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Tracking silent hypersensitivity reactions to asparaginase during leukemia therapy using single-chip indirect plasmonic and fluorescence immunosensing David M. Charbonneau, Julien Breault-Turcot, Daniel Sinnett, Maja Krajinovic, Jean-Marie Leclerc, Jean-François Masson, and Joelle N. Pelletier ACS Sens., Just Accepted Manuscript • DOI: 10.1021/acssensors.7b00584 • Publication Date (Web): 23 Nov 2017 Downloaded from http://pubs.acs.org on November 24, 2017
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ACS Sensors
Tracking silent hypersensitivity reactions to asparaginase during leukemia therapy using single-chip indirect plasmonic and fluorescence immunosensing David M. Charbonneau1,2, Julien Breault-Turcot1,3, Daniel Sinnett4,5, Maja Krajinovic4, Jean-Marie Leclerc4, Jean-François Masson1,3, and Joelle N. Pelletier1,2,5,6,7* 1.
Département de chimie, Université de Montréal, Montréal QC H3T 1J4, Canada
2.
PROTEO Network, Université Laval, Québec QC G1V 0A6, Canada
3.
Centre Québécois sur les Matériaux Fonctionnels (CQMF), Université de Sherbrooke, Québec QC J1K 2R1, Canada
4.
Centre de recherche, CHU Sainte-Justine, Montréal QC H3T 1C5, Canada
5.
Département de pédiatrie, Université de Montréal, Montréal QC H3T 1J4, Canada
6.
Center for Green Chemistry and Catalysis (CGCC), Montréal QC H3A 0B8, Canada
7.
Département de biochimie, Université de Montréal, Montréal QC H3T 1J4, Canada
Supporting Information Placeholder ABSTRACT: Microbial asparaginase is an essential component of chemotherapy for the treatment of childhood acute lymphoblastic leukemia (cALL). Silent hypersensitivity reactions to this microbial enzyme need to be monitored accurately during treatment to avoid adverse effects of the drug and its silent inactivation. Here, we present a dualresponse anti-asparaginase sensor that combines indirect SPR and fluorescence on a single chip to perform ELISA-type immunosensing, and correlate measurements with classical ELISA. Analysis of serum samples from children undergoing cALL therapy revealed a clear correlation between singlechip indirect SPR/fluorescence immunosensing and ELISA 2 used in clinical settings (R > 0.9). We also report that the portable SPR/fluorescence system had a better sensitivity than classical ELISA to detect antibodies in clinical samples with low antigenicity. This work demonstrates the reliability of dual sensing for monitoring clinically relevant antibody titers in clinical serum samples.
Microbial asparaginase is an essential component of chemotherapy for childhood acute lymphoblastic leukemia (cALL). However, clinical application of Escherichia coli asparaginase II (EcAII) is complicated by the frequent devel1 2 opment of allergy and silent hypersensitivity reactions . Silent immunological responses to EcAII are associated with the development of antibodies that may interfere with the efficacy of the treatment. The detection of anti-EcAII antibodies (mainly IgG) has been reported to have a prognostic 3 significance for treatment efficacy . The main method for measuring antibodies associated with silent immunological responses, ELISA, is not ideally suited for point-of-care testing (POCT) as it is lengthy and multi-step. Surface plasmon resonance (SPR) sensing has been increas4-5 ingly applied for monitoring and quantifying biomolecules . Commercial sensing instruments such as the Biacore (GE Healthcare) offer an alternative to classical ELISA based on immunoblotting, and thus, they have been applied for monitoring markers and molecules in clinical samples for a series
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of diseases . Despite the fact that SPR sensing is perceived as a potential POCT technology, commercial instruments are not adapted for POCT because of their cost, size and complexity. Smaller and portable SPR sensors have thus been developed in the past decade to facilitate application of SPR 7 sensors for monitoring markers near the patient . Furthermore, plasmonic sensing in complex biological samples such as serum or plasma required improved sensor surfaces to limit surface fouling and detection strategies which are in6, 8 creasingly available . The combination of smaller portable SPR instruments and better surface chemistry/sensing strategy is thus promising for the use of SPR in clinical settings. To address the challenges associated with POCT and plasmonic sensing in serum, we recently reported a highsensing and low-fouling anti-asparaginase sensor chip for use 9 in a portable SPR sensing device . We demonstrated the necessity to monitor an indirect SPR signal using a secondary antibody for accurate detection of anti-EcAII antibodies in undiluted clinical serum because sample-to-sample variation in the bulk medium affected the reliability of direct plas10-11 monic sensing . Dual SPR/fluorescence detection should reduce the incidence of false positives/negatives because positive signals must be generated in both channels and be in quantitative agreement for a result to be valid. It will also increase the sensitivity and specificity of the sensor because the methods are not sensitive to the same interference. We also demonstrated that fluorescence detection can be more sensitive than SPR sensing, therefore extending the dynamic 12 range of a dual sensor . Thus, the use of a dual readout using SPR and on-chip fluorescence immunosensing is attractive for improving the confidence in results. Here, we report an optimized secondary SPR sensor with parallel fluorescence detection. As a proof-of-concept experiment, we tested our portable dual SPR-fluorescence immunosensing device by monitoring anti-asparaginase antibodies in serum from children undergoing cALL chemotherapy. This device was built from a standard P4-SPR unit (Affinité Instruments) above which a specifically designed fluorescent microscope was mounted (Figure 1). A broadband
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white light LED illuminates the gold mirror on the SPR chip in total internal reflection mode and is collected with optical fibers for wavelength interrogation, which is is a robust ap13 proach to miniaturization of SPR sensing devices . This monitors the shift of the resonance wavelength as a function of the analytes bound to the gold surface. Measurement of the fluorescence generated by an HRP-conjugated secondary antibody (in this case, or a source of fluorescence in general) occurs on the same chip: a fluorescence epi-microscope with a 532 nm fiber-coupled laser source is focused in the solution of the P4-SPR fluidic cell. The emitted photons are collected, directed through a long-pass 532 nm emission filter to reduce background and focused on an avalanche photodiode. We report an improved correlation with classical ELISA that we performed in parallel, according to the standard method used in clinical settings for detecting silent hypersensitivity reactions to EcAII. The standard immunoblotting method involves indirect detection through use of a secondary antibody that is HRP-conjugated to detect conversion of ophenylenediamine dihydrochloride (OPD) by absorbance at 490 nm, and is referred to as ‘ELISA absorption detection’ 14 hereafter .
Figure 1. Configuration of the dual SPR-fluorescence de12 vice, described in . Additional details on the optical system are provided in the Supporting Information. EcAII is the main asparaginase preparation used in frontline cALL therapy. As it originates from E. coli, it is a potential immunogen. EcAII is used in its native form (Elspar®, TM Kidrolase® and L-asparaginase Medac ) or in a PEGylated form designed to reduce immune response (Oncaspar® and Calspargase Pegol®). In the case where allergy to EcAII is observed, the asparaginase preparation is changed to ErAII (Erwinase®) from Erwinia chrysanthemi which exhibits low 15 cross-reactivity . A recent study from St. Jude Children’s Research Hospital reported an occurrence of 41% (n = 410) clinical allergy to native Elspar. Out of these 169 patients with overt allergy, antibodies were detected in 147 patients (87%). However, among 241 patients (59%) who did not display symptoms of clinical allergy, 89 patients (37%) had detectable anti-EcAII antibodies. Such silent immunological response may result in silent inactivation by neutralizing antibodies, directly interfering with enzyme activity and/or by binding antibodies leading to antibody opsonization and 2, 16 drug clearance. . Such immune response adds to the
metabolic burden of patients and should be rapidly detected to halt administration of the allergen. Surprisingly, a study from the Dana Farber Cancer Institute showed that 12% (n=232) of children treated with the PEGylated Oncaspar also developed clinical allergy, com17 pared to 9% (n = 231) for Kidrolase . Furthermore, the Dutch Childhood Oncology Group has reported that 22% (n=91) of children treated with the native Medac during the induction phase of cALL treatment developed clinical allergy to the PEGylated Oncaspar during the post-induction phase, while 18 8% showed silent inactivation . Overall, silent hypersensitivity occurs in 5-46% of the children treated with native and 15, 19-21 PEGylated EcAII . This highlights the need for rapid and accurate detection of anti-EcAII antibodies in a timely manner to prevent potential future allergic reactions and improve the global benefit of the chemotherapy treatment. At the outset of this study, 87 serum samples obtained from 18 children undergoing cALL chemotherapy at CHU Sainte-Justine (9 males aged from 3-15 years old and 9 females aged from 2-11 years old) were analyzed by standard ELISA absorption detection. The samples were divided into 5 groups according to whether the patients were being actively treated or had completed treatment, and whether they received PEGylated or non-PEGylated EcAII. Table S1 provides detail about the treatments that were administered along with the associated risk factor, observation of clinical allergy and toxicity. Serum samples from 10 healthy children (3 males aged from 15-17 years old and 7 females aged 2-17 years old) who never received asparaginase served as the reference (negative controls), Table S2. The ELISA absorption detection was conducted for total anti-EcAII IgG antibodies according to a protocol adapted from Wang and coau14 thors (Figure S1; complete dataset is shown in Figure S2, subset shown in Figure 2). Samples were determined as positive or negative according to thresholds determined as defined in methods (Supplementary materials). Only two patients (11%, n= 18) developed overt clinical hypersensitivity (anaphylaxis) during the course of treatment (PO02 and FPO01), both treated with PEGylated EcAII (Oncaspar) which was subsequently substituted with Erwinase. Surprisingly, these two patients did not display antiEcAII antibody levels above the defined threshold. It should be noted that these two patients were treated with PEGylated EcAII and may have developed an immune response specific to PEG or to PEGylated EcAII, which was not detected by the standard ELISA protocol using the native EcAII as the anti22-23 genic bioreceptor . Two patients (11%; n=18) with a positive ELISA readout in the absence of clinical allergy were considered to have developed silent hypersensitivity during the course of treatment: patient PO01 treated with PEGylated Oncaspar (samples PO01-S1 to PO01-S4) and patient FK04 treated with Kidrolase (Figure 2). Patient PO01 showed an antibody peak at week 3, followed by a progressive decrease from week 4-10 after which an increase was observed (weeks 11-16) while remaining below the threshold (Figure 2 and Figure S2). Thus, PEGylation did not prevent immunologic responses specific to EcAII. The antibody level determined for patient FK04 was dramatically higher than the threshold (Figure 2 and Figure S2). It held an antibody titer of 1:51 200 (Figure S3), consistent with titers measured for serum samples from patients having developed clinical allergy to EcAII with the produc-
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tion of neutralizing antibodies . The sensitivity of the ELISA absorption detection measurements was modulated by varying serum and secondary antibody (sAb) dilution and the H2O2 concentration used in revelation of the HRP-catalyzed reaction. The trends were identical for ELISA absorption detection assays performed with 1:200 serum / 1:10 000 sAb / 0.02% H2O2 and 1:32 serum / 1:1000 sAb / 0.16% H2O2 relative to standard conditions (1:400 serum / 1:10 000 sAb / 0.01% H2O2; data not shown), highlighting the robustness and the reliability of the ELISA absorption detection assays.
Figure 2. Anti-asparaginase antibodies monitored by indirect ELISA absorption detection in clinical sera. The assay was performed at serum dilution of 1:400 (1:10 000 sAb / 0.01% H2O2). Negative controls are shown in pink and the pooled negative control sample (equal mixture) is in dark pink. Serum samples from treated patients (15 out of 87) are shown in grey. The threshold for determination of silent hypersensitivity is defined at 2.58 standard deviations above the mean value of the pooled negative controls (pink dashed 2, 14 line) . Results from two triplicate experiments are shown (n=6), p-value < 0.0001. In parallel with the ELISA absorption detection assays, we applied our recently reported bioreceptor for detecting antiEcAII antibodies in serum using surface plasmon resonance (SPR). The sensor biochip consists of a gold-coated glass prism modified with a low-fouling peptide to which EcAII is 9 immobilized with a high surface density . We previously demonstrated the necessity of monitoring a secondary antibody to counteract the high sample-to-sample variation in refractive index of serum samples, for accurate sensing of 10 anti-EcAII antibodies in undiluted serum . Use of the anti-human HRP-conjugated IgG secondary antibody to monitor a secondary SPR signal is conceptually comparable to performing an ELISA assay on the SPR sensor chip, except that the binding events are monitored in realtime. Binding can additionally be monitored in parallel by detecting the fluorescence associated to the HRP-catalyzed TM conversion of Ampliflu Red into resorufin using our 12 adapted dual SPR/fluorescence instrument . Thus, an HRPconjugated secondary antibody procures both a secondary SPR signal, as well as catalyzing the formation of a fluores-
cent product; this will be referred to as SPR and ELISA fluorescence detection hereafter. We thus performed dual indirect SPR and ELISA fluorescence detection of anti-EcAII in undiluted sera from two positive samples (PO01-S3, PO01-S4) as well as three negative samples (PO01-S5, PO02-S1 and PSC01-S2), as determined by ELISA absorption detection. Optimized secondary detection 2 showed an excellent correlation (R = 0.9721) between indirect SPR and fluorescence measurements on the same chip for each sample (Figure 3). Most importantly, a good correlation was observed between indirect ELISA absorption detec2 tion and both indirect SPR (R = 0.9473) and ELISA fluores2 cence detection (R = 0.9301) measurements performed on the gold chip (Figure 3A). The strong correlation observed between either SPR or fluorescence (using undiluted sera) with ELISA absorption detection at 1:400 serum dilution was 2 2 confirmed at 1:200 serum dilution (R = 0.9784 and R =0.9680) (Figure S4).
Figure 3. Reliability of indirect SPR and related fluorescence measurements. Correlation plot between the indirect SPR signal (binding of secondary antibody) and the relative fluorescence signal generated by the conversion of AmplifluRed. Samples in the upper right quadrant are undiluted clinical samples from patients treated with asparaginase (PO01-S3, PO01-S4, PO01-S5, PSC01-S2, P02-S1) while samples in the lower left quadrant are negative controls (commercial human serum: HS and Blank 6). To our surprise, both SPR and ELISA fluorescence detection measurements in undiluted serum identified all the testset of five samples as being positive for anti-EcAII antibodies. This demonstrates the greater signal-to-noise ratio for onchip SPR/fluorescence sensing than ELISA absorption detection (Figure 4A). Thus, the strong correlation observed between ELISA absorption detection and SPR or ELISA fluorescence detection does not suffice to lead to the same conclusions: the signal-to-noise ratio is also critical to avoid false negatives and correctly identify silent hypersensitivity reactions. Sample FK04 was an outlier in ELISA absorption detection, as its signal was 5 times greater than any of the other samples
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(Figure 2). Upon performing the SPR and ELISA fluorescence detection measurements in undiluted serum, we were surprised to observe no correlation with ELISA absorption detection: the absolute response was similar to the other samples (Figure 4B). However, repeating the SPR and fluorescence analysis of a 1:32 dilution of FK04 provided an excellent correlation with ELISA absorption detection and an excellent fit with the samples having low antibody titers (Figure 4B). Again, the excellent correlations with ELISA absorption detection at 1:400 serum dilution were confirmed at 1:200 serum dilution (Figure S4).
Figure 4. Correlation plot for anti-asparaginase antibody detection in undiluted clinical serum samples by indirect SPR/ELISA fluorescence detection and by ELISA absorption detection. A. Correlation between ELISA absorption detection (1:400 serum / 1: 10,000 sAb / 0.01% H2O2) and indirect SPR for undiluted serum (in black) or fluorescence (in green). The threshold for positive antibodies is defined as 2.58 SD over the mean for pooled negative controls in ELISA absorption detection (pink dashes) or 2.58 SD over the mean for commercial serum in SPR and ELISA fluorescence detection (black and green dashes, respectively). B. Correlation plot as in panel A (outlined in blue) with the addition of sample FK04, the outlier in ELISA absorption detection analysis. The SPR/ELISA fluorescence analysis for FK04 was per-
formed using either undiluted serum (no fit is provided) or at 1:32 dilution with correction for the dilution factor. The thresholds are defined as in panel A, using 1:32 diluted commercial serum as appropriate. The poor correlation of the undiluted sample FK04 in SPR and ELISA fluorescence detection analyses could result from aggregation or oligomerization of the high concentration of antibodies in that sample, masking the antigen-binding sites and thus reducing the detectable signal above a certain critical antibody concentration. Such a ‘fishhook’ or prozone effect (a peak in signal, followed by a decrease) could also result from high surface packing of the anti-EcAII antibodies 9 (bound to high density antigenic EcAII; Ag receptor) , masking the secondary antibody-binding sites and thus impairing the indirect SPR signal. Support for this hypothesis is provided in the calibration curve of rabbit anti-EcAII polyclonal antibodies (Figure S5). Direct titration of rabbit anti-EcAII antibodies spiked in undiluted human serum allowed SPR -1 detection above 0.75 mg mL (5 µM), while indirect titration using a goat anti-rabbit HRP-conjugated secondary antibody resulted in a clear fishhook effect at anti-EcAII antibody -1 concentrations above 67.5 µg mL (0.45 µM). Considering that quantitative, direct SPR detection was possible above that concentration, our observations are consistent with epitope masking on the tightly packed, surface-bound antiEcAII antibodies. Those results, obtained in a controlled serum background, suggest that direct SPR detection should be more effective than indirect SPR detection at high antiEcAII antibody concentrations. However, we previously demonstrated that sample-to-sample variations in clinical sera render direct SPR quantitation of anti-EcAII impracticable while performing indirect SPR with a secondary antibody was robust. We estimated the anti-EcAII antibody concentration in the FK04 serum samples by ELISA absorption detection. To this end, we first calculated the titer for known concentrations of the commercial rabbit anti-EcAII IgG antibody (Figure S6), and compared it to the titer determined for sample FK04 (Figure S3). This provides only a rough estimate of the concentration of human EcAII, because the rabbit anti-EcAII IgG and its secondary antibody, the goat anti-rabbit HRPconjugated secondary IgG are different from the human antiEcAII IgG analyte and goat anti-human γ-chain specific HRPconjugated IgG secondary antibody; they may exhibit different affinities and thus different concentrations for a given titer. This comparison allowed estimating an anti-EcAII -1 concentration of ~ 76 µg mL (0.5 µM) for FK04 which is similar to specific IgG concentrations observed following 24 anaphylactic shock . We note that this concentration is greater than the rabbit anti-EcAII concentration where the fishhook effect was observed in the indirect -1 SPR/fluorescence calibration (67.5 µg mL ; Figure S6), which is consistent with the false negative signal observed with the undiluted FK04 sample. Despite the high accuracy of indirect SPR sensing of low antibody titers in undiluted serum, this observation highlights the importance of performing paired assays of diluted and undiluted samples to prevent false negatives where antibody titers are unusually high. Among the challenges encountered during this study, we noted that there is no ideal reference (blank) sample: even the ten samples used as negative controls showed a significant variation in their ELISA absorption detection readout.
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ACS Sensors For example, negative control sample #6 shows a high signal relative to the nine other reference samples. This might be due to a previous exposure to E. coli, or an immunological condition displaying some cross-reactivity. A physical pool consisting of multiple serum samples from reference individuals is crucial to minimize the impact of any outliers, because the average reference signal serves to set the threshold and avoid false positives or false negatives. Another observation is that many of the children undergoing chemotherapy and treated with EcAII display a lower anti-EcAII antibody level than the reference samples (see PSC01-S1, PSC01-S2, PSC02-S2, PSC02-S3, FK01, FPO01 and FPO03; Figure 2). This may reflect immunosuppression of the patients who did not develop hypersensitivity, resulting in very low antibody ex25-27 pression . In conclusion, we have developed and adapted the SPR/fluorescence dual detection device to monitor serum antibodies (IgG) associated with silent hypersensitivity reactions to E. coli asparaginase during chemotherapy for cALL. Our results highlight the importance of an optimized indirect SPR detection (secondary signal) for accurate detection of low anti-EcAII antibody titers in undiluted serum during cALL therapy. Dual SPR/fluorescence detection should reduce the incidence of false positives/negatives and increase the sensitivity and specificity of the sensor. Serum dilution is however necessary for detecting high antibody titers by indirect SPR and fluorescence due to an observable fishhook effect, apparently resulting from steric hindrance of highly packed anti-asparaginase antibodies on the biosensor surface. This study suggests that silent hypersensitivity can be monitored using the portable SPR/ELISA fluorescence detection sensor. The portable sensor may improve the accessibility for point-of-care analyses and improve the accuracy of diagnosis for silent hypersensitivity reactions during the course of cALL therapy. Keywords: Dual SPR/fluorescence sensing; ELISA; LAsparaginase; immunosensing; portable sensor.
ASSOCIATED CONTENT Supporting Information Available: The following file is available free of charge: Supplementary information_Charbonneau et al.pdf. The file contains all supporting tables and figures as well as the material and methods.
AUTHOR INFORMATION Corresponding Author *E-mail :
[email protected] Author Contributions DS, MK, J-ML, J-FM and JNP designed the study. DMC organized the collection of serum samples, performed the ELISA assays. JBT performed the SPR and fluorescence measurements. DMC analyzed the results and wrote the manuscript with JNP. All authors revised the manuscript before publication.
Notes The authors declare the following competing financial inter-
est: J.-F.M. and J.N.P. are the scientific founders of Affinité Instruments and have an equity interest in the company.
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