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Effect of pre-existing anti-PEG antibodies on PEG-ASNase
Table 3. Distribution of pre-existing anti-PEG IgG levels (at various thresholds) among patients of ALL-cohort 1 with and without first-exposure hyper- sensitivity reactions to PEG-asparaginase.
Anti-PEG IgG level prior to first PEG-ASNase
Hypersensitivity reaction to first PEG-ASNase
Statistics PPV (95% CI)
0.30 (0.07-0.65)
0.13 (0.04-0.31)
lower PEG-ASNase activity levels, which, depending on the dose and protocol, may interfere with the targeted PEG-ASNase treatment intensity.
Disclosures
MS and the ALL-BFM Study Center have received funding from medac, Shire, SigmaTau, Servier, and Jazz Pharmaceuticals for research, and MS has participated in advi- sory boards. CR received institutional grants for PEG-asparagi- nase pharmacological studies aimed at the therapeutic monitor- ing of asparaginase activity within the AIEOP-BFM ALL 2009 study, as well as fees for participation in advisory boards and invited lectures for the companies involved in marketing different asparaginase products, medac GmbH, Sigma-Tau, Baxalta, Shire, Servier. CLK has held invited talks for Sigma tau, Erytech and Jazz Pharmaceuticals, received honoraria for con- sultancy from Erytech and travel expenses from Erytech and Servier. AA has consulting and advisory roles for Jazz Pharmaceuticals, and has also received travel and accommoda- tion fees and expenses from Jazz Pharmaceuticals. AM has received honoraria from Baxter. JB has served personally as a consultant and participated in advisory as well as in safety boards for medac GmbH; he has received support for travel from Eusa Pharma, Jazz Pharmaceuticals, Baxalta Shire and Servier; has held invited lectures for medac GmbH, Eusa Pharma, Jazz Pharmaceuticals, Baxalta, Servier, Shire and Sigma-Tau; and, in addition, he has received institutional grants in the context of ASNase drug monitoring from more or less all ASNase providers contributing to the therapeutic drug monitor- ing program, including medac GmbH, Eusa Pharma, Jazz Pharmaceuticals, Baxalta, Servier, Shire, and Sigma-Tau (all representing the varying marketing authorization holders of E. coli ASNase, PEG-ASNase and Erwinase). NG has received research support from Jazz Pharmaceuticals and honoraria as an advisory board member from Jazz Pharmaceuticals and Baxalta. The other authors declare that they have no potential conflicts of interest.
Contributions
AK, CLK, GW and JB designed the research. CR, MZu, VC, CN, AA, AM, MS, JB, AvS and NG collected data. AA, CN, MZu, MF, CLK, GH and JB analyzed and interpreted the data. AK, GW, JG, MZi, AM and CLK performed the statistical analy- sis. AK and CLK wrote the manuscript.
Acknowledgments
The authors would like to thank Ms Schulze Westhoff, Ms Hoogestraat and Ms Günter for their excellent technical assistance. We acknowledge support from the Open Access Publication Fund of the University of Muenster.
No
Yes
3 4
4 3
4
Odds ratio (95% CI)
70.6 (10.1-497)
32.8 (5.80-197)
vation of PEG-ASNase is defined by PEG-ASNase activi- ties ≤100 U/L within 7 days and undetectable PEG- ASNase activities within 14 days after administration.24 Neutralizing antibodies but also an accelerated elimina- tion of antigen-antibody complexes are being discussed as the underlying cause for the rapid decrease in ASNase activity.24,25 We could not detect any inhibition of asparagine hydrolysis by anti-PEG antibodies (Online Supplementary Figure S4). Animal studies have shown an increased clearance of pegylated proteins, liposomes and nanoparticles in the presence of anti-PEG IgM and anti- PEG IgG.15,16 In nude mice, anti-PEG IgM induced a rapid clearance of pegylated protein from serum with simulta- neous accumulation in the liver. Similar processes could also be conceivable in humans. The increased clearance of PEG uricase in gout patients was associated with an increase in anti-PEG IgG and IgM levels.18,19 The lower PEG-ASNase activity levels in patients with pre-existing antibodies might have been caused by an increased clear- ance of PEG-ASNase.
When comparing the distribution of PEG-ASNase activ- ities above and below 400 U/L, 100 U/L and the LLOQ (5 U/L), we found a significant difference between patients with and without pre-existing anti-PEG antibodies only at 400 U/L. The 400 U/L value was chosen in addition to the generally accepted target activity of 100 U/L and the LLOQ because 400 U/L have been shown to result in deeper asparagine depletion.46,47 This higher activity level and its associated glutaminase activity have been suggest- ed to increase the effectiveness of ASNase against leukemic blasts with residual asparagine synthetase activ- ity.48 Several studies have recently shown that PEG- ASNase clearance in a patient can vary significantly between different parts of the protocol.49,50 Thus, the effect of increased PEG-ASNase clearance due to pre- existing antibodies on the intensity of ASNase therapy would depend on the dose and concomitant ALL treat- ment. Therefore, the effects of pre-existing anti-PEG anti- bodies on the pharmacokinetics of PEG-ASNase must be determined separately for each protocol.
In summary, we observed a considerable number of patients with pre-existing antibodies against PEG. Anti- PEG antibody kinetics after PEG-ASNase administration were not the same in patients with pre-existing antibod- ies as in patients with hypersensitivity reactions after repeated PEG-ASNase administration.23,37 Pre-existing anti-PEG antibodies may cause mild to moderate symp- toms of hypersensitivity reaction with the first adminis- tration of PEG-ASNase, which might be addressed by re- challenge. They do not inhibit PEG-ASNase activity but
MFI>25 7 MFI ≤ 25 659
MFI > 15 26 MFI ≤ 15 640
MFI>8 90
Pa 0.00008
0.0001 0.009
Relative risk (95% CI)
49.7 (9.33-228)
28.6 (5.57-157)
NPV (95% CI)
0.99 (0.98-1.00)
0.99 (0.99-1.00)
Sensitivity (95% CI)
0.43 (0.10-0.82)
0.57 (0.18-0.90)
Specificity (95% CI)
0.99 (0.98-1.00)
0.96 (0.94-0.97)
3
8.53 (1.59-48.9)
8.21 (1.58-45.7)
0.04 (0.01-0.11)
0.99 (0.98-1.00)
0.57 (0.18-0.90)
0.86 (0.84-0.89)
MFI ≤ 8 576
aFisher exact test; PEG-ASNase: polyethylene glycol asparaginase; 95% CI: 95% confidence interval; PPV: positive predictive value; NPV: negative predictive value; MFI: mean fluorescence
intensity
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