Effect of Premedications in a Murine Model of Asparaginase Hypersensitivity

Abstract

A murine model was developed that recapitulates key features of clinical hypersensitivity to Escherichia coli asparaginase. Sensitized mice developed high levels of anti-asparaginase IgG antibodies and had immediate hypersensitivity reactions to asparaginase upon challenge. Sensitized mice had complete inhibition of plasma asparaginase activity (P 5 4.2 Â 10 213) and elevated levels of mouse mast cell protease 1 (P 5 6.1 Â 10 23) compared with nonsensitized mice. We investigated the influence of pretreatment with triprolidine, cimetidine, the platelet activating factor (PAF) receptor antagonist CV-6209 [2-(2-acetyl-6-methoxy-3,9-dioxo-4,8-dioxa-2,10-diazaoctacos-1-yl)-1-ethyl-pyridinium chloride], or dexamethasone on the severity of asparaginase-induced allergies. Combining triprolidine and CV-6209 was best for mitigating asparaginase-induced hypersensitivity compared with nonpretreated, sensitized mice (P 5 1.2 Â 10 25 ). However, pretreatment with oral dexamethasone was the only agent capable of mitigating the severity of the hypersensitivity (P 5 0.03) and partially restoring asparaginase activity (P 5 8.3 Â 10 24 ). To rescue asparaginase activity in sensitized mice without requiring dexamethasone, a 5-fold greater dose of asparaginase was needed to restore enzyme activity to a similar concentration as in nonsensitized mice. Our results suggest a role of histamine and PAF in asparaginase-induced allergies and indicate that mast cell-derived proteases released during asparaginase allergy may be a useful marker of clinical hypersensitivity.

Impact of anti-PEG IgM antibodies on the pharmacokinetics of pegylated asparaginase preparations in mice

“…Complete neutralisation of ASNase activity by anti-ASNase IgG antibodies was not achieved assuming further mechanisms involved in rapid loss of enzyme activity. Pretreatment of mice with glucocorticoids (dexamethasone) before ASNase administration lowered anti-ASNase IgG levels and ASNase activity was partially maintained (Fernandez et al, 2015). Early or accelerated inactivation that has been reported for some pegylated drugs is obviously a rather complex process.…”

“…These investigations show that early inactivation of pegaspargase activity is caused by pre-treatment with native E. coli ASNase and is related to anti-protein antibodies triggered mostly by IgG antibodies (Cheung et al, 1986). Recently, a murine model of immediate hypersensitivity reaction to ASNase was described by Fernandez et al, 2015. BALB/c mice were repeatedly sensitised with non-pegylated E. coli asparaginase resulting in the development of an ASNase-mediated immune response with a similar phenotype as clinical hypersensitivity to E. coli asparaginase.…”

Clinical Characteristics of Intravenous PEG-Asparaginase Hypersensitivity Reactions in Patients Undergoing Treatment for Acute Lymphoblastic Leukemia

“…Patients may have developed anti-asparaginase antibodies by experiencing subclinical hypersensitivity or mild reactions that may have gone unreported, and thus they were not included in this study. Glucocorticoids may mitigate hypersensitivity reaction severity, but may also decrease serum asparaginase activity (Fernandez et al, 2015). Thus, patients receiving glucocorticoids concomitantly or as premedication should be closely monitored for symptoms of milder reactions.…”

L-Asparaginase Isolated from Phaseolus vulgaris Seeds Exhibited Potent Anti-Acute Lymphoblastic Leukemia Effects In-Vitro and Low Immunogenic Properties In-Vivo

“…The first group is negative control (non-sensitized) that received normal saline, while the rest of animals were sensitized using the adjuvant aluminum hydroxide on days 0 and 14 of treatment. Each of mice groups from the third to the fifth group received adjuvant plus 10 μg of asparaginase preparations (2.25–2.5 IU per mouse) as previously described [23]. Induction of asparaginase allergies in sensitized mice was performed by challenging with a 100 μg i.v.…”

“…The measuring of antibody levels and mouse mast cell protease 1 (mMCP-1) levels was performed as previously described [23]. Briefly, 100 μL of standards, blank or diluted serum samples were added into wells of 96-well plates precoated with each specific antigen.…”