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 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.

Safety and immunogenicity of multimeric-001--a novel universal influenza vaccine.

OBJECTIVE: A new vaccine, Multimeric-001, containing conserved linear epitopes from the HA, NP, and M1 proteins of influenza type A and type B strains was designed to protect against seasonal and pandemic influenza virus strains, regardless of mutations. We assessed its safety and tolerability and characterized humoral and cellular immune responses elicited by its administration. METHODS: Sixty healthy volunteers received either 250 or 500 µg injections, with or without adjuvant (Montanide ISA 51VG), or matching placebo. Two intramuscular injections were administered, 21 days apart. RESULTS: Treatment was well tolerated and no significant adverse events were noted. Forty-two days after first injection, there was a 50-fold and 37-fold increase in IgG titers against Multimeric-001 protein, following the adjuvanted 500 and 250 µg doses, respectively. Sera from immunized subjects lysed MDCK cells infected with strains of influenza representing the major strains that infect humans: H1N1, H3N2, and influenza B. Proliferation of peripheral blood mononuclear cells as well as increase in IL-2 and IFN-gamma secretion occurred following incubation with the vaccine. CONCLUSION: This vaccine model differs fundamentally from the current influenza virus vaccines, as it does not contain the variable regions of the virus hemagglutinin and hence does not induce hemagglutination inhibition antibodies that serve as surrogate markers for protection. In order to demonstrate the potential efficacy of the Multimeric-001, an alternative assay was employed, in which the lysis of MDCK cells infected with different virus strains was shown, with the involvement of the complement mechanism. The humoral and cellular responses suggest a cross-immunity of the vaccine toward influenza virus strains regardless of mutations. These results corroborate the protective effect of the vaccine, previously shown in animals. Larger-scale studies are under way to further substantiate the safety and efficacy of the vaccine candidate.