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(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date PCT (10) International Publication Number 24 July 2008 (24.07.2008) WO 2008/088422 A2 (51) International Patent Classification: Beverly, S. [US/US]; 206 Anne Court, Newbury Park, A61K 38/00 (2006.01) CA 91320 (US). MARTIN, Francis, H. [US/US]; 865 Fernhill Court, Newbury Park, CA 91320 (US). (21) International Application Number: PCT/US2007/022831 (74) Agent: STEINBERG, Nisan, A.; Patent Operations M/S 28-2-C, One Amgen Center Drive, Thousand Oaks, CA (22) International Filing Date: 25 October 2007 (25.10.2007) 91320-1799 (US). (25) Filing Language: English (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, AT,AU, AZ, BA, BB, BG, BH, BR, BW, BY,BZ, CA, CH, (26) Publication Language: English CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, (30) Priority Data: IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, 60/854,674 25 October 2006 (25.10.2006) US LR, LS, LT, LU, LY,MA, MD, ME, MG, MK, MN, MW, 60/995,370 25 September 2007 (25.09.2007) US MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, (71) Applicant (for all designated States except US): AMGEN TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, INC. [US/US]; Patent Operations M/S 28-2-C, One Amgen ZM, ZW Center Drive, Thousand Oaks, CA 91320-1799 (US). (84) Designated States (unless otherwise indicated, for every (72) Inventors; and kind of regional protection available): ARIPO (BW, GH, (75) Inventors/Applicants (for US only): SULLIVAN, John, GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, K. [US/US]; 1085 Rotella Street, Newbury Park, CA ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), 91320 (US). MCGIVERN, Joseph, G. [GB/US]; 6208 European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, Normandy Terrace, Oak Park, CA 91377 (US). MI¬ FR, GB, GR, HU, IE, IS, IT, LT,LU, LV,MC, MT, NL, PL, RANDA, Leslie, P. [AU/US]; 3586 Mapleknoll Place, PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, Thousand Oaks, CA 91362 (US). NGUYEN, Hung, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). Q. [US/US]; 881 Saint Charles Drive, Apt. 10, Thou sand Oaks, CA 91360 (US). WALKER, Kenneth, W. Declaration under Rule 4.17: [US/US]; 175 Mesa Avenue, Newbury Park, CA 91320 — as to applicant's entitlement to applyfor and be granted a (US). HU, Shaw-Fen, Sylvia [US/US]; 986 Lynnmere patent (Rule 4.17(U)) Drive, Thousand Oaks, CA 91360 (US). GEGG, Colin, V., Jr. [US/US]; 3357 Corning Street, Newbury Park, Published: CA 91320 (US). ARORA KHARE, Taruna [US/US]; — without international search report and to be republished 5380 Via Pisa, Thousand Oaks, CA 91320 (US). ADLER, upon receipt of that report (54) Title: TOXIN PEPTIDE THERAPEUTIC AGENTS NMR Structure of OSK1 : some amino acid residues important for Kv1 .3 activity (Fig 89B) and analog sites that improve Kv1 3 selectivity relative to Kv1 1 (Fig 89D). (57) Abstract: Disclosed is a composition of matter comprising an OSKl peptide analog, and in some embodiments, a pharmaceu- tically acceptable salt thereof. A pharmaceutical composition comprises the composition and a pharmaceutically acceptable carrier. Also disclosed are DNAs encoding the inventive composition of matter, an expression vector comprising the DNA, and host cells comprising the expression vector. Methods of treating an autoimmune disorder and of preventing or mitigating a relapse of a symp- torn of multiple sclerosis are also disclosed. Toxin Peptide Therapeutic Agents This application claims priority from U.S. Provisional Application no. 60/854,674, filed October 25, 2006, and U.S. Application no. 60/995,370, filed September 25, 2007, both of which are hereby incorporated by reference. The instant application contains a "lengthy" Sequence Listing which has been submitted via CD-R in lieu of a printed paper copy, and is hereby incorporated by reference in its entirety. Four copies of said CD-R1 recorded on October 19, 2007 are labeled CRF, "Copy 1" , "Copy 2" and "Copy 3", respectively, and each contains only one identical 2.60 Mb file (A-1 186-WO-PCT SeqList.txt). Throughout this application various publications are referenced within parentheses or brackets. The disclosures of these publications in their entireties are hereby incorporated by reference in this application in order to more fully describe the state of the art to which this invention pertains. Background of the Invention 1. Field of the Invention The present invention is related to the biochemical arts, in particular to therapeutic peptides and conjugates. 2 . Discussion of the Related Art Ion channels are a diverse group of molecules that permit the exchange of small inorganic ions across membranes. All cells require ion channels for function, but this is especially so for excitable cells such as those present in the nervous system and the heart. The electrical signals orchestrated by ion channels control the thinking brain, the beating heart and the contracting muscle. Ion channels play a role in regulating cell volume, and they control a wide variety of signaling processes. The ion channel family includes Na , K , and Ca2+ cation and Ch anion channels. Collectively, ion channels are distinguished as either ligand-gated or voltage-gated. Ligand-gated channels include both extracellular and intracellular ligand-gated channels. The extracellular ligand-gated channels include the nicotinic acetylcholine receptor (nAChR), the serotonin (5- hdroxytryptamine, 5-HT) receptors, the glycine and γ-butyric acid receptors (GABA) and the glutamate-activated channels including kanate, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and N-methyl-D-aspartate receptors (NMDA) receptors. (Harte and Ouzounis (2002), FEBS Lett. 514: 129-34). Intracellular ligand gated channels include those activated by cyclic nucleotides (e.g. cAMP, cGMP), Ca2+ and G-proteins. (Harte and Ouzounis (2002), FEBS Lett. 514: 129-34). The voltage-gated ion channels are categorized by their selectivity for inorganic ion species, including sodium, potassium, calcium and chloride ion channels. (Harte and Ouzounis (2002), FEBS Lett. 514: 129-34). A unified nomenclature for classification of voltage-gated channels was recently presented. (Catterall et al. (2000), Pharmacol. Rev. 55: 573-4; Gutman et al. (2000), Pharmacol. Rev. 55, 583-6; Catterall et al. (2000) Pharmacol. Rev. 55: 579-81; Catterall et al. (2000), Pharmacol. Rev. 55: 575-8; Hofmann et al. (2000), Pharmacol. Rev. 55: 587-9; Clapham et al. (2000), Pharmacol Rev. 55: 591-6; Chandy (1991), Nature 352: 26; Goldin et al. (2000), Neuron 28: 365-8; Ertel et al. (2000), Neuron 25: 533-5). The K+ channels constitute the largest and best characterized family of ion channels described to date. Potassium channels are subdivided into three general groups: the 6 transmembrane (6TM) K+ channels, the 2TM-2TM/leak K+ channels and the 2TM/Kir inward rectifying channels. (Tang et al. (2004), Ann. Rev. Physiol. 66, 131-159). These three groups are further subdivided into families based on sequence similarity. The voltage-gated K+ channels, including (Kv1-6, Kv8-9), EAG1 KQT, and SIo (BKCa), are family members of the 6TM group. The 2TM-2TM group comprises TWIK 1 TREK, TASK, TRAAK, and THIK, whereas the 2TM/Kir group consists of Kir1-7. Two additional classes of ion channels include the inward rectifier potassium (IRK) and ATP-gated purinergic (P2X) channels. (Harte and Ouzounis (2002), FEBS Lett. 514: 129-34). Toxin peptides produced by a variety of organisms have evolved to target ion channels. Snakes, scorpions, spiders, bees, snails and sea anemone are a few examples of organisms that produce venom that can serve as a rich source of small bioactive toxin peptides or "toxins" that potently and selectively target ion channels and receptors. In most cases, these toxin peptides have evolved as potent antagonists or inhibitors of ion channels, by binding to the channel pore and physically blocking the ion conduction pathway. In some other cases, as with some of the tarantula toxin peptides, the peptide is found to antagonize channel function by binding to a region outside the pore (e.g., the voltage sensor domain). The toxin peptides are usually between about 20 and about 80 amino acids in length, contain 2-5 disulfide linkages and form a very compact structure (see, e.g., Figure 10). Toxin peptides (e.g., from the venom of scorpions, sea anemones and cone snails) have been isolated and characterized for their impact on ion channels. Such peptides appear to have evolved from a relatively small number of structural frameworks that are particularly well suited to addressing the critical issues of potency and stability. The majority of scorpion and Conus toxin peptides, for example, contain 10-40 amino acids and up to five disulfide bonds, forming extremely compact and constrained structure (microproteins) often resistant to proteolysis. The conotoxin and scorpion toxin peptides can be divided into a number of superfamilies based on their disulfide connections and peptide folds. The solution structure of many of these has been determined by NMR spectroscopy, illustrating their compact structure and verifying conservation of their family fold. (E.g., Tudor et al., lonisation behaviour and solution properties of the potassium-channel blocker ShK toxin, Eur. J. Biochem. 251 (1-2):1 33-41 (1998); Pennington et al., Role of disulfide bonds in the structure and potassium channel blocking activity of ShK toxin, Biochem.
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  • WO 2015/010100 A2 22 January 2015 (22.01.2015) P O P C T

    WO 2015/010100 A2 22 January 2015 (22.01.2015) P O P C T

    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2015/010100 A2 22 January 2015 (22.01.2015) P O P C T (51) International Patent Classification: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, C40B 30/04 (2006.01) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, (21) International Application Number: KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, PCT/US20 14/0473 15 MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, (22) International Filing Date: OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, 18 July 2014 (18.07.2014) SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, (25) Filing Language: English ZW. (26) Publication Language: English (84) Designated States (unless otherwise indicated, for every (30) Priority Data: kind of regional protection available): ARIPO (BW, GH, 61/856,010 18 July 2013 (18.07.2013) US GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, (71) Applicant: FABRUS, INC. [US/US]; 11099 North Torrey TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, Pines Road, Suite 230, La Jolla, CA 92037 (US). EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, (72) Inventors: BAZIRGAN, Omar; 11099 North Torrey TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, Pines Road, Suite 230, La Jolla, CA 92037 (US).