immunity on the growing clinical development of PEGylated therapeutics and
underscore the rationale for testing for anti-PEG antibodies in clinical trials of
PEGylated therapeutics. It is worth noting that anti-PEG immunity not only contributes to the compromised therapeutic efficacy of PEGylated therapeutics, but also
participates to the development of severe side effects as well [60, 61]. In the case of
PEGylated phenylalanine ammonia lyase (PEG-PAL), despite the fact that neither
pre-existing nor induced anti-PEG antibodies affected the therapeutic efficacy of the
injected drug, severe adverse reactions were observed in two patients who had
further treated with an intramuscular injections of medroxyprogestrone acetate, a
drug containing free PEG and polysorbate as excipients [60]. Ganson et al. [61] also
revealed the contribution of pre-existing anti-PEG antibodies to the safety profile of
a PEGylated RNA aptamer used in the treatment of acute coronary syndrome
(ACS); pegnivacogin. They demonstrated that treatment with pegnivacogin could
elicit the development of severe life-threatening allergic reactions in three ACS
patients upon their first exposure to pegnivacogin leading to early termination of the
trial.
20.8 Non-antibody Mediated Hypersensitivity Reactions
Besides the slow specific immunogenic response manifested in antibody formation
against PEGylated nanocarriers [11, 40, 42], a mounting body of evidences has also
revealed that intravenous administration of nanocarriers could provoke acute hypersensitivity reactions (HSR) that are classified as complement activation-related
pseudoallergy (CARPA) since they are not initiated/mediated by pre-existing IgE
antibodies but rather arise as a consequence of activation of complement system
[39, 67–69]. Such “hypersensitivity reactions” or “anaphylactoid reactions” typically occur directly at first exposure to the nanocarriers without prior sensitization,
and the symptoms usually lessen and/or disappear on later treatment, that is why
these reactions have recently been called “pseudoallergic” [70]. The symptoms of
HSR are mostly minor and transient and include cardiopulmonary distress such as
tachypnea, dyspnea, tachycardia, hypertension/hypotension, chest pain and back
pain. However, life-threatening or even deadly reactions can occur occasionally in
hypersensitive individuals [71].
Drugs and agents causing CARPA include radio-contrast media, liposomal drugs
(Ambisome
® , Doxil
® and DaunoXome
® ), micellar solvents (e.g. Cremophore EL;
the vehicle of Taxol), PEGylated proteins and monoclonal antibodies [70–76]. The
first direct evidence for the causal relationship between complement activation and
hypersensitivity reactions (CARPA) to PEGylated liposomes was provided by
Brouwers et al. [77], who reported that three out of nine patients receiving
99m Tclabeled PEGylated liposomes for scintigraphic detection of bowel inflammation
have developed severe hypersensitivity reactions. Later on, Szebeni and his colleges, in a series of their studies [39, 68, 73, 78], have emphasized the potential
contribution of complement activation to infusion reactions encountered in one
20 Immune Response to PEGylated Nanomedicines …
379
underscore the rationale for testing for anti-PEG antibodies in clinical trials of
PEGylated therapeutics. It is worth noting that anti-PEG immunity not only contributes to the compromised therapeutic efficacy of PEGylated therapeutics, but also
participates to the development of severe side effects as well [60, 61]. In the case of
PEGylated phenylalanine ammonia lyase (PEG-PAL), despite the fact that neither
pre-existing nor induced anti-PEG antibodies affected the therapeutic efficacy of the
injected drug, severe adverse reactions were observed in two patients who had
further treated with an intramuscular injections of medroxyprogestrone acetate, a
drug containing free PEG and polysorbate as excipients [60]. Ganson et al. [61] also
revealed the contribution of pre-existing anti-PEG antibodies to the safety profile of
a PEGylated RNA aptamer used in the treatment of acute coronary syndrome
(ACS); pegnivacogin. They demonstrated that treatment with pegnivacogin could
elicit the development of severe life-threatening allergic reactions in three ACS
patients upon their first exposure to pegnivacogin leading to early termination of the
trial.
20.8 Non-antibody Mediated Hypersensitivity Reactions
Besides the slow specific immunogenic response manifested in antibody formation
against PEGylated nanocarriers [11, 40, 42], a mounting body of evidences has also
revealed that intravenous administration of nanocarriers could provoke acute hypersensitivity reactions (HSR) that are classified as complement activation-related
pseudoallergy (CARPA) since they are not initiated/mediated by pre-existing IgE
antibodies but rather arise as a consequence of activation of complement system
[39, 67–69]. Such “hypersensitivity reactions” or “anaphylactoid reactions” typically occur directly at first exposure to the nanocarriers without prior sensitization,
and the symptoms usually lessen and/or disappear on later treatment, that is why
these reactions have recently been called “pseudoallergic” [70]. The symptoms of
HSR are mostly minor and transient and include cardiopulmonary distress such as
tachypnea, dyspnea, tachycardia, hypertension/hypotension, chest pain and back
pain. However, life-threatening or even deadly reactions can occur occasionally in
hypersensitive individuals [71].
Drugs and agents causing CARPA include radio-contrast media, liposomal drugs
(Ambisome
® , Doxil
® and DaunoXome
® ), micellar solvents (e.g. Cremophore EL;
the vehicle of Taxol), PEGylated proteins and monoclonal antibodies [70–76]. The
first direct evidence for the causal relationship between complement activation and
hypersensitivity reactions (CARPA) to PEGylated liposomes was provided by
Brouwers et al. [77], who reported that three out of nine patients receiving
99m Tclabeled PEGylated liposomes for scintigraphic detection of bowel inflammation
have developed severe hypersensitivity reactions. Later on, Szebeni and his colleges, in a series of their studies [39, 68, 73, 78], have emphasized the potential
contribution of complement activation to infusion reactions encountered in one
20 Immune Response to PEGylated Nanomedicines …
379