Systems, compositions, and methods for transplantation and treating conditions
Inventors
HANNA, Lewis • Laughlin, John David • BROWNING, Shawn Robert
Assignees
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Publication Number
US-9498514-B2
Publication Date
2016-11-22
Expiration Date
Abstract
Systems and methods for purification and concentration of autologous alpha-2 macroglobulin (A2M) from whole blood and or recombinant A2M are provided. Also provided are methods of treating wounds with A2M. Methods for utilizing A2M in combination with other treatments (e.g., platelets and other growth factors) are provided in addition to combinations with exogenous drugs or carriers. Also provided is a method of producing recombinant A2M wild type or variants thereof where the bait region was modified to enhance the inhibition characteristics of A2M and/or to prolong the half-life of the protein for treating wounds.
Core Innovation
The invention relates to recombinant alpha-2-macroglobulin (A2M) polypeptides engineered to comprise a non-natural bait region that replaces a wild-type A2M bait region. The engineered recombinant A2M is described for use in compositions that target chronic wounds in mammalian subjects, and the recombinant concept is tied to reducing protease activity and/or protease-dependent activity.
The patent links chronic wound complications to protease activity, inflammatory processes, and fibronectin-aggrecan complex formation (FAC formation / FACC) and related aggrecan fragments. It also describes chronic wound healing in which protease inhibition addresses elevated proteases, including matrix metalloproteinases (MMPs) such as MMP-1, MMP-2, and MMP-3, and interactions involving TIMPs and inhibition of protease activity.
The invention further describes topical application of compositions comprising the engineered recombinant A2M for chronic wound treatment or prophylaxis. It also includes systems and methods for enriching and concentrating autologous alpha-2-macroglobulin (A2M) from whole blood, including recombinant A2M variants, to produce an A2M-enriched retentate for use in treating chronic wounds.
Claims Coverage
The provided claim set includes two independent claims. Both independent claims center on the same engineered recombinant alpha-2-macroglobulin (A2M) construct, namely a non-natural bait region replacing the wild-type A2M bait region, in a topical treatment method and a wound dressing composition.
Topical chronic wound treatment or prophylaxis using recombinant A2M with non-natural bait region
A method for the treatment or prophylaxis of a chronic wound in a mammalian subject, comprising topically applying to the chronic wound an effective amount of a composition comprising a recombinant alpha-2-macroglobulin polypeptide (A2M) comprising a non-natural bait region that replaces a wild-type A2M bait region.
Chronic wound dressing comprising recombinant A2M with non-natural bait region
A wound dressing comprising an effective amount of a composition for the treatment or prophylaxis of a chronic wound in a mammalian subject, wherein the composition comprises a recombinant alpha-2-macroglobulin polypeptide (A2M) comprising a non-natural bait region that replaces a wild-type A2M bait region.
Across the two independent claims, the core inventive coverage is the use of a recombinant A2M polypeptide engineered with a non-natural bait region replacing the wild-type A2M bait region, applied topically either as part of a method of treatment or prophylaxis or formulated as a wound dressing for treating or preventing chronic wounds in mammalian subjects.
Stated Advantages
Enrichment and concentration of autologous A2M from whole blood while reducing cells and particles and optionally reducing non-A2M protein fractions.
Low-cost, minimally mechanized, rapid processing with low-foam characteristics and an intent to reduce platelet activation.
Topical treatment or prophylaxis of chronic wounds using protease inhibition, including addressing elevated matrix metalloproteinases (MMPs).
Compositions are described as non-immunogenic or substantially non-immunogenic for topical application to chronic wounds.
Reduces protease activity at the site of topical application.
Exhibits enhanced protease inhibition relative to wild-type A2M.
Does not elicit an immune response when the composition is topically applied to a chronic wound (as stated in dependent claim language).
Documented Applications
Topically applying an effective amount of a recombinant A2M composition to a chronic wound for the treatment or prophylaxis in a mammalian subject.
Using the recombinant A2M composition as part of a wound dressing for the treatment or prophylaxis of a chronic wound in a mammalian subject.
Topical treatment or prophylaxis of a chronic wound in a mammalian subject using a composition comprising engineered recombinant A2M with a non-natural bait region replacing a wild-type A2M bait region.
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