Therapeutic variant alpha-2-macroglobulin compositions
Inventors
HANNA, Lewis • Laughlin, John David • BROWNING, Shawn Robert
Assignees
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Publication Number
US-10889631-B2
Publication Date
2021-01-12
Expiration Date
Abstract
A2M polypeptide compositions containing a non-natural bait region are disclosed. Methods of producing wild-type and variant A2M polypeptides and polynucleotides containing a non-natural bait region are also disclosed. The bait regions of the variant A2M polypeptides demonstrate enhanced protease inhibitory characteristics compared to wild-type A2M. Variant A2M polypeptides that demonstrate longer half-lives upon administration to an organism compared to wild-type A2M are disclosed. The A2M compositions are useful in treating a number of diseases and conditions including inflammation, chronic wounds, and diseases with a pathology associated with proteases.
Core Innovation
The invention relates to therapeutic alpha-2-macroglobulin (A2M) variant compositions comprising a recombinant alpha-2-macroglobulin (A2M) polypeptide with a non-natural bait region. The non-natural bait region comprises a sequence with at least 80% identity to SEQ ID NO: 20, and the recombinant A2M compositions are formulated with a pharmaceutically acceptable carrier for treatment of a mammalian subject.
The patent describes non-natural bait region designs intended to increase protease inhibitory potency and prolong in vivo half-life. The bait region is associated with protease recognition and protease inhibitory action against protease-driven pathology, including inflammation and extracellular matrix degradation, and the patent further links the activity to fibronectin-aggrecan complex (FAC) formation and protease substrate bait regions arranged in series.
The patent also describes variant A2M polypeptides and polynucleotides, including recombinant production approaches and protease recognition site design elements. The document references protease classes including matrix metalloproteinases (MMPs) and ADAMTS proteases, and describes possible suicide inhibitor bait elements configured to covalently attach proteases, with PEG and glycosylation engineering concepts described in connection with extending residence time.
Claims Coverage
The document provides one independent claim directed to a method of treating a mammalian subject with an inflammatory disease or condition by administering a pharmaceutical composition containing a recombinant A2M polypeptide with a non-natural bait region. The claim set includes dependent refinements that adjust bait-region identity, specify protease recognition sequence classes, and add a suicide inhibitor mechanism for covalent protease attachment.
Recombinant alpha-2-macroglobulin polypeptide with a non-natural bait region
A pharmaceutical composition is administered that comprises a recombinant alpha-2-macroglobulin (A2M) polypeptide comprising a non-natural bait region, wherein the non-natural bait region comprises a sequence with at least 80% identity to SEQ ID NO: 20.
Treatment of inflammatory disease or condition by administration with carrier
A method of treating a mammalian subject with an inflammatory disease or condition includes administering a pharmaceutically effective amount of the recombinant A2M polypeptide with a non-natural bait region together with a pharmaceutically acceptable carrier.
Overall, the claim coverage is anchored on administering a recombinant A2M polypeptide carrying a non-natural bait region with at least 80% identity to SEQ ID NO: 20 in a pharmaceutical composition with a pharmaceutically acceptable carrier, for treating an inflammatory disease or condition. Dependent claims further refine the bait-region identity threshold, protease recognition sequence classes (MMP and ADAMTS), and include a suicide inhibitor operable to covalently attach a protease.
Stated Advantages
Increases protease inhibitory potency.
Prolongs in vivo half-life.
Inhibits proteases, aggrecan/FAC formation, and slows tissue degeneration.
Documented Applications
Treating a mammalian subject with an inflammatory disease or condition, including inflammatory disease or condition associated with injury selected from ligament injury, tendon injury, bone injury, spine injury, and cartilage injury.
Use in connection with protease-driven pathology including inflammation and extracellular matrix degradation, including fibronectin-aggrecan complex (FAC) formation.
Wound dressing context for chronic wounds.
Spine/joint delivery context, including disc, epidural space, and facet joints.
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