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An application of mass spectrometry for quality control of biologicals : highly sensitive profiling of plasma residuals in human plasma-derived immunoglobulin

(2017) JOURNAL OF PROTEOMICS. 152. p.312-320
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Abstract
Thromboembolic events (TEE) associated to trace amounts of plasmatic activated coagulation factor XI (FXIa) in administrated immunoglobulin (Ig) have recently raised concerns and hence there is a need for highly sensitive profiling of residual plasma source proteins. This study aims to consider LC-ESI-QTOF data-dependent acquisition in combination with sample fractionation for this purpose. Sample fractionation proved mandatory to enable identification of plasma residuals. Two approaches were compared: Ig depletion with protein G- protein A affinity chromatography and low-abundant protein enrichment with a combinatorial peptide ligand library (ProteoMinerTm, Bio-Rad). The latter allowed a higher number of identifications. Highly sensitive detection of prothrombotic FXIa was assessed with confident identification of a 1 ng/mg spike. Moreover, different residuals compositions were profiled for various commercial Ig products. Using a quantitative label free analysis, a TEE positive Ig batch was distinguished from other regular Ig products, with increased levels of FXIa but also other unique proteins. This could have prevented the recently observed TEE problems with Ig. The method is a convenient tool to better characterize Ig products after any plasma pool or manufacture process change, gaining insights in the product quality profile without any prior information required. Biological significance: This study characterized residual plasma proteins in Ig products, using bottom-up LC-MS/MS with conventional data-dependent acquisition, preceded by sample fractionation. Without any prior information or target-specific development, >30 proteins were identified in a commercial Ig product. Quality control relevance was demonstrated with the identification of FXIa spiked at 1 ng/mg in Ig, which is below the minimal thrombotic dose of 3 ng/mg observed in an in vivo model. Relative label-free quantitation highlighted significant differences in normalized abundances of residual proteins between Ig products. A TEE-positive batch was distinguished by unique profile of residual proteins, including FXIa but also various blood stream-regulator proteins (fibrinogen, angiotensinogen, antithrombin-III, complement component C8, ...). Those results emphasize that MS screening is a relevant first-line test to prevent any undesired concentration of plasma impurities after a plasma pool or manufacturing process change.
Keywords
Biologicals proteomics, Quality control, Plasma residuals, Immunoglobulin, Coagulation factor Xia, Combinatorial peptide ligand library, PEPTIDE LIGAND LIBRARIES, PROTEIN-CONCENTRATION RANGE, HIGH-ABUNDANCE PROTEINS, IN-DEPTH EXPLORATION, EXCHANGE CHROMATOGRAPHY, ANTIBODY PURIFICATION, PROTEOMIC ANALYSIS, HUMAN SERUM, DEPLETION, AFFINITY

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Chicago
Limonier, Franck, Katleen Van Steendam, Geneviève Waeterloos, Koen Brusselmans, Myriam Sneyers, and Dieter Deforce. 2017. “An Application of Mass Spectrometry for Quality Control of Biologicals : Highly Sensitive Profiling of Plasma Residuals in Human Plasma-derived Immunoglobulin.” Journal of Proteomics 152: 312–320.
APA
Limonier, F., Van Steendam, K., Waeterloos, G., Brusselmans, K., Sneyers, M., & Deforce, D. (2017). An application of mass spectrometry for quality control of biologicals : highly sensitive profiling of plasma residuals in human plasma-derived immunoglobulin. JOURNAL OF PROTEOMICS, 152, 312–320.
Vancouver
1.
Limonier F, Van Steendam K, Waeterloos G, Brusselmans K, Sneyers M, Deforce D. An application of mass spectrometry for quality control of biologicals : highly sensitive profiling of plasma residuals in human plasma-derived immunoglobulin. JOURNAL OF PROTEOMICS. 2017;152:312–20.
MLA
Limonier, Franck et al. “An Application of Mass Spectrometry for Quality Control of Biologicals : Highly Sensitive Profiling of Plasma Residuals in Human Plasma-derived Immunoglobulin.” JOURNAL OF PROTEOMICS 152 (2017): 312–320. Print.
@article{8593809,
  abstract     = {Thromboembolic events (TEE) associated to trace amounts of plasmatic activated coagulation factor XI (FXIa) in administrated immunoglobulin (Ig) have recently raised concerns and hence there is a need for highly sensitive profiling of residual plasma source proteins. This study aims to consider LC-ESI-QTOF data-dependent acquisition in combination with sample fractionation for this purpose. Sample fractionation proved mandatory to enable identification of plasma residuals. Two approaches were compared: Ig depletion with protein G- protein A affinity chromatography and low-abundant protein enrichment with a combinatorial peptide ligand library (ProteoMinerTm, Bio-Rad). The latter allowed a higher number of identifications. Highly sensitive detection of prothrombotic FXIa was assessed with confident identification of a 1 ng/mg spike. Moreover, different residuals compositions were profiled for various commercial Ig products. Using a quantitative label free analysis, a TEE positive Ig batch was distinguished from other regular Ig products, with increased levels of FXIa but also other unique proteins. This could have prevented the recently observed TEE problems with Ig. The method is a convenient tool to better characterize Ig products after any plasma pool or manufacture process change, gaining insights in the product quality profile without any prior information required. 
Biological significance: This study characterized residual plasma proteins in Ig products, using bottom-up LC-MS/MS with conventional data-dependent acquisition, preceded by sample fractionation. Without any prior information or target-specific development, >30 proteins were identified in a commercial Ig product. Quality control relevance was demonstrated with the identification of FXIa spiked at 1 ng/mg in Ig, which is below the minimal thrombotic dose of 3 ng/mg observed in an in vivo model. Relative label-free quantitation highlighted significant differences in normalized abundances of residual proteins between Ig products. A TEE-positive batch was distinguished by unique profile of residual proteins, including FXIa but also various blood stream-regulator proteins (fibrinogen, angiotensinogen, antithrombin-III, complement component C8, ...). Those results emphasize that MS screening is a relevant first-line test to prevent any undesired concentration of plasma impurities after a plasma pool or manufacturing process change.},
  author       = {Limonier, Franck and Van Steendam, Katleen and Waeterloos, Geneviève and Brusselmans, Koen and Sneyers, Myriam and Deforce, Dieter},
  issn         = {1874-3919},
  journal      = {JOURNAL OF PROTEOMICS},
  keywords     = {Biologicals proteomics,Quality control,Plasma residuals,Immunoglobulin,Coagulation factor Xia,Combinatorial peptide ligand library,PEPTIDE LIGAND LIBRARIES,PROTEIN-CONCENTRATION RANGE,HIGH-ABUNDANCE PROTEINS,IN-DEPTH EXPLORATION,EXCHANGE CHROMATOGRAPHY,ANTIBODY PURIFICATION,PROTEOMIC ANALYSIS,HUMAN SERUM,DEPLETION,AFFINITY},
  language     = {eng},
  pages        = {312--320},
  title        = {An application of mass spectrometry for quality control of biologicals : highly sensitive profiling of plasma residuals in human plasma-derived immunoglobulin},
  url          = {http://dx.doi.org/10.1016/j.jprot.2016.11.007},
  volume       = {152},
  year         = {2017},
}

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