Abstract
SZ-123, a murine monoclonal antibody that targets the human von Willebrand factor (VWF) A3 domain and blocks the binding of collagen, is a powerful antithrombotic. In a Rhesus monkey model of thrombosis, SZ-123 had no side effects, such as bleeding or thrombocytopenia. The mouse/human chimeric version of SZ-123, MHCSZ-123, was developed and maintained inhibitory capacities in vitro and ex vivo after injection into monkeys. CHO-S cells were selected for stable expression of MHCSZ-123. Cell clones with high levels of MHCSZ-123 expression were screened with G418 then adapted to serum-free suspension culture. The antithrombotic effect of MHCSZ-123 on acute platelet-mediated thrombosis was studied in monkeys where thrombus formation was induced by injury and stenosis of the femoral artery, which allowed for cyclic flow reductions (CFRs). CFRs were measured in the femoral artery of anesthetized Rhesus monkeys before and after intravenous administration of MHCSZ-123. Ex vivo VWF binding to collagen, platelet aggregation, platelet counts, and template bleeding time were used as measurements of antithrombotic activity. In addition, plasma VWF and VWF occupancy were measured by ELISA. Injection of 0.1, 0.3, and 0.6 mg/kg MHCSZ-123 signif...Continue Reading
References
Sep 23, 1997·British Journal of Pharmacology·S KageyamaR Yoshimoto
Apr 26, 2000·The Journal of Biological Chemistry·C H YehT F Huang
May 16, 2000·Arteriosclerosis, Thrombosis, and Vascular Biology·N CauwenberghsH F Kotzé
Apr 12, 2001·Thrombosis Research·S KageyamaR Yoshimoto
Jan 15, 2002·Arteriosclerosis, Thrombosis, and Vascular Biology·Shunsuke KageyamaRyota Yoshimoto
Feb 9, 2002·Arteriosclerosis, Thrombosis, and Vascular Biology·Dongmei WuNancy Cauwenberghs
May 3, 2002·Blood·Dongmei WuHans Deckmyn
Aug 17, 2002·Science·Eric G HuizingaPiet Gros
Oct 4, 2003·Nature Reviews. Drug Discovery·Shaun P Jackson, Simone M Schoenwaelder
Apr 19, 2005·Applied Microbiology and Biotechnology·Michael Butler
Apr 26, 2005·Methods : a Companion to Methods in Enzymology·William Ying Khee Hwang, Jefferson Foote
Mar 10, 2006·Thrombosis and Haemostasis·James K HennanGeorge P Vlasuk
May 19, 2006·Journal of Thrombosis and Haemostasis : JTH·U M Vischer
Aug 28, 2007·Thrombosis and Haemostasis·Michael WadanoliQinheng Huang
Aug 29, 2007·Journal of Thrombosis and Haemostasis : JTH·Y ZhaoC Ruan
Nov 21, 2007·Circulation·James C GilbertRobert G Schaub
Mar 19, 2008·Circulation·Alexander O SpielBernd Jilma
Jun 3, 2008·British Journal of Haematology·Simon F De MeyerHans Deckmyn
Oct 9, 2008·Thrombosis and Haemostasis·Alexandre FontayneHans Deckmyn
Mar 10, 2010·Current Pharmaceutical Biotechnology·Takeshi OmasaWook-Dong Kim
Jul 3, 2010·Science China. Life Sciences·Qian JiaMatthew Mizhou Hui
Jan 9, 2013·Biochemical Pharmacology·Yi-ming ZhaoChang-geng Ruan
Aug 3, 2013·Current Vascular Pharmacology·Peter J LentingNikolett Wohner
Apr 29, 2015·Clinical and Applied Thrombosis/hemostasis : Official Journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis·Le QuYiming Zhao
Jun 20, 2015·Journal of Hematology & Oncology·Jie YinChanggeng Ruan