLEUKIN vials for injection should be protected from light.
When reconstituted with 1.2mL sterile water for injection (SWFI) USP, each mL contains 1800 ten thousand IU (1.1 mg) PROLEUKIN, 50mg mannitol and 0.18mg sodium dodecyl sulfate, buffered to pH 7.5 (range 7.2 to 7.8) with approximately 0.17mg sodium dihydrogen and 0.89mg disodium hydrogen phosphate.
Under sterile conditions with a laminar flow hood, the PROLEUKIN vial was reconstituted with 1.2mL SWFI and with D 5 The samples were further diluted to a concentration of 200 μg/mL with W (5% glucose in water) and stored in Becton-Dickinson (B-D) plastic syringes at 2 ℃ to 8 ℃ (36°f to 46°f). Under these conditions, stability and sterility can be maintained for up to 14 days. After delivery of the diluted syringes to study participants, the syringes should also be refrigerated (2 ℃ to 8 ℃) at home prior to use.
The reconstituted IL-2 solution vial is further treated with an appropriate volume of D 5 W is diluted so that 100 ten thousand units of subcutaneous dose can be administered per dose (subcutaneous dose should not exceed 2 mL).
The biological potency of PROLEUKIN is determined by lymphocyte proliferation bioassay and is expressed in International Units (IU) established for the first international standard of the world health organization for human IL-2. The relationship between potency and protein mass is as follows: 1800 ten thousand (18 x 106) IU proleukin=1.1 mg protein.
Abappl.Abatopirane is an FDA approved drug, commercially available as ORENCIA, and has been shown to be useful as monotherapy or in combination with other anti-inflammatory drugs to regulate inflammation in autoimmune disorders.
The ORENCIA (Abamectin) dose of this study was a fixed dose of 87.5mg/0.7mL. The amount of dose of the study was consistent with the current approved marketing ORENCIA label listing the following approved injection doses: 50mg/0.4mL, 87.5mg/0.7mL and 125mg/mL of clear to slightly milky, colorless to pale yellow solutions in a single dose pre-filled glass syringe.
Abappl is a recombinant soluble fusion protein containing the extracellular domain of human cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) linked to the modified Fc (hinge, CH2 and CH3 domains) portion of human immunoglobulin G1.
6.2.5. Duration of administration
PROLEUKIN. The study was performed using PROLEUKIN, 3 day cycle,for 15 weeks, rest once every other week. The approved PROLEUKIN administration duration was a 5 day period with rest in between and a total treatment period of 19 days. The longer total treatment duration of this study was confirmed by prior phase I studies and preclinical evidence of acceptable tolerability.
ORENCIA。The study suggests once weekly ORENCIA administration for a total of 16 weeks with a rest every other week. The duration of approved orenca administration is introduced by loading or fixed dose, followed by continuous treatment according to the dosing schedule which varies with the indication. The duration of treatment used in this study was paired with IL-2 administration and no continuous treatment was required.
6.2.6. Patient evaluation
6.2.6.1 before beginning treatment
The following pre-treatment evaluations were completed prior to the first injection of abamectin/IL-2:
(a) Baseline medical history and physical examination;
(b) Vital signs, body weight;
(c) Pulse oximetry;
(d) Laboratory: whole blood count, PT/PTT, chemical analysis, liver function test, thyroid function test, quantiFERON;
(e) A baseline ECG; and
(f) Baseline study laboratory: treg, th1 and Treg suppression.
6.2.6.2 treatment period
The following data were obtained on the first day and every two weeks of receiving an infusion of abamectin/IL-2:
(a) Physical examination; and
(b) Vital signs, body weight, pulse oximetry.
The following laboratory tests were performed every two weeks during the treatment of abamectin/IL-2: whole blood cell count, chemical analysis, liver function test.
The following laboratory tests were performed on day 1 and every two weeks during the treatment of abamectin/IL-2: research laboratory (Treg analysis): treg, th1 and Treg suppression.
6.2.6.3 after treatment
Once the IL-2 treatment cycle was completed, the treated patients received the following study at weeks 17 and 24:
(a) Physical examination;
(b) Vital signs, body weight, and pulse oximetry; and
(c) Laboratory: whole blood count, chemical analysis, liver function test, thyroid function test, treg analysis.
6.2.6.4 disease specificity evaluation
Cognitive states (including MMSE) were performed at baseline and weeks 5, 9, 13, 17 and 24 of the trial.
Cognitive states (including ADAS-Cog and CDR-SB) were performed at baseline and weeks 13 and 24.
6.2.6.5 immune reconstitution assay
Depending on the availability of patient samples and reagents, the immunophenotyping studies, including immunophenotyping and functional analysis, were performed continuously at the following time points before, during and after treatment.
Approximately 1-2 tablespoons (15-30 ml) of patient blood were collected at baseline visit and day 1 (prior to abac treatment) and weeks 17 and 24 of each treatment cycle during the treatment period, if applicable.
If the patient's hemoglobin is below 8.0g/dL at any evaluation time, the amount of blood drawn for evaluation will decrease and, if necessary, can be obtained by more than one venipuncture.
Management of 6.2.6.6 hypotension
IL-2 is interrupted due to grade 3 or more hypotension. An appropriate hydration liquid should be administered to maintain blood pressure. If this procedure fails, the patient will manage according to the guidelines of the intensive care unit.
Management of 6.2.6.7 respiratory distress/dyspnea
The patient was given supplemental oxygen and appropriate imaging studies. If not, the patient is managed in the intensive care unit.
6.2.6.8 infection management
Patients who develop new infections when receiving the treatment of abapple should be closely monitored and receive standard treatment. If the patient develops a severe infection, the administration of abacavir should be stopped. Patients will be screened for tuberculosis prior to treatment with abacavir. If the patient's tuberculosis screening is positive, the patient should be treated according to standard medical practice and excluded from the study.
Improvements in 6.2.6.9 therapy
The treatment with abamectin/IL-2 is applicable to the following cases: patients with hypotension and no response to fluid, dyspnea or oxygen saturation of <90% at 2 liters of supplemental oxygen; acute mental state changes; grade 3 ventricular or supraventricular arrhythmias; evidence of myocarditis or ischemia; bilirubin or creatinine >5mg/dL; evidence of sepsis; or any other grade 3 or grade 4 intolerant toxicity. Except for grade 3 or grade 4 ventricular arrhythmias, myocardial infarction, intubation, sepsis, coma, dialysis or any toxicity deemed life threatening, all toxicities return to grade 1 or less within 72 hours, and treatment can be restarted with a 50% reduction in dose.
6.2.7. Inclusion criteria for initial study inclusion group
Patients were eligible to participate in the initial group entry of the study if they met the following criteria:
(a) Diagnosing possible Alzheimer's disease according to national institute of aging-Alzheimer's disease Association (NIA-AA) standard 13;
(b) Men or women aged 60 to 86 years old;
(c) MMSE is between 12-25;
(d) Total bilirubin is less than or equal to 1.5mg/dL;
(e) Alanine Aminotransferase Levels (ALT) are five times lower than normal and albumin is 3.0gm/dL higher;
(f) Serum creatinine is below 1.5mg/dL;
(g) English speaking;
(h) The family members or caregivers should be always present, administer abasic and IL-2 study drugs, and participate in the study visit throughout the course of the study; and
(i) For AD patients with limited decision-making capability, a Legal Agent (LAD) should be present and indicate consent based on the maximum benefit of the patient.
6.2.8. Exclusion criteria for initial study inclusion group
The patient will not be eligible to participate if any of the following is true:
(a) Severe, active bacterial, fungal or viral infections, active or latent tuberculosis;
(b) Severe pulmonary dysfunction. FEV1 and FVC are below 40% of baseline predicted values (or below normal 3 SD) if a lung function test is clinically needed. Cannula history >72 hours;
(c) Severe cardiac dysfunction is defined as a left ventricular ejection fraction <40% if echocardiography is medically indicated to clarify persistent symptoms or EKG results; a history of uncontrolled arrhythmias; there is a history of cardiac tamponade; unstable angina or MI in the past 3 months;
(d) Hypersensitivity or allergy to IL-2 or abafpgas;
(e) There is a history of bowel ischemia/perforation, or a history of gastrointestinal bleeding requiring surgery;
(f) A history of refractory seizures, a history of coma, or a history of toxic psychosis lasting >48 hours;
(g) Platelets<100,000/mm 3 The method comprises the steps of carrying out a first treatment on the surface of the Hematocrit (HCT)<30％；
(h) History of cancer (except basal cell carcinoma or squamous cell carcinoma of the skin) has been observed over the past 5 years; or (b)
(i) A history of immunosuppressive therapy including IL-2 administration was received over the past 90 days.
6.2.9. Concomitant medication
Antibiotics, antifungals, antivirals, G/GM-CSF and immunoglobulin would be allowed to be used and used according to the standard procedure outlined. Nutritional support, including tube feeding and/or total parenteral nutrition, is also allowed. The tenor (Tylenol) required for fever and the appropriate clinical response to fever should be performed according to standard procedures.
6.2.10. Excluded medicine
The biological response modifiers interferon and tnfα blocker should not be used in combination with the IL-2/abacavir treatment regimen. The continued use of steroids should not be used in combination with IL-2.
6.2.11. Subject withdrawal
6.2.11.1 subject withdrawal criteria
Criteria for subject withdrawal included:
(a) Any patient who develops irreversible or life threatening or is considered non-hematologic grade 3 or 4 toxicity primarily associated with abamectin or IL-2;
(b) Serious, life threatening infections;
(c) A cannula;
(d) Coma, coma;
(e) Severe cardiac dysfunction, including ischemia, sudden cardiac arrest, LVSF (left ventricular contractile function) drop below 25%, evidence of life threatening arrhythmias;
(f) Severe pulmonary dysfunction or severe pulmonary insufficiency, more than 2 liters of oxygen are required to maintain oxygen saturation greater than 90%;
(g) Severe renal dysfunction or renal dialysis with creatinine >5 mg/dL; or (b)
(h) Direct bilirubin >5mg/dL for severe liver dysfunction or liver failure.
6.3 example 3: phase I study with a combination of Abaulper and Interleukin-2 (IL-2) after Low dose IL-2 in two Alzheimer's Disease (AD) patients
It has been previously documented that Treg immunophenotype and function are impaired in AD patients, however, dysfunctional AD tregs can be normalized by amplifying them in vitro in the presence of IL-2 (Faridar et al Brain Commun.2.2 (2020): fca).
The in vitro data described in example 1 demonstrate the synergistic effect of IL-2 and albazedox in remodeling the immune pathway of alzheimer's disease; the addition of abamectin to IL-2 treated tregs significantly improved the immunomodulatory function of the cells. To evaluate this finding in a clinical setting, two patients initially receiving a low dose of IL-2 monotherapy for four months were subsequently administered an abamectin/IL-2 combination therapy.
In particular, two AD patientsSubcutaneous low doses of IL-2 (1X 10) were received for four months 6 Unit/day) treatment. Patients received low doses of IL-2 5 days (weeks 1, 5, 9 and 13 (days 1-5) (D1-5)) tregs were isolated from patients and co-cultured with T responders (Tresp) at a ratio of 1:1 IL-2 monotherapy enhanced the immunosuppressive function of tregs on proliferation of T responders (Treg: tresp ratio 1:1) (see e.g., fig. 6 and 7, "4 month IL-2 monotherapy").
Table 6: IL-2 administration schedule
During the period of about ten months after the end of the four month low dose IL-2 monotherapy, two patients initially receiving the monotherapy received abacavir alone, followed by low dose IL-2 and 87.5mg abacavir administration according to the three day administration regimen described in table 5 (see, e.g., fig. 6 and 7, "abamectin alone" and "abamectin+il-2 treatment", respectively).
The inhibitory function of Treg as a surrogate biomarker of therapeutic response on Tresp proliferation was monitored. IL-2 gabexa Brazil therapy has a synergistic effect in restoring Treg immunosuppressive function, as described below. Furthermore, as also described below, restoration of Treg immunomodulatory function enhances cognitive function in AD patients who enter the group.
IL-2 and Abelip treatment in restoring Treg and cognitive function in AD patients
Two Alzheimer's patients received a single course of low dose IL-2 for 4 months via subcutaneous injection to expand tregs in vivo, as described herein. IL-2 administration selectively expands the population of peripheral Tregs and enhances their immunosuppressive function. As described in section 6.3 above, two AD patients subsequently received abacavir alone and a combination of low dose IL-2 and 87.5mg abacavir according to the three day dosing regimen described in table 5. See, for example, fig. 6-8.
Figure 6 illustrates that patient AD-01 showed an increase in Treg inhibition of 53.5% at the fourth IL-2 first therapy cycle, but subsequently showed a rapid decrease in Treg inhibition. The patient also exhibited concomitant decline in cognitive function as measured by MMSE, as shown in figure 8. Once AD-01 was administered to patients with a combination of abasic and IL-2, the suppressive function of Treg on Tresp proliferation increased to 85.2% beyond that observed for IL-2 (53.5%) or abasic alone (27.3%), fig. 6. Patient AD-01 also showed improvement in cognitive function (fig. 8).
Similarly, as shown in fig. 7, patient AD-02 showed a 27% increase in Treg inhibition at day 98 of IL-2 monotherapy treatment, followed by a significant decrease in Treg inhibition at day 280. Patient AD-02 exhibited concomitant decline in cognitive function as measured by MMSE (fig. 8). Following initiation of abamectin/IL-2 combination therapy, the patient showed an increase in Treg inhibition of Tresp proliferation by 60.5% after the second abamectin/IL-2 administration, which levels exceeded those observed in IL-2 (27.3%) or abamectin (13%) responses alone (fig. 7), and further showed a concomitant increase in cognitive function as measured by MMSE (fig. 8).
Comparison of MMSE score and Treg suppression in IL-2 monotherapy versus IL-2 plus abarelip therapy in additional AD patients
In addition to the two Alzheimer's disease patients described in the previous section, six additional Alzheimer's disease patients received subcutaneous injection of low dose IL-2 monotherapy for a period of 4 months (eight AD patients total). Cognitive status was assessed in 8 AD patients with MMSE testing 2 weeks after baseline and last cycle of IL-2 immunotherapy (monotherapy) (fig. 9, left panel). Treg inhibition function was also assessed in 8 AD patients, as shown in figure 10 (left panel).
Three patients (patient AD-01, AD02 as described above, and a third patient who had not previously received IL-2 monotherapy) received abacavir alone and a combination of low dose IL-2 and 87.5mg abacavir according to the three-day dosing regimen described in section 6.3 and table 5 above. Cognitive status was monitored with MMSE changes at baseline and 2 weeks after the last IL-2 plus abacavir immunotherapy cycle, as shown in figure 9 (right panel). Treg inhibition function was evaluated in these 3 patients as shown in figure 10 (right panel).
The results shown in figure 9 demonstrate the beneficial effect of IL-2/abacavir combination therapy on cognition compared to IL-2 alone. In particular, the results show that the administration of IL-2/abapple resulted in 15.7% increase in MMSE score, compared to pre-treatment screening, two weeks after treatment, whereas IL-2 alone was only 3.3% increase. This corresponds to a 4.75-fold increase in MMSE score with IL-2/Abelip compared to IL-2 alone. The results shown in fig. 10 show the percent change in Treg inhibition function over the course of the study relative to the pre-treatment baseline. The results show an increase in Treg inhibition function in AD patients receiving IL-2/abacavir compared to patients receiving IL-2 alone, demonstrating the synergistic effect of combination therapy on Treg inhibition function. Furthermore, the data indicate that IL-2/abapple treatment maintains Treg inhibition function after treatment more successfully than IL-2 treatment alone, the latter indicating a substantial decrease in Treg inhibition function over the same post-treatment time.
6.4 example 4: phase I trial using a combination of Abelip and Interleukin-2 (II-2) in Alzheimer's disease patients
The purpose of this study was to assess the effect of IL-2 and low dose abacavir administration on AD patients. In particular, this is a phase I open-label study for assessing safety and tolerability of subcutaneous administration of IL-2 and low dose abacavir in a single formulation. Changes in inflammatory markers were measured during the study period.
6.4.1. Main objective
To assess the safety and tolerability of IL-2 and low dose abacavir in AD patients, the doses described in this protocol were administered as a single formulation.
6.4.2. Secondary target
To study the immunomodulatory effects of IL-2 and low dose abacavir administered as a single formulation in AD patients, pre-treatment, during treatment and post-treatment were compared: (a) monitoring changes in Treg numbers and immunophenotype; (b) Monitoring the change in the inhibitory activity of cd4+cd25+foxp3+ Treg on proliferation of T effectors; (c) Monitoring the change in the level of cytokines secreted by PBMCs throughout the course of the study; and (d) measuring disease progression throughout the course of the test.
6.4.3. Study design
This is a phase I open-labeled, uncontrolled study for the safety and tolerability of administration of IL-2 and low dose abanaproxen administered subcutaneously in a single formulation.
AD patients with mild clinical dementia (MMSE between 12-25) received fixed low doses of IL-2 and abacavir for a total of 4 months, with IL-2 and abacavir administered as a single formulation.
In addition to assessing safety and toxicity of administration in treating AD progression, the goal of this phase I study was to assess the extent of enhancement of Treg inhibition function in subjects. The metric used to evaluate Treg inhibition enhancement was area under the curve (AUC).
Patients received 1x10 subcutaneously delivered in a single formulation per day 6 The combination of the units IL-2 (PROLEUKIN; aldesleukin) and 29.17mg of Abelip lasted 3 days (days 1-3; D1-3) on week 1. If this treatment regimen is tolerable, the patient receives a further similar course of treatment of a combination of subcutaneous IL-2 and abacavir every two weeks for the next 15 weeks. Alternative treatment strategies may be employed. For example, patients receive 1x10 subcutaneously delivered in a single formulation per day 6 The combination of unit IL-2 (PROLEUKIN; aldesleukin) and 17.5mg of abacavir was continued for 5 days of week 1 (days 1-5; D1-5), after which the patient received a further course of treatment of a similar combination of subcutaneous IL-2 and abacavir every two weeks for the next 15 weeks. In another alternative, the patient receives 1x10 delivered subcutaneously in a single formulation per day 6 The combination of unit IL-2 (PROLEUKIN; aldesleukin) and 12.5mg of abarelip was continued for 7 days of week 1 (days 1-7; D1-7), after which the patient received a further course of treatment of similar subcutaneous combination of IL-2 and abarelip every two weeks for the next 15 weeks. See table 7.
Table 7: albazedox/IL-2 combination administration schedule
The patient evaluation criteria, inclusion and exclusion criteria, and information regarding concomitant and exclusion medications and subject withdrawal for this study were the same as the study presented in example 1.
6.5 example 5: stability of IL-2/Abelip combination formulation
This example demonstrates that an aqueous formulation comprising IL-2 and abacavir remains stable for up to 24 hours at room temperature under Standard Test Conditions (STC).
IL-2 (PROLEUKIN (Aldi interleukin), clinigen,1.3 mg/vial, freeze-dried) was reconstituted with 1.2mL of water to 1.1mg/mL and mixed with Abiotic acid (ORENCIA, bristol Myers Squibb,87.5mg/0.7mL, PFS (prefilled syringe) to obtain a combination formulation of IL-2: abiotic acid mass ratio 480:1 (101 mg/mL Abiotic acid and 0.21mg/mL IL-2.) the solution was kept under STC, sampled at start, 3 hours, 6 hours and 24 hours, and evaluated by UV spectroscopy (A280/340), light shielding (HIAC) and Dynamic Light Scattering (DLS).
For UV spectroscopy, samples of the combined formulation were diluted 135-fold with saline and absorbance was measured at 280nm and 340nm on a Thermo Scientific Evolution UV/Vis spectrophotometer (sample volume 0.45 mL). An Aggregation Index (AI) is determined, where ai=100 (a 340)/(a 280-a 340). The results are shown in Table 8, where the concentration varies over the process variability. These results indicate that the IL-2/Abelip solution concentration (mg/mL) was stable for 24 hours at room temperature (time point of last test).
Table 8: absorbance of IL-2/abacavir co-formulation
Undiluted triplicate samples (0.05 mL) were added to the wells of a Thermo Scientific flat bottom transparent 96-well plate and light scattering measurements were made at a280 and a340 in a BioTeck Synergy HTX multimode reader. The results are shown in Table 9. These results show that light scattering is stable for at least 24 hours at room temperature (time point of last test), indicating that the IL-2/abacavir combination formulation is stable and has no tendency to form aggregates and particles within at least 24 hours at room temperature.
Table 9: IL-2/Abarzepine coformulation light scattering
The HIAC results for the samples of sub-visible particles from the BioTeck Synergy HTX multi-mode reader are shown in table 10. These results demonstrate that sub-visible particle counts of >2 μm and >5 μm remain stable for at least 24 hours (the time point of the last test), and sub-visible particle counts of >10 μm and >25 μm remain stable for 24 hours and meet EU and USP requirements.
Table 10: IL-2/abamectin co-formulation-sub-visible particles.
The DLS results are summarized in table 11. The DLS results indicate that the particle size in the IL-2/Abelip combination formulation is stable over 24 hours. Most of the particles are located in the main peak. The PDI is high. This is probably because the particle size distribution outside the main peak is different.
Table 11: IL-2/abamectin co-formulation-particle size by DLS.
6.6 example 6: phase I trial with Abelip and Interleukin-2 (II-2) in Amyotrophic Lateral Sclerosis (ALS) patients
The purpose of this study was to evaluate the effect of low dose abacavir, followed by IL-2 administration on ALS patients. In particular, this phase 1 study was aimed at determining subcutaneous IL-2 and AbelipWhether the combination therapy is safe and tolerating for ALS patientsGood sex, and whether the therapy can enhance Treg number and inhibit function in vivo.
6.6.1. Main objective
To assess the safety and tolerability of abatopiramate, followed by IL-2 administration in ALS patients, administration was performed according to the doses described in this protocol.
6.6.2. Secondary target
To study the immunomodulatory effects of abamectin, followed by IL-2 in ALS patients, pre-treatment, during treatment and post-treatment were compared: (a) the number of tregs; (b) the inhibitory activity of tregs on T effector proliferation; (c) Cytokine levels secreted by PBMCs throughout the study; and (d) disease progression as determined by ALS clinical outcome measurements, including the Appel ALS rating scale (AALS) and ALS function rating scale revision (ALSFRS-R) scores, as well as Forced Vital Capacity (FVC) and Maximum Inspiratory Pressure (MIP).
6.6.3. Study design
This is a phase I open-label, non-control study for assessing the safety of administration of abacavir, followed by subcutaneous IL-2 administration. In addition to assessing the safety and toxicity of low dose abacavir, followed by IL-2 administration in the treatment of ALS progression, the goal of this phase I study was to assess the extent of Treg population enhancement in subjects.
ALS patients received fixed low doses of abasic and IL-2 for a total of 4 months. In particular, patients received a fixed dose of subcutaneous abacavir (125 mg/mL) on day 1 of week 1. Two weeks later (day 1 of week 3), the patient received a second dose of subcutaneous abacavir (125 mg/mL). In addition, patients received subcutaneous IL-2 (1X 10 6 Units/day) for 5 days (days 2-5 of week 3). If this regimen is tolerable, the patient receives 6 additional courses of similar abasic and IL-2 every two weeks. The administration schedule is shown in table 12 below.
Table 12: albazedox/IL-2 administration schedule
6.6.4. Drug information
The recombinant human IL-2 used was PROLEUKIN (aldesleukin). The abacavir used is that of ORENCIA. See section 6.2.4 above.
6.6.5. Patient evaluation
6.6.5.1 before beginning treatment
The following pre-treatment evaluations were completed prior to the first injection of abamectin/IL-2: (a) a baseline medical history and physical examination; (b) vital signs, body weight; (c) pulse oximetry; (d) safety laboratory: whole blood count, PT/PTT, chemical analysis, liver function test, thyroid function test, quantiFERON; (e) a baseline ECG; and (f) research laboratory: immune biomarkers and Treg function and flow assays.
6.6.5.2 treatment period
The following data were obtained on the first day and every two weeks of receiving an infusion of abamectin/IL-2: vital signs, body weight, pulse oximetry.
The following laboratory tests were performed every two weeks during the treatment of abamectin/IL-2: whole blood cell count, chemical analysis, liver function test.
During the treatment period of abacavir/IL-2, the following laboratory tests were performed twice every two weeks (day 1 and day 8 of each treatment cycle): immune biomarkers: plasma, serum and messenger RNA.
The following laboratory tests were obtained on days 1, 8, 22, 50, 78 and 106 during the treatment of abamectin/IL-2: treg function and blood flow determination.
6.6.5.3 after treatment
Once the IL-2 treatment cycle is completed, the treated patients receive the following examinations at weeks 17 and 24: (a) physical examination; (b) vital signs, body weight and pulse oximetry; and (c) laboratory: whole blood count, chemical analysis, liver function test, thyroid function test, immune biomarkers, treg function and blood flow assays (week 24 only).
6.6.5.4 disease specificity evaluation
Measurements of disease progression were made at screening, baseline (week 1), and weeks 5, 9, 13, 17, and 24 of the trial, including the Appel ALS rating scale (AALS), ALS function rating scale revision (ALSFRS-R), forced Vital Capacity (FVC), and Mean Inspiratory Pressure (MIP).
6.6.5.5 immune reconstitution assay
Depending on the availability of patient samples and reagents, the immunophenotyping studies, including immunophenotyping and functional analysis, were performed continuously at the following time points before, during and after treatment.
If applicable, about 2-5 tablespoons (30-75 cc) of patient blood were collected at baseline visit and days 1 and 8, and then at weeks 17 and 24, for each treatment cycle (twice every two weeks) during treatment.
If the patient's hemoglobin is below 8.0g/dL at any evaluation time, the amount of blood drawn for evaluation will decrease and, if necessary, can be obtained by more than one venipuncture.
Management of hypotension, management of respiratory distress/dyspnea, management of infection, and improvement in treatment are as described in example 2 above.
6.6.6. Inclusion criteria for inclusion group
Subjects were eligible to participate in the initial group entry of the study if they met the following criteria:
(a) Informed consent is provided and use of Protected Health Information (PHI) is authorized in accordance with national and local patient privacy regulations.
(b) ALS meets the standard of El Escorial for possible, likely, laboratory supported possible or definitive ALS.
(c) At least 18 years old.
(d) Total bilirubin is less than or equal to 1.5mg/dL.
(e) Alanine Aminotransferase Level (ALT) was five times lower than normal and albumin was 3.0gm/dL higher.
(f) Serum creatinine is below 1.5mg/dL.
(g) All study procedures, including study drug delivery, can be followed.
(h) If the participants were unable to do so, the family member or caretaker should be always present and the abamectin and IL-2 study medication administered.
(i) A stable riluzole regimen was used at the time of screening for at least 30 days. If riluzole is not taken at the beginning of the study, it is desirable to avoid starting the dose during the trial.
(j) Patients taking edaravone (edaravone) were willing to take no edaravone on the same day that the abapple injection was received during the trial. If edaravone is not taken at the beginning of the study, it is desirable to avoid the use of the agent during the trial.
(k) Forced Vital Capacity (FVC) > 50% of age, height and gender predictive capacity at screening, or if FVC < 50% of age, height and gender predictive at screening, noninvasive ventilation therapy is received.
6.6.7. Exclusion criteria for group entry
The patient is not eligible to participate if any of the following is true at the time of screening:
(a) Severe, active bacterial, fungal or viral infections, active or latent tuberculosis.
(b) Tracheotomy.
(c) Severe cardiac dysfunction is defined as a left ventricular ejection fraction <40% if echocardiography is medically indicated to clarify persistent symptoms or EKG results; a history of uncontrolled arrhythmias; there is a history of cardiac tamponade; unstable angina or MI has been known for the past 3 months.
(d) Hypersensitivity or allergy to IL-2 or aba pup.
(e) There is a history of bowel ischemia/perforation, or a history of gastrointestinal bleeding requiring surgery.
(f) History of refractory seizures, history of coma, or history of toxic psychosis lasting >48 hours.
(g) Platelets <100,000/mm3; hematocrit <30%.
(h) There was a history of cancer (except basal cell carcinoma or squamous cell carcinoma of the skin) over the last 5 years.
(i) A history of immunosuppressive therapy including administration of IL-2 or abacavir was received over the past 90 days.
(j) Treatment with another study drug, biologic or device was performed within 30 days or 5 half-lives (whichever is longer) after screening.
(k) In the case of females, breast feeding, known pregnancy, scheduled pregnancy during the study, or unwilling to use effective contraceptive measures during the trial period and within 90 days after treatment.
(l) In the case of fertility men, effective contraceptive measures are not preferred during the trial period and within 90 days after treatment.
6.7 example 7: metaphase results of ongoing phase I trials with Abelip and Interleukin-2 (II-2) in Amyotrophic Lateral Sclerosis (ALS) patients
Phase I trial described in example 6 above involved abasic and IL-2 treatment for a total of 4 months. To date, subjects enrolled in the trial have received treatment for at least 3 weeks and the trial is in progress. In this example, the interim results (i.e., the results available so far as the trial is in progress) are provided by 4 ALS patients who are enrolled in the trial.
Table 13 below provides demographic data and baseline characteristics for the subjects in the group.
Table 13: demographic data and baseline characteristics of group-entered subjects
Figures 11-13 show Treg inhibition function (figure 11), cd4+cd25+foxp3+ Treg cell surface phenotype (figure 12) and cd8+ cell surface phenotype (figure 13) from each of these subjects. Immediately on day 1 after baseline measurement, abacavir alone was administered. In fig. 11 to 13, "week 1" refers to measurements taken one week after administration of only abacavir. As described above, the abamectin/IL-2 combination therapy starts two weeks after the administration of abamectin alone and thereafter continues once every two weeks during the course of the therapy. In fig. 11 to 13, "week 3" refers to the measurement taken one week after the first administration of abamectin/IL-2, and "week 7" refers to the measurement taken one week after the third administration of abamectin/IL-2.
Figure 11 shows Treg inhibition function in tregs of each subject. As shown, an improvement in Treg inhibition function was observed for each subject relative to the respective baseline value following the introduction of dual abacavir/IL-2 administration.
The percentage of cells expressing the cd4+cd25+foxp3+ Treg phenotype in the subjects is shown in figure 12. As shown, the percentage of cells that exhibited this Treg phenotype in each of the four subjects increased relative to baseline as the treatment regimen progressed.
The percentage of tregs expressing cd8+ cytotoxicity and pro-inflammatory phenotype is shown in figure 13. As shown, by week 3 (i.e., one week after the first abacavir/IL-2 administration), the percentage of cells that exhibited such a phenotype in each of the four subjects remained stable or improved (decreased) relative to baseline. Interestingly, an improvement (decrease) in the percentage of cd8+ cells was observed in two subjects (subjects 2 and 4) at week 7 of the treatment regimen (one week after the third abamectin/IL-2 administration).
Disease progression was monitored by ALSFRS-R score of 4 subjects receiving abamectin/IL-2 treatment (fig. 14). ALSFRS-R is a widely accepted and validated measure of the activity restriction outcome of ALS patients. It includes 12 items, with scores ranging from 0 to 4 (4=normal function; 0=complete loss of function). These 12 items fall into 4 areas: bulbar, fine exercise, coarse exercise, and respiration. Each drop-off point of ALSFRS-R represents a loss of ability to perform basic activities of daily living. Thus, ALS progression is reflected in the decrease in ALSFRS-R score over time.
As shown in fig. 14, each subject progressed at a different rate ("pretreatment (screening)") prior to study participation. After group entry, ALSFRS-R was measured at baseline (i.e., prior to administration of the abamectin dose alone) and then once every 4 weeks ("week 4" and "week 8") during the study. Overall, disease progression as assessed by ALSFRS-R score was stable in four subjects since the initiation of abamectin/IL-2 treatment, as shown in fig. 14.
Disease progression was monitored by Maximum Inspiratory Pressure (MIP) of 4 subjects receiving abamectin/IL-2 treatment (fig. 14). Maximum Inspiratory Pressure (MIP) is a measure of inspiratory muscle (mainly diaphragm) strength and can be used to assess ventilatory failure, restrictive lung disease and respiratory muscle strength. The reduction of MIPs has been associated with worsening of clinical progression in patients with various diseases, including ALS. Fig. 15 shows MIP values before and after the start of treatment with IL-2 and abacavir for 4 subjects who entered the group I phase trial. Overall, disease progression assessed by MIP in four subjects was stable since the initiation of abamectin/IL-2 treatment, as shown in figure 15.
All publications, patents, and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference.
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 of ordinary skill in the art in light of the teachings of this invention that changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.
The scope of the invention is not limited by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description and accompanying drawings. Such modifications are intended to fall within the scope of the appended claims.
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Claims (151)

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 the method reduces one or more symptoms associated with a neurodegenerative or neuroinflammatory disease or disorder in the subject being treated.
2. The method of claim 1, wherein the CTLA-4-containing protein comprises a human CTLA-4 extracellular domain.
3. The method of claim 1 or 2, wherein the CTLA-4-containing protein is a fusion protein.
4. The method of claim 3, wherein the fusion protein comprises a human CTLA-4 extracellular domain and a human immunoglobulin Fc domain.
5. The method of claim 4, wherein the Fc domain is a modified Fc domain comprising an immunoglobulin hinge region, a CH2 region, and a CH 3.
6. The method of claim 4 or 5, wherein the human immunoglobulin Fc domain is a human IgG1 Fc domain.
7. The method of any one of claims 1-6, wherein the CTLA-4-containing protein is glycosylated.
8. The method of any one of claims 1-7, wherein the CTLA-4-containing protein comprises the following amino acid sequence monomers:
MHVAQPAVVLASSRGIASFVCEYASPGKATEVRVTVLRQADSQVTEVCAATYMMGNELTFLDDSICTGTSSGNQVNLTIQGLRAMDTGLYICKVELMYPPPYYLGIGNGTQIYVIDPEPCPDSDQEPKSSDKTHTSPPSPAPELLGGSSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:1)。
9. the method of claim 8, wherein the CTLA-4-containing protein comprises a homodimer of two monomers, each monomer comprising the amino acid sequence of SEQ ID No. 1.
10. The method of claim 1, wherein the CTLA-4-containing protein is abacavir.
11. The method of any one of claims 1-10, wherein the IL-2 protein is a human IL-2 protein.
12. The method of claim 11, wherein the human IL-2 protein comprises serine at an amino acid position corresponding to naturally occurring mature human IL-2 amino acid residue 125.
13. The method of claim 11 or 12, wherein the human IL-2 protein lacks an N-terminal alanine amino acid.
14. The method of any one of claims 11-13, wherein the human IL-2 protein comprises the amino acid sequence:
PTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFK FYMPKKATELKHLQLEEELKPLEEVLNLAQSKNFHLRPRDLISNIN VIVLELKGSETTFMCEYADETATIVEFLNRWITFSQSIISTLT(SEQ ID NO:3)。
15. the method of any one of claims 1-14, wherein the IL-2 protein is not glycosylated.
16. The method of claim 11, wherein the IL-2 protein is an aldesleukin.
17. A method of treating a neurodegenerative or neuroinflammatory disease or disorder in a subject in need thereof, comprising administering to the subject:
i) Abacavir; and
ii) aldesleukin;
wherein the method reduces one or more symptoms associated with a neurodegenerative or neuroinflammatory disease or disorder in the subject being treated.
18. The method of claim 17, wherein the abacavir is administered by injection or infusion.
19. The method of claim 18, wherein the abamectin is administered subcutaneously.
20. The method of claim 18, wherein the abacavir is administered intravenously.
21. The method of claim 17, wherein the aldesleukin is administered by injection or infusion.
22. The method of claim 21, wherein the aldesleukin is administered subcutaneously.
23. The method of claim 21, wherein the aldesleukin is administered intravenously.
24. The method of claim 17, wherein the abacavir and the aldesleukin are administered subcutaneously.
25. The method of claim 17, wherein the abacavir and the aldesleukin are administered intravenously.
26. The method of any one of claims 17-25, wherein the abacavir is administered once every two weeks.
27. The method of claim 26, wherein the abacavir is administered subcutaneously once every two weeks.
28. The method of claim 26 or 27, wherein the abacavir is administered once every two weeks for 15 weeks.
29. The method of any one of claims 17-28, wherein the aldesleukin is administered once daily for three consecutive days.
30. The method of claim 29, wherein the aldesleukin is administered subcutaneously once daily for three consecutive days.
31. The method of any one of claims 17-25, wherein:
a) Administering said abacavir once every two weeks; and is also provided with
b) The aldehydic interleukin is administered once daily for three consecutive days, starting on the day of administration of the abacavir.
32. The method of claim 31, wherein the abacavir and the aldesleukin are administered subcutaneously.
33. The method of any one of claims 17-25, wherein:
a) Administering said abacavir once every two weeks for fifteen weeks;
b) The administration of aldesleukin starting from the third week; and is also provided with
c) Once the administration of the aldesleukin is started, the aldesleukin is administered once daily for three consecutive days starting from the day of administration of the abacavir.
34. The method of claim 33, wherein the abacavir and the aldesleukin are administered subcutaneously.
35. The method of any one of claims 17-34, wherein the abacavir is administered in an amount ranging from 50mg to 125 mg.
36. The method of claim 35, wherein the abacavir is administered in an amount of 50 mg.
37. The method of claim 36, wherein the abacavir is administered subcutaneously in a volume of 0.4 mL.
38. The method of claim 35, wherein the abacavir is administered in an amount of 87.5 mg.
39. The method of claim 38, wherein the abacavir is administered subcutaneously in a volume of 0.7 mL.
40. The method of claim 35, wherein the abacavir is administered in an amount of 125 mg.
41. The method of claim 40, wherein the abacavir is administered subcutaneously in a volume of 1.0 mL.
42. The method of any one of claims 17-41, wherein the aldesleukin is administered in an amount in the range of 500,000 units to 3,000,000 units.
43. The method of claim 42, wherein the aldesleukin is administered in an amount in the range of 500,000 units to 2,000,000 units.
44. The method of claim 43, wherein the aldesleukin is administered in an amount of 1,000,000 units.
45. The method of any one of claims 42-44, wherein the aldesleukin is administered subcutaneously.
46. A method of treating a neurodegenerative or neuroinflammatory disease or disorder in a subject in need thereof, comprising starting on day 1 and comprising administering to the subject a dosing cycle comprising a formulation of:
i) Abacavir; and
ii) aldesleukin;
wherein the method reduces one or more symptoms associated with a neurodegenerative or neuroinflammatory disease or disorder in the subject being treated.
47. The method of claim 46, wherein the formulation is administered by injection or infusion.
48. The method of claim 46, wherein the formulation is administered subcutaneously.
49. The method of claim 46, wherein the formulation is administered intravenously.
50. The method of any one of claims 46-49, wherein the dosing cycle comprises administering the formulation to the subject 1-10 times.
51. The method of any one of claims 46-49, wherein the dosing cycle comprises a single administration of the formulation to the subject on day 1 of the dosing cycle.
52. The method of any one of claims 46-49, wherein the dosing cycle comprises administering the formulation to the subject daily for two consecutive days starting on day 1 of the dosing cycle.
53. The method of any one of claims 46-49, wherein the dosing cycle comprises administering the formulation to the subject daily for three consecutive days starting on day 1 of the dosing cycle.
54. The method of any one of claims 46-49, wherein the dosing cycle comprises administering the formulation to the subject daily for four consecutive days starting on day 1 of the dosing cycle.
55. The method of any one of claims 46-49, wherein the dosing cycle comprises administering the formulation to the subject daily for five consecutive days starting on day 1 of the dosing cycle.
56. The method of any one of claims 46-55, wherein the dosing cycle is repeated 1-12 times.
57. The method of any one of claims 46-55, wherein the dosing cycle is repeated 6 times.
58. The method of claim 56 or 57, wherein each repeated dosing cycle begins 10-28 days after day 1 of the previous dosing cycle.
59. The method of any one of claims 56-58, wherein each repeated dosing cycle begins 14 days after day 1 of the previous dosing cycle.
60. The method of any one of claims 46-49, wherein a first dosing cycle comprises administering the formulation to the subject three days a day, starting on day 1 of the dosing cycle, and the first dosing cycle is repeated 6 times, wherein each repeated dosing cycle starts 14 days after day 1 of the previous dosing cycle.
61. The method of any one of claims 46-49, wherein the dosing cycle comprises administering to the subject a formulation comprising about 5mg to about 125mg abamectin and about 3x10 4 Up to about 3x10 7 Units of aldesleukin.
62. The method of any one of claims 46-49, wherein the dosing cycle comprises administering to the subject a formulation comprising about 8.75mg to about 87.5mg abasic and about 3x10 4 Up to about 3x10 7 Units of aldesleukin.
63. The method of any one of claims 46-49, wherein the dosing cycle comprises administering to the subject a formulation comprising about 29.17mg abamectin and about 1x10 5 Units of aldesleukin.
64. The method of any one of claims 46-49, wherein the dosing cycle comprises administering to the subject a formulation comprising about 29.17mg abamectin and about 1x10 6 Units of aldesleukin.
65. The method of any one of claims 46-49, wherein the dosing cycle comprises administering to the subject a formulation comprising about 29.17mg abamectin and about 1x10 7 Units of aldesleukin.
66. The method of any one of claims 46-49, wherein the dosing cycle comprises administering to the subject a formulation comprising about 5mg to about 50mg abamectin and about 3x10 4 Up to about 3x10 7 Units of aldesleukin.
67. The method of any one of claims 46-49, wherein the dosing cycle comprises administering to the subject a formulation comprising about 16.67mg of abasic and about 1x10 5 Units of aldesleukin.
68. The method of any one of claims 46-49, wherein the dosing cycle comprises administering to the subject a formulation comprising about 16.67mg of abasic and about 1x10 6 Units of aldesleukin.
69. The method of any one of claims 46-49, wherein the dosing cycle comprises administering to the subject a formulation comprising about 16.67mg of abasic and about 1x10 7 Units of aldesleukin.
70. The method of any one of claims 46-49, wherein the dosing cycle comprises administering to the subject a formulation comprising about 12.5mg to about 125mg abamectin and about 3x10 4 Up to about 3x10 7 Units of aldesleukin.
71. The method of any one of claims 46-49, wherein the dosing cycle comprises administering to the subject a formulation comprising about 41.67mg abamectin and about 1x10 5 Unit (B)Is an aldesleukin of (a).
72. The method of any one of claims 46-49, wherein the dosing cycle comprises administering to the subject a formulation comprising about 41.67mg abamectin and about 1x10 6 Units of aldesleukin.
73. The method of any one of claims 46-49, wherein the dosing cycle comprises administering to the subject a formulation comprising about 41.67mg abamectin and about 1x10 7 Units of aldesleukin.
74. The method of any one of claims 46-49, wherein the dosing cycle comprises daily administration of the formulation to the subject for three consecutive days starting on day 1 of the dosing cycle, wherein the formulation comprises about 29.17mg of abamectin and about 1x10 6 Units of aldesleukin.
75. The method of any one of claims 46-49, wherein a total of 50mg of abacavir and 3x10 are administered to the subject per dosing cycle 5 Units of aldesleukin.
76. The method of claim 75, wherein the dosing cycle comprises 1-10 administrations of an abasic/aldesleukin formulation as shown in table 1A.
77. The method of any one of claims 46-49, wherein a total of 50mg of abacavir and 3x10 are administered to the subject per dosing cycle 6 Units of aldesleukin.
78. The method of claim 77, wherein the dosing cycle comprises 1-10 administrations of an abamectin/aldesleukin formulation as shown in table 1B.
79. Any one of claims 46-49The method wherein a total of 50mg of abacavir and 3x10 are administered to the subject per dosing cycle 7 Units of aldesleukin.
80. The method of claim 79, wherein the dosing cycle comprises 1-10 administrations of an abasic/aldesleukin formulation as shown in table 1C.
81. The method of any one of claims 46-49, wherein a total of 87.5mg of abacavir and 3x10 are administered to the subject per dosing cycle 5 Units of aldesleukin.
82. The method of claim 81, wherein the dosing cycle comprises 1-10 administrations of an abasic/aldesleukin formulation as shown in table 2A.
83. The method of any one of claims 46-49, wherein a total of 87.5mg of abacavir and 3x10 are administered to the subject per dosing cycle 6 Units of aldesleukin.
84. The method of claim 83, wherein the dosing cycle comprises 1-10 administrations of an abamectin/aldesleukin formulation as shown in table 2B.
85. The method of any one of claims 46-49, wherein a total of 87.5mg of abacavir and 3x10 are administered to the subject per dosing cycle 7 Units of aldesleukin.
86. The method of claim 85, wherein the dosing cycle comprises 1-10 administrations of an abasic/aldesleukin formulation as shown in table 2C.
87. The method of any one of claims 46-49, wherein a total of 125mg of abacavir and 3x10 are administered to the subject per dosing cycle 5 Unit (B)Is an aldesleukin of (a).
88. The method of claim 87, wherein the dosing cycle comprises 1-10 administrations of an abasic/aldesleukin formulation as shown in table 3A.
89. The method of any one of claims 46-49, wherein a total of 125mg of abacavir and 3x10 are administered to the subject per dosing cycle 6 Units of aldesleukin.
90. The method of claim 89, wherein the dosing cycle comprises 1-10 administrations of an abasic/aldesleukin formulation as shown in table 3B.
91. The method of any one of claims 46-49, wherein a total of 125mg of abacavir and 3x10 are administered to the subject per dosing cycle 7 Units of aldesleukin.
92. The method of claim 91, wherein the dosing cycle comprises 1-10 administrations of an abasic/aldesleukin formulation as shown in table 3C.
93. The method of any one of claims 46-92, wherein the dosing cycle is repeated 6 times, wherein each repeated dosing cycle begins 14 days after day 1 of the previous dosing cycle.
94. The method of any one of claims 46-92, wherein the formulation is administered by injection or infusion.
95. The method of any one of claims 46-92, wherein the formulation is administered subcutaneously.
96. The method of any one of claims 46-92, wherein the formulation is administered intravenously.
97. The method of any one of claims 46-96, further comprising administering to the subject an abacavir formulation 14 days before day 1 of the first dosing cycle, wherein the abacavir formulation comprises abamectin.
98. The method of claim 97, wherein the abacavir formulation comprises 50mg to 125mg of abacavir.
99. The method of claim 97, wherein the abacavir formulation comprises 87.5mg of abamectin.
100. The method of any one of claims 97-99, wherein the abacavir formulation is administered by injection or infusion.
101. The method of any one of claims 97-99, wherein the abacavir formulation is administered subcutaneously.
102. The method of any one of claims 97-99, wherein the abacavir formulation is administered intravenously.
103. The method of any one of claims 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.
104. The method of claim 103, wherein the neurodegenerative disease or disorder is alzheimer's disease.
105. The method of any one of claims 1-104, wherein the neuroinflammatory disease or disorder is associated with: stroke, acute disseminated encephalomyelitis, acute optic neuritis, acute inflammatory demyelinating polyneuropathy, chronic inflammatory demyelinating polyneuropathy, guillain-barre syndrome, transverse myelitis, optic neuromyelitis, epilepsy, traumatic brain injury, spinal cord injury, encephalitis, central nervous system vasculitis, sarcoidosis, autoimmune or post-infection encephalitis, or chronic meningitis.
106. The method of any one of claims 1-105, wherein the method further comprises performing additional therapeutic interventions including cognitive rehabilitation procedures, neurostimulation techniques, or combinations thereof.
107. The method of claim 106, wherein the cognitive rehabilitation program is a computer-implemented cognitive rehabilitation program.
108. The method of claim 105 or 106, wherein the neural stimulation technique is an Invasive Brain Stimulation (IBS) technique.
109. The method of claim 105 or 106, wherein the neural stimulation technique is a non-invasive brain stimulation (NIBS) technique.
110. The method of claim 108, wherein the IBS technique is selected from the group consisting of: deep Brain Stimulation (DBS) and invasive Vagal Nerve Stimulation (VNS).
111. The method of claim 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 (tcacs), electroconvulsive therapy (ECT), magnetic epileptic therapy (MST), craniocerebral Electrical Stimulation (CES), and non-invasive VNS.
112. A kit comprising i) one or more doses of a formulation comprising 50 to 125mg of albazedox, and ii) one or more doses of a formulation comprising 500,000 to 3,000,000 units of albazedox, in separate containers.
113. The kit of claim 112, wherein the kit comprises one or more doses of a formulation comprising 50mg of abacavir.
114. The kit of claim 112, wherein the kit comprises one or more doses of a formulation comprising 87.5mg of abacavir.
115. The kit of claim 112, wherein the kit comprises one or more doses of a formulation comprising 125mg of abacavir.
116. The kit of any one of claims 112-115, wherein the kit comprises one or more doses of a formulation comprising 500,000 to 2,000,000 units of aldesleukin.
117. The kit of any one of claims 112-116, wherein the kit comprises one or more doses of a formulation comprising 1,000,000 units of aldesleukin.
118. The kit of any one of claims 112-117, wherein the one or more doses of abacavir are present in lyophilized form.
119. The kit of claim 118, wherein the one or more doses of abacavir are in the form of a lyophilized powder or a lyophilized cake.
120. The kit of any one of claims 112-119, wherein the one or more doses of aldesleukin are present in lyophilized form.
121. The kit of claim 120, wherein the one or more doses of aldesleukin are present in the form of a lyophilized powder or a lyophilized cake.
122. The kit of any one of claims 112-121, wherein the formulation of one or more doses of abacavir is suitable for subcutaneous administration.
123. The kit of any one of claims 112-121, wherein the formulation of one or more doses of abacavir is suitable for intravenous administration.
124. The kit of any one of claims 112-123, wherein the formulation of one or more doses of aldesleukin is suitable for subcutaneous administration.
125. The kit of any one of claims 112-123, wherein the formulation of one or more doses of aldesleukin is suitable for intravenous administration.
126. A pharmaceutical composition comprising one or more abasic pro/aldesleukin doses.
127. The pharmaceutical composition of claim 126, wherein the dose of abasic prine/aldesleukin comprises 5mg to 125mg of abasic prine and 3x10 4 Up to 3x10 7 Units of aldesleukin.
128. The pharmaceutical composition of claim 126, wherein the dose of abasic prine/aldesleukin comprises 8.75mg to about 87.5mg of abasic prine and 3x10 4 Up to 3x10 7 Units of aldesleukin.
129. The pharmaceutical composition of claim 126, wherein the dose of abamectin/aldesleukin comprises about 29.17mg abamectin and about 1x10 5 Units of aldesleukin.
130. The pharmaceutical composition of claim 126, wherein the dose of abamectin/aldesleukin comprises about 29.17mg abamectin and about 1x10 6 Units of aldesleukin.
131. The pharmaceutical composition of claim 126, wherein the dose of abamectin/aldesleukin comprises about 29.17mg abamectin and about 1x10 7 Units of aldesleukin.
132. The pharmaceutical composition of claim 126, wherein the dose of abamectin/aldesleukin comprises about 5mg to about 50mg abamectin and about 3x10 4 Up to about 3x10 7 Units of aldesleukin.
133. The pharmaceutical composition of claim 126, wherein the dose of abamectin/aldesleukin comprises about 16.67mg abamectin and about 1x10 5 Units of aldesleukin.
134. The pharmaceutical composition of claim 126, wherein the dose of abamectin/aldesleukin comprises about 16.67mg abamectin and about 1x10 6 Units of aldesleukin.
135. The pharmaceutical composition of claim 126, wherein the dose of abamectin/aldesleukin comprises about 16.67mg abamectin and about 1x10 7 Units of aldesleukin.
136. The pharmaceutical composition of claim 126, wherein the dose of abamectin/aldesleukin comprises about 12.5mg to about 125mg abamectin and about 3x10 4 Up to about 3x10 7 Units of aldesleukin.
137. The pharmaceutical composition of claim 126, wherein the dose of abamectin/aldesleukin comprises about 41.67mg abamectin and about 1x10 5 Units of aldesleukin.
138. The pharmaceutical composition of claim 126, wherein the dose of abamectin/aldesleukin comprises about 41.67mg abamectin and about 1x10 6 Units of aldesleukin.
139. The pharmaceutical composition of claim 126, wherein the dose of abamectin/aldesleukin comprises about 41.67mg abamectin and about 1x10 7 Units of aldesleukin.
140. The pharmaceutical composition of claim 126, wherein the pharmaceutical composition comprises one or more of the abasic/aldesleukin doses as shown in table 4.
141. The pharmaceutical composition of any one of claims 126-140, wherein the pharmaceutical composition is in lyophilized form.
142. The pharmaceutical composition of claim 141, wherein the pharmaceutical composition is in the form of a lyophilized powder or a lyophilized cake.
143. The pharmaceutical composition of any one of claims 126-140, wherein the pharmaceutical composition is a solution.
144. The pharmaceutical composition of claim 143, wherein the pharmaceutical composition is in the form of an aqueous solution.
145. The pharmaceutical composition of claim 143 or 144, wherein the one or more abasic/aldesleukin doses are present at a concentration of 1 abasic/aldesleukin dose per 0.4 ml.
146. The pharmaceutical composition of claim 143 or 144, wherein the one or more abasic/aldesleukin doses are present at a concentration of 1 abasic/aldesleukin dose per 0.7 ml.
147. The pharmaceutical composition of claim 143 or 144, wherein the one or more abasic/aldesleukin doses are present at a concentration of 1 abasic/aldesleukin dose/1.0 ml.
148. The pharmaceutical composition of claim 143 or 144, wherein the one or more abasic/aldesleukin doses are present at a concentration of 1 abasic/aldesleukin dose/1.5 ml.
149. The pharmaceutical composition of claim 143 or 144, wherein the one or more abasic/aldesleukin doses are present at a concentration of 1 abasic/aldesleukin dose/2.0 ml.
150. The pharmaceutical composition of any one of claims 126-149, wherein the pharmaceutical composition is suitable for subcutaneous administration.
151. The pharmaceutical composition of any one of claims 126-149, wherein the pharmaceutical composition is suitable for intravenous administration.
CN202280034612.5A 2021-03-11 2022-03-10 Methods and compositions for treating diseases Pending CN117337189A (en)

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US63/310,839 2022-02-16
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