phenomenon. Currently, the ABC phenomenon is of clinical concern because it
compromises the therapeutic efficiency of PEGylated therapeutics upon repeated
administration, in tandem with, eliciting the development of adverse effects.
20.4 Mechanism of the ABC Phenomenon
Since the first report concerning the pharmacokinetic irregularities upon repeated
injections of PEGylated liposomes (the ABC phenomenon) by Dams el al. [10],
research efforts have focused on elucidating the underlying mechanism of the ABC
phenomenon. Laverman et al. [11] identified 2 phases of the ABC phenomenon: the
induction phase, in which the host immune system is “primed” by the first injection
of PEGylated liposome, and, the effectuation phase, in which a subsequent dose of
PEGylated liposomes is rapidly opsonized and cleared from systemic circulation by
the cells of MPS. Later on, in a series of our studies [14, 40, 43–45], we emphasized
the crucial role of anti-PEG antibodies, mainly anti-PEG IgM, elicited in response
to the first dose, in the induction of the ABC phenomenon. In addition, we
emphasized the vital role of the spleen in the induction of anti-PEG IgM immune
response [46]. Where, splenectomy was found to significantly alleviate the production of anti-PEG IgM and consequently attenuate the induction of the ABC
phenomenon following the administration of PEGylated liposomes, suggesting that
splenic cells serve as the primary site of anti-PEG IgM induction [27, 47].
Furthermore, it has been reported that the ABC phenomenon was only observed in
T-cell-deficient BALB/c nude mice but not in BALB/c SCID mice (T and B
cells-deficient mice) [47, 48]. Consequently, the ABC phenomenon seems to
involve B cells functioning through T-cell independent (TI) mechanism.
Collectively, based on the aforementioned data, we postulated the following
mechanism to explain the ABC phenomenon (Fig. 20.1): anti-PEG IgM, produced
in the spleen in response to the first dose, selectively bind to the PEG upon the
second dose of PEGylated liposome injected several days later and subsequently
activates the complementary system, and, as a consequence, the liposomes are taken
up by the Kupffer cells via complement receptor-mediated endocytosis.
20.5 Correlation Between Complement Activation
and the ABC Phenomenon
Many reports have highlighted the role of the complement system in the accelerated
blood clearance of PEGylated nanocarriers from blood circulation upon repeated
injection [49–51]. It is well recognized that IgM antibodies per se are unable to
directly induce phagocytosis via specific receptor on phagocytic cells such as
macrophages because IgM is not an opsonizing antibody due to the absence of
374
A. S. Abu Lila and T. Ishida
compromises the therapeutic efficiency of PEGylated therapeutics upon repeated
administration, in tandem with, eliciting the development of adverse effects.
20.4 Mechanism of the ABC Phenomenon
Since the first report concerning the pharmacokinetic irregularities upon repeated
injections of PEGylated liposomes (the ABC phenomenon) by Dams el al. [10],
research efforts have focused on elucidating the underlying mechanism of the ABC
phenomenon. Laverman et al. [11] identified 2 phases of the ABC phenomenon: the
induction phase, in which the host immune system is “primed” by the first injection
of PEGylated liposome, and, the effectuation phase, in which a subsequent dose of
PEGylated liposomes is rapidly opsonized and cleared from systemic circulation by
the cells of MPS. Later on, in a series of our studies [14, 40, 43–45], we emphasized
the crucial role of anti-PEG antibodies, mainly anti-PEG IgM, elicited in response
to the first dose, in the induction of the ABC phenomenon. In addition, we
emphasized the vital role of the spleen in the induction of anti-PEG IgM immune
response [46]. Where, splenectomy was found to significantly alleviate the production of anti-PEG IgM and consequently attenuate the induction of the ABC
phenomenon following the administration of PEGylated liposomes, suggesting that
splenic cells serve as the primary site of anti-PEG IgM induction [27, 47].
Furthermore, it has been reported that the ABC phenomenon was only observed in
T-cell-deficient BALB/c nude mice but not in BALB/c SCID mice (T and B
cells-deficient mice) [47, 48]. Consequently, the ABC phenomenon seems to
involve B cells functioning through T-cell independent (TI) mechanism.
Collectively, based on the aforementioned data, we postulated the following
mechanism to explain the ABC phenomenon (Fig. 20.1): anti-PEG IgM, produced
in the spleen in response to the first dose, selectively bind to the PEG upon the
second dose of PEGylated liposome injected several days later and subsequently
activates the complementary system, and, as a consequence, the liposomes are taken
up by the Kupffer cells via complement receptor-mediated endocytosis.
20.5 Correlation Between Complement Activation
and the ABC Phenomenon
Many reports have highlighted the role of the complement system in the accelerated
blood clearance of PEGylated nanocarriers from blood circulation upon repeated
injection [49–51]. It is well recognized that IgM antibodies per se are unable to
directly induce phagocytosis via specific receptor on phagocytic cells such as
macrophages because IgM is not an opsonizing antibody due to the absence of
374
A. S. Abu Lila and T. Ishida