Anti-HK antibody inhibits the plasma contact system by blocking prekallikrein and factor XI activation in vivo

Abstract

A dysregulated plasma contact system is involved in various pathological conditions, such as hereditary angioedema, Alzheimer's disease, and sepsis. We previously showed that the 3E8 anti-HK antibody blocks HK cleavage and bradykinin generation in human plasma ex vivo. Here we show that 3E8 prevented not only HK cleavage but also factor XI (FXI) and prekallikrein (PK) activation by blocking their binding to HK in mouse plasma in vivo. 3E8 also inhibited contact system-induced bradykinin generation in vivo. Interestingly, factor XII (FXII) activation was also inhibited, likely due to the ability of 3E8 to block the positive feed-back activation of FXII by kallikrein (PKa). In human plasma, 3E8 also blocked PK and FXI binding to HK and inhibited both thrombotic (FXI activation) and inflammatory pathways (PK activation and HK cleavage) of the plasma contact system activation ex vivo. Moreover, 3E8 blocked PKa binding to HK and dose-dependently inhibited PKa cleavage of HK. Our results reveal a novel strategy to inhibit contact system activation in vivo, which may provide an effective method to treat human diseases involving contact system dysregulation.

Drugs of the Kallikrein–Kinin System: An Overview

“…The proof of the concept for a further level of intervention on the contact system has been recently reported in a preclinical study, whereby the mAb 3E8 targets domain 6 (D6) of HK, thus inhibiting the assembly of the trimolecular complex HK-prekallikrein-factor XI (mode of action 7 in Figure 1). In transgenic mice that express human HK, mAb 3E8 inhibits dextran-sulfate-induced BK formation and FXII activation [36].…”

Vascular Dysfunction in Alzheimer’s Disease: Alterations in the Plasma Contact and Fibrinolytic Systems

“…The use of antibodies that inhibit the plasma contact system could prove beneficial as well. Administration of 3E8, a novel anti-HK antibody, has been shown to inhibit activation of the plasma contact system ex vivo and in vivo [ 42 , 43 , 127 ]. 3E8 targets HK and prevents the binding of PK and FXI to HK, thereby inhibiting both the inflammatory and thrombotic arms of the contact system [ 127 ].…”

“…Administration of 3E8, a novel anti-HK antibody, has been shown to inhibit activation of the plasma contact system ex vivo and in vivo [ 42 , 43 , 127 ]. 3E8 targets HK and prevents the binding of PK and FXI to HK, thereby inhibiting both the inflammatory and thrombotic arms of the contact system [ 127 ]. Of note, inhibition of the intrinsic clotting pathway does not lead to bleeding complications [ 128 ], making this an attractive therapeutic approach.…”