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-9352021-B2
Publication Date
2016-05-31
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 treatment or prophylaxis of a chronic wound in a mammalian subject by topically applying an effective amount of a composition comprising an alpha-2-macroglobulin polypeptide (A2M) isolated from a biological sample from the mammalian subject. The composition does not elicit an immune response by the mammalian subject when topically applied to the chronic wound. The approach is framed around wound pathophysiology involving protease imbalance, inflammation, extracellular matrix degradation, protease activity, and matrix interactions.
The disclosure further includes A2M variants and engineered A2M-related constructs. Variant A2M includes modifications in the bait region to enhance protease inhibition and/or to prolong half-life. The disclosure also describes compositions enriched for A2M, including enrichment and concentration features, and defines targets such as A2M enrichment and reductions or exclusions of cells and particles and certain molecular-weight fractions.
The compositions can be combined with other wound-related agents, including growth factors and platelet-related components such as platelets/PRP and platelet-poor plasma (PPP). The disclosure also includes implementation concepts for system and processing features such as manual operation with minimal mechanization and reduced platelet activation/degranulation, as well as disposable or minimal parts.
Claims Coverage
The independent claims focus on topical treatment or prophylaxis of chronic wounds using a subject-derived A2M composition that does not elicit an immune response when applied. Three inventive features are present across the independent claims, with additional compositional constraints in the broader coverage.
Immune non-eliciting subject-derived A2M topical treatment
Topically applying to a chronic wound an effective amount of a composition comprising an alpha-2-macroglobulin polypeptide (A2M) isolated from a biological sample from the mammalian subject, wherein the composition does not elicit an immune response by the mammalian subject when topically applied to the chronic wound.
Immune non-eliciting enriched A2M plus body fluid composition
Topically applying to the chronic wound an effective amount of a composition comprising A2M isolated from a biological sample from the mammalian subject, wherein the composition comprises the A2M at a concentration of at least 1.1 times higher than a concentration of A2M present in the biological sample and a body fluid from the biological sample, and wherein the composition does not elicit an immune response by the mammalian subject when topically applied to the chronic wound.
Immune non-eliciting dual non-A2M protein fraction composition
Topically applying to the chronic wound an effective amount of a composition comprising an alpha-2-macroglobulin polypeptide (A2M) isolated from a biological sample from the mammalian subject, wherein the composition comprises a first and second plurality of non-A2M proteins, the first plurality having a molecular weight of more than 10 kDa and present at a concentration at least 1.1 times higher than those proteins in the biological sample, the second plurality having a molecular weight less than 500 kDa and present at an amount less than 90% of an amount of those proteins in the biological sample, and wherein the composition does not elicit an immune response by the mammalian subject when topically applied to the chronic wound.
The independent claims require topical application of an A2M-containing composition derived from the mammalian subject’s biological sample that does not elicit an immune response. The additional independent coverage specifies A2M concentration increased to at least 1.1 times the sample level with inclusion of body fluid, or specific two non-A2M protein fractions defined by molecular weight and relative abundance constraints.
Stated Advantages
The composition does not elicit an immune response by the mammalian subject when topically applied to the chronic wound.
Documented Applications
Treatment or prophylaxis of a chronic wound in a mammalian subject by topical application of an effective A2M-containing composition.
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