(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 25 March 2010 (25.03.2010) WO 2010/033207 Al (51) International Patent Classification: [US/US]; 126 Fred Atkinson Road, Huntsville, AL 35806 A61K 47/48 (2006.01) (US). ALI, Cherie [US/US]; 315 Howard Avenue, Burlingame, CA 94010 (US). BREW, Christine, Taylor (21) International Application Number: [US/US]; 836 Corona Drive, Pacifica, CA 94044 (US). PCT/US2009/005 192 (74) Agents: WILSON, Mark, A. et al; Nektar Therapeutics, (22) International Filing Date: 201 Industrial Road, San Carlos, CA 94070 (US). 17 September 2009 (17.09.2009) (81) Designated States (unless otherwise indicated, for every (25) Filing Language: English kind of national protection available): AE, AG, AL, AM, (26) Publication Language: English AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, (30) Priority Data: DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, 61/192,672 19 September 2008 (19.09.2008) US HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, 61/208,089 18 February 2009 (18.02.2009) US KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, 61/153,966 19 February 2009 (19.02.2009) us ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, (71) Applicant (for all designated States except US): NEK- NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, TAR THERAPEUTICS [US/US]; 201 Industrial Road, SE, SG, SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT, San Carlos, CA 94070 (US). TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (72) Inventors; and (84) Designated States (unless otherwise indicated, for every (75) Inventors/Applicants (for US only): BOSSARD, Mary, kind of regional protection available): ARIPO (BW, GH, J. [US/US]; 120 Kelvingrove Drive, Madison, AL 35758 GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, (US). ROCZNIAK, Steven, O. [US/US]; 678 Emerald ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, Hill Road, Redwood City, CA 94061 (US). ZAPPE, TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, Harold [ZA/US]; 505 Orville Smith Road, Harvest, CA ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, SM, 35759 (US). WANG, Yujun [CN/US]; 160 Rainbow TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, Glen Circle, Madison, CA 35758 (US). ZHANG, Ping ML, MR, NE, SN, TD, TG). [US/US]; 215 Park Stone Drive, Madison, AL 35758 (US). SHENG, Dawei [CN/US]; 158 Silo Hill Road, Published: Madison, AL 35758 (US). JUDE-FISHBURN, C , Si- — with international search report (Art. 21(3)) mone [GB/US]; 186 Elwood Street, Redwood City, AL 94062 (US). MINAMITANI, Elizabeth [US/US]; 144 — before the expiration of the time limit for amending the Nappier Lane, Laceys Spring, AL 35754 (US). LIU, Xi- claims and to be republished in the event of receipt of aofeng [CN/US]; 5170 Seaside Court, Union City, CA amendments (Rule 48.2(h)) 94587 (US). MOSKOWITZ, Haim [US/US]; 6159 Blue — with sequence listing part of description (Rule 5.2(a)) Dawa Trail, San Diego, CA 92130 (US). FRY, Dennis (54) Title: POLYMER CONJUGATES OF THERAPEUTIC PEPTIDES (57) Abstract: The invention provides peptides that are chemically modified by covalent attachment of a water-soluble oligomer. A conjugate of the invention, when administered by any of a number of administration routes, exhibits characteristics that are dif ferent from the characteristics of the peptide not attached to the water-soluble oligomer. POLYMER CONJUGATES OF THERAPEUTIC PEPTIDES CROSS REFERENCE TO RELATED APPLICATION [0001] This application claims the benefit of priority under 35 U.S.C. § 1 19(e) to U.S. Provisional Patent Application Serial No. 61/153,966, filed 19 February 2009, to U.S. Provisional Patent Application Serial No. 61/208,089, filed 18 February 2009, to U.S. Provisional Patent Application Serial No. 61/192,672, filed 19 September 2009,the disclosures of which are incorporated herein by reference in their entirety. FIELD OF THE INVENTION [0002] Among other things, the present invention relates to conjugates comprising a therapeutic peptide moiety covalently attached to one or more water-soluble polymers. BACKGROUND OF THE INVENTION [0003] In many ways, the chemical and biological properties of peptides make them very attractive candidates for use as therapeutic agents. Peptides are naturally occurring molecules made up of amino acid building blocks, and are involved in countless physiological processes. With 20 naturally occurring amino acids, and any number of non- naturally occurring amino acids, a nearly endless variety of peptides may be generated. Additionally, peptides display a high degree of selectivity and potency, and may not suffer from potential adverse drug-drug interactions or other negative side effects. Moreover, recent advances in peptide synthesis techniques have made the synthesis of peptides practical and economically viable. Thus peptides hold great promise as a highly diverse, highly potent, and highly selective class of therapeutic molecules with low toxicity. [0004] A number of peptides have been identified as therapeutically promising; however in vitro results have often not proven to bear out in vivo. Significantly, peptides suffer from a short in vivo half life, sometimes mere minutes, making them generally impractical, in their native form, for therapeutic administration. Thus there exists a need in the art for modified therapeutic peptides having an enhanced half-life and/or reduced clearance as well as additional therapeutic advantages as compared to the therapeutic peptides in their unmodified form. SUMMARY OF THE INVENTION [0005] Accordingly, the present invention provides conjugates comprising a therapeutic peptide moiety covalently attached to one or more water-soluble polymers. The water-soluble polymer may be stably bound to the therapeutic peptide moiety, or it may be releasably attached to the therapeutic peptide moiety. [0006] The invention further provides methods of synthesizing such therapeutic peptide polymer conjugates and compositions comprising such conjugates. The invention further provides methods of treating, preventing, or ameliorating a disease, disorder or condition in a mammal comprising administering a therapeutically effective amount of a therapeutic peptide polymer conjugate of the invention. [0007] Additional embodiments of the present conjugates, compositions, methods, and the like will be apparent from the following description, examples, and claims. As can be appreciated from the foregoing and following description, each and every feature described herein, and each and every combination of two or more of such features, is included within the scope of the present disclosure provided that the features included in such a combination are not mutually inconsistent. In addition, any feature or combination of features may be specifically excluded from any embodiment of the present invention. Additional aspects and advantages of the present invention are set forth in the following description and claims, particularly when considered in conjunction with the accompanying examples and drawings. BRIEF DESCRIPTION OF DRAWINGS Figure KISSl .1 : Cation exchange purification of the PEGylation reaction mixture. Figure KISSl. 2: RP-HPLC analysis of purified [mono]-[mPEG-ButyrALD-30K]- [Kisspeptin-13]. Figure KISS 1.3 MALDI-TOF spectrum of purified [mono]-[mPEG-ButyrALD-30K]- [Kisspeptin-13]. Figure KISS2.1 . Typical reversed phase purification profile of [mono]-[mPEG- ButyAldehyde-10K]-[Kisspeptin- 10]. Figure KISS2.2 Purity analysis of mono-[ButyrAldehyde-10K]-[Kisspeptin-10] by Reversed Phase HPLC. Figure KISS2.3. MALDI-TOF spectrum of purified mono-[mPEG-butyraldehyde-1 Ok]- [Kisspeptin-10]. Figure KISS3 .1. Typical reversed phase purification profile of [mono]-[mPEG- ButyAldehyde-30K]-[Kisspeptin-10]. Figure KISS3.2. Purity analysis of mono-[ButyrAldehyde-30K]-[Kisspeptin-l] by Reversed Phase HPLC. Figure KISS3.3. MALDI-TOF spectrum of purified mono-[mPEG-Butyraldehyde-30K]- [Kisspeptin-10]. Figure KISS4. 1. Typical reversed phase purification profile of mono-[mPEG2-CAC-FMOC- 40K]-[Kisspeptin-10]. Figure KISS4.2. Purity analysis of [mono]-[CAC-PEG2-FOMC- 40K]-[Kisspeptin-10] by Reversed Phase HPLC. Figure KISS4.3. MALDI-TOF spectrum of purified mono-[CAC-PEG2-FMOC-40K]- [Kisspeptin-10]. Figure KISS5. 1. Typical reversed phase purification profile of mono-[mPEG-SBC-30K]- [Kisspeptin-10]. Figure KISS5.2. SDS-PAGE, with Coomassie blue staining) of purified mono-[mPEG-SBC- 30K]-[Kisspeptin-10]. Figure KISS5.3. Purity analysis of mono-[mPEG-SBC-30K]-[Kisspeptin-10] by Reversed Phase HPLC. Figure KISS5.4. MALDI-TOF spectrum of purified mono-[mPEG-SBC-30k]-[Kisspeptin- 10]. Figure KISS6.1 Typical cation exchange purification profile of mono-[mPEG2- ButyrAldehyde-40K]-[Kisspeptin-54]. Figure KISS6.2. Purity analysis of [mono]-[mPEG2-ButyrAldehyde-40K]-[Kisspeptin-54] conjugate by Reversed Phase HPLC. Figure KISS6.3. SDS-PAGE with Coomassie staining of purified [mono]-[mPEG2- ButyrAldehyde-40K]-[Kisspeptin-54]. Figure KISS6.4. MALDI-TOF spectrum of purified [mono]-[mPEG2-ButyrAldehyde-40K]- [Kisspeptin-54]. Figure KISS8.1 . Agonist activity at GPR54 for stable PEG conjugates of Kisspeptin 10, Kisspeptin 13, and Kisspeptin 54. Figure KISS8.2. Agonist activity at GPR54 for releasable PEG conjugate of Kisspeptin 10. Figure KISS8.3. Agonist activity at GPR54 for releasable PEG conjugate of Kisspeptin 10. Figure ZIC2.1: Cation exchange purification of mono-mPEG-C2-FMOC-20K-ziconotide from the PEGylation reaction mixture. Figure ZIC2.2: RP-HPLC analysis of purified mono-mPEG-C2-FMOC-20K-ziconotide. Figure ZIC2.3: MALDI-TOF analysis of purified mono-mPEG-C2-FMOC-20K-ziconotide. Figure ZIC3.1: Cation exchange purification of mono-mPEG-CAC-FMOC-40K-ziconotide from the PEGylation reaction mixture. Figure ZIC3.2: RP-HPLC analysis of purified mono-mPEG-CAC-FMOC-40K-ziconotide.