Dextrose-mediated aggregation of therapeutic monoclonal antibodies in human plasma: Implication of isoelectric precipitation of complement proteins

MAbs
Shen Luo, Baolin Zhang

Abstract

Many therapeutic monoclonal antibodies (mAbs) are clinically administered through intravenous infusion after mixing with a diluent, e.g., saline, 5% dextrose. Such a clinical setting increases the likelihood of interactions among mAb molecules, diluent, and plasma components, which may adversely affect product safety and efficacy. Avastin® (bevacizumab) and Herceptin® (trastuzumab), but not Remicade® (infliximab), were shown to undergo rapid aggregation upon dilution into 5% dextrose when mixed with human plasma in vitro; however, the biochemical pathways leading to the aggregation were not clearly defined. Here, we show that dextrose-mediated aggregation of Avastin or Herceptin in plasma involves isoelectric precipitation of complement proteins. Using mass spectrometry, we found that dextrose-induced insoluble aggregates were composed of mAb itself and multiple abundant plasma proteins, namely complement proteins C3, C4, factor H, fibronectin, and apolipoprotein. These plasma proteins, which are characterized by an isoelectronic point of 5.5-6.7, lost solubility at the resulting pH in the mixture with formulated Avastin (pH 6.2) and Herceptin (pH 6.0). Notably, switching formulation buffers for Avastin (pH 6.2) and Remicade (p...Continue Reading

References

Dec 1, 1992·Archives of Disease in Childhood·J W PuntisI W Booth
Apr 2, 1988·British Medical Journal·A J CantN Kirkham
Feb 1, 1995·Current Opinion in Immunology·V D Miletic, M M Frank
Jan 1, 1996·JPEN. Journal of Parenteral and Enteral Nutrition·S E HillJ C Perkinson
Mar 29, 2001·Journal of Chromatography. B, Biomedical Sciences and Applications·R J HarrisA B Chen
Oct 10, 2006·The AAPS Journal·Amy S Rosenberg
Aug 16, 2008·Journal of Pharmaceutical Sciences·John F CarpenterBarry Cherney
Jun 12, 2013·PDA Journal of Pharmaceutical Science and Technology·Stephen E Langille
Jul 25, 2014·Free Radical Biology & Medicine·Shen LuoEmily Shacter

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Citations

May 18, 2016·Journal of Immunology Research·Roy Jefferis
Nov 5, 2016·International Journal of Pharmaceutics·Adam C FisherJanet Woodcock
May 16, 2017·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Flávia SousaMaria Teresa Neves-Petersen
May 13, 2017·Journal of Biomedical Materials Research. Part a·M N BiaoB C Yang
Jan 5, 2020·Pharmaceutical Research·Joachim SchusterRoman Mathaes
Jan 8, 2019·Oncotarget·Julianne D TwomeyBaolin Zhang
Jun 12, 2020·Expert Opinion on Drug Delivery·Suchada NiamsuphapChristopher B Howard
Jan 10, 2021·Journal of Pharmaceutical Sciences·Joachim SchusterRoman Mathaes
Dec 4, 2020·Journal of Pharmaceutical Sciences·Miguel SagguAnthony Tomlinson
Jun 13, 2020·International Journal of Pharmaceutics·Ngoc B Pham, Wilson S Meng
Aug 30, 2019·Journal of Pharmaceutical Sciences·Yoann Le BasleValérie Sautou
May 3, 2021·Journal of Pharmaceutical Sciences·Joachim SchusterRoman Mathaes
Jul 9, 2021·European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Für Pharmazeutische Verfahrenstechnik E.V·Nam Ah KimSeong Hoon Jeong

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Methods Mentioned

BETA
membrane filtration

Software Mentioned

Agilent Spectrum Mill

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