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

  • Rotem Edgar
  • Margarite L. Tarrio
  • Greg Maislin
  • Feng Chiguang
  • Raymond Kaempfer
  • Alan Cross
  • Steven M. Opal
  • Anat ShirvanEmail author
Article
  • 5 Downloads

Abstract

Soft-tissue bacterial infection can progress to severe sepsis and septic shock as a result of a disproportionate inflammatory response, characterized by an excessive release of cytokines and influx 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-inflammatory cytokines. Consequently, reltecimod has demonstrated beneficial effects against different bacterial infections, their exotoxins and endotoxins, and ionizing radiation. The dosing regimen of reltecimod was evaluated in three mouse models of infection. The effect of the number of reltecimod doses with respect to survival, cytokine/chemokine levels, and blood leukocyte profiles was assessed. Overall, mice treated with a single intravenous dose of reltecimod (5 mg/kg) at 1–2 h after infection showed significantly 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 effects 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 profiling 

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

NOAEL

No-observable-adverse-effect level

PBS

Phosphate-buffered saline

RP-HPLC

Reversed-phase high-performance liquid chromatography

SEB

Staphylococcal enterotoxin B

TNF-α

Tumor necrosis factor α

UPLC

Ultra-performance liquid chromatography

Notes

Acknowledgements

This study was supported by Atox Bio (to RK, SMO, AC and GM). We would like to thank Tsufit Gross for critically reviewing the manuscript.

Author Contributions

Concept and design of the study: SMO, AC, MLT, CF, RE, and AS contributed. RE wrote the first draft of the manuscript. Acquisition of data: SMO, AC, MLT, CF. Analysis and interpretation of data: SMO, AC, MLT, CF, GM, RE, and AS. Critical revision of the manuscript for important intellectual content: SMO, AC, MLT, RK, CF, RE, and AS. Study supervision: SMO, AC, RE, and AS.

Funding

This study was supported by Atox Bio (to RK, SMO, AC and GM).

Compliance with Ethical Standards

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. AS and RE are employees of Atox Bio. RK, AC, GM and SMO have received funding from Atox Bio. MLT, and CF have no relevant financial relationships to disclose.

Ethics Approval

All animal studies were approved by the Brown University/Rhode Island Hospital and University of Maryland Institutional Animal Care and Use Committees (IACUCs) before experiments were initiated. Animals were housed in an IACUC-approved facility under biosafety level 2 safety conditions and were monitored by Brown University/Rhode Island Hospital and University of Maryland veterinary staffs.

Informed Consent

Not Applicable.

Supplementary material

10989_2019_9974_MOESM1_ESM.docx (49 kb)
Electronic supplementary material 1 (DOCX 49 kb)

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Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  • 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
    Email author
  1. 1.Atox BioNess ZionaIsrael
  2. 2.Department of Molecular Microbiology and ImmunologyBrown UniversityProvidenceUSA
  3. 3.Biomedical Statistical ConsultingWynnewoodUSA
  4. 4.Department of Microbiology and ImmunologyUniversity of Maryland School of MedicineBaltimoreUSA
  5. 5.Department of Biochemistry and Molecular Biology, The Institute for Medical Research Israel-CanadaThe Hebrew University-Hadassah Medical SchoolJerusalemIsrael
  6. 6.Center for Vaccine DevelopmentUniversity of Maryland Medical SchoolBaltimoreUSA
  7. 7.Faculty of MedicineThe Alpert Medical School at Brown University and Rhode Island HospitalProvidenceUSA

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