Upon exposure to PEG in the daily use of common products, PEG is likely
introduced to sites of inflammation and to come into close vicinity to highly active
immune cells, which in turn may trigger the induction of anti-PEG antibodies.
20.7.2 Clinical Implications of Anti-PEG Antibodies
on the Efficacy of PEGylated Therapeutics
To date, with an increasing number of PEGylated products entering the clinic, many
reports have emphasized the immunogenicity of PEGylated therapeutics and have
claimed the reconsideration of the safety profile of PEGylated products [28, 62].
Nonetheless, the issue of the clinical implications of anti-PEG antibodies on the
efficiency of PEGylated therapeutics is controversial. In 1984, Richter and
Akerblom [28] have revealed that pre-existing anti-PEG antibodies did not ruin
hypersensitization treatment of allergic patients with PEG-modified honeybee
venom or ragweed extract. In the same context, Tillmann et al. [62] have demonstrated that, despite the high prevalence of pre-existing anti-PEG antibodies in 44%
of patients with hepatitis C, the presence of pre-existing anti-PEG antibodies was
found not to compromise the therapeutic efficacy of PEG-INF-a. However, the
impact of impaired immunity and hepatic damage induced by hepatitis C virus on
the therapeutic efficacy of PEG-INF-a has not been justified. Furthermore, unlike
most reports demonstrate that the presence of anti-PEG response in a subset of
patients, anti-PEG antibodies were detected in all phenylketonurea patients treated
with PEGylated phenylalanine ammonia lyase (PEG-PAL). Nonetheless, neither
pre-existing nor induced anti-PEG antibodies adversely affected the therapeutic
efficiency of a single dose of PEG-PAL [60]. Collectively, these findings played an
integral role in creating the perception that anti-PEG antibody response has no
clinical implications for the therapeutic efficacy of PEGylated therapeutics in
humans.
By contrary, recent reports have highlighted the detrimental effect of anti-PEG
antibodies on the therapeutic efficiency of PEGylated therapeutic [17, 31, 64, 65].
In pediatric patients treated with PEG-Asparaginase (PEG-ASNase) for acute
lymphoblastic leukemia, anti-PEG IgM antibodies were detected in about half of
the patients and the presence of such anti-PEG antibodies was reported to correlate
closely to the enhanced clearance of PEG-ASNase and loss of therapeutic efficiency. Notably, anti-PEG antibodies present in the sera of patients treated with
unmodified ASNase affected neither the systemic clearance nor the therapeutic
efficiency of the therapeutic protein (ASNase). In the same context, the clinical use
of Pegloticase, a PEGylated uric acid-specific enzyme, in patients with chronic gout
has been hampered by the occurrence of PEG antibodies; anti-PEG antibodies was
detected in 89% of patients treated with Pegloticase, resulting in enhanced
Pegloticase clearance, loss of activity and increased risk of treatment-induced
infusion reactions [66]. These findings highlight the potential impact of anti-PEG
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A. S. Abu Lila and T. Ishida
introduced to sites of inflammation and to come into close vicinity to highly active
immune cells, which in turn may trigger the induction of anti-PEG antibodies.
20.7.2 Clinical Implications of Anti-PEG Antibodies
on the Efficacy of PEGylated Therapeutics
To date, with an increasing number of PEGylated products entering the clinic, many
reports have emphasized the immunogenicity of PEGylated therapeutics and have
claimed the reconsideration of the safety profile of PEGylated products [28, 62].
Nonetheless, the issue of the clinical implications of anti-PEG antibodies on the
efficiency of PEGylated therapeutics is controversial. In 1984, Richter and
Akerblom [28] have revealed that pre-existing anti-PEG antibodies did not ruin
hypersensitization treatment of allergic patients with PEG-modified honeybee
venom or ragweed extract. In the same context, Tillmann et al. [62] have demonstrated that, despite the high prevalence of pre-existing anti-PEG antibodies in 44%
of patients with hepatitis C, the presence of pre-existing anti-PEG antibodies was
found not to compromise the therapeutic efficacy of PEG-INF-a. However, the
impact of impaired immunity and hepatic damage induced by hepatitis C virus on
the therapeutic efficacy of PEG-INF-a has not been justified. Furthermore, unlike
most reports demonstrate that the presence of anti-PEG response in a subset of
patients, anti-PEG antibodies were detected in all phenylketonurea patients treated
with PEGylated phenylalanine ammonia lyase (PEG-PAL). Nonetheless, neither
pre-existing nor induced anti-PEG antibodies adversely affected the therapeutic
efficiency of a single dose of PEG-PAL [60]. Collectively, these findings played an
integral role in creating the perception that anti-PEG antibody response has no
clinical implications for the therapeutic efficacy of PEGylated therapeutics in
humans.
By contrary, recent reports have highlighted the detrimental effect of anti-PEG
antibodies on the therapeutic efficiency of PEGylated therapeutic [17, 31, 64, 65].
In pediatric patients treated with PEG-Asparaginase (PEG-ASNase) for acute
lymphoblastic leukemia, anti-PEG IgM antibodies were detected in about half of
the patients and the presence of such anti-PEG antibodies was reported to correlate
closely to the enhanced clearance of PEG-ASNase and loss of therapeutic efficiency. Notably, anti-PEG antibodies present in the sera of patients treated with
unmodified ASNase affected neither the systemic clearance nor the therapeutic
efficiency of the therapeutic protein (ASNase). In the same context, the clinical use
of Pegloticase, a PEGylated uric acid-specific enzyme, in patients with chronic gout
has been hampered by the occurrence of PEG antibodies; anti-PEG antibodies was
detected in 89% of patients treated with Pegloticase, resulting in enhanced
Pegloticase clearance, loss of activity and increased risk of treatment-induced
infusion reactions [66]. These findings highlight the potential impact of anti-PEG
378
A. S. Abu Lila and T. Ishida