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

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 50 nmol/kg PRX-105, 2 min before being exposed to 1.33 × LD{sub 50} and 1.5 × LD{sub 50} of toxin and 10 min after exposure to 1.5 × LD{sub 50} survived. The pharmacokinetic and toxicity profiles of PRX-105 were evaluated in mice and mini-pigs. Following single and multiple IV doses (50 to 200 mg/kg) no deaths occurred and no significant laboratory and histopathological changes were observed. The overall elimination half-life (t{sub ½}) 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 t{sub ½} in humans wasmore » substantially longer than in mice (average 26.7 h). 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. - Highlights: • PRX-105 is a PEGylated plant-derived recombinant human acetylcholinesterase-R. • PRX-105 is a promising bio-scavenger for organophosphorous toxins at lethal doses. • PRX-105 was shown to protect animals both prophylactically and post-poisoning. • First-in-human study exhibited its safety, tolerability and pharmacokinetics. • Toxicokinetic animal studies have shown a favorable safety profile.« less
Authors:
 [1] ;  [2] ; ; ; ;  [3] ; ; ;  [1] ;  [2] ;  [3] ;  [3] ; ; ;  [3] ;  [4] ;  [3]
  1. Clinical Research Center, Tel Aviv Sourasky Medical Center, Tel Aviv (Israel)
  2. (Israel)
  3. Protalix Biotherapeutics, Science Park, Carmiel (Israel)
  4. Department of Biological Chemistry, Institute of Life Sciences, The Hebrew University of Jerusalem (Israel)
Publication Date:
OSTI Identifier:
22465820
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 287; Journal Issue: 3; Other Information: Copyright (c) 2015 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; AFFINITY; CHEMICAL WARFARE AGENTS; DIAGRAMS; EVALUATION; HALF-LIFE; HUMAN POPULATIONS; LETHAL DOSES; MICE; PESTICIDES; PLANTS; POISONING; PREVENTIVE MEDICINE; SAFETY; SWINE; TOXICITY; TOXINS