title: Preclinical and first-in-human evaluation of PRX-105, a PEGylated, plant-derived, recombinant human acetylcholinesterase-R.
abstract: PRX-105 is a plant-derived recombinant version of the human 'read-through' acetylcholinesterase splice variant (AChE-R). Its active site structure is similar to that of the synaptic variant, and it displays the same affinity towards organophosphorus (OP) compounds. As such, PRX-105 may serve as a bio-scavenger for OP pesticides and chemical warfare agents. To assess its potential use in prophylaxis and treatment of OP poisoning we conducted several preliminary tests, reported in this paper. Intravenous (IV) PRX-105 was administered to mice either before or after exposure to an OP toxin. All mice who received an IV dose of 50nmol/kg PRX-105, 2min before being exposed to 1.33×LD50 and 1.5×LD50 of toxin and 10min after exposure to 1.5×LD50 survived. The pharmacokinetic and toxicity profiles of PRX-105 were evaluated in mice and mini-pigs. Following single and multiple IV doses (50 to 200mg/kg) no deaths occurred and no significant laboratory and histopathological changes were observed. The overall elimination half-life (t½) in mice was 994 (±173) min. Additionally, a first-in-human study, to assess the safety, tolerability and pharmacokinetics of the compound, was conducted in healthy volunteers. The t½ in humans was substantially longer than in mice (average 26.7h). Despite the small number of animals and human subjects who were assessed, the fact that PRX-105 exerts a protective and therapeutic effect following exposure to lethal doses of OP, its favorable safety profile and its relatively long half-life, renders it a promising candidate for treatment and prophylaxis against OP poisoning and warrants further investigation.
authors.affiliation: Clinical Research Center, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Sackler Faculty of Medicine, Tel Aviv University, Israel.
authors.forename: Jacob
authors.initials: J
authors.lastname: Atsmon
authors.affiliation: Protalix Biotherapeutics, Science Park, Carmiel, Israel.
authors.forename: Einat
authors.initials: E
authors.lastname: Brill-Almon
authors.affiliation: Protalix Biotherapeutics, Science Park, Carmiel, Israel.
authors.forename: Carmit
authors.initials: C
authors.lastname: Nadri-Shay
authors.affiliation: Protalix Biotherapeutics, Science Park, Carmiel, Israel.
authors.forename: Raul
authors.initials: R
authors.lastname: Chertkoff
authors.affiliation: Protalix Biotherapeutics, Science Park, Carmiel, Israel.
authors.forename: Sari
authors.initials: S
authors.lastname: Alon
authors.affiliation: Clinical Research Center, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Sackler Faculty of Medicine, Tel Aviv University, Israel.
authors.forename: Dimitri
authors.initials: D
authors.lastname: Shaikevich
authors.affiliation: Clinical Research Center, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Sackler Faculty of Medicine, Tel Aviv University, Israel.
authors.forename: Inna
authors.initials: I
authors.lastname: Volokhov
authors.affiliation: Clinical Research Center, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Sackler Faculty of Medicine, Tel Aviv University, Israel.
authors.forename: Kirsten Y
authors.initials: KY
authors.lastname: Haim
authors.affiliation: Protalix Biotherapeutics, Science Park, Carmiel, Israel.
authors.forename: Daniel
authors.initials: D
authors.lastname: Bartfeld
authors.affiliation: Protalix Biotherapeutics, Science Park, Carmiel, Israel. Electronic address: avidors@protalix.com.
authors.forename: Avidor
authors.initials: A
authors.lastname: Shulman
authors.affiliation: Protalix Biotherapeutics, Science Park, Carmiel, Israel.
authors.forename: Ilya
authors.initials: I
authors.lastname: Ruderfer
authors.affiliation: Protalix Biotherapeutics, Science Park, Carmiel, Israel.
authors.forename: Tehila
authors.initials: T
authors.lastname: Ben-Moshe
authors.affiliation: Protalix Biotherapeutics, Science Park, Carmiel, Israel.
authors.forename: Orit
authors.initials: O
authors.lastname: Shilovitzky
authors.affiliation: Department of Biological Chemistry, Institute of Life Sciences, The Hebrew University of Jerusalem, Israel.
authors.forename: Hermona
authors.initials: H
authors.lastname: Soreq
authors.affiliation: Protalix Biotherapeutics, Science Park, Carmiel, Israel.
authors.forename: Yoseph
authors.initials: Y
authors.lastname: Shaaltiel
mesh_terms: D000110:Acetylcholinesterase / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000328:Adult; D000818:Animals; D000931:Antidotes / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D002626:Chemistry, Pharmaceutical; D004195:Disease Models, Animal; D005260:Female; D058851:GPI-Linked Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D007275:Injections, Intravenous; D007557:Israel; D008297:Male; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D062025:Organophosphate Poisoning / Q000188:drug therapy* / Q000517:prevention & control*; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D011994:Recombinant Proteins; D013552:Swine; D013556:Swine, Miniature; D055815:Young Adult
chemical_list: D000931:Antidotes; D058851:GPI-Linked Proteins; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; C548244:ACHE protein, human; D000110:Acetylcholinesterase; C000602637:PRX-105
keywords: AChE-R; First-in-human; Organophosphorous; Preclinical; Prophylaxis