title: CBLB613: a TLR 2/6 agonist, natural lipopeptide of Mycoplasma arginini , as a novel radiation countermeasure.
abstract: To date, there are no safe and effective drugs available for protection against ionizing radiation damage. Therefore, a great need exists to identify and develop non-toxic agents that will be useful as radioprotectors or postirradiation therapies under a variety of operational scenarios. We have developed a new pharmacological agent, CBLB613 (a naturally occurring Mycoplasma-derived lipopeptide ligand for Toll-like receptor 2/6), as a novel radiation countermeasure. Using CD2F1 mice, we investigated CBLB613 for toxicity, immunogenicity, radioprotection, radiomitigation and pharmacokinetics. We also evaluated CBLB613 for its effects on cytokine induction and radiation-induced cytopenia in unirradiated and irradiated mice. The no-observable-adverse-effect level of CBLB613 was 1.79 mg/kg and 1 mg/kg for single and repeated doses, respectively. CBLB613 significantly protected mice against a lethal dose of (60)Co γ radiation. The dose reduction factor of CBLB613 as a radioprotector was 1.25. CBLB613 also mitigated the effects of (60)Co γ radiation on survival in mice. In both irradiated and unirradiated mice, the drug stimulated induction of interleukin-1β (IL-1β), IL-6, IL-10, IL-12, keratinocyte-derived chemokine, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, and tumor necrosis factor-1α. CBLB613 also reduced radiation-induced cytopenia and increased bone marrow cellularity in irradiated mice. Our immunogenicity study demonstrated that CBLB613 is not immunogenic in mice, indicating that it could be developed as a radioprotector and radiomitigator for humans against the potentially lethal effects of radiation exposure.
authors.affiliation: Radiation Countermeasures Program, Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20889-5603, USA. singh@afrri.usuhs.mil
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Singh
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Ducey
authors.forename: Oluseyi O
authors.initials: OO
authors.lastname: Fatanmi
authors.forename: Pankaj K
authors.initials: PK
authors.lastname: Singh
authors.forename: Darren S
authors.initials: DS
authors.lastname: Brown
authors.forename: Andrei
authors.initials: A
authors.lastname: Purmal
authors.forename: Vera V
authors.initials: VV
authors.lastname: Shakhova
authors.forename: Andrei V
authors.initials: AV
authors.lastname: Gudkov
authors.forename: Elena
authors.initials: E
authors.lastname: Feinstein
authors.forename: Alexander
authors.initials: A
authors.lastname: Shakhov
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D016207:Cytokines / Q000096:biosynthesis / Q000097:blood* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical; D005720:Gamma Rays / Q000009:adverse effects*; D057809:HEK293 Cells / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D055666:Lipopeptides / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D008297:Male; D051379:Mice; D009174:Mycoplasma / Q000737:chemistry*; D016328:NF-kappa B / Q000378:metabolism; D010198:Pancytopenia / Q000097:blood / Q000209:etiology / Q000517:prevention & control*; D011833:Radiation Injuries, Experimental / Q000097:blood / Q000188:drug therapy* / Q000517:prevention & control; D011837:Radiation-Protective Agents / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D013154:Spleen / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D051195:Toll-Like Receptor 2 / Q000819:agonists*; D051216:Toll-Like Receptor 6 / Q000819:agonists*
chemical_list: D016207:Cytokines; D055666:Lipopeptides; D016328:NF-kappa B; D011837:Radiation-Protective Agents; C495342:TLR2 protein, human; C495368:TLR6 protein, human; D051195:Toll-Like Receptor 2; D051216:Toll-Like Receptor 6