Direct Mass Spectrometry-Based Detection and Antibody Sequencing of Monoclonal Gammopathy of Undetermined Significance from Patient Serum: A Case Study

Weiwei Peng, Maurits A den Boer, Sem Tamara, Nadia J Mokiem, Sjors P A van der Lans, Albert Bondt, Douwe Schulte, Pieter-Jan Haas, Monique C Minnema, Suzan H M Rooijakkers, Arjan D van Zuilen, Albert J R Heck, Joost Snijder*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Monoclonal gammopathy of undetermined significance (MGUS) is a plasma cell disorder characterized by the presence of a predominant monoclonal antibody (i.e., M-protein) in serum, without clinical symptoms. Here we present a case study in which we detect MGUS by liquid-chromatography coupled with mass spectrometry (LC-MS) profiling of IgG1 in human serum. We detected a Fab-glycosylated M-protein and determined the full heavy and light chain sequences by bottom-up proteomics techniques using multiple proteases, further validated by top-down LC-MS. Moreover, the composition and location of the Fab-glycan could be determined in CDR1 of the heavy chain. The outlined approach adds to an expanding mass spectrometry-based toolkit to characterize monoclonal gammopathies such as MGUS and multiple myeloma, with fine molecular detail. The ability to detect monoclonal gammopathies and determine M-protein sequences straight from blood samples by mass spectrometry provides new opportunities to understand the molecular mechanisms of such diseases.

Original languageEnglish
Pages (from-to)3022-3028
Number of pages7
JournalJournal of Proteome Research
Volume22
Issue number9
Early online date27 Jul 2023
DOIs
Publication statusPublished - 1 Sept 2023

Bibliographical note

Publisher Copyright:
© 2023 The Authors. Published by American Chemical Society.

Funding

This research was funded by the Dutch Research Council NWO Gravitation 2013 BOO, Institute for Chemical Immunology (ICI; 024.002.009) to J.S and through the NWO TTW-NACTAR Grant #16442 (to A.J.R.H. and S.H.M.R.). We additionally acknowledge support from NWO, funding the MS facilities through the X-omics Road Map program (project 184.034.019).

FundersFunder number
Dutch Research Council NWO024.002.009
Nederlandse Organisatie voor Wetenschappelijk Onderzoek184.034.019, 16442

    Keywords

    • M-protein
    • antibody
    • de novo sequencing
    • glycosylation
    • middle-down
    • monoclonal gammopathy

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