KMRC011, an agonist of toll-like receptor 5, mitigates irradiation-induced tissue damage and mortality in cynomolgus monkeys

Abstract

In the study here, the potential applicability of KMRC011-an agonist of toll-like receptor-5as a countermeasure for radiation toxicities was evaluated. Following a single 5.5 Gy total body irradiation (TBI, surface absorbed dose ¼ 7 Gy) of Co 60 c-rays, mortality rates and degrees of pathological lesions that developed over 80 days were compared in monkeys that received TBI only and a group that was injected once with KMRC011 (10 lg/kg) after TBI. Compared to the TBI-only hosts (80%), the death rate was significantly improved by the use of KMRC011 (40%), all deaths in both groups occurred in the period from Days 19-24 post-TBI. Further analysis of monkeys that survived until the end of the experiment showed that AST and ALT levels were elevated only in the TBI group, and that radiation-induced tissue damage was alleviated by the KMRC011 injection. Additionally, expression of cell death-related proteins was lower in tissues from the KMRC011-treated hosts than in those in the TBI-only group. Other measured parameters, including body weight, food uptake, and hematological values did not significantly differ between the two groups over the entire period. The results of this study, thus demonstrate that KMRC011 could potentially be used as a medical countermeasure for the treatment of acute radiation exposure.

Clinical evaluation of toll-like receptor-5 agonist for radiation-induced oral mucositis in beagle dogs

“…To overcome this disadvantage, the KMRC011, the flagellin without a histidine tag, was developed recently (Korea Institute of Industrial Technology, Yeongcheon, Korea). Its ability as a TLR-5 agonist and radiation countermeasure was also reported using mice and cynomolgus monkeys (15)(16)(17).…”

The Role of the Innate Immune Response in Oral Mucositis Pathogenesis

“…The TLR5 agonist BLB502 (developed as CBLB502 entolimod) has been shown to be effective at alleviating mucositis following single-dose and fractionated radiotherapy to the head and neck [89]. Similarly, TLR5 agonist KMRC011 has been explored in multiple models of OM and found to provide some protection against ulcer development [90,91]. The proposed mechanisms of protection appear to be through NF-κB signaling, leading to superoxide dismutase 2 induction and granulocyte-colony-stimulating factor production.…”

A first‐in‐human study of KMRC011, a potential treatment for acute radiation syndrome, to explore tolerability, pharmacokinetics, and pharmacodynamics

“…KMRC011 is a novel TLR5 agonist, a slightly modified version of entolimod, and its efficacy was demonstrated in murine and nonhuman primate models of irradiation. 13 , 14 , 15 The purpose of this study was to investigate the tolerability, pharmacokinetics (PK), and pharmacodynamics (PDs) of KMRC011 following a single intramuscular administration in healthy subjects.…”