TAILIEUCHUNG - Báo cáo khoa học: Design and humanization of a murine scFv that blocks human platelet glycoprotein VI in vitro

Platelet adhesion and aggregation at the site of vascular injury is essential for hemostasis, but can also lead to arterial occlusion in thrombotic disor-ders. Glycoprotein (GP) VI is the major platelet membrane receptor that interacts directly with collagen, the most thrombogenic compound in the blood vessels. | ỊFEBS Journal Design and humanization of a murine scFv that blocks human platelet glycoprotein VI in vitro Julien Muzard1 2 Maxime Bouabdelli2 Muhammad Zahid3 Veronique Ollivier2 Jean Jacques Lacapere4 Martine Jandrot-Perrus2 and Philippe Billiald1 3 1 Museum nationald Histoire naturelle CNRS FRE 3206 CP39 Paris France 2 Inserm U698 HopitalBichat Universite Paris 7 France 3 Universite Paris-Sud 11 JE 2493 Faculte de Pharmacie Chatenay-Malabry France 4 Inserm U733 CRB3 Faculte Xavier Bichat Universite Paris 7 France Keywords antibody humanization arterialthrombosis collagen platelet Correspondence P. Billiald Museum nationald Histoire naturelle CNRS FRE 3206 CP39 12 rue Buffon 75231 Paris cedex 05 France Fax 33 140 793 594 Tel 33 140 793 155 E-mail billiald@ M. Jandrot-Perrus Inserm U698 Hopital Bichat 46 rue Henri Huchard University Paris 7 Paris France Fax 33 140 258 602 Tel 33 140 256 531 E-mail Received 15 October 2007 accepted 3 June 2009 doi Platelet adhesion and aggregation at the site of vascular injury is essential for hemostasis but can also lead to arterial occlusion in thrombotic disorders. Glycoprotein GP VI is the major platelet membrane receptor that interacts directly with collagen the most thrombogenic compound in the blood vessels. GPVI could therefore be a major therapeutic target. Fab fragments of the anti-GPVI murine monoclonal IgG 9O12 have previously been shown to completely block collagen-induced platelet aggregation to inhibit the procoagulant activity of collagen-stimulated platelets and to prevent thrombus formation under arterial flow conditions without significantly prolonging the bleeding time. Here we engineered recombinant scFvs that preserve the functional properties of 9O12 and could constitute building blocks for designing new compounds with potentially therapeutic antithrombotic properties. First the 9O12 variable domains were cloned sequenced and expressed .

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