7. R.P. Garay, R. El-Gewely, J.K. Armstrong, G. Garratty, P. Richette, Antibodies against
polyethylene glycol in healthy subjects and in patients treated with PEG-conjugated agents.
Expert Opin. Drug Deliv. 9(11), 1319–1323 (2012)
8. C. Li, J. Cao, Y. Wang, X. Zhao, C. Deng, N. Wei et al., Accelerated blood clearance of
pegylated liposomal topotecan: influence of polyethylene glycol grafting density and animal
species. J. Pharm. Sci. 101(10), 3864–3876 (2012)
9. T. Suzuki, M. Ichihara, K. Hyodo, E. Yamamoto, T. Ishida, H. Kiwada et al., Influence of
dose and animal species on accelerated blood clearance of PEGylated liposomal doxorubicin.
Int. J. Pharm. 476(1–2), 205–212 (2014)
10. E.T. Dams, P. Laverman, W.J. Oyen, G. Storm, G.L. Scherphof, J.W. van Der Meer et al.,
Accelerated blood clearance and altered biodistribution of repeated injections of sterically
stabilized liposomes. J. Pharmacol. Exp. Ther. 292(3), 1071–1079 (2000)
11. P. Laverman, M.G. Carstens, O.C. Boerman, E.T. Dams, W.J. Oyen, N. van Rooijen et al.,
Factors affecting the accelerated blood clearance of polyethylene glycol-liposomes upon
repeated injection. J. Pharmacol. Exp. Ther. 298(2), 607–612 (2001)
12. R. Saadati, S. Dadashzadeh, Z. Abbasian, H. Soleimanjahi, Accelerated blood clearance of
PEGylated PLGA nanoparticles following repeated injections: effects of polymer dose, PEG
coating, and encapsulated anticancer drug. Pharm. Res. 30(4), 985–995 (2013)
13. H.J. Im, C.G. England, L. Feng, S.A. Graves, R. Hernandez, R.J. Nickles et al., Accelerated
blood clearance phenomenon reduces the passive targeting of PEGylated nanoparticles in
peripheral arterial disease. ACS Appl. Mater. Interfaces. 8(28), 17955–17963 (2016)
14. T. Ishida, R. Maeda, M. Ichihara, Y. Mukai, Y. Motoki, Y. Manabe et al., The accelerated
clearance on repeated injection of pegylated liposomes in rats: laboratory and histopathological study. Cell. Mol. Biol. Lett. 7(2), 286 (2002)
15. A.S. Abu Lila, H. Kiwada, T. Ishida, The accelerated blood clearance (ABC) phenomenon:
clinical challenge and approaches to manage. J. Control Release 172(1), 38–47 (2013)
16. T.J. Povsic, M.G. Lawrence, A.M. Lincoff, R. Mehran, C.P. Rusconi, S.L. Zelenkofske et al.,
Pre-existing anti-PEG antibodies are associated with severe immediate allergic reactions to
pegnivacogin, a PEGylated aptamer. J. Allergy Clin. Immunol. 138(6), 1712–1715 (2016)
17. J.K. Armstrong, G. Hempel, S. Koling, L.S. Chan, T. Fisher, H.J. Meiselman et al., Antibody
against poly(ethylene glycol) adversely affects PEG-asparaginase therapy in acute lymphoblastic leukemia patients. Cancer 110(1), 103–111 (2007)
18. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/
19. I. Wala, S.J. Swanson, S. Jing, A non-radioactive method for detecting neutralizing antibodies
against therapeutic proteins in serum. J. Pharm. Biomed. Anal. 45(4), 583–589 (2007)
20. P.S. Sorensen, Neutralizing antibodies against interferon-Beta. Ther. Adv. Neurol. Disord. 1
(2), 125–141 (2008)
21. T. Ishida, H. Kiwada, Anti-polyethyleneglycol antibody response to PEGylated substances.
Biol. Pharm. Bull. 36(6), 889–891 (2013)
22. E.A. Bell, G.C. Wall, Pediatric constipation therapy using guidelines and polyethylene glycol
3350. Ann. Pharmacother. 38(4), 686–693 (2004)
23. R. Webster, E. Didier, P. Harris, N. Siegel, J. Stadler, L. Tilbury et al., PEGylated proteins:
evaluation of their safety in the absence of definitive metabolism studies. Drug Metab. Dispos.
35(1), 9–16 (2007)
24. Y. Mima, Y. Hashimoto, T. Shimizu, H. Kiwada, T. Ishida, Anti-PEG IgM is a major
contributor to the accelerated blood clearance of polyethylene glycol-conjugated protein. Mol.
Pharm. 12(7), 2429–2435 (2015)
25. Q. Yang, S.K. Lai, Anti-PEG immunity: emergence, characteristics, and unaddressed
questions. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 7(5), 655–677 (2015)
26. A.W. Richter, E. Akerblom, Antibodies against polyethylene glycol produced in animals by
immunization with monomethoxy polyethylene glycol modified proteins. Int. Arch. Allergy
Appl. Immunol. 70(2), 124–131 (1983)
384
A. S. Abu Lila and T. Ishida
polyethylene glycol in healthy subjects and in patients treated with PEG-conjugated agents.
Expert Opin. Drug Deliv. 9(11), 1319–1323 (2012)
8. C. Li, J. Cao, Y. Wang, X. Zhao, C. Deng, N. Wei et al., Accelerated blood clearance of
pegylated liposomal topotecan: influence of polyethylene glycol grafting density and animal
species. J. Pharm. Sci. 101(10), 3864–3876 (2012)
9. T. Suzuki, M. Ichihara, K. Hyodo, E. Yamamoto, T. Ishida, H. Kiwada et al., Influence of
dose and animal species on accelerated blood clearance of PEGylated liposomal doxorubicin.
Int. J. Pharm. 476(1–2), 205–212 (2014)
10. E.T. Dams, P. Laverman, W.J. Oyen, G. Storm, G.L. Scherphof, J.W. van Der Meer et al.,
Accelerated blood clearance and altered biodistribution of repeated injections of sterically
stabilized liposomes. J. Pharmacol. Exp. Ther. 292(3), 1071–1079 (2000)
11. P. Laverman, M.G. Carstens, O.C. Boerman, E.T. Dams, W.J. Oyen, N. van Rooijen et al.,
Factors affecting the accelerated blood clearance of polyethylene glycol-liposomes upon
repeated injection. J. Pharmacol. Exp. Ther. 298(2), 607–612 (2001)
12. R. Saadati, S. Dadashzadeh, Z. Abbasian, H. Soleimanjahi, Accelerated blood clearance of
PEGylated PLGA nanoparticles following repeated injections: effects of polymer dose, PEG
coating, and encapsulated anticancer drug. Pharm. Res. 30(4), 985–995 (2013)
13. H.J. Im, C.G. England, L. Feng, S.A. Graves, R. Hernandez, R.J. Nickles et al., Accelerated
blood clearance phenomenon reduces the passive targeting of PEGylated nanoparticles in
peripheral arterial disease. ACS Appl. Mater. Interfaces. 8(28), 17955–17963 (2016)
14. T. Ishida, R. Maeda, M. Ichihara, Y. Mukai, Y. Motoki, Y. Manabe et al., The accelerated
clearance on repeated injection of pegylated liposomes in rats: laboratory and histopathological study. Cell. Mol. Biol. Lett. 7(2), 286 (2002)
15. A.S. Abu Lila, H. Kiwada, T. Ishida, The accelerated blood clearance (ABC) phenomenon:
clinical challenge and approaches to manage. J. Control Release 172(1), 38–47 (2013)
16. T.J. Povsic, M.G. Lawrence, A.M. Lincoff, R. Mehran, C.P. Rusconi, S.L. Zelenkofske et al.,
Pre-existing anti-PEG antibodies are associated with severe immediate allergic reactions to
pegnivacogin, a PEGylated aptamer. J. Allergy Clin. Immunol. 138(6), 1712–1715 (2016)
17. J.K. Armstrong, G. Hempel, S. Koling, L.S. Chan, T. Fisher, H.J. Meiselman et al., Antibody
against poly(ethylene glycol) adversely affects PEG-asparaginase therapy in acute lymphoblastic leukemia patients. Cancer 110(1), 103–111 (2007)
18. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/
19. I. Wala, S.J. Swanson, S. Jing, A non-radioactive method for detecting neutralizing antibodies
against therapeutic proteins in serum. J. Pharm. Biomed. Anal. 45(4), 583–589 (2007)
20. P.S. Sorensen, Neutralizing antibodies against interferon-Beta. Ther. Adv. Neurol. Disord. 1
(2), 125–141 (2008)
21. T. Ishida, H. Kiwada, Anti-polyethyleneglycol antibody response to PEGylated substances.
Biol. Pharm. Bull. 36(6), 889–891 (2013)
22. E.A. Bell, G.C. Wall, Pediatric constipation therapy using guidelines and polyethylene glycol
3350. Ann. Pharmacother. 38(4), 686–693 (2004)
23. R. Webster, E. Didier, P. Harris, N. Siegel, J. Stadler, L. Tilbury et al., PEGylated proteins:
evaluation of their safety in the absence of definitive metabolism studies. Drug Metab. Dispos.
35(1), 9–16 (2007)
24. Y. Mima, Y. Hashimoto, T. Shimizu, H. Kiwada, T. Ishida, Anti-PEG IgM is a major
contributor to the accelerated blood clearance of polyethylene glycol-conjugated protein. Mol.
Pharm. 12(7), 2429–2435 (2015)
25. Q. Yang, S.K. Lai, Anti-PEG immunity: emergence, characteristics, and unaddressed
questions. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 7(5), 655–677 (2015)
26. A.W. Richter, E. Akerblom, Antibodies against polyethylene glycol produced in animals by
immunization with monomethoxy polyethylene glycol modified proteins. Int. Arch. Allergy
Appl. Immunol. 70(2), 124–131 (1983)
384
A. S. Abu Lila and T. Ishida