The effect of a next generation factor VIII mimetic bispecific antibody (Mim8) on assays of factor VIII activity and thrombin generation

Mim8 is a next generation bispecific antibody developed for the prophylactic treatment of hemophilia A. The sensitivity of activated plasma thromboplastin time (APTT), assays measuring factor VIII activity (FVIII:C) and thrombin generation to plasma containing Mim8 was assessed. Congenital severe he...

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Bibliographic Details
Published in:Journal of thrombosis and haemostasis Vol. 21; no. 3; pp. 480 - 487
Main Authors: Bowyer, Annette Elizabeth, Kitchen, Steve, Ezban, Mirella
Format: Journal Article
Language:English
Published: England Elsevier Inc 01.03.2023
Subjects:
Animals
Antibodies, Bispecific - therapeutic use
bispecific antibody
Cattle
chromogenic
Factor VIII - metabolism
FVIII
hemophilia
Hemophilia A - drug therapy
Hemostatics - therapeutic use
Humans
Indicators and Reagents
one-stage
Partial Thromboplastin Time
Thrombin - metabolism
Thromboplastin - therapeutic use
one-stage
bispecific antibody
hemophilia
chromogenic
FVIII
ISSN:1538-7836, 1538-7836
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Summary:Mim8 is a next generation bispecific antibody developed for the prophylactic treatment of hemophilia A. The sensitivity of activated plasma thromboplastin time (APTT), assays measuring factor VIII activity (FVIII:C) and thrombin generation to plasma containing Mim8 was assessed. Congenital severe hemophilia A plasma was spiked with Mim8 at 0 μg/mL to 20 μg/mL. APTT was measured with 4 reagents, one-stage FVIII with 9 reagents, and chromogenic FVIII with 6 assays. Thrombin generation was assessed in a low tissue factor system. At 1-μg/mL Mim8, the APTT was shortened to within normal limits and one-stage FVIII:C was >1.00 IU/mL with all APTT reagents. Modified one-stage assays calibrated with Mim8 reference material calibrated recovered within 20% of the target Mim8 concentration with most APTT reagents. Factor VIII:C of bovine only chromogenic assays was <0.04 IU/mL at all Mim8 concentrations. Factor VIII:C of human only chromogenic assay was >4.00 IU/mL at 20-μg/mL Mim8. Factor VIII:C of hybrid bovine FX, human FIXa chromogenic assays ranged from 0.076 to >3.00 IU/mL at 20-μg/mL Mim8. Normal thrombin generation was restored at 5-μg/mL Mim8. APTT-based assays are sensitive to Mim8 and should not be performed in the presence of the drug. Chromogenic assays containing human proteins or hybrid human/bovine proteins demonstrated variable sensitivity to Mim8. Bovine only chromogenic assays were largely insensitive to the presence of Mim8. Thrombin generation normalized at increased Mim8 concentrations. Modified one-stage and chromogenic assays could be used to quantify the Mim8 concentration in plasma. •Mim8 is a next generation bispecific antibody for the prophylactic treatment of hemophilia A.•Measurement of factor VIII (FVIII) activity and thrombin generation was performed in plasma spiked with Mim8.•Modified Mim8 reference calibrated one-stage FVIII assays accurately measured the drug concentration.•Chromogenic FVIII assays varied in their sensitivity to Mim8.
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ISSN:1538-7836
1538-7836
DOI:10.1016/j.jtha.2022.12.023