Recombinant polypeptides comprising modified MHC class II DRa1 domains and methods of use
Inventors
Meza-Romero, Roberto • Vandenbark, Arthur A. • Offner, Halina
Assignees
Oregon Health and Science University • US Department of Veterans Affairs
Publication Number
US-11945855-B2
Publication Date
2024-04-02
Expiration Date
2039-10-04
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
Recombinant polypeptides comprising a modified DRα1 domain are provided. In some embodiments, the polypeptides include the modified DRα1 domain, an antigenic peptide, and optionally a linker sequence. Pharmaceutical compositions comprising the recombinant polypeptides, methods of treating inflammatory disease using said recombinant polypeptides or pharmaceutical compositions, and expression constructs comprising nucleic acids that encode the recombinant polypeptides are also provided.
Core Innovation
The invention provides recombinant polypeptides comprising a modified major histocompatibility complex (MHC) class II DRα1 domain in which a native leucine residue at amino acid position 14 of SEQ ID NO: 1 is substituted with a glutamine residue (L14Q mutation). Some polypeptides include the modified DRα1 domain linked to an antigenic peptide, such as myelin oligodendrocyte glycoprotein (MOG)-35-55, optionally with a linker sequence. The polypeptides exhibit altered affinity for CD74 and compete with macrophage migration inhibitory factor (MIF) for binding to CD74 without affecting the molecule's structure.
The problem addressed is the need for improved therapies for inflammatory diseases such as multiple sclerosis (MS), a chronic inflammatory autoimmune disorder characterized by demyelination and neurodegeneration. Existing disease-modifying treatments for MS are numerous but insufficient, and there remains a continuous demand for more effective therapeutic agents. The disclosed recombinant polypeptides aim to provide improved therapeutic effects by targeting CD74, the receptor for MIF, thereby modulating inflammatory signaling pathways involved in MS and related disorders.
Claims Coverage
The patent includes multiple independent claims covering recombinant polypeptides, nucleic acids, expression constructs, cell lines, pharmaceutical compositions, and methods of treatment, focusing on key inventive features related to the modified DRα1 domain and compositions thereof.
Recombinant polypeptide with a modified DRα1 domain
A recombinant polypeptide comprising an MHC class II DRα1 domain that includes a glutamine residue substituting a leucine at the position corresponding to amino acid 14 of SEQ ID NO: 1.
Recombinant polypeptide including an antigenic peptide and an optional linker
Recombinant polypeptides comprising the modified DRα1 domain covalently linked to an antigenic peptide such as human or mouse MOG-35-55, optionally including a linker with features such as first and second glycine-serine spacers and a thrombin cleavage site.
Nucleic acids and expression constructs encoding the modified polypeptides
Nucleic acid molecules encoding the recombinant polypeptides with the modified DRα1 domain, including sequences corresponding to SEQ ID NOs: 4-6, incorporated within expression constructs and cell lines for polypeptide production.
Pharmaceutical compositions comprising the modified recombinant polypeptides or nucleic acids
Pharmaceutical compositions containing an effective amount of the recombinant polypeptides or nucleic acid molecules with a pharmaceutically acceptable carrier, including compositions with at least 5 mg/kg of the recombinant polypeptide.
Methods of treating inflammatory disorders with the recombinant polypeptides or compositions
Administering an effective amount of the pharmaceutical composition containing the recombinant polypeptides with the modified DRα1 domain to a subject suffering from inflammatory disorders, specifically multiple sclerosis or experimental autoimmune encephalopathy (EAE).
The claims comprehensively cover the modified DRα1 domain polypeptides, their nucleic acid encoding sequences, recombinant expression systems, pharmaceutical formulations, and their therapeutic methods for treating inflammatory diseases such as MS by targeting the CD74 receptor with enhanced binding properties.
Stated Advantages
The modified DRα1 polypeptides exhibit an 8- to 10-fold increased affinity for CD74 compared to the native polypeptides, enhancing their competitive inhibition of MIF binding to CD74.
The L14Q mutation does not alter the overall structure or immunological recognition of the polypeptide but improves therapeutic efficacy, as demonstrated by increased potency in treating experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis.
Treatment with the modified polypeptides reduces phosphorylation levels of ERK1/2 in splenocytes, indicating downregulation of inflammatory signaling pathways associated with MS.
Documented Applications
Treatment of inflammatory disorders, specifically multiple sclerosis (MS) and its mouse model, experimental autoimmune encephalopathy (EAE).
Therapeutic administration to subjects suffering from autoimmune and inflammatory diseases mediated by MIF and CD74.
Interested in licensing this patent?