Acute lymphoblastic leukaemia patients treated with PEGasparaginase develop antibodies to PEG and the succinate
Robin Kloos1, Inge M van der Sluis2, Enrico Mastrobattista3
1Erasmus MC - Sophia Children's Hospital, Rotterdam, the Netherlands.
Insights
Hypersensitivity reactions to polyethylene glycol (PEG) asparaginase in children with leukaemia are linked to anti-PEG and anti-linker antibodies. Pre-existing antibodies were common, suggesting alternative treatments like native E. coli asparaginase may be necessary.
Area of Science:
- Immunology
- Pharmacology
- Paediatric Oncology
Background:
- Polyethylene glycol (PEG) conjugated asparaginase (PEGasparaginase) is a critical treatment for paediatric acute lymphoblastic leukaemia.
- Hypersensitivity reactions (HSRs) to PEGasparaginase pose a significant challenge in patient management.
- Identifying the immunogenic components of PEGasparaginase is crucial for understanding and mitigating HSRs.
Purpose of the Study:
- To develop and utilize an assay for detecting antibodies against PEGasparaginase components (PEG-moiety, linker, and drug) in patients experiencing HSRs.
- To investigate the prevalence and timing of antibody development against PEGasparaginase during different treatment phases.
- To assess the role of pre-existing antibodies in HSRs to PEGasparaginase.
Main Methods:
- Enzyme-Linked Immunosorbent Assay (ELISA) was employed to measure specific antibodies.
- Assay utilized conjugates of the succinimidyl succinate (SS) linker, PEGfilgrastim, and Escherichia coli asparaginase for coating.
- Hydrolyzed PEGasparaginase and mPEG5000 were used for antibody competition assays.
Main Results:
- Anti-PEG antibodies (IgG and IgM) were detected in all patients experiencing HSRs.
- A significant proportion of patients (39%) had exclusive anti-PEG antibodies.
- Pre-existing anti-PEG antibodies were found in 58% (IgG) and 21% (IgM) of patients, even those without prior PEGylated therapy.
- Antibodies against the SS-linker were more prevalent during induction (50% IgG, 42% IgM).
- Anti-asparaginase antibodies were detected in 11% during induction and 94% during intensification.
Conclusions:
- Anti-PEG and anti-SS-linker antibodies are key contributors to the immunogenic response during the induction phase of PEGasparaginase treatment.
- The presence of pre-existing anti-PEG antibodies highlights potential challenges for patients receiving PEGasparaginase.
- Switching to native E. coli asparaginase presents a viable therapeutic option for patients with HSRs to PEGasparaginase.
Abstract:
Polyethylene glycol (PEG) conjugated asparaginase (PEGasparaginase) is essential for treatment of paediatric acute lymphoblastic leukaemia. We developed an assay identifying antibodies against the PEG-moiety, the linker and the drug itself in patients experiencing hypersensitivity reactions to PEGasparaginase. Eighteen patients treated according to the DCOG ALL-11 protocol, with a neutralizing hypersensitivity reaction to PEGasparaginase to the first PEGasparaginase doses in induction (12 patients) or during intensification after interruption of several months (6 patients) were included. ELISA was used to measure antibodies, coating with the succinimidyl succinate linker conjugated to BSA, PEGfilgrastim and Escherichia coli asparaginase, and using hydrolysed PEGasparaginase and mPEG5,000 for competition. Anti-PEG antibodies were detected in all patients (IgG 100%; IgM 67%) of whom 39% had anti-PEG antibodies exclusively. Pre-existing anti-PEG antibodies were also detected in patients who not previously received a PEGylated therapeutic (58% IgG; 21% IgM). Antibodies against the SS-linker were predominantly detected during induction (50% IgG; 42% IgM). Anti-asparaginase antibodies were detected in only 11% during induction but 94% during intensification. In conclusion, anti-PEG and anti-SS-linker antibodies predominantly play a role in the immunogenic response to PEGasparaginase during induction. Thus, switching to native E. coli asparaginase would be an option for adequate asparaginase treatment.
