Emerging PEGylated non-biologic drugs

References

• Kang JS, DeLuca PP, Lee KC. Emerging PEGylated drugs. Expert Opin Emerg Dr. 2009;14:363–380.
   PubMed Web of Science ®Google Scholar
• D‘Souza AA, Shegokar R. Polyethylene glycol (PEG): a versatile polymer for pharmaceutical applications. Expert Opin Drug Del. 2016;13:1257–1275.
   PubMed Web of Science ®Google Scholar
• Caliceti P, Veronese FM. Pharmacokinetic and biodistribution properties of poly(ethylene glycol)-protein conjugates. Adv Drug Deliv Rev. 2003;55:1261–1277.
   PubMed Web of Science ®Google Scholar
• Pasut G, Veronese FM. State of the art in PEGylation: the great versatility achieved after forty years of research. J Control Release. 2012;161:461–472.
   PubMed Web of Science ®Google Scholar
• Turecek PL, Bossard MJ, Schoetens F, et al. PEGylation of Biopharmaceuticals: A Review of Chemistry and Nonclinical Safety Information of Approved Drugs. J Pharm Sci. 2016;105:460–475.
   PubMed Web of Science ®Google Scholar
• Hoffman AS. The early days of PEG and PEGylation (1970s-1990s). Acta Biomater. 2016;40:1–5.
   PubMed Web of Science ®Google Scholar
• Zhao N, Woodle MC, Mixson AJ. Advances in delivery systems for doxorubicin. J Nanomed Nanotechnol. 2018;9:519.
   PubMedGoogle Scholar
• Kim CH, Lee SG, Kang MJ, et al. Surface modification of lipid-based nanocarriers for cancer cell-specific drug targeting. J Pharm Investig. 2017;47:203–227.
   Google Scholar
• Ivens IA, Achanzar W, Baumann A, et al. PEGylated biopharmaceuticals: current experience and considerations for nonclinical development. Toxicol Pathol. 2015;43:959–983.
   PubMed Web of Science ®Google Scholar
• Li WJ, Zhan P, De Clercq E, et al. Current drug research on PEGylation with small molecular agents. Prog Polym Sci. 2013;38:421–444.
   Web of Science ®Google Scholar
• Sapra P, Zhao H, Mehlig M, et al. Novel delivery of SN38 markedly inhibits tumor growth in xenografts, including a camptothecin-11 - refractory model. Clin Cancer Res. 2008;14:1888–1896.
   PubMed Web of Science ®Google Scholar
• Yang X, Yp D, Tj J, et al. Improvement of the in vitro safety profile and cytoprotective efficacy of amifostine against chemotherapy by PEGylation strategy. Biochem Pharmacol. 2016;108:11–21.
   PubMed Web of Science ®Google Scholar
• Canal F, Mj V, Pasut G, et al. Relevance of folic acid/polymer ratio in targeted PEG–epirubicin conjugates. J Control Release. 2010;146:388–399.
   PubMed Web of Science ®Google Scholar
• Clementi C, Miller K, Mero A, et al. Dendritic poly (ethylene glycol) bearing paclitaxel and alendronate for targeting bone neoplasms. Mol Pharm. 2011;8:1063–1072.
   PubMed Web of Science ®Google Scholar
• Floettmann E, Bui K, Sostek M, et al. Pharmacologic profile of naloxegol, a peripherally acting µ-opioid receptor antagonist, for the treatment of opioid-induced constipation. J Pharmacol Exp Ther. 2017;361:280–291.
   PubMed Web of Science ®Google Scholar
• Gong YH, Leroux JC, Gauthier MA. Releasable conjugation of polymers to proteins. Bioconjugate Chem. 2015;26:1172–1181.
   PubMed Web of Science ®Google Scholar
• Erak M, Bellmann-Sickert K, Els-Heindl S, et al. Peptide chemistry toolbox - Transforming natural peptides into peptide therapeutics. Bioorgan Med Chem. 2018;26:2759–2765.
   PubMed Web of Science ®Google Scholar
• Choi YL, Park EJ, Kim E, et al. Dermal stability and in vitro skin permeation of collagen pentapeptides (KTTKS and palmitoyl-KTTKS). Biomol Ther. 2014;22:321–327.
   PubMed Web of Science ®Google Scholar
• Na DH, Youn YS, Park EJ, et al. Stability of PEGylated salmon calcitonin in nasal mucosa. J Pharm Sci-Us. 2004;93:256–261.
   PubMed Web of Science ®Google Scholar
• Na DH, Faraj J, Capan Y, et al. Stability of antimicrobial decapeptide (KSL) and its analogues for delivery in the oral cavity. Pharm Res. 2007;24:1544–1550.
   PubMed Web of Science ®Google Scholar
• Dozier JK, Distefano MD. Site-specific PEGylation of therapeutic proteins. Int J Mol Sci. 2015;16:25831–25864.
   PubMed Web of Science ®Google Scholar
• Youn YS, Na DH, Lee KC. High-yield production of biologically active mono-PEGylated salmon calcitonin by site-specific PEGylation. J Control Release. 2007;117:371–379.
   PubMed Web of Science ®Google Scholar
• Kim MS, Park EJ, Na DH. Synthesis and characterization of monodisperse poly(ethylene glycol)-conjugated collagen pentapeptides with collagen biosynthesis-stimulating activity. Bioorg Med Chem Lett. 2015;25:38–42.
   PubMed Web of Science ®Google Scholar
• Lee W, Park EJ, Kwak S, et al. Trimeric PEG-conjugated exendin-4 for the treatment of sepsis. Biomacromolecules. 2016;17:1160–1169.
   PubMed Web of Science ®Google Scholar
• Yoon S, Rossi JJ. Aptamers: uptake mechanisms and intracellular applications. Adv Drug Deliv Rev. 2018;134:22–35.
   PubMed Web of Science ®Google Scholar
• Ni SJ, Yao HZ, Wang LL, et al. Chemical modifications of nucleic acid aptamers for therapeutic purposes. Int J Mol Sci. 2017;18:1683.
   Web of Science ®Google Scholar
• Zhou JH, Rossi J. Aptamers as targeted therapeutics: current potential and challenges. Nat Rev Drug Discov. 2017;16:181–202.
   PubMed Web of Science ®Google Scholar
• Sosic A, Pasqualin M, Pasut G, et al. Enzymatic formation of PEGylated oligonucleotides. Bioconjugate Chem. 2014;25:433–441.
   PubMed Web of Science ®Google Scholar
• Yh L, Kkl P, Leong KW. Aptamer nanomedicine for cancer therapeutics: barriers and potential for translation. Acs Nano. 2015;9:2235–2254.
   PubMed Web of Science ®Google Scholar
• Boomer RM, Lewis SD, Healy JM, et al. Conjugation to polyethylene glycol polymer promotes aptamer biodistribution to healthy and inflamed tissues. Oligonucleotides. 2005;15:183–195.
   PubMed Web of Science ®Google Scholar
• Garnock-Jones KP. Naloxegol: a review of its use in patients with opioid-induced constipation. Drugs. 2015;75:419–425.
   PubMed Web of Science ®Google Scholar
• Fishbane S, Schiller B, Locatelli F, et al. Peginesatide in patients with anemia undergoing hemodialysis. New Engl J Med. 2013;368:307–319.
   PubMed Web of Science ®Google Scholar
• Green JM, Leu K, Worth A, et al. Peginesatide and erythropoietin stimulate similar erythropoietin receptor-mediated signal transduction and gene induction events. Exp Hematol. 2012;40:575–587.
   PubMed Web of Science ®Google Scholar
• Kaushik T, Yaqoob MM. Lessons learned from peginesatide in the treatment of anemia associated with chronic kidney disease in patients on dialysis. Biologics. 2013;7:243.
   PubMedGoogle Scholar
• Hermanson T, Bennett CL, Macdougall IC. Peginesatide for the treatment of anemia due to chronic kidney disease - an unfulfilled promise. Expert Opin Drug Saf. 2016;15:1421–1426.
   PubMed Web of Science ®Google Scholar
• Weaver JL, Boyne M, Pang E, et al. Nonclinical evaluation of the potential for mast cell activation by an erythropoietin analog. Toxicol Appl Pharmacol. 2015;287:246–252.
   PubMed Web of Science ®Google Scholar
• Ng EWM, Shima DT, Calias P, et al. Pegaptanib, a targeted anti-VEGF aptamer for ocular vascular disease. Nat Rev Drug Discov. 2006;5:123–132.
   PubMed Web of Science ®Google Scholar
• Hussain RM, Ciulla TA. Emerging vascular endothelial growth factor antagonists to treat neovascular age-related macular degeneration. Expert Opin Emerg Dr. 2017;22:235–246.
   PubMed Web of Science ®Google Scholar
• Macugen AMD Study Group, Apte RS, Modi M, et al. Pegaptanib 1-year systemic safety results from a safety–pharmacokinetic trial in patients with neovascular age-related macular degeneration. Ophthalmology 2007;114:1702–1712.
   Google Scholar
• Basile AS, Hutmacher M, Nickens D, et al. Population pharmacokinetics of pegaptanib in patients with neovascular, age-related macular degeneration. J Clin Pharmacol. 2012;52:1186–1199.
   PubMed Web of Science ®Google Scholar
• Swierczewska M, Lee KC, Lee S. What is the future of PEGylated therapies? Expert Opin Emerg Dr. 2015;20:531–536.
   PubMed Web of Science ®Google Scholar
• Hoy SM. Pegfilgrastim-jmdb/MYL-1401H: A Pegfilgrastim Biosimilar. Biodrugs. 2019;;33:117–120.
   Web of Science ®Google Scholar
• Global Market Insights. NorthAmerica and Europe PEGylated drugs market size by disease indication (Cancer, Hepatitis, Multiple Sclerosis, Gastrointestinal Disorders), by type (Monoclonal Antibodies, Colony Stimulating Factors, Interferons), industry analysis report, regional outlook (U.S.,Canada, Germany, UK, France, Italy, Spain, Sweden), application potential, price trends, competitive market share & forecast, 2018 – 2024. https://www.gminsights.com/industry-analysis/north-america-and-europe-pegylated-drugs-market
   Google Scholar
• Lau JL, Dunn MK. Therapeutic peptides: historical perspectives, current development trends, and future directions. Bioorgan Med Chem. 2018;26:2700–2707.
   PubMed Web of Science ®Google Scholar
• Grand View Research, Peptide therapeutics market by application (cancer, cardiovascular disorder, metabolic disorder, respiratory disorder, pain, dermatology), by type (generic, innovative) by type of manufacturers (in-house, outsourced), and segment forecasts, 2018 – 2025. https://www.grandviewresearch.com/industry-analysis/peptide-therapeutics-market.
   Google Scholar
• Stein CA, Castanotto D. FDA-approved oligonucleotide therapies in 2017. Mol Ther. 2017;25:1069–1075.
   PubMed Web of Science ®Google Scholar
• Park EJ, Na DH. Characterization of the reversed-phase chromatographic behavior of PEGylated peptides based on the poly(ethylene glycol) dispersity. Anal Chem. 2016;88:10848–10853.
   PubMed Web of Science ®Google Scholar
• Na DH, Youn YS, Lee KC. Optimization of the PEGylation process of a peptide by monitoring with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Rapid Commun Mass Spectrom. 2003;17:2241–2244.
   PubMed Web of Science ®Google Scholar
• Gaberc-Porekar V, Zore I, Podobnik B, et al. Obstacles and pitfalls in the PEGylation of therapeutic proteins. Curr Opin Drug Disc. 2008;11:242–250.
   PubMed Web of Science ®Google Scholar
• Lee KC, Moon SC, Park MO, et al. Isolation, characterization, and stability of positional isomers of mono-PEGylated salmon calcitonins. Pharm Res. 1999;16:813–818.
   PubMed Web of Science ®Google Scholar
• Na DH, Youn YS, Lee KC. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry for monitoring and optimization of site-specific PEGylation of ricin A-chain. Rapid Commun Mass Spectrom. 2004;18:2185–2189.
   PubMed Web of Science ®Google Scholar
• Park EJ, Lee KC, Na DH. Separation of positional isomers of mono-poly(ethylene glycol)-modified octreotides by reversed-phase high-performance liquid chromatography. J Chromatogr A. 2009;1216:7793–7797.
   PubMed Web of Science ®Google Scholar
• Kim TH, Jiang HH, Lim SM, et al. Site-specific pegylated exendin-4 modified with a high molecular weight trimeric PEG reduces steric hindrance and increases type 2 antidiabetic therapeutic effects. Bioconjugate Chem. 2012;23:2214–2220.
   PubMed Web of Science ®Google Scholar
• Roberts MJ, Bentley MD, Harris JM. Chemistry for peptide and protein PEGylation. Adv Drug Deliv Rev. 2002;54:459–476.
   PubMed Web of Science ®Google Scholar
• Kinstler O, Molineux G, Treuheit M, et al. Mono-N-terminal poly(ethylene glycol)-protein conjugates. Adv Drug Deliv Rev. 2002;54:477–485.
   PubMed Web of Science ®Google Scholar
• Na DH, Lee KC, DeLuca PP. PEGylation of octreotide: II. Effect of N-terminal mono-PEGylation on biological activity and pharmacokinetics. Pharm Res. 2005;22:743–749.
   PubMed Web of Science ®Google Scholar
• Lee W, Park EJ, Kwak S, et al. PEGylated lysozymes with anti-septic effects in human endothelial cells and in mice. Biochem Biophys Res Commun. 2015;459:662–667.
   PubMed Web of Science ®Google Scholar
• Piedmonte DM, Treuheit MJ. Formulation of Neulasta (R) (pegfilgrastim). Adv Drug Deliv Rev. 2008;60:50–58.
   PubMed Web of Science ®Google Scholar
• Park EJ, Lee KS, Lee KC, et al. Application of microchip CGE for the analysis of PEG-modified recombinant human granulocyte-colony stimulating factors. Electrophoresis. 2010;31:3771–3774.
   PubMed Web of Science ®Google Scholar
• Mero A, Grigoletto A, Maso K, et al. Site-selective enzymatic chemistry for polymer conjugation to protein lysine residues: pEGylation of G-CSF at lysine-41. Polym Chem. 2016;7:6545–6553.
   Web of Science ®Google Scholar
• Fipula D, Zhao H. Releasable PEGylation of proteins with customized linkers. Adv Drug Deliv Rev. 2008;60:29–49.
   PubMed Web of Science ®Google Scholar
• Maeda H. Polymer therapeutics and the EPR effect. J Drug Target. 2017;25:781–785.
   PubMed Web of Science ®Google Scholar
• Pasut G, Veronese FM. PEG conjugates in clinical development or use as anticancer agents: an overview. Adv Drug Deliv Rev. 2009;61:1177–1188.
   PubMed Web of Science ®Google Scholar
• Greenwald RB, Choe YH, McGuire J, et al. Effective drug delivery by PEGylated drug conjugates. Adv Drug Deliv Rev. 2003;55:217–250.
   PubMed Web of Science ®Google Scholar
• Yamaoka T, Tabata Y, Ikada Y. Fate of water‐soluble polymers administered via different routes. J Pharm Sci-Us. 1995;84:349–354.
   PubMed Web of Science ®Google Scholar
• Lopez-Miranda E, Cortes J. Etirinotecan pegol for the treatment of breast cancer. Expert Opin Pharmaco. 2016;17:727–734.
   PubMed Web of Science ®Google Scholar
• Huisman SA, de Bruijn P, Moghaddam Helmantel IMG, et al. Fasting protects against the side effects of irinotecan treatment but does not affect anti‐tumour activity in mice. Br J Pharmacol. 2016;173:804–814.
   PubMed Web of Science ®Google Scholar
• Kim Y, Park EJ, Na DH. Recent progress in dendrimer-based nanomedicine development. Arch Pharm Res. 2018;41:571–582.
   PubMed Web of Science ®Google Scholar
• Hoch U, Staschen CM, Johnson RK, et al. Nonclinical pharmacokinetics and activity of etirinotecan pegol (NKTR-102), a long-acting topoisomerase 1 inhibitor, in multiple cancer models. Cancer Chemoth Pharm. 2014;74:1125–1137.
   PubMed Web of Science ®Google Scholar
• Jameson GS, Hamm JT, Weiss GJ, et al. A multicenter, phase i, dose-escalation study to assess the safety, tolerability, and pharmacokinetics of etirinotecan pegol in patients with refractory solid tumors. Clin Cancer Res. 2013;19:268–278.
   PubMed Web of Science ®Google Scholar
• Alemany C. Etirinotecan pegol development of a novel conjugated topoisomerase i inhibitor. Curr Oncol Rep. 2014;16:367.
   PubMed Web of Science ®Google Scholar
• Awada A, Garcia AA, Chan S, et al. Two schedules of etirinotecan pegol (NKTR-102) in patients with previously treated metastatic breast cancer: a randomised phase 2 study. Lancet Oncol. 2013;14:1216–1225.
   PubMed Web of Science ®Google Scholar
• Vergote IB, Garcia A, Micha J, et al. Randomized multicenter phase ii trial comparing two schedules of etirinotecan pegol (NKTR-102) in women with recurrent platinum-resistant/refractory epithelial ovarian cancer. J Clin Oncol. 2013;31:4060.
   PubMed Web of Science ®Google Scholar
• Rustin G, Vergote I, Micha JP, et al. A multicenter, open-label, expanded phase 2 study to evaluate the safety and efficacy of etirinotecan pegol, a polymer conjugate of irinotecan, in women with recurrent platinum-resistant or refractory ovarian cancer. Gynecol Oncol. 2017;147:276–282.
   PubMed Web of Science ®Google Scholar
• Miyazaki T, Choi IY, Rubas W, et al. NKTR-181: A novel Mu-opioid analgesic with inherently low abuse potential. J Pharmacol Exp Ther. 2017;363:104–113.
   PubMed Web of Science ®Google Scholar
• Webster L, Henningfield J, Buchhalter AR, et al. Human abuse potential of the new opioid analgesic molecule NKTR-181 compared with oxycodone. Pain Med. 2018;19:307–318.
   PubMed Web of Science ®Google Scholar
• Zhao H, Rubio B, Sapra P, et al. Novel prodrugs of SN38 using multiarm poly(ethylene glycol) linkers. Bioconjugate Chem. 2008;19:849–859.
   PubMed Web of Science ®Google Scholar
• Patnaik A, Papadopoulos KP, Tolcher AW, et al. Phase I dose-escalation study of EZN-2208 (PEG-SN38), a novel conjugate of poly(ethylene) glycol and SN38, administered weekly in patients with advanced cancer. Cancer Chemoth Pharm. 2013;71:1499–1506.
   PubMed Web of Science ®Google Scholar
• Park EJ, Lim SM, Lee KC, et al. Exendins and exendin analogs for diabetic therapy: a patent review (2012-2015). Expert Opin Ther Pat. 2016;26:833–842.
   PubMed Web of Science ®Google Scholar
• Pocai A. Action and therapeutic potential of oxyntomodulin. Mol Metab. 2014;3:241–251.
   PubMed Web of Science ®Google Scholar
• Yu MZ, Benjamin MM, Srinivasan S, et al. Battle of GLP-1 delivery technologies. Adv Drug Deliv Rev. 2018;130:113–130.
   PubMed Web of Science ®Google Scholar
• Pegbio Co., Ltd. Novel exendin variant and conjugate thereof. US0196795. 2012.
   Google Scholar
• Yun SP, Kam TI, Panicker N, et al. Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson‘s disease. Nat Med. 2018;24:931-+.
   Web of Science ®Google Scholar
• Floege J, Ostendorf T, Janssen U, et al. Novel approach to specific growth factor inhibition in vivo - Antagonism of platelet-derived growth factor in glomerulonephritis by aptamers. Am J Pathol. 1999;154:169–179.
   PubMed Web of Science ®Google Scholar
• Dyke CK, Steinhubl SR, Kleiman NS, et al. First-in-human experience of an antidote-controlled anticoagulant using RNA aptamer technology - A phase 1a pharmacodynamic evaluation of a drug-antidote pair for the controlled regulation of factor IXa activity. Circulation. 2006;114:2490–2497.
   PubMed Web of Science ®Google Scholar
• Tanaka KA, Szlam F, Rusconi CP, et al. In-vitro evaluation of anti-factor IXa aptamer on thrombin generation, clotting time, and viscoelastometry. Thromb Haemostasis. 2009;101:827–833.
   PubMed Web of Science ®Google Scholar
• Lincoff AM, Mehran R, Povsic TJ, et al. Effect of the REG1 anticoagulation system versus bivalirudin on outcomes after percutaneous coronary intervention (REGULATE-PCI): a randomised clinical trial. Lancet. 2016;387:349–356.
   PubMed Web of Science ®Google Scholar
• Ganson NJ, Povsic TJ, Sullenger BA, et al. Pre-existing anti-polyethylene glycol antibody linked to first-exposure allergic reactions to pegnivacogin, a PEGylated RNA aptamer. J Allergy Clin Immun. 2016;137:1610–1613.
   PubMed Web of Science ®Google Scholar
• Bae ON. Targeting von Willebrand factor as a novel anti-platelet therapy; Application of ARC1779, an Anti-vWF aptamer, against thrombotic risk. Arch Pharm Res. 2012;35:1693–1699.
   PubMed Web of Science ®Google Scholar
• Biesecker G, Dihel L, Enney K, et al. Derivation of RNA aptamer inhibitors of human complement C5. Immunopharmacology. 1999;42:219–230.
   PubMed Web of Science ®Google Scholar
• Kaur H, Bruno JG, Kumar A, et al. Aptamers in the therapeutics and diagnostics pipelines. Theranostics. 2018;8:4016–4032.
   PubMed Web of Science ®Google Scholar
• Vater A, Klussmann S. Turning mirror-image oligonucleotides into drugs: the evolution of Spiegelmer therapeutics. Drug Discov Today. 2015;20:147–155.
   PubMed Web of Science ®Google Scholar
• Klussmann S, Nolte A, Bald R, et al. Mirror-image RNA that binds D-adenosine. Nat Biotechnol. 1996;14:1112–1115.
   PubMed Web of Science ®Google Scholar
• Hoellenriegel J, Zboralski D, Maasch C, et al. The Spiegelmer NOX-A12, a novel CXCL12 inhibitor, interferes with chronic lymphocytic leukemia cell motility and causes chemosensitization. Blood. 2014;123:1032–1039.
   PubMed Web of Science ®Google Scholar
• Vater A, Sahlmann J, Kroger N, et al. Hematopoietic stem and progenitor cell mobilization in mice and humans by a first-in-class mirror-image oligonucleotide inhibitor of CXCL12. Clin Pharmacol Ther. 2013;94:150–157.
   PubMed Web of Science ®Google Scholar
• Oberthur D, Achenbach J, Gabdulkhakov A, et al. Crystal structure of a mirror-image L-RNA aptamer (Spiegelmer) in complex with the natural L-protein target CCL2. Nat Commun. 2015;6:6923.
   PubMed Web of Science ®Google Scholar
• Baggiolini M, Dewald B, Moser B. Human chemokines: an update. Annu Rev Immunol. 1997;15:675–705.
   PubMed Web of Science ®Google Scholar
• Menne J, Eulberg D, Beyer D, et al. C-C motif-ligand 2 inhibition with emapticap pegol (NOX-E36) in type 2 diabetic patients with albuminuria. Nephrol Dial Transpl. 2017;32:307–315.
   PubMed Web of Science ®Google Scholar
• Schwoebel F, van Eijk LT, Zboralski D, et al. The effects of the anti-hepcidin Spiegelmer NOX-H94 on inflammation-induced anemia in cynomolgus monkeys. Blood. 2013;121:2311–2315.
   PubMed Web of Science ®Google Scholar
• Boyce M, Warrington S, Cortezi B, et al. Safety, pharmacokinetics and pharmacodynamics of the anti-hepcidin Spiegelmer lexaptepid pegol in healthy subjects. Br J Pharmacol. 2016;173:1580–1588.
   PubMed Web of Science ®Google Scholar
• Becker R, Dembek C, White LA, et al. The cost offsets and cost-effectiveness associated with pegylated drugs: a review of the literature. Expert Rev Pharm Out. 2012;12:775–793.
   Google Scholar
• Schellekens H, Hennink WE, Brinks V. The Immunogenicity of polyethylene glycol: facts and fiction. Pharm Res. 2013;30:1729–1734.
   PubMed Web of Science ®Google Scholar
• Zhang P, Sun F, Liu SJ, et al. Anti-PEG antibodies in the clinic: current issues and beyond PEGylation. J Control Release. 2016;244:184–193.
   PubMed Web of Science ®Google Scholar
• Garay RP, El-Gewely R, Armstrong JK, et al. Antibodies against polyethylene glycol in healthy subjects and in patients treated with PEG-conjugated agents. Expert Opin Drug Deliv. 2012;9:1319–1323.
   PubMed Web of Science ®Google Scholar
• Abu Lila AS, Kiwada H, Ishida T. The accelerated blood clearance (ABC) phenomenon: clinical challenge and approaches to manage. J Control Release. 2013;172:38–47.
   PubMed Web of Science ®Google Scholar
• Lubich C, Allacher P, de la Rosa M, et al. The mystery of antibodies against polyethylene Glycol (PEG) - what do we know? Pharm Res. 2016;33:2239–2249.
   PubMed Web of Science ®Google Scholar
• Forest T, Xu Q, Kuruvilla S, et al. Magnetic resonance and ultrastructural characterization of pegylation-associated vacuolation in nonclinical models. Toxicol Pathol. 2017;45:604–613.
   PubMed Web of Science ®Google Scholar
• Fosgerau K, Hoffmann T. Peptide therapeutics: current status and future directions. Drug Discov Today. 2015;20:122–128.
   PubMed Web of Science ®Google Scholar
• Povsic TJ, Lawrence MG, Lincoff AM, et al. Pre-existing anti-PEG antibodies are associated with severe immediate allergic reactions to pegnivacogin, a PEGylated aptamer. J Allergy Clin Immun. 2016;138:1712–1715.
   PubMed Web of Science ®Google Scholar
• Grigoletto A, Maso K, Mero A, et al. Drug and protein delivery by polymer conjugation. J Drug Deliv Sci Tec. 2016;32:132–141.
   Web of Science ®Google Scholar