IgG Antibodies Cannot Explain Silent Inactivation in PEG-Asparaginase Treatment

• Background/Objectives: PEG-asparaginase represents a key element in the treatment of acute lymphoblastic leukemia (ALL), however allergic reactions and lack of asparaginase enzyme activity shortly after administration (silent inactivation) constitutes a significant challenge. Anti-PEG antibodies formed prior to PEG-asparaginase exposure are suggested to cause the latter accelerated clearance phenomenon. We investigated anti-PEG antibody responses before and during PEG-asparaginase therapy, in children treated according to NOPHO ALL2008 protocol, with and without silent inactivation and hypersensitivity. Design/Methods: PEG-asparaginase enzyme activity was determined in patients aged 1-17.9 years as part of the NOPHO ALL2008 protocol. These measurements were used to categorize patients with or without enzyme activity. In this case control study, recovery of spiked PEG-asparaginase activity after IgG complex depletion with protein G affinity chromatography was used to evaluate IgG antibodies to PEGasparaginase. 359 samples were analyzed from 40 patients with: i) no adverse phenotype (n=10), ii) silent inactivation (n=10), iii) allergy and asparaginase enzyme inactivation (n=10), iv) allergy and asparaginase enzyme activity (n=10) Results: No patients with PEG-asparaginase enzyme activity had or developed anti-PEG antibodies during treatment. Thus children with and without clinical allergy and enzyme activity could not be distinguished serologically. In contrast, IgG antibodies were detected in 19 of 20 of children without enzyme activity, regardless of allergy status. The lack of in vivo asparaginase enzyme activity was always displaying from the first PEG-asparaginase administration, but anti-PEG antibodies were only detected in pre-exposure samples in 2 of 38 patients (5%). 2 patients had missing pre-exposure samples. Conclusions: IgG responses to repeated PEG-asparaginase administrations are not the primary driver of PEGasparaginase inactivation. However these antibodies may accelerate the drug clearance. Further validation and investigation of IgM antibodies is warranted in order to gain more knowledge about the inactivation of PEG-asparaginase.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Pediatrik (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Pediatrics (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Cancer och onkologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cancer and Oncology (hsv//eng)

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