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(12) Patent Application Publication (10) Pub. No.: US 2016/0184445 A1 Perroth Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2016/0184445 A1 Perroth Et Al US 2016O184445A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0184445 A1 Perroth et al. (43) Pub. Date: Jun. 30, 2016 (54) BUTYRYLCHOLINESTERASE Publication Classification ZWITTERONIC POLYMER CONUGATES (51) Int. Cl. (71) Applicant: Kodiak Sciences Inc., Palo Alto, CA A647/48 (2006.01) (US) CI2N 9/18 (2006.01) CI2N 9/96 (2006.01) (72) Inventors: D. Victor Perlroth, Palo Alto, CA (US); A638/46 (2006.01) Stephen A. Charles, Ravenna, OH (US); C07K 7/08 (2006.01) Wayne To, San Mateo, CA (US); (52) U.S. Cl. Xiaojian Huang, Mountain View, CA CPC ......... A61K 47/48 176 (2013.01); A61 K38/465 (US); Martin Linsell, San Mateo, CA (2013.01); C07K 7/08 (2013.01); C12N 9/96 (US); Didier Benoit, San Jose, CA (US) (2013.01); C12N 9/18 (2013.01); C07K 2319/30 (2013.01); C12Y-301/01008 (2013.01) (21) Appl. No.: 14/932,913 (22) Filed: Nov. 4, 2015 (57) ABSTRACT Related U.S. Application Data The present invention provides recombinant butyrylcho (63) Continuation of application No. PCT/US2015/ linesterase fusion proteins, including Fc fusion proteins and 0561 12, filed on Oct. 16, 2015. multi-armed high MW polymers containing hydrophilic (60) Provisional application No. 62/065,471, filed on Oct. groups conjugated to the fusion proteins, and methods of 17, 2014. preparing Such polymers. Patent Application Publication Jun. 30, 2016 Sheet 1 of 5 US 2016/O1844.45 A1 900 800 700 600 500 400 300 200 100 -5 5 15 25 35 TIME (DAYS) FIG. 1 Patent Application Publication Jun. 30, 2016 Sheet 2 of 5 US 2016/O1844.45 A1 800 700 600 500 --R2709 at 37 degree 400 -A-R5743 at 37 degree -HR2709 at 4 degree 300 -A-R5743 at 4 degree 2 12 22 32 TIME (DAYS) FIG.2 Patent Application Publication Jun. 30, 2016 Sheet 3 of 5 US 2016/O1844.45 A1 §===========(---) 0'08 0'000€ 0'0007 0'000€ Patent Application Publication Jun. 30, 2016 Sheet 4 of 5 US 2016/O1844.45 A1 25% 20% 15% 10% 5% O% O 5 10 15 20 25 30 TIME (DAYS) FIG. 4 Patent Application Publication Jun. 30, 2016 Sheet 5 of 5 US 2016/O1844.45 A1 FIG. 5 O CH HC O O R1 O O ouls O NH ul AMAC CH - 1n- N-1\-1N-1 N CH3 o O C MPC O US 2016/01 84445 A1 Jun. 30, 2016 BUTYRYLCHOLINESTERASE serum-derived), the same enzyme which OPs irreversibly ZWITTERONIC POLYMER CONUGATES inactivate, when administered prophylactically was able to protect rhesus monkeys against a challenge of two to five CROSS REFERENCE TO RELATED times the LD50 of 3,3-Dimethylbutan-2-yl methylphospho APPLICATIONS nofluoridate (soman) a highly toxic OP nerve agent designed 0001. The present application is a continuation of PCT for chemical warfare. Wolfe, A. D., et al., (1992) Use of PCT/US2015/0561 12 filed Oct. 16, 2015, which is a nonpro cholinesterases as pretreatment drugs for the protection of visional of 62/065,471 filed Oct. 17, 2014, each incorporated rhesus monkeys against Soman toxicity. Toxicol. Appl Phar by reference in its entirety for all purposes. macol. 117:189-193. 0007 AChE is a member of the carboxyl/cholinesterases (CE/ChEs), a multi-gene family of enzymes that hydrolyze a REFERENCE TO ASEQUENCE LISTING diverse range of carboxylesters. Members of the family 0002 Sequences are provided in an ASCII txt filed desig include AChE, human carboxylesterase 1 (hCE1) and 2 nated 470678 SEQLST.TXT, of 84,727 bytes, created Oct. (hCE2) and butyrylcholinesterase (BuChE). Of these, BChE 16, 2015, incorporated by reference. has generated the greatest interest as a bioscavenger. BuChE is the major cholinesterase in human serum. Although the BACKGROUND closely related enzyme AChE is well described as the primary synaptic regulator of cholinergic transmission, a definitive 1. BioScavengers physiological role for BChE has not yet been demonstrated. 0003 Organophosphorus compounds (OPs) are highly 0008 BuOhE is catalytically promiscuous and hydrolyzes toxic to humans. First developed in the 1930s as insecticides, not only acetylcholine (ACh), but also longer-chain choline the extreme toxicity of OPs to humans eventually led to their esters (e.g., butyrylcholine, its preferred Substrate, and Succi development as nerve agents for warfare. Today, although nylcholine) and a variety of non-choline esters, such as ace generally banned by international law, OPs are considered an tylsalicylic acid (aspirin) and cocaine. Moreover, BuChE ever increasing military and civilian threat. In 1995, the binds most environmentally occurring ChE inhibitors as well Tokyo Subway system was the Subject of a sarin attack, killing as man-made OP pesticides and nerve agents. However, the over a dozen passengers and injuring scores of others. Sarin physiologically available levels of natural BuChE are too low gas has also been reported to have been recently used on to give any meaningful protection with regard to OPs. surface to surface missiles in conflicts in Syria with lethal 0009 BuChE purified from human serum has been used to effect. treat humans Patients successfully received a partially puri 0004 OP nerve agents such as sarin are potent inhibitors fied human BuOhE to counteract the effects of muscle relax of acetylcholinesterase. In vertebrates, acetylcholine is the ants and for OP pesticide poisoning. Cascio, C., et al. (1988) neurotransmitter used to transmit signals from the nervous The use of serum cholinesterase in severe phosphorous poi system to muscle fibers. Normally, acetylcholine is released soning. Minerva Anestesiol (Italian) 54:337-345. However, from a neuron to stimulate a muscle. After stimulation, ace products purified from human serum are highly undesirable tylcholinesterase metabolizes acetylcholine, allowing the due to the threat of contamination by unknown blood borne muscle to relax. OPs such as sarin, however, irreversibly pathogens which of course cannot be tested for. In this regard, inhibit acetylcholinesterase, inhibiting degradation of acetyl for example, FVIII for treatment of hemophilia is produced choline. OP nerve agents are generally lethal at very small today by recombinant DNA technology and is no longer doses with Subjects generally Succumbing to Some type of purified from human serum after thousands of patients asphyxia. Subjects receiving less than lethal doses of OPs became infected with the HIV virus in the late 70s and early may develop permanent neurological damage. In addition, 80s. In addition, production of serum purified BuChE is OP pesticides are still in wide use. Although OP pesticides are severely limited by the volume of serum available. Lockridge, far less toxic than nerve agents, OP pesticide toxicity to O., et al. (2005) J. Med. Chem. Biol. Radiol. Def. humans is still of great concern. 3:nimhS5095. 0005 Antidotes and treatment for OP poising are 0010. To avoid using blood serum purified BuChE, recom extremely limited. There are small molecule treatments for binant BuChE (rBuChE) was produced in Escherichia coli. OP poisoning symptoms (e.g. tremors). Overall, however, Masson, P. (1992) in Multidisciplinary Approaches to Cho these therapies are of very limited benefit. Atropine may be linesterase Functions, eds Shafferman, A., Velan, B. (Plenum, administered for muscarinic ACh receptor blockade and diaz New York) pp. 49-52. The produced protein, however, was epam for symptomatic management of convulsions. Lee E.C. non-functional. rBuChE was also produced in mammalian (2003) Clinical manifestations of sarin nerve gas exposure. J. 293T (Altamirano, C. V. and Lockridge, O. (1999) Chem. Am. Med. Assoc. 290:659-662. Additionally, oxime therapy Biol. Interact. 119-120:53-60) and CHO (Millard, C. B., with 2-pralidoxime (2-PAM) can effectively reactivate some Lockridge, O., and Broomfield, C. A. (1995) Biochemistry but not all OP-AChE adducts. Cannard, K. (2006) The acute 34:15925-15933). The mammalian expression systems, how treatment of nerve agent exposure. J Neurol Sci 249:86-94. ever, failed to produce Sufficient quantities of protein Such Although these therapies can reduce mortality in cases of less that the need for plasma purified BuChE could be eliminated. toxic OPs such as insecticides or very low doses of nerve Given the difficulties experienced with mammalian cellular agents, they are generally seen by clinicians as highly inef expression systems, transgenic goats were created having the fective with regard to possible battlefield levels of exposure to human BuChE gene under the control of the goat B-casein OP nerve agents. promoter, allowing the produced rBuChE to be purified from 0006 For prophylactic anti-OP therapy, it has been found goat milk. Huang, Y. J. et al (2007) Recombinant human that certain enzymes will detoxify OPs such as sarin by acting butyrylcholinesterase from milk of transgenic animals to pro as bioscavengers. Acetylcholinesterase (AChE) (fetal bovine tect against organophosphate poisoning. Proc. Nat. Acad. Sci. US 2016/01 84445 A1 Jun. 30, 2016 104(34): 13603-13608. However, when the transgenic goat which is necessary for reductive animation conjugation. rBuChE was tested in animals, the PK and bioavailability Wang, X. Kumar, S., and Singh, S. (2011) Disulfide Scram results were very disappointing for the enzyme both itself and bling in IgG2 Monoclonal Antibodies: Insights from Molecu the enzyme conjugated to PEG. rBuChE produced in trans lar Dynamics Simulations. Pharm. Res. 28, 3128-3143. genic goats did not apparently have a residence time similar to Moreover, most proteins have several amine residues avail native human BuChE purified from plasma to allow it to be able for reaction. Hence, amine PEG conjugates tend not to be developed as an agent for the prophylaxis of OP poisoning. site specific, resulting in heterogeneous mixtures of different 0.011 Thus there remains a need for recombinant versions PEG-protein conjugates in the final product. Veronese, F.
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