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(12) United States Patent (10) Patent No.: US 8,008,435 B2 Bentley Et Al

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(12) United States Patent (10) Patent No.: US 8,008,435 B2 Bentley Et Al USOO80084.35B2 (12) United States Patent (10) Patent No.: US 8,008,435 B2 Bentley et al. (45) Date of Patent: Aug. 30, 2011 (54) POLYMER STABILIZED NEUROPEPTIDES 2003. O139346 A1 7/2003 Bentley et al. 2003. O144207 A1 7/2003 Bentley et al. (75) Inventors: Michael David Bentley, Huntsville, AL 2004/0038899 A1 2/2004 Bentley et al. (US); Michael James Roberts, FOREIGN PATENT DOCUMENTS Madison, AL (US) WO WO91f16355 10, 1991 WO WO91f16929 A 11, 1991 (73) Assignee: Nektar Therapeutics, San Francisco, WO WO95/OO162 A 1, 1995 WO WO96/03984 2, 1996 CA (US) WO WO98,524.15 11, 1998 WO WOOOf78302 A1 12/2000 (*) Notice: Subject to any disclaimer, the term of this WO WO 01/12230 A1 2, 2001 patent is extended or adjusted under 35 WO WOO1, 19406 A2 * 3, 2001 U.S.C. 154(b) by 513 days. OTHER PUBLICATIONS (21) Appl. No.: 10/647,561 Inada, et al., “Modification of Proteins with Polyethylene Glycol Derivatives.” Methods in Enzymology, (1994), vol. 242, 65-90.* Delgado C. Francis GE. Fisher D., “The uses and properties of (22) Filed: Aug. 25, 2003 PEG-linked proteins.” Crit Rev. Ther Drug Carrier Syst. 1992:9(3- 4):249-304.* (65) Prior Publication Data Wu D. Pardridge W.M., “Neuroprotection with noninvasive neurotrophin delivery to the brain.” Proc Natl AcadSci USA Jan 5, US 2004/OO38899 A1 Feb. 26, 2004 1999;96(1):254-9.* Delgado C. Francis GE. Fisher D., “The uses and properties of Related U.S. Application Data PEG-linked proteins.” Crit Rev. Ther Drug Carrier Syst. 1992:9(3- 4):249-304.* (63) Continuation of application No. 09/678,997, filed on Wu D. Pardridge W.M., “Neuroprotection with noninvasive Oct. 4, 2000, now abandoned. neurotrophin delivery to the brain.” Proc Natl AcadSci USA. Jan 5, 1999;96(1):254-259.* (60) Provisional application No. 60/166,589, filed on Nov. Sakane et al., “Carboxyl-directed Pegylation of Brain-derived 19, 1999. Neurotrophic Factor Markedly Reduces Systemic Clearance with Minimal Loss of Biological Activity.” Pharm Res., 14(8): 1085-1091 (1997).* (51) Int. Cl. Abbruscato TJ, et al. “Blood-to-central nervous system entry and A6 IK38/00 (2006.01) stability of biphalin, a unique double-enkephalin analog, and its (52) U.S. Cl. ....................................................... S30/345 halogenated derivatives.” J Pharmacol Exp Ther. Mar. 1996:276(3):1049-57.* (58) Field of Classification Search ........................ None Witt et al., “Pharmacodynamic and Pharmacokinetic Characteriza See application file for complete search history. tion of Poly(Ethylene Glycol) Conjugation of Met-Enkephalin Ana log D-Pen, D-Pen-enkephalin (DPDPE),” Journal of Pharmacol (56) References Cited ogy and Experimental Therapeutics, vol. 298, No. 2, Aug. 2001; pp. 848-856. Kurihara, A. et al., “Epidermal Growth Factor U.S. PATENT DOCUMENTS Radiopharmaceuticals: 111 In Chelation, Conjugation to a Blood 4,179,337 A 12/1979 Davis et al. Brain Barrier Delivery Vector via a Biotin-Polyethylene Linker, ...”. 4.462,941 A 7, 1984 Lee et al. Bioconjugate Chem... vol. 10, pp. 502-511, May 17, 1995. 4,468,383 A 8, 1984 Rodbard et al. Patel D. et al., “Peptide Targetting and Delivery across the Blood 4,518,711 A 5/1985 Hruby et al. Brain Barrier Utilizing Synthetic Triglyceride Esters: Design, Syn 4,684,624 A 8, 1987 Hosobuchi et al. thesis and Bioactivity.” Bioconjugate Chem... vol. 8, pp. 434-441 4.902,505 A 2/1990 Pardridge et al. (1997). 5,017,689 A 5/1991 Hruby et al. Pardridge, “Physiologic-bases strategies for protein drug delivery to 5,286,637 A 2f1994 Veronese et al. 5,326,751 A 7, 1994 Haaseth et al. the brain.” Journal of Controlled Release, 39 pp. 281-286 (1996). 5,359,030 A 10, 1994 Ekwuribe Brownlees et al., “Peptidases, Peptides, and the Mammalian Blood 5,428,128 A 6, 1995 Mensi-Fattohi et al. Brain Barrier.” Journal of Neurochemistry, vol. 60, No. 3, pp. 793 5,442,043 A 8, 1995 Fukuta et al. 803 (1993). 5,629,384 A 5, 1997 Veronese et al. 5,631,322 A 5, 1997 Veronese et al. (Continued) 5,670477 A 9, 1997 Poduslo et al. 5,681,811 A 10, 1997 Ekwurbe Primary Examiner — Cecilia Tsang 5,833,988 A 11/1998 Friden Assistant Examiner — Thomas S Heard 5,932,462 A 8, 1999 Harris et al. 5.948,389 A 9, 1999 Stein (74) Attorney, Agent, or Firm — Susan T. Evans 5.990,237 A 1 1/1999 Bentley et al. 6,024,977 A 2/2000 Yatvin et al. (57) ABSTRACT 6,046,305 A 4, 2000 Choi 6,309.633 B1 10/2001 Ekwuribe et al. A Substantially hydrophilic conjugate is provided having a 6,362.254 B2 3, 2002 Harris et al. peptide that is capable of passing the blood-brain barrier 6,433,135 B1 8/2002 El-Tayar et al. covalently linked to a water-soluble nonpeptidic polymer 6,552,170 B1 4/2003 Thompson et al. Such as polyethylene glycol. The conjugate exhibits improved 6,703,381 B1 3, 2004 Ekwuribe et al. 6,899,867 B2 5/2005 Bentley et al. solubility and in vivo Stability and is capable of passing the 7,056,500 B2 6/2006 Bentley et al. blood-brain barrier of an animal. 2002fOO 13266 A1 1/2002 Bentley et al. 2002fOO1934.0 A1 2/2002 Bentley et al. 20 Claims, 6 Drawing Sheets US 8,008.435 B2 Page 2 OTHER PUBLICATIONS Shearwater Polymers, Inc., Catalog., “Functionalized Biocompat ible Polymers for Research Polyethylene Glycol and Derivatives.” Friden, "Utilization of an endogenous cellular transport system for pp. 2-49 (Mar. 1995). the delivery oftherapeutics across the blood-brainbarrier.” Journal of Shearwater Polymers, Inc., Catalog, "Functionalized Biocompatible Controlled Release, 46, pp. 117-128 (1996). Pardridge et al., “Combined Use of Carboxyl-Directed Protein Polymers for Research and Pharmaceuticals: Polyethylene Glycol Pegylation and Vector-Mediated Blood-Brain Barrier Drug Delivery and Derivatives.” pp: 2-53 (1997-1998). System Optimizes Brain Uptake of Brain-Derived Neurotrophic Fac Shearwater Polymers, Inc., Catalog, "Functionalized Biocompatible tor Following Intravenous Administration.” Pharmaceutical Polymers for Research and Pharmaceuticals: Polyethylene Glycol Research, vol. 15, No. 4, pp. 576-582 (1998). and Derivatives.” pp. 2-50 (2000). Kawasaki et al., “Amino Acids and Peptides. XIX. Preparation of Bryan, Jenny, “Crossing the Blood-Brain Barrier: Drug Delivery to Enkephalin-Poly(Ethylene Glycol) Hybrid and Evaluation of Its the Brain is Still Elusive'. The Pharmaceutical Journal, 273:475-476 Analgesic Activity.” Chem Pharm Bull., 41(11)pp. 2053-2054 (2004). (1993). Maeda et al., “Amino Acids and Peptides. XXII. Preparation and Jeffrey, Susan, “Manipulating the Blood-Brain Barrier-A Realistic Antinociceptive Effect of D-Ala)Leu-Enkephalin-Poly(Ethylene Therapeutic Goal?”. Neurology Reviews.com, Clinical Trends and Glycol) Hybrid.” Chem Pharm Bull., 17(6) pp. 823-825 (1994). News in Neurology, 8(7): 6 pages (2000). Williams et al., “Passage of a 6-Opioid Receptor Selective Arap, et al., “Cancer Treatment by Targeted Drug Delivery to Tumor Enkephalin, D-Penicillamine Enkephalin, Across the Blood Vasculature in a Mouse Model.” Science 279:377-380 (1998). Brain and the Blood-Cerebrospinal Fluid Barriers,” J. of Berendsen, "A Glimpse of the Holy Grail.” Science 282:642-643 Neurochemistry, vol. 66, No. 3, pp. 1289-1299 (1996). (1998). Zalipsky, "Chemistry of polyethylene glycol conjugates with bio Messer, "Vasopressin and Oxytocin.” Web Document Updated Apr. logically active molecules.” Advanced Drug Delivery Review, 16, pp. 3, 2000; http://www.neuroscipharm.utoledo.edu/MBC3320, 157-182 (1995). vasopressin.htm; 5 pages. Zalipsky et al., “Copolymers of Lysine and Polyethylene Glycol: A Nagey, et al., “Cytotoxic Analogs of Luteinizing Hormone-Contain New Family of Functionalized Drug Carriers.” Bioconjugate Chem. ing Doxorubicin or 2-Pyrrolinodoxorubicin, A Derivative 500-1000 vol. 4, No. 1, pp. 54-62 (1993). Times More Potent.” PNAS USA93:7269-7273 (1996). Hruby et al., “Recent Developments in the Design of Receptor Spe Rudinger, "Characteristics of the Amino Acids as Components of a cific Opioid Peptides.” Medicinal Research Review, vol.9, No. 3, pp. Peptide Hormone Sequence.” JA Parsons, ed. pp. 1-7 (1976). 343-401 (1989). Sigma, “Designing Custom Peptides.' http://www.sigma-genosys. Non-Final rejection in U.S. Appl. No. 10/354,683, dated May 3, com/peptide design.asp. (1998). 2007. Smilek, et al., “A Single Amino Acid Change in a Myelin Basic Amendment by Applicant to Non-Final Rejection in U.S. Appl. No. Protein Peptide Confers the Capacity to Prevent Rather than Induce 10/354,683 dated Jan. 23, 2007. Experimental Autoimmune Encephalomyelitis.” PNAS USA Non-Final Rejection in U.S. Appl. No. 10/354,683, dated Aug. 23, 88:9633-9637 (1991). 2006. Voet, et al., “Abnormal Hemoglobins.” Biochemistry, 2" ed., pp. Amendment by Applicant to Non-Final Rejection in U.S. Appl. No. 235-241 (1995). 10/354,683, dated May 18, 2006. Maeda, et al., “Amino Acids and Peptides. XXIV. Preparation and Non-Final Rejection in U.S. Appl. No. 10/354,683, dated Feb. 28, Antinociceptive Effect of D-Ala2.(N-Me)PheaEnkephalin Analog 2006. Poly(Ethylene Glycol) Hybrids.” Chem. Pharm. Bull, vol. 42, No. 9, Response to Election/Restriction filed in U.S. Appl. No. 10/354,683. pp. 1859-1863, (1994). dated Dec. 2, 2005. Munson, et al., “Pharmacokinetics: Disposition and Metabolism of Election/Restriction filed in U.S. Appl. No. 10/354,683, dated Nov. Drugs'. Principles of Pharmacology Basic Concepts & Clinical 22, 2005. Applications, Champman & Hall, Chapter 2, pp.39-48, (1995). Preliminary Amendment by Applicant for U.S. Appl. No. PCT International Search Report corresponding to PCT Application 10/354,683, dated Jan.
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