Analysis of small molecule antibody–drug conjugate catabolites in rat liver and tumor tissue by liquid extraction surface analysis micro‐capillary liquid chromatography/tandem mass spectrometry

Lanshoeft, Christian; Stutz, Gerhard; Elbast, Walid; Wolf, Thomas; Walles, Markus; Stoeckli, Markus; Picard, Franck; Kretz, Olivier

doi:10.1002/rcm.7511

Cited by 15 publications

(9 citation statements)

References 40 publications

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“…Figure 5 shows the tumor profiles acquired by SEC-RA and it is obvious that after 1 hour tumor tissue mainly contained ADC, while after 24 hours the catabolite LYS-MCC-DM1 (M2) was the predominant component (Table 6). To see if the catabolite M2 was evenly distributed in tumor tissue, the newly developed LESA-mLC-MS/MS (Lanshoeft et al, 2016) was applied. The acquired quantitative LESA data showed no significant difference over tumor tissue (Table 7) and the measured concentration data were well in line with the results from RA profiling in tissues (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…The main advantages of the LESA-mLC-MS/MS method are that no radiolabel is ultimately needed and no sample processing is required, thus it can provide complimentary data. For quantitative assessments without radiolabel, more thorough validation using internal standards to correct for different tissue responses would need to be applied (Lanshoeft et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

“…The extraction with 2 ml of extraction solvent resulted in a spatial resolution of 2 mm, observing specific transitions for MCC-DM1 and LYS-MCC-DM1 in the mass-to-charge ratio (m/z) range from 100 to 1300. A detailed overview of the principle experimental setup has been described recently (Lanshoeft et al, 2016).…”

Section: Methodsmentioning

confidence: 99%

“…To investigate if the radioactivity (RA) in tumors can be attributed mainly to intact ADC or small molecule catabolites, tumors were analyzed at different time points to establish kinetics. In addition, complimentary investigations using the newly developed liquid extraction surface analysis microliquid chromatography-tandem mass spectrometry (LESA-mLC-MS/ MS) technique (Lanshoeft et al, 2016) were performed on tumor tissue for the first time. For the bioanalytical methods applied, we wanted to investigate if size exclusion chromatography (SEC) coupled to RA detection provides similar results for pharmacokinetic assessments of ADC as can be obtained by the enzyme-linked immunosorbent assay (ELISA), and/or if SEC-RA can provide additional benefits.…”

Section: Introductionmentioning

confidence: 99%

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New Insights in Tissue Distribution, Metabolism, and Excretion of [3H]-Labeled Antibody Maytansinoid Conjugates in Female Tumor-Bearing Nude Rats

Walles

Rudolph

Wolf

et al. 2016

Drug Metabolism and Disposition

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For antibody drug conjugates (ADCs), the fate of the cytotoxic payload in vivo needs to be well understood to mitigate toxicity risks and properly design the first in-patient studies. Therefore, a distribution, metabolism, and excretion (DME) study with a radiolabeled rat cross-reactive ADC ([ 3 H]DM1-LNL897) targeting the P-cadherin receptor was conducted in female tumor-bearing nude rats. Although multiple components [total radioactivity, conjugated ADC, total ADC, emtansine (DM1) payload, and catabolites] needed to be monitored with different technologies (liquid scintillation counting, liquid chromatography/mass spectrometry, enzyme-linked immunosorbent assay, and size exclusion chromatography), the pharmacokinetic data were nearly superimposable with the various techniques. liquid extraction surface analysis coupled to micro-liquid chromatography-tandem mass spectrometry data proved that the lysine (LYS)-4(maleimidylmethyl) cyclohexane-1-carboxylate-DM1 (LYS-MCC-DM1) catabolite was the only detectable component distributed evenly in the tumor and liver tissue. The mass balance was complete with up to 13.8% 6 0.482% of the administered radioactivity remaining in carcass 168 hours postdose. LNL897-derived radioactivity was mainly excreted via feces (84.5% 6 3.12%) and through urine only to a minor extent (4.15% 6 0.462%). In serum, the major part of radioactivity could be attributed to ADC, while small molecule disposition products were the predominant species in excreta. We show that there is a difference in metabolite profiles depending on which derivatization methods for DM1 were applied. Besides previously published results on LYS-MCC-DM1 and MCC-DM1, maysine and a cysteine conjugate of DM1 could be identified in serum and excreta.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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New Insights in Tissue Distribution, Metabolism, and Excretion of [3H]-Labeled Antibody Maytansinoid Conjugates in Female Tumor-Bearing Nude Rats

Walles

Rudolph

Wolf

et al. 2016

Drug Metabolism and Disposition

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“…1-2 Increasingly, MALDI IMS is used in the pharmaceutical industry to measure the distributions of therapeutic agents and their metabolites in tissue specimens. 3 Classical analytical approaches such as autoradiography 4-5 and tissue homogenate LC-MS 6-8 analysis have been used extensively in drug and metabolite characterizations; however, these often provide an incomplete analysis. For example, though autoradiography provides a quantitative measure of localization, it often lacks the molecular specificity to distinguish between a drug and its metabolites.…”

Section: Introductionmentioning

confidence: 99%

Absolute Quantification of Rifampicin by MALDI Imaging Mass Spectrometry Using Multiple TOF/TOF Events in a Single Laser Shot

Prentice

Chumbley

Caprioli

2016

J. Am. Soc. Mass Spectrom.

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Matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) allows for the visualization of molecular distributions within tissue sections. While providing excellent molecular specificity and spatial information, absolute quantification by MALDI IMS remains challenging. Especially in the low molecular weight region of the spectrum, analysis is complicated by matrix interferences and ionization suppression. Though tandem mass spectrometry (MS/MS) can be used to ensure chemical specificity and improve sensitivity by eliminating chemical noise, typical MALDI MS/MS modalities only scan for a single MS/MS event per laser shot. Herein, we describe TOF/TOF instrumentation that enables multiple fragmentation events to be performed in a single laser shot, allowing the intensity of the analyte to be referenced to the intensity of the internal standard in each laser shot while maintaining the benefits of MS/MS. This approach is illustrated by the quantitative analyses of rifampicin (RIF), an antibiotic used to treat tuberculosis, in pooled human plasma using rifapentine (RPT) as an internal standard. The results show greater than 4-fold improvements in relative standard deviation as well as improved coefficients of determination (R2) and accuracy (>93% quality controls, <9% relative errors). This technology is used as an imaging modality to measure absolute RIF concentrations in liver tissue from an animal dosed in vivo. Each microspot in the quantitative image measures the local RIF concentration in the tissue section, providing absolute pixel-to-pixel quantification from different tissue microenvironments. The average concentration determined by IMS is in agreement with the concentration determined by HPLC-MS/MS, showing a percent difference of 10.6%.

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The direct analysis of drug distribution of rotigotine-loaded microspheres from tissue sections by LESA coupled with tandem mass spectrometry

Wang

Geng

et al. 2017

Anal Bioanal Chem

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The direct analysis of drug distribution of rotigotine-loaded microspheres (RoMS) from tissue sections by liquid extraction surface analysis (LESA) coupled with tandem mass spectrometry (MS/MS) was demonstrated. The RoMS distribution in rat tissues assessed by the ambient LESA-MS/MS approach without extensive or tedious sample pretreatment was compared with that obtained by a conventional liquid chromatography tandem mass spectrometry (LC-MS/MS) method in which organ excision and subsequent solvent extraction were commonly employed before analysis. Results obtained from the two were well correlated for a majority of the organs, such as muscle, liver, stomach, and hippocampus. The distribution of RoMS in the brain, however, was found to be mainly focused in the hippocampus and striatum regions as shown by the LESA-imaged profiles. The LESA approach we developed is sensitive enough, with an estimated LLOQ at 0.05 ng/mL of rotigotine in brain tissue, and information-rich with minimal sample preparation, suitable, and promising in assisting the development of new drug delivery systems for controlled drug release and protection. Graphical abstract Workflow for the LESA-MS/MS imaging of brain tissue section after intramuscular RoMS administration.

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Analysis of small molecule antibody–drug conjugate catabolites in rat liver and tumor tissue by liquid extraction surface analysis micro‐capillary liquid chromatography/tandem mass spectrometry

Abstract: Both analytical assays (LESA-μLC/MS/MS and QWBA) are complementary to each other and provide useful quantitative and qualitative information in spatial tissue distribution of ADCs and their related catabolites. Copyright © 2016 John Wiley & Sons, Ltd.

Cited by 15 publications

References 40 publications

New Insights in Tissue Distribution, Metabolism, and Excretion of [3H]-Labeled Antibody Maytansinoid Conjugates in Female Tumor-Bearing Nude Rats

New Insights in Tissue Distribution, Metabolism, and Excretion of [3H]-Labeled Antibody Maytansinoid Conjugates in Female Tumor-Bearing Nude Rats

Absolute Quantification of Rifampicin by MALDI Imaging Mass Spectrometry Using Multiple TOF/TOF Events in a Single Laser Shot

The direct analysis of drug distribution of rotigotine-loaded microspheres from tissue sections by LESA coupled with tandem mass spectrometry

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