Repeated injection of KMRC011, a medical countermeasure for radiation, can cause adverse health effects in cynomolgus monkeys

Abstract

High‐dose radiation‐induced tissue damage is a major limiting factor in the medical application of nuclear technology. Herein, we tested 28‐day repeated‐dose toxicity of KMRC011, an agonist of toll‐like receptor (TLR) 5, which is being developed as a medical countermeasure for radiation, using cynomolgus monkeys. KMRC011 (0.01, 0.02 or 0.04 mg/kg/day) was intramuscularly injected once daily for 4 weeks, and each two monkeys in both control and 0.04 mg/kg/day group were observed for an additional 2‐week recovery period. There were no dose‐related toxicological changes in mortality, clinical observations, body weight, food consumption, ophthalmological findings, electrocardiographs, coagulation, serum chemistry, organ weights, or urinalysis and urine chemistry. Although treatment‐related changes, such as increased white blood cells, increased absolute and relative neutrophils, decreased relative lymphocytes and inflammatory lesions, were noted in the maximum dose group, these findings were not observed after the 2‐week recovery period. Further, we considered that the kidneys and heart may be target organs of TLR5 agonists, as well as the spleen, and that autophagic signals can be triggered in tissue damage and the repair process. Importantly, accumulation of p62 protein, an indicator of autophagy, and a decrease of caveolin‐1 protein, a regulator of TLR5 protein half‐life, were found in both tissues from the highest dose group. Therefore, we conclude that the no‐observed‐adverse‐effect level for KMRC011 may be greater than 0.04 mg/kg/day in male and female monkeys. Additionally, we propose that further studies are needed to identify the molecular signals, which are related to KMRC011‐induced adverse effects.

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

“…was closely involved in KMRC011-induced tissue damage (Lee et al 2019). That this MRC is having desired TLR5-related effects was confirmed by the findings here that KMRC011 treatment led to an inhibited expression of proteins (cytochrome C and p62) that are related to cell death after TBI exposure.…”

“…KMRC011 was obtained from Advanced Protein Technologies Corp. (Suwon, Korea); distilled water (DW) containing 10 mM L-histidine (pH 7.0) was used as matrix/vehicle. For the monkeys that were to receive KMRC011, the agent was given by intramuscular (IM) injection at %25 h after completion of their TBI (Lee et al 2019) Monkeys in the TBI-only group were not injected with the test article. Weights of the monkeys were monitored for 80 days after irradiation.…”

“…However, this agent contains an N-terminal region that might induce adverse immunogenic effects in humans (Song et al 2019). In this regard, toxic responses from repeated-dosing with KMRC011 (a potential TLR5 agonist agent) were assessed using cynomolgus monkeys (Lee et al 2019). In that study, it was seen that by the end of the exposures, there were no dose-related changes in body weight gain, food consumption, in absolute and relative organ weights, or in serum chemistry parameters in the treated animals.…”

Radioprotective effect of newly synthesized toll-like receptor 5 agonist, KMRC011, in mice exposed to total-body irradiation

“…When considering repeated injection, adverse health effects should be considered. As a result of 28‐day repeated‐dose toxicity of KMRC011, the no‐observed‐adverse‐effect level of KMRC011 was <0.25 mg/kg/day in rats [19] and <0.04 mg/kg/day in cynomolgus monkeys [20].…”