Development of a Targeted Mass-Spectrometry Serum Assay To Quantify M‑Protein in the Presence of Therapeutic Monoclonal Antibodies

• Published in: Journal of proteome research Vol. 17; no. 3; pp. 1326 - 1333
• Main Authors: Zajec, Marina, Jacobs, Joannes F. M, Groenen, Patricia J. T. A, de Kat Angelino, Corrie M, Stingl, Christoph, Luider, Theo M, De Rijke, Yolanda B, VanDuijn, Martijn M
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 02.03.2018
• Subjects: Amino Acid Sequence; Antibodies, Monoclonal - blood; Antibodies, Monoclonal - therapeutic use; Antineoplastic Agents - blood; Antineoplastic Agents - therapeutic use; Biological Assay; Biomarkers, Tumor - blood; Biomarkers, Tumor - genetics; Biomarkers, Tumor - immunology; Gene Expression; Humans; Ipilimumab - blood; Ipilimumab - therapeutic use; Isotope Labeling - methods; Mass Spectrometry - methods; Multiple Myeloma - blood; Multiple Myeloma - diagnosis; Multiple Myeloma - drug therapy; Multiple Myeloma - immunology; Myeloma Proteins - genetics; Myeloma Proteins - immunology; Myeloma Proteins - metabolism; Neoplasm, Residual; Peptides - chemistry; Peptides - immunology; Sensitivity and Specificity; multiple myeloma; nivolumab; ipilimumab; response assessment; M-protein; targeted mass-spectrometry; daratumumab; therapeutic monoclonal antibody
• ISSN: 1535-3893; 1535-3907
• DOI: 10.1021/acs.jproteome.7b00890

M-protein diagnostics can be compromised for patients receiving therapeutic monoclonal antibodies as treatment in multiple myeloma. Conventional techniques are often not able to distinguish between M-proteins and therapeutic monoclonal antibodies administered to the patient. This may prevent correct response assessment and can lead to overtreatment. We have developed a serum-based targeted mass-spectrometry assay to detect M-proteins, even in the presence of three therapeutic monoclonal antibodies (daratumumab, ipilimumab, and nivolumab). This assay can target proteotypic M-protein peptides as well as unique peptides derived from therapeutic monoclonal antibodies. We address the sensitivity in M-protein diagnostics and show that our mass-spectrometry assay is more than two orders of magnitude more sensitive than conventional M-protein diagnostics. The use of stable isotope-labeled peptides allows absolute quantification of the M-protein and increases the potential of assay standardization across multiple laboratories. Finally, we discuss the position of mass-spectrometry assays in monitoring minimal residual disease in multiple myeloma, which is currently dominated by molecular techniques based on plasma cell assessment that requires invasive bone marrow aspirations or biopsies.