Preclinical and first-in-human evaluation of PRX-105, a PEGylated, plant-derived, recombinant human acetylcholinesterase-R

Atsmon, Jacob; Brill‐Almon, Einat; Nadri-Shay, Carmit; Chertkoff, Raul; Alon, Sari; Shaikevich, Dimitri; Volokhov, Inna; Haim, Kirsten Y.; Bartfeld, Daniel; Shulman, Avidor; Ruderfer, Ilya; Ben-Moshe, Tehila; Shilovitzky, Orit; Soreq, Hermona; Shaaltiel, Yoseph

doi:10.1016/j.taap.2015.06.004

Cited by 16 publications

(7 citation statements)

References 40 publications

(46 reference statements)

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“…Last but not least, in addition to preclinical trials in mice, a safety and pharmacokinetic study of a PEGylated plant‐derived huAChE has been performed in humans, from which positive results would give a green light to further clinical investigation (Atsmon et al . ).…”

Section: Pretreatmentmentioning

confidence: 97%

Cholinesterase reactivators and bioscavengers for pre‐ and post‐exposure treatments of organophosphorus poisoning

Masson

Nachon²

2017

Journal of Neurochemistry

123

105

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Organophosphorus agents (OPs) irreversibly inhibit acetylcholinesterase (AChE) causing a major cholinergic syndrome. The medical counter-measures of OP poisoning have not evolved for the last 30 years with carbamates for pretreatment, pyridinium oximes-based AChE reactivators, antimuscarinic drugs and neuroprotective benzodiazepines for postexposure treatment. These drugs ensure protection of peripheral nervous system and mitigate acute effects of OP lethal doses. However, they have significant limitations. Pyridostigmine and oximes do not protect/reactivate central AChE. Oximes poorly reactivate AChE inhibited by phosphoramidates. In addition, current neuroprotectants do not protect the central nervous system shortly after the onset of seizures when brain damage becomes irreversible. New therapeutic approaches for pre-and post-exposure treatments involve detoxification of OP molecules before they reach their molecular targets by administrating catalytic bioscavengers, among them phosphotriesterases are the most promising. Novel generation of broad spectrum reactivators are designed for crossing the blood-brain barrier and reactivate central AChE.

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Section: Pretreatmentmentioning

confidence: 97%

Cholinesterase reactivators and bioscavengers for pre‐ and post‐exposure treatments of organophosphorus poisoning

Masson

Nachon²

2017

Journal of Neurochemistry

123

105

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“…42 In a recent phase I, nonrandomized and single-dose study in humans, it was shown that the application of a plant-derived recombinant version of human AChE did not raise any concerns regarding the safety and tolerability. 71 Nevertheless, the principle of using human AChE as stoichiometric bioscavenger would face the same challenges as the abovementioned application of BChE. 42 To overcome the current limitations, the use of blood components in combination with an oxime to facilitate pseudocatalytic scavenging might be successful.…”

Section: Stoichiometric Bioscavengersmentioning

confidence: 99%

“…The concept of using human AChE as a stoichiometric scavenger has received less attention, even though it might provide a superior capability to detoxify chiral OPs (e.g., V‐type nerve agents) 42 . In a recent phase I, nonrandomized and single‐dose study in humans, it was shown that the application of a plant‐derived recombinant version of human AChE did not raise any concerns regarding the safety and tolerability 71 . Nevertheless, the principle of using human AChE as stoichiometric bioscavenger would face the same challenges as the abovementioned application of BChE 42 .…”

Section: Treatmentmentioning

confidence: 99%

Diagnostics and treatment of nerve agent poisoning—current status and future developments

Amend¹,

Niessen²,

Seeger³

et al. 2020

Annals of the New York Academy of Sciences

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Although 193 states have committed to the Chemical Weapons Convention and 98% of the declared chemical weapons stockpiles have been destroyed so far, nerve agent poisoning remains a lingering threat. The recent dissemination of sarin in Syria, the assassination of Kim Jong-Nam in Malaysia, and the assault on Sergei Skripal in the United Kingdom underline the need for effective treatment. The current therapeutic options of a muscarinic receptor antagonist, an oxime, and an anticonvulsant have been unchanged for decades. Therefore, new therapeutic strategies, for example, bioscavengers and receptor-active substances, are promising concepts that have to be examined for their benefits and limitations. In order to facilitate rapid diagnosis in challenging clinical situations, point-of-care diagnostics and detection are of importance. Therapeutic guidance concerning the duration and success of the current oxime therapy via determination of the cholinesterase status can contribute to an optimal use of resources. In summary, the challenges of current and future therapies for nerve agent poisoning and key diagnostic devices will be discussed.

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“…Production of recombinant human AChE from transgenic plants or mammal cell lines can eliminate the dependence on human blood. An Agrobacterium ‐mediated transient coexpression system in Nicotiana benthamiana plants reported by Rosenberg et al .…”

Section: Exogenous Achementioning

confidence: 99%

“…Radić and coworkers reported a Y337A/F338A mutant of human AChE, which proved resistant against soman aging. Atsmon et al . reported a PEGylated recombinant human AChE with a long plasma half‐life (26.7 h in humans).…”

Section: Exogenous Achementioning

confidence: 99%

Efforts toward treatments against aging of organophosphorus‐inhibited acetylcholinesterase

Zhuang

Young

Callam

et al. 2016

Annals of the New York Academy of Sciences

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Aging is a dealkylation reaction of organophosphorus (OP)-inhibited acetylcholinesterase (AChE). Despite many studies to date, aged AChE cannot be reactivated directly by traditional pyridinium oximes. This review summarizes strategies that are potentially valuable in the treatment against aging in OP poisoning. Among them, retardation of aging seeks to lower the rate of aging through the use of AChE effectors. These drugs should be administered before AChE is completely aged. For postaging treatment, realkylation of aged AChE by appropriate alkylators may pave the way for oxime treatment by neutralizing the oxyanion at the active site of aged AChE. The other two strategies, upregulation of AChE expression and introduction of exogenous AChE, cannot resurrect aged AChE but may compensate for lowered active AChE levels by in situ production or external introduction of active AChE. Upregulation of AChE expression can be triggered by some peptides. Sources of exogenous AChE can be whole blood or purified AChE, either from human or nonhuman species.

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Preclinical and first-in-human evaluation of PRX-105, a PEGylated, plant-derived, recombinant human acetylcholinesterase-R

Cited by 16 publications

References 40 publications

Cholinesterase reactivators and bioscavengers for pre‐ and post‐exposure treatments of organophosphorus poisoning

Cholinesterase reactivators and bioscavengers for pre‐ and post‐exposure treatments of organophosphorus poisoning

Diagnostics and treatment of nerve agent poisoning—current status and future developments

Efforts toward treatments against aging of organophosphorus‐inhibited acetylcholinesterase

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