systemic circulation [1, 2]. The hydrophilic nature of PEG is reported to favor the
formation of a hydration layer on the surface of nanocarriers-based and/or protein
therapeutics, resulting in decreased adsorption of opsonins and serum proteins and,
thus, less recognition and uptake by the cells of the mononuclear phagocyte system
(MPS), which would lead to extended blood circulation [3, 4]. In addition, PEG has
been reported to silence both humoral and cellular immunogenicity [5].
Nonetheless, in contrast to the typical assertion that PEG is non-immunogenic, a
mounting body of literature has emerged claiming PEG to be immunogenic [6, 7].
Many reports have demonstrated that an intravenous administration of PEGylated
substances in rats, rabbits, dogs and Rhesus monkeys could elicit antibody
responses against PEG (anti-PEG antibodies) limiting the therapeutic efficiency
and/or reducing the tolerance of PEGylated therapeutics [8, 9]. In addition, an
emerging body of literature has demonstrated that anti-PEG antibodies produced in
response to the first dose may harmfully trigger the rapid systemic clearance of
subsequently injected doses of PEGylated nanocarriers- the so-called “accelerated
blood clearance (ABC)” phenomenon [10–15]. Such phenomenon is of concern for
clinical translation of nanocarriers systems as it limits their passive accumulation in
many disease sites.
Of interest, the existence of naturally occurring anti-PEG antibodies in normal
individuals who have never received PEGylated therapeutics have been recently
emphasized [5, 16, 17]. Armstrong et al. [17] revealed that these naturally occurring
anti-PEG antibodies could prime the host immune system against administered
PEGylated therapeutics, and thereby, compromise their therapeutic efficacies.
Consequently, the US Food and Drug Administration (FDA) has recently emphasized the need for assessing the immunogenicity of PEGylated therapeutics, to
assure their safety, prior their approval for clinical use [18].
20.2 Anti-PEG IgM Response to PEGylated Proteins
Biomedicines, such as protein drugs, have received much attention because of their
high biological activity and specificity against target molecules. Nevertheless,
limitations regarding to their ability to generate neutralizing antibodies, in tandem
with, rapid systemic clearance have potentially compromised their clinical applications [19–21]. As described earlier, covalent conjugation of PEG to biologically
active molecules is considered one of the promising strategies to circumvent such
limitations. PEG is generally believed to be a biologically inert, non-immunogenic
polymer that is commonly used in the production of cosmetics and many pharmaceuticals, and is approved by FDA as a constituent of various medicines and
medical procedures [22, 23]. Therefore, the immunogenicity of PEGylated substances was formerly and directly tested against a primary substance, rather than
against covalently coupled PEG. However, a strong anti-PEG immunological
response, exemplified by the extensive production of anti-PEG antibodies, was
reported upon conjugating this hydrophilic polymer to some proteins, particularly
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A. S. Abu Lila and T. Ishida
formation of a hydration layer on the surface of nanocarriers-based and/or protein
therapeutics, resulting in decreased adsorption of opsonins and serum proteins and,
thus, less recognition and uptake by the cells of the mononuclear phagocyte system
(MPS), which would lead to extended blood circulation [3, 4]. In addition, PEG has
been reported to silence both humoral and cellular immunogenicity [5].
Nonetheless, in contrast to the typical assertion that PEG is non-immunogenic, a
mounting body of literature has emerged claiming PEG to be immunogenic [6, 7].
Many reports have demonstrated that an intravenous administration of PEGylated
substances in rats, rabbits, dogs and Rhesus monkeys could elicit antibody
responses against PEG (anti-PEG antibodies) limiting the therapeutic efficiency
and/or reducing the tolerance of PEGylated therapeutics [8, 9]. In addition, an
emerging body of literature has demonstrated that anti-PEG antibodies produced in
response to the first dose may harmfully trigger the rapid systemic clearance of
subsequently injected doses of PEGylated nanocarriers- the so-called “accelerated
blood clearance (ABC)” phenomenon [10–15]. Such phenomenon is of concern for
clinical translation of nanocarriers systems as it limits their passive accumulation in
many disease sites.
Of interest, the existence of naturally occurring anti-PEG antibodies in normal
individuals who have never received PEGylated therapeutics have been recently
emphasized [5, 16, 17]. Armstrong et al. [17] revealed that these naturally occurring
anti-PEG antibodies could prime the host immune system against administered
PEGylated therapeutics, and thereby, compromise their therapeutic efficacies.
Consequently, the US Food and Drug Administration (FDA) has recently emphasized the need for assessing the immunogenicity of PEGylated therapeutics, to
assure their safety, prior their approval for clinical use [18].
20.2 Anti-PEG IgM Response to PEGylated Proteins
Biomedicines, such as protein drugs, have received much attention because of their
high biological activity and specificity against target molecules. Nevertheless,
limitations regarding to their ability to generate neutralizing antibodies, in tandem
with, rapid systemic clearance have potentially compromised their clinical applications [19–21]. As described earlier, covalent conjugation of PEG to biologically
active molecules is considered one of the promising strategies to circumvent such
limitations. PEG is generally believed to be a biologically inert, non-immunogenic
polymer that is commonly used in the production of cosmetics and many pharmaceuticals, and is approved by FDA as a constituent of various medicines and
medical procedures [22, 23]. Therefore, the immunogenicity of PEGylated substances was formerly and directly tested against a primary substance, rather than
against covalently coupled PEG. However, a strong anti-PEG immunological
response, exemplified by the extensive production of anti-PEG antibodies, was
reported upon conjugating this hydrophilic polymer to some proteins, particularly
372
A. S. Abu Lila and T. Ishida