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Application of triple quadrupole mass spectrometry for the characterization of antibody-drug conjugates
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry. Recipharm OT Chem AB, Virdings Alle 32b, S-75450 Uppsala, Sweden.
Recipharm OT Chem AB, Virdings Alle 32b, S-75450 Uppsala, Sweden.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.ORCID iD: 0000-0002-5520-0179
Oncopeptides AB, Luntmakargatan 46, SE-11137 Stockholm, Sweden.
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2019 (English)In: Analytical and Bioanalytical Chemistry, ISSN 1618-2642, E-ISSN 1618-2650, Vol. 411, no 12, p. 2569-2576Article in journal (Refereed) Published
Abstract [en]

Antibody-drug conjugates (ADCs) are an inherently heterogeneous class of biotherapeutics, the development of which requires extensive characterization throughout. During the earliest phases of preclinical development, when synthetic routes towards the desired conjugate are being assessed, the main interest lies in the determination of the average drug-to-antibody ratio (DAR) of a given batch as well as information about different conjugation species. There has been a trend in mass spectrometry (MS)-based characterization of ADCs towards the use of high-resolving mass spectrometry for many of these analyses. Considering the high cost for such an instrument, the evaluation of cheaper and more accessible alternatives is highly motivated. We have therefore tested the applicability of a quadrupole mass analyzer for the aforementioned characterizations. Eight ADCs consisting of trastuzumab and varying stoichiometries of Mc-Val-Cit-PABC-monomethyl auristatin E conjugated to native cysteines were synthesized and served as test analytes. The average DAR value and molecular weights (Mw) of all detected chains from the quadrupole mass analyzer showed surprisingly high agreement with results obtained from a time-of-flight (TOF) mass analyzer and hydrophobic interaction chromatography (HIC)-derived values for all investigated ADC batches. Acquired Mw were within 80ppm of TOF-derived values, and DAR was on average within 0.32 DAR units of HIC-derived values. Quadrupole mass spectrometers therefore represent a viable alternative for the characterization of ADC in early-stage development.

Place, publisher, year, edition, pages
SPRINGER HEIDELBERG , 2019. Vol. 411, no 12, p. 2569-2576
Keywords [en]
Reversed-phase liquid chromatography, Antibody-drug conjugates, Drug-to-antibody ratio, Triple quadrupole mass spectrometry
National Category
Analytical Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-383155DOI: 10.1007/s00216-019-01699-0ISI: 000464948100011PubMedID: 30848315OAI: oai:DiVA.org:uu-383155DiVA, id: diva2:1315055
Funder
Swedish Foundation for Strategic Research , ID14-0081Swedish Foundation for Strategic Research , SB16-0039Swedish Research Council, 2015-4870Available from: 2019-05-10 Created: 2019-05-10 Last updated: 2019-05-10Bibliographically approved

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