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-10717763-B2
Publication Date
2020-07-21
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 invention relates to native and reconstituted HC-HA/PTX3 complexes comprising heavy chain-hyaluronic acid/pentraxin 3. It describes identifying and isolating nHC-HA/PTX3 complexes from fetal tissues, including amniotic membrane and umbilical cord, and using the resulting complex as a native reference for subsequent complex work. The overview also includes formation and characterization of rcHC-HA/PTX3 complexes, including complex formation approaches described as sequential or simultaneous assembly.
The invention further describes reconstituting HC-HA/PTX3 complexes by assembling an immobilized high molecular weight hyaluronan with PTX3 and transferring inter-α-inhibitor material via HC1/TSG-6-mediated transfer, optionally including IαI/HC2 and small leucine-rich proteoglycans such as decorin, biglycan, osteoadherin, or other SLRPs. The resulting rcHC-HA/PTX3 complexes are presented in contexts of native-like complex activity and complex-specific biological effects.
The disclosed complexes are associated with biological activities and therapeutic uses. These activities include promotion of M2 macrophage polarization, reduction of pro-inflammatory cytokines including IL-12p40, IL-12p70, and IL-23, and increase of IL-10, along with induction of apoptosis of LPS-stimulated neutrophils and enhanced phagocytosis of apoptotic neutrophils. The document additionally describes anti-scarring, anti-inflammatory, anti-angiogenic, and tissue-regenerative uses, and it links complex interactions to attachment and signaling contexts involving receptors such as CD44 and TLR4.
Claims Coverage
The provided independent claim focuses on reducing pain by administering a composition that includes a reconstituted HC-HA/PTX3 complex together with a natural polymer and/or formulation components. Based on the provided claim excerpt and referenced refinements, the inventive content is centered on use of rcHC-HA/PTX3 to treat pain associated with specified conditions.
Reducing pain by administering rcHC-HA/PTX3 plus a natural polymer
A method of reducing pain in an individual in need thereof by administering a therapeutically effective amount of a composition comprising (i) a reconstituted HC-HA/PTX3 (heavy chain-hyaluronic acid/pentraxin3) complex and (ii) a natural polymer and/or formulation components selected from adjuvant, excipient, preservative, agent for delaying absorption, filler, binder, adsorbent, buffer, or combination thereof, thereby reducing pain associated with chemical burns, severe bacterial keratitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, irradiation of ocular tumors, arthritis, or bone spurs.
RcHC-HA/PTX3 defined by HA, HC1, HC2, and PTX3
The method includes that the rcHC-HA/PTX3 complex contains hyaluronic acid (HA), inter-α-inhibitor (IαI) protein heavy chain 1 (HC1) and heavy chain 2 (HC2), and pentraxin 3 (PTX3).
RcHC-HA/PTX3 consisting of HMW HA, HC1, HC2, PTX3, and TSG-6
The method includes that the rcHC-HA/PTX3 complex consists of HMW HA, HC1, HC2, PTX3, and TSG-6.
Specified administration routes for the pain-reducing composition
The method specifies administration via topical administration, injection, infusion, inhalation, or implantation.
Formulation options using particulate delivery systems
The method provides that the composition includes one or more delivery system particles selected from liposomes, niosomes, pharmacosomes, microspheres, microparticles, or nanoparticles.
Across the independent claim and the highlighted refinements, the claim coverage centers on administering a therapeutically effective composition that includes a defined reconstituted HC-HA/PTX3 complex (with specified components and optionally TSG-6) formulated with a natural polymer and excipient/formulation components, for reducing pain associated with the enumerated conditions, using specified administration routes and optional particulate delivery systems.
Stated Advantages
Reducing pain associated with chemical burns, severe bacterial keratitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, irradiation of ocular tumors, arthritis, or bone spurs.
Promotion of M2 macrophage polarization.
Reduction of pro-inflammatory cytokines including IL-12p40, IL-12p70, and IL-23, with increase of IL-10.
Induction of apoptosis of LPS-stimulated neutrophils and enhanced phagocytosis of apoptotic neutrophils.
Anti-scarring, anti-inflammatory, anti-angiogenic, and tissue-regenerative uses.
Documented Applications
Therapeutic use for reducing pain in an individual having a chemical burn, severe bacterial keratitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, irradiation of ocular tumors, arthritis, or bone spurs.
Topical, parenteral, and ocular formats.
Implant/device coatings and depots, including ocular implants and glaucoma drainage devices.
cGVHD dry eye.
HSV keratitis inflammation.
Excimer laser PRK scarring inhibition.
Atherosclerosis.
Obesity/insulin resistance.
Type 1 diabetes via coated insulin-cell microcapsules.
Fibrosis.
Rheumatoid arthritis and other inflammatory states.
Cancer.
Non-healing skin wounds/ulcers.
High-risk corneal transplants.
Medical-device coating to reduce inflammation and infectious biofilm formation.
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