PASylation of murine leptin leads to extended plasma half-life and enhanced in vivo efficacy

Molecular Pharmaceutics

Volumn 12, Issue 5, 2015, Pages 1431-1442

  Morath, Volker ^a   Bolze, Florian ^a   Schlapschy, Martin ^a   Schneider, Sarah ^a   Sedlmayer, Ferdinand ^a   Seyfarth, Katrin ^a   Klingenspor, Martin ^a   Skerra, Arne ^a,b  

^a TECHNICAL UNIVERSITY OF MUNICH   (Germany)

^b XL Protein GmbH   (Germany)

Author keywords

adipokine; drug development; kidney; obesity; PEGylation; pharmacokinetics; satiety hormone; therapeutic protein

Indexed keywords

LEPTIN; LEPTIN PROLYLALANYLSERYL POLYPEPTIDE; MACROGOL; POLYPEPTIDE; STAT3 PROTEIN; UNCLASSIFIED DRUG; ADIPOCYTOKINE; MACROGOL DERIVATIVE;

ANIMAL CELL; AREA UNDER THE CURVE; ARTICLE; BINDING AFFINITY; BLOOD SAMPLING; BODY WEIGHT; CIRCULAR DICHROISM; CONFORMATION; CONTROLLED STUDY; DRUG BLOOD LEVEL; DRUG DELIVERY SYSTEM; DRUG EFFICACY; DRUG HALF LIFE; ELIMINATION HALF-LIFE; FEMALE; FOOD INTAKE; GEL PERMEATION CHROMATOGRAPHY; GENE FUSION; GLOMERULUS FILTRATION; HEK293 CELL LINE; HYDRODYNAMICS; IN VIVO STUDY; INTRACELLULAR SIGNALING; LIGHT SCATTERING; MALE; MOLECULAR SIZE; MOUSE; MURINAE; NONHUMAN; PASYLATION; PHARMACODYNAMICS; PLASMA HALF LIFE; PRIORITY JOURNAL; PROTEIN PHOSPHORYLATION; RECEPTOR BINDING; WEIGHT REDUCTION; ANIMAL; BLOOD; CHEMISTRY; DRUG EFFECTS; ENZYME LINKED IMMUNOSORBENT ASSAY; HUMAN; METABOLISM; PHOSPHORYLATION; PHOTON CORRELATION SPECTROSCOPY; SIZE EXCLUSION CHROMATOGRAPHY; SURFACE PLASMON RESONANCE;

ADIPOKINES; ANIMALS; CHROMATOGRAPHY, GEL; CIRCULAR DICHROISM; DYNAMIC LIGHT SCATTERING; ENZYME-LINKED IMMUNOSORBENT ASSAY; FEMALE; HEK293 CELLS; HUMANS; LEPTIN; MALE; MICE; PHOSPHORYLATION; POLYETHYLENE GLYCOLS; STAT3 TRANSCRIPTION FACTOR; SURFACE PLASMON RESONANCE;

EID: 84929169007     PISSN: 15438384     EISSN: 15438392     Source Type: Journal    
DOI: 10.1021/mp5007147     Document Type: Article

References (74)

1. Zhang, Y.; Proenca, R.; Maffei, M.; Barone, M.; Leopold, L.; Friedman, J. M. Positional cloning of the mouse obese gene and its human homologue Nature 1994, 372, 425-432
2. Maffei, M.; Halaas, J.; Ravussin, E.; Pratley, R. E.; Lee, G. H.; Zhang, Y.; Fei, H.; Kim, S.; Lallone, R.; Ranganathan, S. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects Nat. Med. 1995, 1, 1155-1161
3. Friedman, J. M. Leptin at 14 y of age: an ongoing story Am. J. Clin. Nutr. 2009, 89, 973S-979S
4. Banks, W. A.; Kastin, A. J.; Huang, W.; Jaspan, J. B.; Maness, L. M. Leptin enters the brain by a saturable system independent of insulin Peptides 1996, 17, 305-311
5. Vaisse, C.; Halaas, J. L.; Horvath, C. M.; Darnell, J. E., Jr.; Stoffel, M.; Friedman, J. M. Leptin activation of Stat3 in the hypothalamus of wild-type and ob/ob mice but not db/db mice Nat. Genet. 1996, 14, 95-97
6. Ghilardi, N.; Skoda, R. C. The leptin receptor activates janus kinase 2 and signals for proliferation in a factor-dependent cell line Mol. Endocrinol. 1997, 11, 393-399
7. Varela, L.; Horvath, T. L. Leptin and insulin pathways in POMC and AgRP neurons that modulate energy balance and glucose homeostasis EMBO Rep. 2012, 13, 1079-1086
8. Farooqi, I. S.; O'Rahilly, S. Leptin: a pivotal regulator of human energy homeostasis Am. J. Clin. Nutr. 2009, 89, 980S-984S
9. Paz-Filho, G.; Wong, M. L.; Licinio, J. Ten years of leptin replacement therapy Obes. Rev. 2011, 12, e315-e323
10. Ingalls, A. M.; Dickie, M. M.; Snell, G. D. Obese, a new mutation in the house mouse J. Hered. 1950, 41, 317-318
11. Montague, C. T.; Farooqi, I. S.; Whitehead, J. P.; Soos, M. A.; Rau, H.; Wareham, N. J.; Sewter, C. P.; Digby, J. E.; Mohammed, S. N.; Hurst, J. A.; Cheetham, C. H.; Earley, A. R.; Barnett, A. H.; Prins, J. B.; O'Rahilly, S. Congenital leptin deficiency is associated with severe early-onset obesity in humans Nature 1997, 387, 903-908
12. D'Souza, A. M.; Asadi, A.; Johnson, J. D.; Covey, S. D.; Kieffer, T. J. Leptin deficiency in rats results in hyperinsulinemia and impaired glucose homeostasis Endocrinology 2014, 155, 1268-1279
13. Halaas, J. L.; Gajiwala, K. S.; Maffei, M.; Cohen, S. L.; Chait, B. T.; Rabinowitz, D.; Lallone, R. L.; Burley, S. K.; Friedman, J. M. Weight-reducing effects of the plasma protein encoded by the obese gene Science 1995, 269, 543-546
14. Farooqi, I. S.; Jebb, S. A.; Langmack, G.; Lawrence, E.; Cheetham, C. H.; Prentice, A. M.; Hughes, I. A.; McCamish, M. A.; O'Rahilly, S. Effects of recombinant leptin therapy in a child with congenital leptin deficiency N. Engl. J. Med. 1999, 341, 879-884
15. Licinio, J.; Caglayan, S.; Ozata, M.; Yildiz, B. O.; de Miranda, P. B.; O'Kirwan, F.; Whitby, R.; Liang, L.; Cohen, P.; Bhasin, S.; Krauss, R. M.; Veldhuis, J. D.; Wagner, A. J.; DePaoli, A. M.; McCann, S. M.; Wong, M. L. Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 4531-4536
16. Wabitsch, M.; Funcke, J. B.; Lennerz, B.; Kuhnle-Krahl, U.; Lahr, G.; Debatin, K. M.; Vatter, P.; Gierschik, P.; Moepps, B.; Fischer-Posovszky, P. Biologically inactive leptin and early-onset extreme obesity N. Engl. J. Med. 2015, 372, 48-54
17. Friedman, J. M.; Halaas, J. L. Leptin and the regulation of body weight in mammals Nature 1998, 395, 763-770
18. Ravussin, E.; Smith, S. R.; Mitchell, J. A.; Shringarpure, R.; Shan, K.; Maier, H.; Koda, J. E.; Weyer, C. Enhanced weight loss with pramlintide/metreleptin: an integrated neurohormonal approach to obesity pharmacotherapy Obesity (Silver Spring) 2009, 17, 1736-1743
19. Heymsfield, S. B.; Greenberg, A. S.; Fujioka, K.; Dixon, R. M.; Kushner, R.; Hunt, T.; Lubina, J. A.; Patane, J.; Self, B.; Hunt, P.; McCamish, M. Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial J. Am. Med. Assoc. 1999, 282, 1568-1575
20. Münzberg, H. Leptin-signaling pathways and leptin resistance Forum Nutr. 2010, 63, 123-132
21. Osborn, O.; Sanchez-Alavez, M.; Brownell, S. E.; Ross, B.; Klaus, J.; Dubins, J.; Beutler, B.; Conti, B.; Bartfai, T. Metabolic characterization of a mouse deficient in all known leptin receptor isoforms Cell. Mol. Neurobiol. 2010, 30, 23-33
22. Tups, A.; Ellis, C.; Moar, K. M.; Logie, T. J.; Adam, C. L.; Mercer, J. G.; Klingenspor, M. Photoperiodic regulation of leptin sensitivity in the Siberian hamster, Phodopus sungorus, is reflected in arcuate nucleus SOCS-3 (suppressor of cytokine signaling) gene expression Endocrinology 2004, 145, 1185-1193
23. Grattan, D. R.; Ladyman, S. R.; Augustine, R. A. Hormonal induction of leptin resistance during pregnancy Physiol. Behav. 2007, 91, 366-374
24. Wang, M. Y.; Chen, L.; Clark, G. O.; Lee, Y.; Stevens, R. D.; Ilkayeva, O. R.; Wenner, B. R.; Bain, J. R.; Charron, M. J.; Newgard, C. B.; Unger, R. H. Leptin therapy in insulin-deficient type I diabetes Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 4813-4819
25. Coppari, R.; Bjorbaek, C. Leptin revisited: its mechanism of action and potential for treating diabetes Nat. Rev. Drug Discovery 2012, 11, 692-708
26. Chou, S. H.; Chamberland, J. P.; Liu, X.; Matarese, G.; Gao, C.; Stefanakis, R.; Brinkoetter, M. T.; Gong, H.; Arampatzi, K.; Mantzoros, C. S. Leptin is an effective treatment for hypothalamic amenorrhea Proc. Natl. Acad. Sci. U.S.A. 2011, 108, 6585-6590
27. Oral, E. A.; Simha, V.; Ruiz, E.; Andewelt, A.; Premkumar, A.; Snell, P.; Wagner, A. J.; DePaoli, A. M.; Reitman, M. L.; Taylor, S. I.; Gorden, P.; Garg, A. Leptin-replacement therapy for lipodystrophy N. Engl. J. Med. 2002, 346, 570-578
28. Chou, K.; Perry, C. M. Metreleptin: first global approval Drugs 2013, 73, 989-997
29. Zhang, F.; Basinski, M. B.; Beals, J. M.; Briggs, S. L.; Churgay, L. M.; Clawson, D. K.; DiMarchi, R. D.; Furman, T. C.; Hale, J. E.; Hsiung, H. M.; Schoner, B. E.; Smith, D. P.; Zhang, X. Y.; Wery, J. P.; Schevitz, R. W. Crystal structure of the obese protein leptin-E100 Nature 1997, 387, 206-209
30. Bravo, J.; Heath, J. K. Receptor recognition by gp130 cytokines EMBO J. 2000, 19, 2399-2411
31. Mancour, L. V.; Daghestani, H. N.; Dutta, S.; Westfield, G. H.; Schilling, J.; Oleskie, A. N.; Herbstman, J. F.; Chou, S. Z.; Skiniotis, G. Ligand-induced architecture of the leptin receptor signaling complex Mol. Cell 2012, 48, 655-661
32. Fong, T. M.; Huang, R. R.; Tota, M. R.; Mao, C.; Smith, T.; Varnerin, J.; Karpitskiy, V. V.; Krause, J. E.; Van der Ploeg, L. H. Localization of leptin binding domain in the leptin receptor Mol. Pharmacol. 1998, 53, 234-240
33. Peelman, F.; Van Beneden, K.; Zabeau, L.; Iserentant, H.; Ulrichts, P.; Defeau, D.; Verhee, A.; Catteeuw, D.; Elewaut, D.; Tavernier, J. Mapping of the leptin binding sites and design of a leptin antagonist J. Biol. Chem. 2004, 279, 41038-41046
34. Shpilman, M.; Niv-Spector, L.; Katz, M.; Varol, C.; Solomon, G.; Ayalon-Soffer, M.; Boder, E.; Halpern, Z.; Elinav, E.; Gertler, A. Development and characterization of high affinity leptins and leptin antagonists J. Biol. Chem. 2011, 286, 4429-4442
35. Cumin, F.; Baum, H. P.; de Gasparo, M.; Levens, N. Removal of endogenous leptin from the circulation by the kidney Int. J. Obes. 1997, 21, 495-504
36. Ahren, B.; Baldwin, R. M.; Havel, P. J. Pharmacokinetics of human leptin in mice and rhesus monkeys Int. J. Obes. 2000, 24, 1579-1585
37. Lo, K. M.; Zhang, J.; Sun, Y.; Morelli, B.; Lan, Y.; Lauder, S.; Brunkhorst, B.; Webster, G.; Hallakou-Bozec, S.; Doare, L.; Gillies, S. D. Engineering a pharmacologically superior form of leptin for the treatment of obesity Protein Eng., Des. Sel. 2005, 18, 1-10
38. Jevsevar, S.; Kunstelj, M.; Porekar, V. G. PEGylation of therapeutic proteins Biotechnol. J. 2010, 5, 113-128
39. Pasut, G.; Veronese, F. M. State of the art in PEGylation: the great versatility achieved after forty years of research J. Controlled Release 2012, 161, 461-472
40. Elinav, E.; Niv-Spector, L.; Katz, M.; Price, T. O.; Ali, M.; Yacobovitz, M.; Solomon, G.; Reicher, S.; Lynch, J. L.; Halpern, Z.; Banks, W. A.; Gertler, A. Pegylated leptin antagonist is a potent orexigenic agent: preparation and mechanism of activity Endocrinology 2009, 150, 3083-3091
41. Müller, T. D.; Sullivan, L. M.; Habegger, K.; Yi, C. X.; Kabra, D.; Grant, E.; Ottaway, N.; Krishna, R.; Holland, J.; Hembree, J.; Perez-Tilve, D.; Pfluger, P. T.; DeGuzman, M. J.; Siladi, M. E.; Kraynov, V. S.; Axelrod, D. W.; DiMarchi, R.; Pinkstaff, J. K.; Tschöp, M. H. Restoration of leptin responsiveness in diet-induced obese mice using an optimized leptin analog in combination with exendin-4 or FGF21 J. Pept. Sci. 2012, 18, 383-393
42. Hukshorn, C. J.; Westerterp-Plantenga, M. S.; Saris, W. H. Pegylated human recombinant leptin (PEG-OB) causes additional weight loss in severely energy-restricted, overweight men Am. J. Clin. Nutr. 2003, 77, 771-776
43. Gaberc-Porekar, V.; Zore, I.; Podobnik, B.; Menart, V. Obstacles and pitfalls in the PEGylation of therapeutic proteins Curr. Opin. Drug Discovery Dev. 2008, 11, 242-250
44. Knop, K.; Hoogenboom, R.; Fischer, D.; Schubert, U. S. Poly(ethylene glycol) in drug delivery: pros and cons as well as potential alternatives Angew. Chem., Int. Ed. 2010, 49, 6288-6308
45. EMA. CHMP Safety Working Party's response to the PDCO regarding the use of PEGylated drug products in the paediatric population. EMA/CHMP/SWP/647258/2012.
46. Verhoef, J. J.; Carpenter, J. F.; Anchordoquy, T. J.; Schellekens, H. Potential induction of anti-PEG antibodies and complement activation toward PEGylated therapeutics Drug Discovery Today 2014, 19, 1945-1952
47. Schlapschy, M.; Binder, U.; Börger, C.; Theobald, I.; Wachinger, K.; Kisling, S.; Haller, D.; Skerra, A. PASylation: a biological alternative to PEGylation for extending the plasma half-life of pharmaceutically active proteins Protein Eng., Des. Sel. 2013, 26, 489-501
48. Binder, U.; Skerra, A. Half-life extension of therapeutic proteins via genetic fusion to recombinant PEG mimetics. In Therapeutic Proteins-Strategies to Modulate Their Plasma Half-lives; Kontermann, R., Ed.; Wiley-VCH: Weinheim, 2012; pp 63-80.
49. Harari, D.; Kuhn, N.; Abramovich, R.; Sasson, K.; Zozulya, A. L.; Smith, P.; Schlapschy, M.; Aharoni, R.; Köster, M.; Eilam, R.; Skerra, A.; Schreiber, G. Enhanced in vivo efficacy of a type I interferon superagonist with extended plasma half-life in a mouse model of multiple sclerosis J. Biol. Chem. 2014, 289, 29014-29029
50. Mendler, C. T.; Friedrich, L.; Laitinen, I.; Schlapschy, M.; Schwaiger, M.; Wester, H.-J.; Skerra, A. High contrast tumor imaging with radio-labeled antibody Fab fragments tailored for optimized pharmacokinetics via PASylation mAbs 2015, 7, 96-109
51. Meerman, H. J.; Georgiou, G. Construction and characterization of a set of E. coli strains deficient in all known loci affecting the proteolytic stability of secreted recombinant proteins Nat. Biotechnol. 1994, 12, 1107-1110
52. Schlapschy, M.; Grimm, S.; Skerra, A. A system for concomitant overexpression of four periplasmic folding catalysts to improve secretory protein production in Escherichia coli Protein Eng., Des. Sel. 2006, 19, 385-390
53. Fling, S. P.; Gregerson, D. S. Peptide and protein molecular weight determination by electrophoresis using a high-molarity Tris buffer system without urea Anal. Biochem. 1986, 155, 83-88
54. Gill, S. C.; von Hippel, P. H. Calculation of protein extinction coefficients from amino acid sequence data Anal. Biochem. 1989, 182, 319-326
55. Schönfeld, D.; Matschiner, G.; Chatwell, L.; Trentmann, S.; Gille, H.; Hülsmeyer, M.; Brown, N.; Kaye, P. M.; Schlehuber, S.; Hohlbaum, A. M.; Skerra, A. An engineered lipocalin specific for CTLA-4 reveals a combining site with structural and conformational features similar to antibodies Proc. Natl. Acad. Sci. U.S.A. 2009, 106, 8198-8203
56. Myszka, D. G. Improving biosensor analysis J. Mol. Recognit. 1999, 12, 279-284
57. Skerra, A. Use of the tetracycline promoter for the tightly regulated production of a murine antibody fragment in Escherichia coli Gene 1994, 151, 131-135
58. Rock, F. L.; Altmann, S. W.; van Heek, M.; Kastelein, R. A.; Bazan, J. F. The leptin haemopoietic cytokine fold is stabilized by an intrachain disulfide bond Horm. Metab. Res. 1996, 28, 649-652
59. Boute, N.; Zilberfarb, V.; Camoin, L.; Bonnafous, S.; Le Marchand-Brustel, Y.; Issad, T. The formation of an intrachain disulfide bond in the leptin protein is necessary for efficient leptin secretion Biochimie 2004, 86, 351-356
60. Peelman, F.; Iserentant, H.; De Smet, A. S.; Vandekerckhove, J.; Zabeau, L.; Tavernier, J. Mapping of binding site III in the leptin receptor and modeling of a hexameric leptin·leptin receptor complex J. Biol. Chem. 2006, 281, 15496-15504
61. Churgay, L. M.; Kovacevic, S.; Tinsley, F. C.; Kussow, C. M.; Millican, R. L.; Miller, J. R.; Hale, J. E. Purification and characterization of secreted human leptin produced in baculovirus-infected insect cells Gene 1997, 190, 131-137
62. Sreerama, N.; Venyaminov, S. Y.; Woody, R. W. Estimation of the number of α-helical and β-strand segments in proteins using circular dichroism spectroscopy Protein Sci. 1999, 8, 370-380
63. Mistrík, P.; Moreau, F.; Allen, J. M. BiaCore analysis of leptin-leptin receptor interaction: evidence for 1:1 stoichiometry Anal. Biochem. 2004, 327, 271-277
64. Meibohm, B. Pharmacokinetics and Pharmacodynamics of Biotech Drugs: Principles and Case Studies in Drug Development; Wiley-VCH: Weinheim, 2006.
65. Mori, H.; Hanada, R.; Hanada, T.; Aki, D.; Mashima, R.; Nishinakamura, H.; Torisu, T.; Chien, K. R.; Yasukawa, H.; Yoshimura, A. Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity Nat. Med. 2004, 10, 739-743
66. Maack, T.; Johnson, V.; Kau, S. T.; Figueiredo, J.; Sigulem, D. Renal filtration, transport, and metabolism of low-molecular-weight proteins: a review Kidney Int. 1979, 16, 251-270
67. Haraldsson, B.; Sörensson, J. Why do we not all have proteinuria? An update of our current understanding of the glomerular barrier News Physiol. Sci. 2004, 19, 7-10
68. Kubetzko, S.; Sarkar, C. A.; Plückthun, A. Protein PEGylation decreases observed target association rates via a dual blocking mechanism Mol. Pharmacol. 2005, 68, 1439-1454
69. Rosenblum, C. I.; Vongs, A.; Tota, M. R.; Varnerin, J. P.; Frazier, E.; Cully, D. F.; Morsy, M. A.; Van der Ploeg, L. H. A rapid, quantitative functional assay for measuring leptin Mol. Cell. Endocrinol. 1998, 143, 117-123
70. Wu, L.; Ji, S.; Shen, L.; Hu, T. Phenyl amide linker improves the pharmacokinetics and pharmacodynamics of N-terminally mono-PEGylated human growth hormone Mol. Pharmaceutics 2014, 11, 3080-3089
71. Klein, S.; Coppack, S. W.; Mohamed-Ali, V.; Landt, M. Adipose tissue leptin production and plasma leptin kinetics in humans Diabetes 1996, 45, 984-987
72. Gegg, C.; Kinstler, O. Site-directed dual pegylation of proteins for improved bioactivity and biocompatibility. US Patent No. US6420339 B1, 2002.
73. Banks, W. A.; Gertler, A.; Solomon, G.; Niv-Spector, L.; Shpilman, M.; Yi, X.; Batrakova, E.; Vinogradov, S.; Kabanov, A. V. Principles of strategic drug delivery to the brain (SDDB): development of anorectic and orexigenic analogs of leptin Physiol. Behav. 2011, 105, 145-149
74. Gertler, A.; Solomon, G. Leptin-activity blockers: development and potential use in experimental biology and medicine Can. J. Physiol. Pharmacol. 2013, 91, 873-882