Pseudo-anaphylaxis
to Polyethylene Glycol (PEG)-Coated
Liposomes: Roles of Anti-PEG IgM and Complement Activation in a Porcine
Model of Human Infusion Reactions
Version 2 2019-10-07, 15:37
Version 1 2019-08-06, 13:04
Posted on 2019-10-07 - 15:37
Polyethylene
glycol (PEG)-coated nanopharmaceuticals can cause
mild to severe hypersensitivity reactions (HSRs), which can occasionally
be life threatening or even lethal. The phenomenon represents an unsolved
immune barrier to the use of these drugs, yet its mechanism is poorly
understood. This study showed that a single i.v. injection in pigs
of a low dose of PEGylated liposomes (Doxebo) induced a massive rise
of anti-PEG IgM in blood, peaking at days 7–9 and declining
over 6 weeks. Bolus injections of PEG-liposomes during seroconversion
resulted in anaphylactoid shock (pseudo-anaphylaxis) within 2–3
min, although similar treatments of naı̈ve animals led to only mild
hemodynamic disturbance. Parallel measurement of pulmonary arterial
pressure (PAP) and sC5b-9 in blood, taken as measures of HSR and complement
activation, respectively, showed a concordant rise of the two variables
within 3 min and a decline within 15 min, suggesting a causal relationship
between complement activation and pulmonary hypertension. We also
observed a rapid decline of anti-PEG IgM in the blood within minutes,
increased binding of PEGylated liposomes to IgM+ B cells in the spleen of immunized animals compared to control,
and increased C3 conversion by PEGylated liposomes in the serum of
immunized pigs. These observations taken together suggest rapid binding
of anti-PEG IgM to PEGylated liposomes, leading to complement activation via the classical pathway, entailing anaphylactoid shock
and accelerated blood clearance of liposome–IgM complexes.
These data suggest that complement activation plays a causal role
in severe HSRs to PEGylated nanomedicines and that pigs can be used
as a hazard identification model to assess the risk of HSRs in preclinical
safety studies.
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Kozma, Gergely
Tibor; Mészáros, Tamás; Vashegyi, Ildikó; Fülöp, Tamás; Örfi, Erik; Dézsi, László; et al. (2019). Pseudo-anaphylaxis
to Polyethylene Glycol (PEG)-Coated
Liposomes: Roles of Anti-PEG IgM and Complement Activation in a Porcine
Model of Human Infusion Reactions. ACS Publications. Collection. https://doi.org/10.1021/acsnano.9b03942
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AUTHORS (12)
GK
Gergely
Tibor Kozma
TM
Tamás Mészáros
IV
Ildikó Vashegyi
TF
Tamás Fülöp
EO
Erik Örfi
LD
László Dézsi
LR
László Rosivall
YB
Yaelle Bavli
RU
Rudolf Urbanics
TM
Tom Eirik Mollnes
YB
Yechezkel Barenholz
JS
János Szebeni