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Ep 2898900 B1 (19) TZZ ZZ_T (11) EP 2 898 900 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 47/60 (2017.01) 15.11.2017 Bulletin 2017/46 (21) Application number: 14200659.2 (22) Date of filing: 17.09.2009 (54) Polymer conjugates of ziconotide Polymerkonjugate von Ziconotid Conjugués polymères de ziconotide (84) Designated Contracting States: • Wang, Yujun AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Freemont, CA 94555 (US) HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL • Zhang, Ping PT RO SE SI SK SM TR Millbrae, CA 94030 (US) Designated Extension States: • Sheng, Dawei AL BA RS Fremont, CA 94555 (US) • Jude-Fishburn, C. Simone (30) Priority: 19.09.2008 US 192672 P Redwood City, AL 94062 (US) 18.02.2009 US 208089 P • Minamitani, Elizabeth 19.02.2009 US 153966 P Lacey’s Spring, AL 35754 (US) • Moskowitz, Haim (43) Date of publication of application: San Diego, CA 92130 (US) 29.07.2015 Bulletin 2015/31 • Fry, Dennis G. Pacifica, CA 94044 (US) (62) Document number(s) of the earlier application(s) in • Ali, Cherie accordance with Art. 76 EPC: Burlingame, CA 94010 (US) 09789327.5 / 2 341 942 • Brew, Christine Taylor Pacifica, CA 94044 (US) (73) Proprietor: Nektar Therapeutics •Liu,Xiaofeng San Francisco, CA 94158 (US) Belmont, CA 94002 (US) (72) Inventors: (74) Representative: Boult Wade Tennant • Bossard, Mary J. Verulam Gardens Madison, AL 35758 (US) 70 Gray’s Inn Road • Roczniak, Steven O. London WC1X 8BT (GB) Prescott, AZ 86301 (US) • Zappe, Harold (56) References cited: Harvest, CA 35759 (US) US-A1- 2006 293 499 US-A1- 2007 071 764 Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 898 900 B1 Printed by Jouve, 75001 PARIS (FR) EP 2 898 900 B1 Description FIELD OF THE INVENTION 5 [0001] The present invention relates to conjugates comprising a therapeutic peptide moiety covalently attached to one or more water-soluble polymers. BACKGROUND OF THE INVENTION 10 [0002] 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 15 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. [0003] 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 20 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 25 [0004] Accordingly, the present invention provides conjugates comprising a therapeutic peptide moiety covalently attached to one or more water-soluble polymers. There are described water-soluble polymers which may be stably bound to the therapeutic peptide moiety, or may be releasably attached to the therapeutic peptide moiety. [0005] The invention further provides methods of synthesizing the therapeutic peptide polymer conjugates of the 30 invention and compositions comprising such conjugates. The invention further provides use of the conjugates and compositions in 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. The invention provides a conjugate having the structure 35 40 or 45 50 55 wherein NH-ZICO is an amino group of the ziconotide moiety of SEQ ID NO: 264 and∼OPEG-m is a methoxy end- capped poly(ethylene glycol). 2 EP 2 898 900 B1 [0006] Additional embodiments of the present conjugates, compositions and methods will be apparent from the fol- lowing description, examples, and claims. 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. 5 BRIEF DESCRIPTION OF DRAWINGS [0007] 10 Figure KISS 1.1: Cation exchange purification of the PEGylation reaction mixture. Figure KISS1.2: 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. 15 Figure KISS2.3. MALDI-TOF spectrum of purified mono-[mPEG-butyraldehyde-10k]-[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-1] 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]. 20 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. 25 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- 30 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. 35 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. 40 Figure ZIC3.1: Cation exchange purification of mono-mPEG-CAC-FMOC-40K-ziconotide from the PEGylation re- action mixture. Figure ZIC3.2: RP-HPLC analysis of purified mono-mPEG-CAC-FMOC-40K-ziconotide. Figure ZIC3.3: MALDI-TOF analysis of purified mono-mPEG-CAC-FMOC-40K-ziconotide. Figure ZIC4.1: Cation exchange purification of mono-mPEG-SBA-30K-ziconotide from the PEGylation reaction 45 mixture. Figure ZIC4.2: RP-HPLC analysis of purified mono-mPEG-SBA-30K -ziconotide. Figure ZIC4.3: MALDI-TOF analysis of purified mono-mPEG-SBA-30K-ziconotide. Figure ZIC5.1: Cation exchange FPLC chromatography of the PEGylation reaction mixture between ziconotide and mPEG-SBC-30K-NHS. 50 Figure ZIC6.1. Mean (6 SEM) percent specific binding of ziconotide conjugates to calcium channel, N-type, in rat cortical membranes. Figure BIP2.1: (SPA-2K)2-biphalin purification with CG-71S resin. Figure BIP2.2: RP-HPLC analysis of reconstituted (SPA-2K)2-biphalin. Figure BIP2.3. MALDI TOF MS analysis of reconstituted (SPA-2K)2-biphalin. 55 Figure BIP3.1: (C2-20K)2-biphalin purification with CG-71S resin. Figure BIP3.2: RP-HPLC analysis of reconstituted (C2-20K) 2-biphalin. Figure BIP3.3 MALDI-TOF analysis of reconstituted (C2-20K) 2-biphalin. Figure BIP4.1: (CAC-20K)2-biphalin purification with CG-71S resin. 3 EP 2 898 900 B1 Figure BIP4.2: (CAC-20K)2-biphalin re-purification with CG-71S resin. Figure BIP4.3: RP-HPLC analysis of reconstituted (CAC-20K) 2-biphalin. BIP4.4: MALDI-TOF analysis of reconsti- tuted (CAC-20K)2-biphalin. Figure BIP5.1: RP-HPLC analysis of SBC-30K and biphalin conjugation reaction mixture. 5 Figure BIP5.2. The purification of (SBC-30K)2-biphalin from the reaction mixture. Figure BIP6.1. Competition binding assay of biphalin and di-CAC-20K-biphalin conjugate at human (A) m opioid and (B) δ opioid receptors. Figure BIP6.2. Competition binding assay of biphalin and di-C2-20K-biphalin, di-SBC-30K-biphalin, and di-SPA-2K- biphalin conjugate at human (A) m opioid and (B) δ opioid receptors. 10 Fig. BNP2.1. PEGylation rate of BNP-32 with mPEG2-40kDa Butyr-ALD. Fig. BNP2.2. Typical purification profile for the 40 kDa mPEG2-Butyr-ALD mono-PEG conjugate of BNP-32.
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