Anti-Ceramide Single-chain Variable Fragment Mitigates Radiation GI Syndrome Mortality Independent of DNA Repair.

After 9/11, threat of nuclear attack on American urban centers prompted government agencies to develop medical radiation countermeasures to mitigate hematopoietic-acute radiation syndrome (H-ARS) and higher-dose gastrointestinal-ARS (GI-ARS) lethality. While re-purposing leukemia drugs that enhance bone marrow repopulation successfully treats H-ARS in pre-clinical models, no mitigator potentially deliverable under mass casualty conditions preserves GI tract. Here we generate anti-ceramide 6B5 single-chain variable fragment (scFv) and show subcutaneous 6B5 scFv delivery at 24h after a 90% lethal GI-ARS dose of 15Gy mitigates mouse lethality, despite administration after DNA repair is complete. We define an alternate target to DNA repair, an evolving pattern of ceramide-mediated endothelial apoptosis post-radiation, which when disrupted by 6B5 scFv, initiates a durable program of tissue repair, permitting crypt, organ and mouse survival. We posit successful pre-clinical development will render anti-ceramide 6B5 scFv a candidate for inclusion in the Strategic National Stockpile for distribution after a radiation catastrophe.