Compositions containing HC-HA/PTX3 complexes and methods of use thereof
Inventors
Tseng, Scheffer • He, Hua • Tighe, Sean • Zhang, Suzhen • Zhu, Ying-Tieng
Assignees
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Publication Number
US-10040821-B2
Publication Date
2018-08-07
Expiration Date
Abstract
Provided herein are methods for the production of native and reconstituted hyaluronan (HA) complexes containing pentraxin-3 (PTX3) and heavy chain 1 (HC1) of inter alpha inhibitor (IαI). Compositions containing the complexes and therapeutic methods using the complexes are provided. Combinations and kits for use in practicing the methods also are provided.
Core Innovation
The patent describes a purified, reconstituted HC-HA/PTX3 complex produced in vitro by contacting high molecular weight hyaluronan (HMW HA) with pentraxin 3 (PTX3) protein, an inter-alpha-inhibitor (IαI) protein comprising heavy chain 1 (HC1) and heavy chain 2 (HC2), and tumor necrosis factor α-stimulated gene 6 (TSG-6) to form an rcHC-HA/PTX3 complex comprising HMW HA, HC1, HC2, and PTX3. The method further purifies the rcHC-HA/PTX3 complex from unwanted components, and the described complexes are positioned as purified reconstituted assemblies built from the stated components.
The patent additionally describes a reconstituted HC-HA/PTX3/SLRP complex comprising HMW-HA, PTX3 protein, HC1 and HC2 of IαI, and a small leucine rich proteoglycan (SLRP). In the described framework, the complex composition is defined by the specific constituent biomolecules and their assembly into a reconstituted complex. The document also characterizes variants of component provenance for PTX3 and TSG-6 as native or recombinant.
From the provided partial content, the invention is further directed to using rcHC-HA/PTX3 and related nHC-HA/PTX3 or rcHC-HA/PTX3 complexes in functional assays and therapeutic contexts. The partial content states that the complexes are associated with effects on macrophage/neutrophil and gene expression, and ties the stated complexes to therapeutic indications including inflammation, scarring/fibrosis, abnormal angiogenesis, wound repair, tissue and soft-tissue repair, and ocular uses.
Claims Coverage
The provided claim set includes two independent claims that define a purified, in vitro produced rcHC-HA/PTX3 complex and a reconstituted HC-HA/PTX3/SLRP complex. Across the independent-claim families, the inventive features are centered on reconstituting defined multi-component complexes from specified biomolecules, and for the first family, purifying the resulting complex from unwanted components.
Purified, reconstituted HC-HA/PTX3 complex produced in vitro from HMW HA, PTX3, IαI (HC1 and HC2), and TSG-6
A purified, reconstituted HC-HA/PTX3 (rcHC-HA/PTX3) complex produced in vitro by contacting high molecular weight hyaluronan (HMW HA) with pentraxin 3 (PTX3) protein, an inter-alpha-inhibitor (IαI) protein comprising heavy chain 1 (HC1) and heavy chain 2 (HC2), and tumor necrosis factor α-stimulated gene 6 (TSG-6) to form an rcHC-HA/PTX3 complex comprising HMW HA, HC1, HC2, and PTX3; and purifying the rcHC-HA/PTX3 complex from unwanted components.
Reconstituted HC-HA/PTX3/SLRP complex comprising HMW-HA, PTX3, IαI (HC1 and HC2), and SLRP
A reconstituted HC-HA/PTX3/SLRP complex comprising high molecular weight hyaluronan (HMW-HA), pentraxin-3 (PTX3) protein, heavy chain 1 (HC1) and heavy chain 2 (HC2) of inter-alpha-inhibitor (IαI), and a small leucine rich proteoglycan (SLRP).
Overall, claim coverage focuses on defined reconstituted multi-component complexes that include HMW HA, PTX3, and IαI components (HC1 and HC2), with the first independent claim additionally requiring TSG-6 and purification from unwanted components, and the second independent claim requiring inclusion of an SLRP.
Stated Advantages
Promotes M2 macrophage polarization, including reduced M1 cytokines IL-12 and IL-23 and increased IL-10.
Induces apoptosis of LPS-stimulated neutrophils.
Enhances macrophage phagocytosis of apoptotic neutrophils.
Modulates macrophage activity/attachment through HA-binding pathways including CD44 and TLR4.
Documented Applications
Inflammation treatment and/or modulation in functional assay contexts as described in the partial content.
Scarring/fibrosis-related therapeutic use as described in the partial content, including inhibition of TGF-β signaling and effects on myofibroblast differentiation.
Abnormal angiogenesis-related therapeutic use as described in the partial content, including VEGF-mediated angiogenesis.
Wound repair use including burns and ulcers as described in the partial content.
Tissue and soft-tissue repair as described in the partial content.
Ocular uses as described in the partial content, including coverage concepts for glaucoma drainage devices (GDD) and depot-like ophthalmic constructs.
Medical device coating applications using the rcHC-HA/PTX3 complex on a substrate as described in the partial content.
Therapeutic cell and stem-cell applications as described in the partial content, including stem cell expansion and modulation of signaling pathways (TGF-β/BMP) and pluripotency induction/maintenance on immobilized substrates.
Combination therapy and kit/manufacturing concepts as described in the partial content.
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