Anti-ceramide ScFv prophylaxis for first responders to a limited nuclear attack Journal Article
| Authors: | Cheng, J.; Nagesh, P. K. B.; Feldman, R.; Shamu, T.; Zhang, Z.; Fuks, Z.; Kolesnick, R. |
| Article Title: | Anti-ceramide ScFv prophylaxis for first responders to a limited nuclear attack |
| Abstract: | Background/Aims: After 9/11, multiple government agencies instituted programs aimed at developing medical radiation countermeasures (MRCs) for two syndromes lethal within weeks of a limited nuclear attack; the hematopoietic-acute radiation syndrome (H-ARS) and the higher-dose gastrointestinal-acute radiation syndrome (GI-ARS). While re-purposing drugs that enhance marrow repopulation treats H-ARS, no mitigator protects GI tract. Methods: We recently reported anti-ceramide 6B5 single-chain variable fragment (scFv) pre-treatment abrogates ongoing small intestinal endothelial apoptosis to rescue Lgr5+ stem cells, preventing GI-ARS lethality in C57B/L6J mice. Here, with US Department of Defense support, we provide evidence that humanized anti-ceramide scFv (CX-01) is a promising prophylactic MRC for first responders, who risk exposure upon entering a radiation-contaminated site. Results: CX-01, when delivered up to 90 min before irradiation, is highly-effective in preventing small intestinal endothelial apoptosis in mice and lethality in both sexes. Unexpectedly, females require an ~2-fold higher CX-01 dose than males for full protection. CX-01 is effective subcutaneously and intramuscularly, a property critical for battlefield use. Increasing the maximally-effective dose 5-fold does not extend duration of bioeffectiveness. Conclusion: While CX-01 prevents GI-ARS lethality, structural modification to extend half-life may be necessary to optimize first responder prophylaxis. © 2024 The Author(s). Published by. |
| Keywords: | controlled study; unclassified drug; drug efficacy; nonhuman; united states; animal cell; mouse; animal; metabolism; animals; mice; apoptosis; animal experiment; drug effect; pathology; mice, inbred c57bl; radiation response; c57bl mouse; endothelium cell; endothelial cells; immunology; prophylaxis; radiation-protective agents; sex difference; drug therapy; small intestine; intestine, small; gastrointestinal disease; single chain fragment variable antibody; concentration response; lethality; prevention and control; radiation protection; ceramide; ceramides; radioprotective agent; asmase; terrorism; scfv; radioactive contamination; humans; human; male; female; article; nuclear accident; ld50; single-chain antibodies; ec50; acute radiation syndrome; nuclear weapon; gi-ars; nuclear weapons; ceramide single chain fragment variable antibody; first responder (person); medical countermeasure |
| Journal Title: | Cellular Physiology and Biochemistry |
| Volume: | 58 |
| Issue: | 4 |
| ISSN: | 1015-8987 |
| Publisher: | Cell Physiol Biochem Press |
| Date Published: | 2024-01-01 |
| Start Page: | 418 |
| End Page: | 430 |
| Language: | English |
| DOI: | 10.33594/000000721 |
| PUBMED: | 39172137 |
| PROVIDER: | scopus |
| PMCID: | PMC11650686 |
| DOI/URL: | |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding author is Richard Kolesnick -- Source: Scopus |
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