Validated detection of anti-GD2 antibody ch14.18/CHO in serum of neuroblastoma patients using anti-idiotype antibody ganglidiomab

Siebert, Nikolai; Seidel, Daniel; Eger, Christin; Brackrock, Diana; Reker, Daniel; Schmidt, Manuela; Lode, Holger N.

doi:10.1016/j.jim.2013.09.008

Cited by 14 publications

(24 citation statements)

References 15 publications

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“…First, the optimal minimal sample dilution factor was evaluated using the reported ELISA protocol (A). 9 Standard samples (1.0, 0.5, 0.25, 0.13, 0.06, 0.03 and 0 mg/ml) were diluted 1:70 (closed triangles), 1:100 (open triangles), 1:200 (closed squares) and 1:400 (open squares) and analyzed by ELISA. Results are presented as mean OD of three replicates § SD from two representative experiments.…”

Section: Resultsmentioning

confidence: 99%

“…6 Here, we report population PK and PD with this novel method of ch14.18/CHO delivery. We first established an improved ELISA technique compared to our previous report, 9 following a three-step analysis procedure with an optimized limit of detection of 58 ng/ml ch14.18/CHO (Fig. 1C).…”

Section: Discussionmentioning

confidence: 99%

“…1C), showing an increased sensitivity by a factor of 9 compared to the previously published LOD (0.5 mg/ml). 9 …”

Section: Determination Of Lodmentioning

confidence: 99%

“…Instead of STI over five days (5 £ 20 mg/m2/d, 8h infusion), 53 high-risk NB patients received the same cumulative dose of 100 mg/m2 ch14.18/CHO given as a continuous long-term infusion (LTI) over 10 days (10£ 10 mg/m2/d). Similar to the reported randomized, open label Phase 3 clinical trial, 4 patients received ch14.18/CHO in combination with a cytokine (6£ 106/d IU/m2 subcutaneous (s.c.) interleukin (IL)-2, d 1-5, followed by a combined application of IL-2 (d [8][9][10][11][12] with LTI of ch14.18/CHO (d 8-18)). A reduced toxicity profile of the new treatment protocol was indicated by significantly decreased morphine usage and low pain scores.…”

Section: Introductionmentioning

confidence: 99%

“…For a comprehensive assessment of ch14.18/CHO PK, we optimized the two previously reported enzyme-linked immunosorbent assay (ELISA) methods based on an anti-idiotype Ab (anti-Id Ab) of ch14.18/CHO (ganglidiomab) to increase sensitivity and reliability of measurements. 9 The limit of detection (LOD) was further improved by the establishment and validation of a third ELISA method. Concentration-time curves of ch14.18/CHO in treated patients were used to calculate PK parameters using a two-compartmental model.…”

Section: Introductionmentioning

confidence: 99%

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Pharmacokinetics and pharmacodynamics of ch14.18/CHO in relapsed/refractory high-risk neuroblastoma patients treated by long-term infusion in combination with IL-2

Siebert

Eger

Seidel

et al. 2016

mAbs

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(2016) Pharmacokinetics and pharmacodynamics of ch14.18/CHO in relapsed/refractory high-risk neuroblastoma patients treated by long-term infusion in combination with IL-2, mAbs, 8:3, 604-616, DOI: 10.1080/19420862.2015 To link to this article: https://doi.org/10. 1080/19420862.2015 .8 mg£d/ml, respectively, were not significantly different. Importantly, we detected ch14.18/CHO trough concentration of 1 mg/ml at time points preceding subsequent antibody infusions after cycle 1, allowing a persistent activation of antibody effector mechanisms over the entire treatment period of 6 months. HACA responses were observed in 10/ 53 (19%) patients, similar to STI (21%), indicating LTI had no effect on the immunogenicity of ch14.18/ CHO. In conclusion, LTI of ch14.18/CHO induced effector mechanisms over the entire treatment period, and may therefore emerge as the preferred delivery method of anti-GD2 immunotherapy to NB patients.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…1C), showing an increased sensitivity by a factor of 9 compared to the previously published LOD (0.5 mg/ml). 9 …”

Section: Determination Of Lodmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pharmacokinetics and pharmacodynamics of ch14.18/CHO in relapsed/refractory high-risk neuroblastoma patients treated by long-term infusion in combination with IL-2

Siebert

Eger

Seidel

et al. 2016

mAbs

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Quantification of total dinutuximab concentrations in neuroblastoma patients with liquid chromatography tandem mass spectrometry

et al. 2018

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Neuroblastoma is one of the most commonly found solid tumors in children. The monoclonal antibody dinutuximab (DNX) targets the sialic acid-containing glycosphingolipid GD2 expressed on almost all neuroblastoma tumor cells and induces cell lysis. However, the expression of GD2 is not limited to tumor cells only, but is also present on central nerve tissue and peripheral nerve cells explaining dinutuximab toxicity. The most common adverse reactions are pain and discomfort, which may lead to discontinuation of the treatment. Furthermore, there is little to no data available on exposure and effect relationships of dinutuximab. We, therefore, developed an easy method in order to quantify dinutuximab levels in human plasma. Ammonium sulfate (AS) was used to precipitate all immunoglobulins (IgGs) in human plasma. After centrifugation, supernatant containing albumin was decanted and the precipitated IgG fraction was re-dissolved in a buffer containing 0.5% sodium dodecyl sulfate (SDS). Samples were then reduced, alkylated, and digested with trypsin. Finally, a signature peptide in complementarity determining region 1 of DNX heavy chain was quantified on LC-MS/MS using a stable isotopically labeled peptide as internal standard. AS purification efficiently removed 97.5% of the albumin fraction in the supernatant layer. The validation performed on DNX showed that within-run and between-run coefficients of variation (CV) for lower limit of quantification (LLOQ) were 5.5 and 1.4%, respectively. The overall CVs for quality control (QC) low, QC med, and QC high levels were < 5%. Linearity in the range 1–32 mg/L was excellent (r2 > 0.999). Selectivity, stability, and matrix effect were in concordance with EMA guidelines. In conclusion, a method to quantify DNX in human plasma was successfully developed. In addition, the high and robust process efficiency enabled the utilization of a stable isotopically labeled (SIL) peptide instead of SIL DNX, which was commercially unavailable. Graphical abstract

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A multifactorial screening strategy to identify anti-idiotypic reagents for bioanalytical support of antibody therapeutics

Salimi-Moosavi

Winters

Abbott

et al. 2015

Analytical Biochemistry

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Validated detection of anti-GD2 antibody ch14.18/CHO in serum of neuroblastoma patients using anti-idiotype antibody ganglidiomab

Cited by 14 publications

References 15 publications

Pharmacokinetics and pharmacodynamics of ch14.18/CHO in relapsed/refractory high-risk neuroblastoma patients treated by long-term infusion in combination with IL-2

Pharmacokinetics and pharmacodynamics of ch14.18/CHO in relapsed/refractory high-risk neuroblastoma patients treated by long-term infusion in combination with IL-2

Quantification of total dinutuximab concentrations in neuroblastoma patients with liquid chromatography tandem mass spectrometry

A multifactorial screening strategy to identify anti-idiotypic reagents for bioanalytical support of antibody therapeutics

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