In vitro validation of chromogenic substrate assay for evaluation of surrogate FVIII-activity of emicizumab.

Autor: Yamaguchi T; Department of Laboratory Medicine, Tokyo Medical University, Tokyo, Japan., Shinozawa K; Department of Laboratory Medicine, Tokyo Medical University, Tokyo, Japan., Nagatoishi S; The Institute of Medical Science, The University of Tokyo, Tokyo, Japan., Mitsuhashi A; Department of Laboratory Medicine, Tokyo Medical University, Tokyo, Japan; Research Resident Fellowship, Japan Foundation for AIDS Prevention, Tokyo, Japan., Bingo M; Department of Laboratory Medicine, Tokyo Medical University, Tokyo, Japan., Inaba H; Department of Laboratory Medicine, Tokyo Medical University, Tokyo, Japan., Amano K; Department of Laboratory Medicine, Tokyo Medical University, Tokyo, Japan., Tsumoto K; The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan., Kinai E; Department of Laboratory Medicine, Tokyo Medical University, Tokyo, Japan. Electronic address: ekinai@tokyo-med.ac.jp.
Jazyk: angličtina
Zdroj: Thrombosis research [Thromb Res] 2023 Feb; Vol. 222, pp. 131-139. Date of Electronic Publication: 2023 Jan 13.
DOI: 10.1016/j.thromres.2023.01.007
Abstrakt: [Introduction] Emicizumab, a bispecific antibody mimicking activated factor VIII (FVIII), is increasingly used in prophylaxis against bleeding in hemophilia A. Human factor-based chromogenic substrate assay (hCSA) shows concentration-dependency between emicizumab and reported FVIII activity. However, the assay measurement settings have not been optimized for emicizumab, and the reported FVIII activity cannot be directly referred as surrogate FVIII activity. [Materials and Methods] For in vitro validation of hCSA-reported surrogate FVIII activity, we compared the equation curves for emicizumab concentration with surrogate FVIII activity using spiked plasma in the thrombin generation assay (TGA), hCSA, and clot waveform analysis (CWA). Then, we generated conversion equations for hCSA-reported surrogate FVIII value to that of TGA. We also assessed the additive effect of rFVIII onto 340 nM (i.e., 50 μg/mL) emicizumab using the same assays. [Results] With 1:20 diluted plasma, halving hCSA-reported surrogate FVIII activity can be approximated to that in TGA triggered by the extrinsic pathway reagent (27.3 IU/dL vs. 13.9 IU/dL) under therapeutic emicizumab concentration. Both in TGA and hCSA, the additive effect of added FVIII on therapeutic emicizumab concentration (340 nM) was maintained at low levels of FVIII but gradually decreased at higher levels. [Conclusions] Surrogate FVIII activity can be estimated simply by halving hCSA-reported FVIII value, and the additive effect of FVIII on emicizumab diminishes at high concentrations. Based on our in vitro study, a clinical study is currently being conducted to compare individual variation of surrogate FVIII activity in hCSA and TGA.
Competing Interests: Declaration of competing interest HI received research grant from Sysmex, consulting fee from CSL-Behring and speaker honoraria from Sanofi, Bayer and CSL-Behring. KS was an endowed Assistant Professor funded by Baxter/Baxalta/Shire and CSL-Behring (until March 2020). KA received research grant from KM Biologics, consulting fee from Chugai Pharmaceutical, and honoraria from Chugai Pharmaceutical, Sanofi, Bayer, Takeda Pharmaceutical, Novo Nordisk, CSL Behring, KM Biologics, Pfizer, Fujimoto Pharmaceutical Corporation and Japan Blood Products Organization. EK received research grants from Chugai Pharmaceutical and CSL-Behring, and honoraria from Chugai Pharmaceutical, Sanofi, Bayer, Takeda Pharmaceutical, Novo Nordisk, Fujimoto Pharmaceutical Corporation and CSL Behring. All other authors declare no conflict of interest.
(Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Databáze: MEDLINE
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