Recombinant polypeptides comprising MHC class II α1 domains
Inventors
Vandenbark, Arthur A. • Meza-Romero, Roberto • Benedek, Gil • Burrows, Gregory G.
Assignees
Oregon Health and Science University • US Department of Veterans Affairs
Publication Number
US-10316075-B2
Publication Date
2019-06-11
Expiration Date
2034-10-03
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Abstract
Recombinant polypeptides comprising a DRα1 domain, an antigenic peptide, and a linker sequence are disclosed. The linker sequence comprises a first glycine-serine spacer, a thrombin cleavage site and a second glycine-serine spacer. Further disclosed are pharmaceutical compositions comprising the recombinant polypeptides, methods of treating inflammatory disease using said pharmaceutical compositions, and expression constructs comprising nucleic acids that encode the recombinant polypeptides.
Core Innovation
The invention discloses recombinant polypeptides comprising a DRα1 domain, an antigenic peptide, and a linker sequence, wherein the linker includes a first glycine-serine spacer, a thrombin cleavage site, and a second glycine-serine spacer. This construct, exemplified by SEQ ID NO: 1, links an antigenic peptide such as MOG-35-55 to the N-terminus of the DRα1 polypeptide via the linker, generating a recombinant polypeptide that excludes MHC Class II α2, β1, and β2 domains.
The recombinant polypeptides show unexpected improvements in the stability of the secondary structure of the DRα1 domain and enhanced efficacy in treating inflammatory diseases compared to polypeptides lacking the antigenic peptide. Pharmaceutical compositions comprising these polypeptides are also disclosed, with effective dosages of at least 5 mg/kg, along with nucleic acid constructs encoding the polypeptides and cell lines containing these constructs.
The problem addressed by the invention arises from the pathology of multiple sclerosis and other autoimmune inflammatory disorders, where abnormal immune responses against self-antigens cause tissue damage. Existing treatments for such autoimmune and inflammatory diseases are inadequate, and partial MHC class II α1 domain polypeptides have shown therapeutic potential. The disclosed recombinant polypeptides aim to improve treatment efficacy and stability relative to prior art MHC class II α1 domain polypeptides lacking antigenic peptides.
Claims Coverage
The patent includes three independent claims focusing on a recombinant polypeptide, a pharmaceutical composition, and a method of treating inflammatory disease.
Recombinant polypeptide composition
A recombinant polypeptide comprising a DRα1 domain, an antigenic peptide, and a linker sequence that includes a first glycine-serine spacer, a thrombin cleavage site, and a second glycine-serine spacer, wherein the polypeptide does not include MHC Class II α2, β1, and β2 domains.
Pharmaceutical composition including recombinant polypeptide
A pharmaceutical composition containing an effective dose of the recombinant polypeptide of the invention and a pharmaceutically acceptable carrier, with the effective dose being at least 5 mg/kg.
Method of treating multiple sclerosis or EAE
A method of treating multiple sclerosis or experimental autoimmune encephalopathy (EAE) by administering to a subject a recombinant polypeptide comprising a DRα1 domain, a mouse or human MOG-35-55 antigenic peptide, and the described linker sequence, excluding MHC Class II α2, β1, and β2 domains.
The claims cover the composition of the recombinant polypeptide with a specific linker and antigenic peptide, pharmaceutical formulations with effective dosing, and therapeutic methods for inflammatory diseases using these recombinant polypeptides.
Stated Advantages
The addition of the antigenic peptide confers unexpected secondary structural stability to the DRα1 domain not present in polypeptides lacking the peptide.
The recombinant polypeptides exhibit significantly greater potency in treating experimental autoimmune encephalomyelitis than compositions comprising only the DRα1 polypeptide, with more than 50-fold increased efficacy.
These polypeptides more effectively down-regulate CD74 expression on human CD11b+ monocytes, enhancing their therapeutic effect relative to DRα1 alone.
Documented Applications
Treatment of inflammatory diseases, including multiple sclerosis and experimental autoimmune encephalopathy (EAE) in animal models.
Use in pharmaceutical compositions for administration to subjects suffering from inflammatory disorders.
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