Methods of treating inflammatory or autoimmune disorders with compounds that bind macrophage migration inhibitory factor
Inventors
Vandenbark, Arthur A. • Benedek, Gil • Meza-Romero, Roberto
Assignees
Oregon Health and Science University • US Department of Veterans Affairs
Publication Number
US-10525101-B2
Publication Date
2020-01-07
Expiration Date
2036-10-21
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Abstract
Recombinant polypeptides, pharmaceutical compositions comprising recombinant polypeptides, and methods of treating autoimmune and/or inflammatory diseases using the pharmaceutical compositions are disclosed. The polypeptides are based upon the trimerization and/or MIF binding domains of CD74.
Core Innovation
The invention provides recombinant polypeptides based on the trimerization and/or macrophage migration inhibitory factor (MIF) binding domains of CD74, compositions comprising these polypeptides, and methods of treating autoimmune and inflammatory disorders by administering these compositions. These polypeptides compete with recombinant T cell receptor ligands and partial MHC molecules for binding to the CD74 ligand MIF, potentially blocking MIF binding and downstream signaling.
The problem addressed is the need for therapeutic agents that inhibit MIF binding to CD74 to modulate inflammatory or autoimmune diseases, such as multiple sclerosis (MS) and its murine model experimental autoimmune encephalomyelitis (EAE). Elevated MIF is implicated in the progression and severity of these diseases. The prior therapeutic agents like RTL1000 require HLA subtyping for efficacy, presenting a challenge for broad application.
The disclosed polypeptides focus on alpha-helical regions of the CD74 trimerization domain, particularly the first and second alpha helices, which synergistically bind to human MIF and compete effectively against full-length CD74 and related therapeutic constructs. These peptides block binding of CD74 to MIF and to recombinant ligands such as RTL1000 or DRα1-mMOG-35-55. The invention also explores compositions comprising these peptides alone or covalently linked with linkers, along with pharmaceutical compositions including these polypeptides for treating inflammation and autoimmune diseases.
Claims Coverage
The patent contains two independent claims directed to methods of treating autoimmune disorders with compositions comprising polypeptides derived from CD74 sequences and their formulations.
Method of treating autoimmune disorders with a two-polypeptide composition
Administering to a subject an effective amount of a composition comprising a first polypeptide having the sequence of SEQ ID NO: 7 (17-25 amino acids long) and a second polypeptide having the sequence of SEQ ID NO: 9 (10-20 amino acids long) to treat an autoimmune disorder comprising an inflammatory component.
Method of treating autoimmune disorders with a single polypeptide composition
Administering to a subject an effective amount of a composition comprising a polypeptide selected from SEQ ID NO: 17, SEQ ID NO: 18, or SEQ ID NO: 19 to treat an autoimmune disorder comprising an inflammatory component.
The independent claims focus on methods of treating autoimmune disorders using compositions that include defined CD74-derived polypeptides or constructs formed by linking these polypeptides, administered in effective amounts and optionally formulated for various administration routes, highlighting the therapeutic use of these compounds to modulate MIF binding.
Stated Advantages
The polypeptides provide similar effects to prior recombinant T cell receptor ligands without requiring HLA subtyping.
The combination of alpha-helix 1 and alpha-helix 2 peptides shows synergistic binding to human MIF, resulting in more potent inhibition of CD74 binding than either peptide alone.
Documented Applications
Treatment of inflammatory or autoimmune disorders comprising an inflammatory component, including multiple sclerosis, rheumatoid arthritis, and autoimmune uveitis.
Pharmaceutical formulations suitable for subcutaneous, intravenous, or intraocular administration.
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