XTEN sequences have been reported to be well-tolerated and being weakly
immunogenic in many animal studies [89]. Currently, an exenatide-XTEN fusion
construct (VRS-859) for the treatment of type II diabetes and a growth
hormone-XTEN fusion construct (VRS 317) for growth hormone deficiency are
undergoing Phase I clinical trials [89–91].
20.10 Conclusion
In contrast to the general perception that PEG is biologically inert, many reports
have clearly underscored the detrimental effect of anti-PEG immunity, elicited by
either pre-existing or treatment-induced antibodies, on the therapeutic efficiency
and/or safety of PEGylated therapeutics. Accordingly, in light of the large arsenal of
PEGylated therapeutics that are FDA-approved or under clinical investigation,
patients should be pre-screened and monitored for anti-PEG antibodies prior to and
throughout a course of treatment with PEGylated therapeutics. Furthermore, a deep
understanding of the mechanism of anti-PEG immunity along with strategies to
avert the challenges of PEG-specific immunity is urgently needed.
Acknowledgements We thank Dr. J. L. McDonald for his helpful advice in writing the manuscript. This study was supported, in part, by a Grant-in-Aid for Scientific Research (B) 15H04639,
the Ministry of Education, Culture, Sports, Science and Technology, Japan.
Disclosures and Conflicts of Interest
The authors declare that they have no conflicts of interest. The authors have received no payment
for the preparation of this chapter.
References
1. D.D. Lasic, F.J. Martin, A. Gabizon, S.K. Huang, D. Papahadjopoulos, Sterically stabilized
liposomes: a hypothesis on the molecular origin of the extended circulation times. Biochim.
Biophys. Acta 1070(1), 187–192 (1991)
2. T.M. Allen, C. Hansen, Pharmacokinetics of stealth versus conventional liposomes: effect of
dose. Biochim. Biophys. Acta 1068(2), 133–141 (1991)
3. V.P. Torchilin, Recent advances with liposomes as pharmaceutical carriers. Nat. Rev. Drug
Discov. 4(2), 145–160 (2005)
4. J.M. Harris, R.B. Chess, Effect of pegylation on pharmaceuticals. Nat. Rev. Drug Discov. 2
(3), 214–221 (2003)
5. B. Gorovits, A. Clements-Egan, M. Birchler, M. Liang, H. Myler, K. Peng et al., Pre-existing
antibody: biotherapeutic modality-based review. AAPS J. 18(2), 311–320 (2016)
6. H. Schellekens, W.E. Hennink, V. Brinks, The immunogenicity of polyethylene glycol: facts
and fiction. Pharm. Res. 30(7), 1729–1734 (2013)
20 Immune Response to PEGylated Nanomedicines …
383
immunogenic in many animal studies [89]. Currently, an exenatide-XTEN fusion
construct (VRS-859) for the treatment of type II diabetes and a growth
hormone-XTEN fusion construct (VRS 317) for growth hormone deficiency are
undergoing Phase I clinical trials [89–91].
20.10 Conclusion
In contrast to the general perception that PEG is biologically inert, many reports
have clearly underscored the detrimental effect of anti-PEG immunity, elicited by
either pre-existing or treatment-induced antibodies, on the therapeutic efficiency
and/or safety of PEGylated therapeutics. Accordingly, in light of the large arsenal of
PEGylated therapeutics that are FDA-approved or under clinical investigation,
patients should be pre-screened and monitored for anti-PEG antibodies prior to and
throughout a course of treatment with PEGylated therapeutics. Furthermore, a deep
understanding of the mechanism of anti-PEG immunity along with strategies to
avert the challenges of PEG-specific immunity is urgently needed.
Acknowledgements We thank Dr. J. L. McDonald for his helpful advice in writing the manuscript. This study was supported, in part, by a Grant-in-Aid for Scientific Research (B) 15H04639,
the Ministry of Education, Culture, Sports, Science and Technology, Japan.
Disclosures and Conflicts of Interest
The authors declare that they have no conflicts of interest. The authors have received no payment
for the preparation of this chapter.
References
1. D.D. Lasic, F.J. Martin, A. Gabizon, S.K. Huang, D. Papahadjopoulos, Sterically stabilized
liposomes: a hypothesis on the molecular origin of the extended circulation times. Biochim.
Biophys. Acta 1070(1), 187–192 (1991)
2. T.M. Allen, C. Hansen, Pharmacokinetics of stealth versus conventional liposomes: effect of
dose. Biochim. Biophys. Acta 1068(2), 133–141 (1991)
3. V.P. Torchilin, Recent advances with liposomes as pharmaceutical carriers. Nat. Rev. Drug
Discov. 4(2), 145–160 (2005)
4. J.M. Harris, R.B. Chess, Effect of pegylation on pharmaceuticals. Nat. Rev. Drug Discov. 2
(3), 214–221 (2003)
5. B. Gorovits, A. Clements-Egan, M. Birchler, M. Liang, H. Myler, K. Peng et al., Pre-existing
antibody: biotherapeutic modality-based review. AAPS J. 18(2), 311–320 (2016)
6. H. Schellekens, W.E. Hennink, V. Brinks, The immunogenicity of polyethylene glycol: facts
and fiction. Pharm. Res. 30(7), 1729–1734 (2013)
20 Immune Response to PEGylated Nanomedicines …
383