PEG groups. Furthermore, due to the difference in the immune responses between
free PEG and PEGylated conjugates, PEG is projected to function as a hapten,
which is a non-immunogenic small molecule that can elucidate an immune response
only when conjugated to a larger carrier [7, 58, 59].
20.7 Anti-PEG Immunity in Humans
Despite the fact that PEGylation has been acknowledged for the success of
numerous PEGylated products currently on the market, an emerging body of literature has emphasized the existence of anti-PEG antibodies in the sera of normal
donors and/or sera of PEGylated therapeutics-treated patients that specifically
recognize and bind to PEG [7, 17, 30]. The presence of anti-PEG antibodies,
consequently, might represent potential challenges against the clinical deployment
of PEGylated therapeutics since such antibodies could compromise the therapeutic
efficiency and increase the risk of treatment-related adverse effects [7, 17, 30, 31,
60].
20.7.1 Pre-existing Anti-PEG Antibodies in Normal Donors
In contrast to the basic perception that anti-PEG immunity arises predominantly by
previous exposure to PEGylated therapeutics, a growing body of literature has
emphasized the elicitation of immunogenic responses against PEGylated substances
in normal subjects upon first exposure to PEGylated therapeutics [17, 25, 28, 31,
33, 60–63]. Richter and Akerlom [28] first noticed that 0.2 and 3.3% of normal
subjects and untreated allergy patients, respectively, exhibits remarkably higher
titers of anti-PEG IgM. Later on, Armstrong et al. [17] declared significantly higher
incidence rates of anti-PEG IgM (*27%) in healthy blood donors. More recently,
Yang and Lai [25] reported an even higher anti-PEG antibody (up to 42%) in
healthy adult individuals. Such variations reflect a significant increment in the
prevalence of pre-existing anti-PEG antibodies in normal subjects over time. The
underlying mechanism of anti-PEG antibodies production in healthy individuals has
not been fully elucidated yet. However, since PEG has been classified by the FDA
under the category of products that are Generally Recognized As Safe (GRAS), it
has become commonly used in processed foods, cosmetics and pharmaceuticals.
Accordingly, frequent exposure to PEG in daily use products is supposed to induce
the production of anti-PEG antibodies. Based on the aforementioned data, Yang
and Lai [25] have recently postulated the following tentative mechanism elucidating
the existence of anti-PEG antibodies in normal subjects: as the human body is
vulnerable to certain conditions such as ulcerations, abrasions and skin tears that
might cause local inflammatory responses and/or recruitment of immune cells.
20 Immune Response to PEGylated Nanomedicines …
377
free PEG and PEGylated conjugates, PEG is projected to function as a hapten,
which is a non-immunogenic small molecule that can elucidate an immune response
only when conjugated to a larger carrier [7, 58, 59].
20.7 Anti-PEG Immunity in Humans
Despite the fact that PEGylation has been acknowledged for the success of
numerous PEGylated products currently on the market, an emerging body of literature has emphasized the existence of anti-PEG antibodies in the sera of normal
donors and/or sera of PEGylated therapeutics-treated patients that specifically
recognize and bind to PEG [7, 17, 30]. The presence of anti-PEG antibodies,
consequently, might represent potential challenges against the clinical deployment
of PEGylated therapeutics since such antibodies could compromise the therapeutic
efficiency and increase the risk of treatment-related adverse effects [7, 17, 30, 31,
60].
20.7.1 Pre-existing Anti-PEG Antibodies in Normal Donors
In contrast to the basic perception that anti-PEG immunity arises predominantly by
previous exposure to PEGylated therapeutics, a growing body of literature has
emphasized the elicitation of immunogenic responses against PEGylated substances
in normal subjects upon first exposure to PEGylated therapeutics [17, 25, 28, 31,
33, 60–63]. Richter and Akerlom [28] first noticed that 0.2 and 3.3% of normal
subjects and untreated allergy patients, respectively, exhibits remarkably higher
titers of anti-PEG IgM. Later on, Armstrong et al. [17] declared significantly higher
incidence rates of anti-PEG IgM (*27%) in healthy blood donors. More recently,
Yang and Lai [25] reported an even higher anti-PEG antibody (up to 42%) in
healthy adult individuals. Such variations reflect a significant increment in the
prevalence of pre-existing anti-PEG antibodies in normal subjects over time. The
underlying mechanism of anti-PEG antibodies production in healthy individuals has
not been fully elucidated yet. However, since PEG has been classified by the FDA
under the category of products that are Generally Recognized As Safe (GRAS), it
has become commonly used in processed foods, cosmetics and pharmaceuticals.
Accordingly, frequent exposure to PEG in daily use products is supposed to induce
the production of anti-PEG antibodies. Based on the aforementioned data, Yang
and Lai [25] have recently postulated the following tentative mechanism elucidating
the existence of anti-PEG antibodies in normal subjects: as the human body is
vulnerable to certain conditions such as ulcerations, abrasions and skin tears that
might cause local inflammatory responses and/or recruitment of immune cells.
20 Immune Response to PEGylated Nanomedicines …
377