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(12) Patent Application Publication (10) Pub. No.: US 2009/0208480 A1 Huang Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2009/0208480 A1 Huang Et Al US 20090208480A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0208480 A1 Huang et al. (43) Pub. Date: Aug. 20, 2009 (54) LONG HALF-LIFE RECOMBINANT Related U.S. Application Data BUTYRYLCHOLINESTERASE (60) Provisional application No. 60/835,827, filed on Aug. 4, 2006. (76) Inventors: Yue Huang, Vaudreuil-Dorion O O (CA); Harvey Wilgus, Beaconsfield Publication Classification (CA) (51) Int. Cl. A638/46 (2006.01) Correspondence Address: CI2N 9/18 (2006.01) Alan J. Grant A6IP39/00 (2006.01) Carella Byrne Brain Giffillan Cecchi StwartOlstein (52) U.S. Cl. ........................................ 424/94.6; 435/197 5 Becker Farm (57) ABSTRACT Roseland, NJ 07068 (US) The present invention provides for butyrylcholinesterase (BChE) attached to polyethylene glycol (PEG) to form a (21) Appl. No.: 12/309,909 complex having greatly increased mean residence time (MRT) in the system of an animal following injection there (22) PCT Filed: Aug. 2, 2007 into. Also disclosed are compositions of Such complexes, methods of preparing these complexes and method for using (86). PCT No.: PCT/US07/17279 these complexesp and compositionsp in the treatment and/or prevention of toxic effects of poisons, such as neurotoxins, to S371 (c)(1), which said animals, such as humans, have been, or may (2), (4) Date: Feb. 2, 2009 become, exposed. 1 2 3 4 Patent Application Publication Aug. 20, 2009 Sheet 1 of 2 US 2009/0208480 A1 Patent Application Publication Aug. 20, 2009 Sheet 2 of 2 US 2009/0208480 A1 SB 4 3 O O S. 2 5. ( 8 CD SS is'a J O N 9 lat1-al- Y O & S & 3 S & (u/n) ANOeguo US 2009/020848.0 A1 Aug. 20, 2009 LONG HALF-ILFE RECOMBINANT (Soman), a highly toxic organophophate compound used as a BUTYRYLCHOLINESTERASE chemical weapon (Broomfield et al., J. Pharmacol. Exp. Ther., 1991, 259:633-638; Wolfe et al., Toxicol, Appl. Phar macol., 1992, I17(2):189-193). Administration of sufficient 0001. This application claims priority of U.S. Provisional exogenous human BChE can protect mice, rats, and monkeys Application 60/835,827, filed 4 Aug. 2006, the disclosure of from multiple lethal-dose organophosphate intoxication which is hereby incorporated by reference in its entirety. (See, e.g., Raveh et al., Biochemical Pharmacology, 1993, 42:2465-2474: Raveh et al., Toxicol. Appi. Pharmacol., 1997, FIELD OF THE INVENTION 145:43-53: Allonetal, Toxicol. Sei., 1998,43:121-128). Puri fied human BChE has been used to treat organophosphate 0002. This invention relates to the chemical modification poisoning in humans, with no significant adverse immuno of butyrylcholinesterase (BChE) by polyethylene glycol logical or psychological effects (Cascio et al., Minerva Anes (PEG) to improve circulatory mean residence time (MRT) of tesiol., 1998, 54:337). the protein and reduce protein immunogenicity for pharma 0007 Titration of organophosphates both in vitro and in ceutical and bio-defense applications. Vivo demonstrates a 1:1 stoichiometry between organophos phate-inhibited enzymes and the cumulative dose of the toxic BACKGROUND OF THE INVENTION nerve agent. 0003 Use of organophosphate and related compounds as 0008 Modification of pharmaceuticals by polyethylene pesticides and in warfare over the last several decades has glycol (PEG) has been reported to improve half-life and resulted in a rising number of cases of acute and delayed reduce immunogenicity. Proteins modified by PEG and intoxication, causing damage to the peripheral and central approved by the FDA include: ADAGENR) (pegademase nervous systems and resulting in myopathy, psychosis, gen bovine) by Enzon, ONCASPAR (Pegaspargase) by Enzon, eral paralysis, and death. Such noxious agents act by inhibit PEGASYSR (peginterferon alfa-2a) by Roche, PEG-IN ing cholinesterase enzymes and thereby prevent the break TRONR) (peginterferon alfa-2b) by Schering-Plough and down of neurotransmitters, such as acetylcholine, causing MACUGENR) (pegabtanib) by Eyetech & Pfizer Inc. hyperactivity of the nervous system. For example, build-up of 0009 PEG can be attached to proteins at a variety of sites, acetylcholine causes continued stimulation of the muscarinic including amino groups, such as those on lysine residues, or receptor sites (exocrine glands and Smooth muscles) and the at the N-terminus, as well as thiol groups on cysteine, or other nicotinic receptor sites (skeletal muscles). In addition, expo reactive groups on the protein Surface. Sure to cholinesterase-inhibiting Substances can cause symp 0010. However, PEG modification of proteins, such as toms ranging from mild (e.g., twitching, trembling) to severe enzymes, is known to present some problems such as: 1) (e.g., paralyzed breathing, convulsions), and in extreme non-specific attachment sites, 2) reduction or loss of biologic cases, death, depending on the type and amount of cholinest activities (such as enzyme activity), and 3) outcome of PEGy erase-inhibiting substances involved. The action of cholinest lation is often unpredictable. Ideally, attachment of a PEG to, erase-inhibiting Substances such as organophosphates and for example, a protein should increase circulatory time of the carbamates makes them very effective as pesticides, such as drug in an animal. Such as a human, as well as reduce immu for controlling insects. When mammals, such as humans, are nogenicity and in vivo degradation. exposed to these compounds (e.g., by inhalation), they often 0011. Butyrylcholinesterase (BChE) can be found in experience the same negative effects. nature in the form of monomers, dimers and tetramers. BChE 0004. The devastating impact of certain cholinesterase may also be produced by recombinant techniques, including inhibiting Substances on humans has led to the development production in transgenic animals. Produced transgenically of these compounds as “nerve gases” or chemical warfare (referred to by the name PROTEXIATM) BChE is a mixture of agents. Nerve agents are among the most toxic. Such com dimer and monomer with a small percentage of tetramer. For pounds are related to organophosphorus insecticides in that example, transgenic recombinant BChE Secreted in goat's they are both esters of phosphoric acid. Major nerve agents milk is about 80% dimers and 20% monomers (determined by include diisopropylfluorophosphate (DFP), GA (tabun), GB SEC-HPLC chromatography followed by Ellman activity (sarin), GD (soman), CF (cyelosarin), GE, CV, yE.V.G (ami assay of collected fractions). ton), VM, VR (RVX or Russian VX), VS, and VX. 0005 Organophosphate poisoning is currently treated by BRIEF SUMMARY OF THE INVENTION intravenous or intramuscular administration of combinations 0012. In one aspect, the present invention relates to PEGy of drugs, including carbamates (e.g., pyridostigmine), anti lated (meaning attached to PEG polyethylene glycol) muscarinics (e.g., atropine), and ChE-reactivators such prali recombinant butyrylcholinesterase (PEG-BChE), such as is doxime chloride (2-PAM, Protopam). One approach has ulti produced in the milk of transgenic goats. lized cholinesterase enzymes for the treatment of 0013. In a specific embodiment, the activated PEG organophosphate exposure. Post-exposure toxicology can be reagents include mono-functional methoxy-activated poly prevented by pretreatment with cholinesterases, which act to mer of Succinimidyl derivatives such as Succinimidyl propi sequester the toxic organophosphates before they reach their onic acid, C.-methylbutanoate, and N-Hydroxysucciminidyl. physiological targets. These reagents facilitate attachment of PEG to the amino 0006 Use of cholinesterases as pre-treatment drugs has groups of the protein. been Successfully demonstrated in animals, including non 0014. In a specific and non-limiting embodiment, the acti human primates. For example, pretreatment of rhesus mon vated PEG reagents are mono-functional methoxy-activated keys with fetal bovine serum-derived AChE or horse serum polymer bearing aldehyde groups such as Butyraldehydyl derived BChE protected them against a challenge of two to PEG. The N-terminal amino group of the protein is specifi five times the LD50 of pinacolyl methylphosphonofluoridate cally targeted by these reagents. US 2009/020848.0 A1 Aug. 20, 2009 0015. In another specific and non-limiting embodiment, comprising providing an effective amount of a nerve agent the activated PEG reagents are mono-functional methoxy neutralizing enzyme, preferably PEG-BChE, especially activated PEG with o-pyridylthioester. N-terminal thiol where said agent is delivered systemically, such as by injec groups (cysteine) is specifically target by these reagents. tion. Specific and non-limiting Subjects are any animals in 0016. In a further specific and non-limiting embodiment, need of protection from nerve agents, preferably mammals, the activated PEG reagents are thiol group specific Such as most preferably human beings. Maleimide coupling PEG. Free thiol group (cysteine) on a 0026. Alternatively, PEG-BChE agent is in a liquid form. protein can be specifically target by these reagents. In a such an embodiment, the PEG-BChE may further com 0017. In another embodiment; the activated PEG reagents prise an excipient. In a further such embodiment, PEG-BChE are linked to sialic acid, which facilitates targeting of glycans is administered with an inhaler or a nebulizer. on BChE. 0027. In still another embodiment, the PEG-BChE is con 0018. In other embodiments, the activated PEG reagents tained in a dry powder form. In Such an embodiment, the can be linear PEG, such as mPEG-SPA, branched PEG, such nerve
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