2016 New Investigator: Christian Lanshoeft

Nominee:

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Supporting Comments:

What made you choose a career in bioanalysis?

As Analytical Chemist, I like the challenges associated with developing bioanalytical assays for qualitative and quantitative analysis with subsequent validation in accordance to internal guidelines. A broad spectrum of sample preparation techniques is required and the correct analytical tool has to be selected in order to reduce the sample complexity and solve specific bioanalytical questions. Depending on the question to be addressed, each project is different and other methodologies are applied as e.g. the analyte(s) could either be based on small molecules including their metabolites or on macromolecules such as monoclonal antibodies (mAbs) or antibody-drug conjugates (ADCs) with their catabolites.

Describe the main highlights of your bioanalytical research, and its importance to the bioanalytical community.

So far, during my Ph.D. thesis, I have focused on the development of generic MS-based methods for the quantification of hIgG1/4-based therapeutic proteins in various preclinical species either with triple quadrupole or quadrupole–time-of-flight mass analyzers with LC upfront. In total, a calibration range over five orders of magnitude (10.0 ng/mL – 1000 μg/mL) was covered with two assays either based on pellet digestion or immunoenrichment.

Furthermore, some efforts focused on turning LESA-μLC-MS/MS in a more quantitative rather than only a qualitative technology to screen ADC catabolites in tissue samples or monitor the penetration of a drug in skin after dermal administration.

During my MSc thesis, ultrafast methods for direct analysis of small molecules in clinical samples without the use of any chromatography prior to MS detection using LDTD-APCI-MS/MS were developed/validated in order to decrease the analytical run time from several minutes to 10 s per sample. This resulted in a 27-fold higher throughput while maintaining the same data quality compared to classical analysis by LC-MS/MS.

What is the impact of your work beyond your home laboratory?

The developed assays are quite interesting from an outsourcing point of view. After validation, they can easily be transferred to CROs to support PK/PD assessment of a specific drug. Furthermore, my published generic LC-MS/MS assays are applicable to any therapeutic protein based on the hIgG1/4 framework in several preclinical species. This means that each organization (academia or industry) analyzing such entities profits from these methods and can apply them directly without any need to develop them first. Regarding the LDTD technology, no mobile phases are used anymore. Consequently, time consuming equilibration steps of the LC system are no longer required between project switching. A simple ‘load and shoot’ principle has to be followed resulting in a higher flexibility to plan the analysis of several studies in parallel and deliver, for instance, PK profiles faster to the project team, as a 96-well plate is analyzed in 15 min.

Describe the most difficult challenge you have encountered in the laboratory and how you overcame it.

The major challenge, I am facing routinely (similar to each bioanalyst) is on the one hand the extraction and enrichment of low abundant target analyte(s) from any kind of complex biological matrix (serum/plasma/tissue) during the analysis of PK/PD study samples. On the other hand, especially with the quantitative analysis of therapeutic proteins where one or more peptides are used as a surrogate for the target protein, an enzymatic digestion has to be incorporated into the sample preparation which further increases the sample complexity. Thus, additional endogenous compounds may interfere with the assay. The resultant sample complexity was further decreased not only by the use of appropriate sample preparation strategies such as solid phase extraction, immunodepletion or immunocapture by magnetic beads or mass spectrometric immunoassay with disposable automation research tips (MSIA-DARTs) but also from an instrumentation point of view with multi-dimensional LC methods, cubic selected reaction monitoring (SRM) acquisition modes using ion trap mass analyzers or even by the use of accurate mass in HRMS. As a consequence, highly sensitive analytical assays could be developed within the lab to support preclinical studies also with MS-based technologies instead of ligand binding assays only, especially at low dosing regimen.

Describe your role in bioanalytical communities/groups.

My role in the bioanalytical group of the Novartis DMPK department is mostly to explore, develop and validate new MS-based methods for the analysis of therapeutic proteins in biological fluids. This means to combine the latest state-of-the-art methodologies developed in academia with new MS technologies from various vendors for their direct applicability in the pharmaceutical industry, for instance, during (pre) clinical trials.

Besides activity as a PhD student, I have no other involvement yet e.g. in any bioanalytical focusing groups, activities in scientific societies or journals.

Please list up to five of your publications in the field of bioanalysis:

1. Lanshoeft C, Heudi O, Cianférani S, Warren AP, Picard F, Kretz O. Quantitative analysis of hIgG1 in monkey serum by LC-MS/MS using mass spectrometric immunoassay. Bioanalysis doi: 10.4155/bio.16.32 (2016) (Epub ahead of print).
2. Lanshoeft C, Wolf T, Heudi O et al. The use of generic surrogate peptides for the quantitative analysis of human immunoglobulin G1 in pre-clinical species with high-resolution mass spectrometry. Bioanal. Chem. 408(6), 1687–1699 (2016).
3. Lanshoeft C, Stutz G, Elbast W et al. 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. Rapid Commun. Mass Spectrom. 30(7), 823–832 (2016).
4. Walles M, Rudolph B, Wolf T et al. New insights in tissue distribution, metabolism and excretion of [3H]-labeled antibody maytansinoid conjugates in female tumor bearing nude rats. Drug Metab. Dispos. (2016) (Under revision).
5. Lanshoeft C, Heudi O, Raccuglia M, Leuthold LA, Picard F, Kretz O. Ultrafast quantitative mass spectrometry based method for ceritinib analysis in human plasma samples from clinical trial. Bioanalysis 7(4), 425-35 (2015).

Please select one publication from above that best highlights your career to date in the field of bioanalysis and provide an explanation for your choice.

The second paper reflects my work/career best as the focus during my industrial PhD thesis is to explore the use of MS-based technologies for the qualitative and quantitative analysis of therapeutic proteins in biological fluids. Besides a full characterization of the investigated mAbs/ADCs and the identification of possible modifications sites (deamidation, oxidations, payload conjugation etc.), several quantitative assays have to be developed and validated to distinguish between the total Ab, total ADC, active ADC or even the small molecule parts of an ADC (linker/payload) in order to support PK/PD or immunogenicity studies of the DMPK department at Novartis.

Find out more about this year’s New Investigator Award, the prize, the judging panel and the rest of our nominees.