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    Treatment with One Dose of Reltecimod is Superior to Two Doses in Mouse Models of Lethal Infection

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    Author
    Edgar, Rotem
    Tarrio, Margarite L.
    Maislin, Greg
    Chiguang, Feng
    Kaempfer, Raymond
    Cross, Alan
    Opal, Steven M.
    Shirvan, Anat
    Date
    2019-11-12
    Journal
    International Journal of Peptide Research and Therapeutics
    Publisher
    Springer Science and Business Media LLC
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1007/s10989-019-09974-5
    Abstract
    Soft-tissue bacterial infection can progress to severe sepsis and septic shock as a result of a disproportionate infammatory response, characterized by an excessive release of cytokines and infux of immune cells. Reltecimod (previously known as AB103 or p2TA), a peptide derived from the T-cell receptor CD28, modulates the host immune response by targeting the co-stimulatory pathway, which is essential for the induction of multiple pro-infammatory cytokines. Consequently, reltecimod has demonstrated benefcial efects against diferent bacterial infections, their exotoxins and endotoxins, and ionizing radiation. The dosing regimen of reltecimod was evaluated in three mouse models of infection. The efect of the number of reltecimod doses with respect to survival, cytokine/chemokine levels, and blood leukocyte profles was assessed. Overall, mice treated with a single intravenous dose of reltecimod (5 mg/kg) at 1–2 h after infection showed signifcantly greater survival as compared with saline-treated controls. Mice treated with a second doses demonstrated improved survival compared with saline-treated controls. However, in all models of infection, administration of a single therapeutic dose of reltecimod was superior to two or multiple doses. Further examination showed that the single therapeutic dose of reltecimod was associated with an early (within 24 h) decrease in cytokine/chemokine levels and most circulating leukocyte subpopulations. A second dose of reltecimod did not improve these early positive efects and appeared to attenuate further changes. These results provided insight into the mechanism of action of reltecimod and established a basis for the dosing regimen utilized in clinical trials, where reltecimod is administered as a single dose.
    Keyword
    Reltecimod
    AB103
    Necrotizing soft tissue infections (NSTI)
    Sepsis
    Cytokines
    Leukocytes profling
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/13475
    ae974a485f413a2113503eed53cd6c53
    10.1007/s10989-019-09974-5
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