Long acting TRAIL receptor agonists for treatment of autoimmune diseases
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Publication Number
US-11299528-B2
Publication Date
2022-04-12
Expiration Date
Abstract
Methods of treating an autoimmune disease such as rheumatoid arthritis, methods of increasing apoptosis of pro-inflammatory immune cells or synoviocytes, methods of increasing the quantity of the anti-inflammatory regulatory T cells, and methods of slowing the progression of inflammation in a subject include systemically administering to the subject a pharmaceutical composition including an effective amount of a TRAIL-conjugate. Preferably, the TRAIL-conjugate is effective for at least 3 days, more preferably at least 7 days, without being part of a nanocomplex that modulates the circulation half-life or release kinetics of the TRAIL-conjugate. Combination therapies including administering a second active agent, most preferably a TNF-α inhibitor, as well as pharmaceutical composition dosage units including a TRAIL-conjugate and a TNF-α inhibitor in an effective amount for a single once weekly dose for treatment of rheumatoid arthritis are also provided.
Core Innovation
The invention provides long-acting tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor agonist therapies for autoimmune diseases, including rheumatoid arthritis. A TRAIL conjugate is systemically administered to a subject with rheumatoid arthritis to induce apoptosis of pro-inflammatory immune cells and synoviocytes.
In particular, PEGylated TRAIL conjugates are used to increase the quantity of anti-inflammatory Foxp3+ regulatory T cells (Treg). The TRAIL conjugate comprises a TRAIL polypeptide fused to a multimerization domain that allows trimerization, and the fusion polypeptide is conjugated to polyethylene glycol (PEG) or a derivative of PEG having a specified molecular weight range.
The disclosure further states that the approach reduces joint inflammation markers and autoantibodies in collagen-induced arthritis (CIA). It also includes combination therapy concepts with TNF-α inhibitors, where a TRAIL conjugate regimen is paired with a TNF-α-reducing agent such as adalimumab, with improved mechanistic and efficacy outcomes described in vitro and in vivo.
Claims Coverage
The partial document contains one independent claim, directed to a method of treating rheumatoid arthritis with a specific long-acting PEGylated TRAIL conjugate formulation and defined systemic injection schedules. The claim includes inventive features regarding the TRAIL fusion architecture, trimerizing multimerization domain, PEGylation with a molecular weight range, the targeted biological effects, and specific administration regimens and dosage range.
Systemic administration schedule for rheumatoid arthritis treatment
Systemically administering a tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) conjugate to a subject with rheumatoid arthritis by injection twice a week, once a week, once every two weeks, or about once every 28 days.
Dose-effective induction of apoptosis and Foxp3+ Treg increase
Administering an amount between 1 mg/kg and 100 mg/kg effective to increase apoptosis of pro-inflammatory immune cells and increase the quantity of anti-inflammatory Foxp3+ regulatory T cells (Treg).
TRAIL polypeptide fused to trimerizing multimerization domain and PEGylation
Formulating the TRAIL-conjugate as a TRAIL polypeptide comprising amino acids 114-281 of SEQ ID NO:1 fused to a multimerization domain that allows trimerization, wherein the fusion polypeptide is conjugated to polyethylene glycol (PEG) or a derivative of PEG having a molecular weight between 5,000 and 60,000 Da.
Across the independent claim, the core claimed inventive concept is a long-acting PEGylated TRAIL conjugate for rheumatoid arthritis in which a TRAIL polypeptide is fused to a trimerizing multimerization domain and PEGylated with a specified PEG molecular weight range. The method uses specified systemic injection intervals and a defined effective dose to increase apoptosis of pro-inflammatory immune cells and increase Foxp3+ regulatory T cells (Treg).
Stated Advantages
Induces apoptosis of pro-inflammatory immune cells.
Increases the quantity of anti-inflammatory Foxp3+ regulatory T cells (Treg).
Reduces joint inflammation markers and autoantibodies in collagen-induced arthritis (CIA).
Exhibits improved effects in combination with adalimumab.
Documented Applications
Treatment of rheumatoid arthritis by systemically administering a TRAIL conjugate.
Treatment of autoimmune disease contexts described as including rheumatoid arthritis, with long-acting TRAIL receptor agonist therapy.
Use in collagen-induced arthritis (CIA) to reduce joint inflammation markers and autoantibodies.
Combination therapy application with TNF-α inhibitors, including adalimumab.
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