Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
6002439 | Thrombosis Research | 2014 | 8 Pages |
Abstract
Concizumab bound to cell surface TFPI on EA.hy926 cells and neutralised TFPI inhibition of Factor X activation. The antibody cross-reacted with rabbit TFPI, but not with rat TFPI, allowing for comparative PK studies. PK data in rats described a log-linear profile typical for a non-binding antibody, whereas PK data in rabbits revealed a non-linear, dose-dependent profile, consistent with a target-mediated clearance mechanism. Immunohistology in rabbits during target-saturation showed localisation of the antibody on the endothelium of the microvasculature in several organs. We observed a marked co-localisation with endogenous rabbit TFPI, but a negligible sub-endothelial build-up. Concizumab binds and neutralises the inhibitory effect of cell surface-bound TFPI. The PK profile observed in rabbits is consistent with a TFPI-mediated drug disposition. Double immunofluorescence shows co-localisation of the antibody with TFPI on the endothelium of the microvasculature and points to this TFPI as a putative target involved in the clearance mechanism.
Keywords
GPiHRPEGFRt½KPIFCSmAbGAGDABCmaxDIFFVIIIFXaNCANon-Compartmental Analysisi.v3,3′-diaminobenzidineAUCMonoclonal antibodyIHCImmunohistochemistryKunitz-type protease inhibitorclearanceFIXmaximum concentrationIntravenousDouble immunofluorescencefetal calf serumFactor VIIIFactor IXFactor Xaarea under the curveHalf-lifeHorseradish peroxidaseGlycosaminoglycansglycosylphosphatidylinositolEpidermal growth factor receptor
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Authors
Lene Hansen, Lars Christian Petersen, Brian Lauritzen, Jes Thorn Clausen, Susanne Nedergaard Grell, Henrik Agersø, Brit Binow Sørensen, Ida Hilden, Kasper Almholt,