Modified Tamm-Horsfall protein and related compositions and methods of use
Inventors
Ashkar, Tarek Maurice • Micanovic, Radmila
Assignees
Indiana University Research and Technology Corp • US Department of Veterans Affairs
Publication Number
US-11053290-B2
Publication Date
2021-07-06
Expiration Date
2036-10-28
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Abstract
Embodiments of the present disclosure provide polypeptides, related materials and compositions, and methods for their use. In certain embodiments, the present disclosure provides a monomeric Tamm-Horsfall Protein polypeptide, or a biologically active truncation thereof. Other embodiments provide polynucleotides encoding a polypeptide described herein, nucleic acid expression vectors including the polynucleotides, and recombinant host cells including the expression vector. Yet other embodiments provide pharmaceutical compositions including a polypeptide described herein. Also provided are methods for treating a renal disease, disorder, or condition in a subject and/or modulating an immune response in a subject.
Core Innovation
The invention provides purified or isolated monomeric Tamm-Horsfall Protein (THP) polypeptides or biologically active truncations thereof, along with related polynucleotides, expression vectors, recombinant host cells, and pharmaceutical compositions containing these polypeptides. The monomeric THP polypeptides include sequences at least 85% identical to specified SEQ ID NOs, and the invention encompasses various truncated forms reducing molecular weight for improved utility.
The problem addressed is the limited understanding and availability of monomeric forms of THP, as urinary THP is predominantly found in a highly aggregated polymeric form. THP plays a regulatory role in renal health and disease, but its deficiency is implicated in conditions such as acute kidney injury (AKI), chronic kidney disease (CKD), sepsis, and transplant rejection. There is a need for compositions and methods using monomeric or truncated THP that can treat renal diseases, modulate immune responses, and serve in pharmaceutical applications.
Claims Coverage
The patent includes multiple independent claims covering polypeptides, pharmaceutical compositions, methods of treating renal conditions, and immunogenic compositions. The following are the main inventive features extracted from these claims.
Purified or isolated polypeptides with defined sequence identity
Polypeptides consisting of amino acid sequences at least 95% identical to any of SEQ ID NO: 2, 3, 4, 5, 6, or 7, including specific truncated monomeric THP variants.
Pharmaceutical compositions comprising monomeric or truncated THP polypeptides
Compositions containing the purified or isolated polypeptides with pharmaceutically acceptable carriers, optionally combined with polypeptides at least 85% identical to SEQ ID NO: 1 (full-length hUMOD).
Methods for treating renal diseases with THP polypeptides or compositions
Administering an effective amount of the polypeptides or pharmaceutical compositions to treat renal diseases, disorders, or conditions including acute kidney injury, sepsis, transplant rejection, and chronic kidney disease.
Various administration routes and dosage ranges for THP treatments
Administration routes include oral, intravenous, intraperitoneal, intramuscular, or subcutaneous injection, with effective dose ranges between about 0.2 mg/kg and about 10.0 mg/kg, or between about 0.2 mg/kg and about 3.0 mg/kg.
Immunogenic compositions and methods to enhance immune responses
Compositions combining immunogenic agents with the purified polypeptides and methods for enhancing immune response by administering effective amounts of the polypeptides to subjects.
The independent claims cover isolated polypeptides of specific monomeric or truncated THP sequences, their pharmaceutical formulations, therapeutic methods for renal diseases, immunogenic compositions, and immune response modulation, specifying administration routes and dosage.
Stated Advantages
Monomeric THP polypeptides can protect from worsening kidney injury following acute kidney injury and improve recovery.
Monomeric THP increases the number and activation state of renal macrophages, enhancing immune response.
Administration of monomeric or truncated THP inhibits inflammatory signaling pathways in the kidney, reducing harmful oxidative stress.
Stability of monomeric THP in formulations enables long-term storage and consistent therapeutic use.
Documented Applications
Treatment of renal diseases including acute kidney injury, chronic kidney disease, sepsis, and transplant rejection.
Modulation of immune responses, including inhibition of inflammatory signaling and activation of renal macrophages.
Use as an adjuvant to enhance immune responses to immunogenic compositions, such as vaccines.
Prevention or reduction of kidney damage in subjects receiving vaccines, including kidney transplant recipients.
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