Alkaline phosphatase agents for treatment of radiation disorders
Inventors
Kaleko, Michael • FURLAN FREGUIA, Christian • Connelly, Sheila
Assignees
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Publication Number
US-11654184-B2
Publication Date
2023-05-23
Expiration Date
Abstract
The present invention relates to, inter alia, compositions and methods, including therapeutic alkaline phosphatases that find use in the treatment or prevention of the effects of radiation exposure and/or chemotherapy.
Core Innovation
The disclosure relates to therapeutic alkaline phosphatase (AP) agents and compositions for radiation/chemotherapy countermeasures, including treatment or prevention of delayed radiation enteropathy. Delayed radiation enteropathy develops after a latency period and involves intestinal, mucosal, vascular, and fibrotic changes, and radiation disorders occur following radiotherapy and other radiation exposures.
The therapeutic approach comprises administering an intestinal alkaline phosphatase (IAP) to a subject in need thereof. The IAP is defined by an amino acid sequence having at least about 90% sequence identity with SEQ ID NO: 2 or SEQ ID NO: 3, and the disclosure frames IAP/AP as relevant to gut homeostasis, dysbiosis, and maintaining gut barrier function after radiation exposure.
The disclosure also describes engineered AP constructs as therapeutic forms, including mammalian intestinal AP and bacterial APs, and examples such as GPI-anchored versus secreted forms, Fc fusion for extended half-life, and pro-enzyme/pro-drug concepts with protease-cleavable carboxy termini. In addition, the disclosure describes formulation and delivery approaches, including immediate versus delayed, enteric, modified-release, and colon-targeting delivery across intestinal regions.
Claims Coverage
The provided claim set includes one independent claim. The independent claim covers administering a defined intestinal alkaline phosphatase (IAP) sequence to treat or prevent delayed radiation enteropathy, with dependent claims further characterizing the radiotherapy side effect context and measurable outcome thresholds such as serum FITC and inflammatory cytokine reductions.
Treating or preventing delayed radiation enteropathy using intestinal alkaline phosphatase
A method of treating or preventing delayed radiation enteropathy in a subject in need thereof comprising administering to the subject an intestinal alkaline phosphatase (IAP).
IAP sequence identity to SEQ ID NO: 2 or SEQ ID NO: 3
The IAP comprises an amino acid sequence having at least about 90% sequence identity with SEQ ID NO: 2 or SEQ ID NO: 3.
Quantitative maintenance of gut barrier via serum FITC reduction
The method results in a human patient having at least an 80% reduction in serum FITC, indicating maintenance of the gut barrier.
Reduced inflammatory cytokine expression
The method results in a human patient presenting at least 60% reduced expression of inflammatory cytokines selected from TNF-α, IL-1β, IL-6, and IL-17.
Overall, the claim coverage centers on administering an IAP defined by amino acid sequence identity to SEQ ID NO: 2 or SEQ ID NO: 3 to treat or prevent delayed radiation enteropathy, with dependent coverage introducing measurable outcome thresholds including serum FITC reduction and reduced inflammatory cytokine expression.
Stated Advantages
Reduced morbidity/mortality and accelerated recovery in the ARS context, as described in the document.
Maintains gut barrier function as indicated by at least an 80% reduction in serum FITC.
Reduces inflammatory cytokine expression, including at least 60% reduced expression of TNF-α, IL-1β, IL-6, and IL-17.
Restoration of endogenous IAP expression and reduction of histologic injury, as described in the document.
Documented Applications
Prevention and treatment of delayed radiation enteropathy in a subject in need thereof.
Treatment or prevention of ARS and radiation-induced organ toxicities, including gastrointestinal, hematopoietic/bone marrow, neurovascular/apoptosis-mediated tissue damage, and radiation-induced intestinal fibrosis, as described in the document.
Countermeasure use for radiation or chemotherapy side effects, including delayed radiation enteropathy developing after a latency period.
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