A human monoclonal antibody against the distal carboxyl terminus of ADAMTS13 modulates its susceptibility to an inhibitor in thrombotic thrombocytopenic purpura

J Thromb Haemost. 2021 Apr 9. doi: 10.1111/jth.15332. Online ahead of print.ABSTRACTBACKGROUND: Immune thrombotic thrombocytopenic purpura (iTTP) is a potentially fatal thrombotic microangiopathy, resulting from a severe deficiency of plasma ADAMTS13 activity. Immunoglobulin (Ig) G-type autoantibodies are primarily responsible for the inhibition of plasma ADAMTS13 activity. However, the mechanism underlying autoantibody-mediated inhibition is not fully understood.OBJECTIVE: The purpose of the present study is to determine the role of IgG autoantibodies against various carboxyl-terminal domains of ADAMTS13 in regulating ADAMTS13 activity and its inhibition.METHOD: Various human monoclonal antibodies isolated by phage display, recombinant protein expression and purification, and biochemical analyses were employed for the study. Results Our results demonstrate for the first time that a human monoclonal antibody fragment, the single chain fragment of the variable region (scFv) isolated from a patient with acute iTTP that binds the distal carboxyl-terminus of ADAMTS13, is able to activate ADAMTS13 and increase the proteolytic cleavage of a FRETS-VWF73 substrate; moreover, binding of such a human monoclonal antibody against the carboxyl-terminus of ADAMTS13 to plasma ADAMTS13 appears to modulate inhibition by another human monoclonal antibody (i.e., scFv4-20), also isolated from an iTTP patient, that targets the spacer domain of ADAMTS13. These results provide new insights into our...

Source: Thrombosis and Haemostasis - April 9, 2021 Category: Hematology Authors: Konstantine Halkidis Don L Siegel X Long Zheng Source Type: research