Vol.:(0123456789) 1 3 International Journal of Peptide Research and Therapeutics (2020) 26:1669–1683 https://doi.org/10.1007/s10989-019-09974-5 Treatment with One Dose of Reltecimod is Superior to Two Doses in Mouse Models of Lethal Infection Rotem Edgar 1  · Margarite L. Tarrio 2  · Greg Maislin 3  · Feng Chiguang 4  · Raymond Kaempfer 5  · Alan Cross 6  · Steven M. Opal 7  · Anat Shirvan 1 Accepted: 5 November 2019 / Published online: 12 November 2019 © Springer Nature B.V. 2019 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, relteci- mod 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 sur- vival 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 asso- ciated 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. Keywords Reltecimod · AB103 · Necrotizing soft tissue infections (NSTI) · Sepsis · Cytokines · Leukocytes profling Abbreviations CLP Cecal ligation and puncture FACS Fluorescent automated cell sorter IFN-γ Interferon γ IL Interleukin IM Intramuscularly IP Intraperitoneal LPS Lipopolysaccharide MCP-1 Monocyte chemoattractant protein 1 Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10989-019-09974-5) contains supplementary material, which is available to authorized users. * Anat Shirvan anatshirvan@gmail.com 1 Atox Bio, Weizmann Science Park, 8 Pinhas Sapir St., 7403631 Ness Ziona, Israel 2 Department of Molecular Microbiology and Immunology, Brown University, Box G-B5, 171 Meeting Street, Providence, RI, USA 3 Biomedical Statistical Consulting, 1357 Garden Road, Wynnewood, PA, USA 4 Department of Microbiology and Immunology, University of Maryland School of Medicine, 685 West Baltimore Street, HSF-I Suite 380, Baltimore, MD, USA 5 Department of Biochemistry and Molecular Biology, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem, Israel 6 Center for Vaccine Development, University of Maryland Medical School, 685 West Baltimore Street, Baltimore, MD, USA 7 Faculty of Medicine, The Alpert Medical School at Brown University and Rhode Island Hospital, Box G-A1, 222 Richmond Street, Providence, RI, USA