Discovery and characterisation of an antibody that selectively modulates the inhibitory activity of plasminogen activator inhibitor-1.

Autor: Vousden KA; MedImmune Ltd, Cambridge, CB21 6GH, UK. vousdenk@medimmune.com., Lundqvist T; AstraZeneca AB R&D, Pepparedsleden 1, 431 50, Mölndal, Sweden., Popovic B; MedImmune Ltd, Cambridge, CB21 6GH, UK., Naiman B; MedImmune LLC, One MedImmune Way, Gaithersburg, MD, 20878, USA., Carruthers AM; MedImmune Ltd, Cambridge, CB21 6GH, UK., Newton P; MedImmune Ltd, Cambridge, CB21 6GH, UK., Johnson DJD; Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK., Pomowski A; Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK., Wilkinson T; MedImmune Ltd, Cambridge, CB21 6GH, UK., Dufner P; MedImmune Ltd, Cambridge, CB21 6GH, UK., de Mendez I; MedImmune Ltd, Cambridge, CB21 6GH, UK., Mallinder PR; MedImmune Ltd, Cambridge, CB21 6GH, UK., Murray C; AstraZeneca R&D, Alderley Park, Macclesfield, Cheshire, SK10 4TF, UK., Strain M; MedImmune Ltd, Cambridge, CB21 6GH, UK., Connor J; MedImmune LLC, One MedImmune Way, Gaithersburg, MD, 20878, USA., Murray LA; MedImmune Ltd, Cambridge, CB21 6GH, UK., Sleeman MA; MedImmune Ltd, Cambridge, CB21 6GH, UK., Lowe DC; MedImmune Ltd, Cambridge, CB21 6GH, UK., Huntington JA; Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK., Vaughan TJ; MedImmune Ltd, Cambridge, CB21 6GH, UK.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2019 Feb 07; Vol. 9 (1), pp. 1605. Date of Electronic Publication: 2019 Feb 07.
DOI: 10.1038/s41598-019-38842-x
Abstrakt: Plasminogen activator inhibitor-1 (PAI-1) is a serine protease inhibitor (serpin) that regulates fibrinolysis, cell adhesion and cell motility via its interactions with plasminogen activators and vitronectin. PAI-1 has been shown to play a role in a number of diverse pathologies including cardiovascular diseases, obesity and cancer and is therefore an attractive therapeutic target. However the multiple patho-physiological roles of PAI-1, and understanding the relative contributions of these in any one disease setting, make the development of therapeutically relevant molecules challenging. Here we describe the identification and characterisation of fully human antibody MEDI-579, which binds with high affinity and specificity to the active form of human PAI-1. MEDI-579 specifically inhibits serine protease interactions with PAI-1 while conserving vitronectin binding. Crystallographic analysis reveals that this specificity is achieved through direct binding of MEDI-579 Fab to the reactive centre loop (RCL) of PAI-1 and at the same exosite used by both tissue and urokinase plasminogen activators (tPA and uPA). We propose that MEDI-579 acts by directly competing with proteases for RCL binding and as such is able to modulate the interaction of PAI-1 with tPA and uPA in a way not previously described for a human PAI-1 inhibitor.
Databáze: MEDLINE
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