OC 49.4 - An effective and safe strategy for anti-thrombosis therapy by monoclonal antibody blocking the interaction of FIXa with FVIIIa

Monday, June 24, 2024

15:30 – 15:45 ICT

Room: 208 A-D

Presenting Author(s)

Xuemei Fan, PhD

professor
Shanghai Jiao Tong University School of Medicine
Shanghai, Shanghai, China (People's Republic)

Co-Author(s)

Junling Liu, PhD

Principle investigator
Shanghai Jiao Tong University School of Medicine
Shanghai, Shanghai, China (People's Republic)
LZ

Lin Zhang

professor
Shanghai Jiao Tong University
Shanghai, Shanghai, China (People's Republic)
XS

Xueqing Sun

professor
Shanghai jiao tong university
Shanghai, Shanghai, China (People's Republic)
YW

Yanhua Wang

manager
Shanghai synvida bio.tech
Shanghai, Shanghai, China (People's Republic)
YL

Yanjun Liu

manager
Shanghai synvida biotech
Shanghai, Shanghai, China (People's Republic)
QL

Qingqin Lai

manager
Shanghai synvida biotech
Shanghai, Shanghai, China (People's Republic)

Background: Current anticoagulants are still unable to provide sufficient safety. Inhibiting intrinsic pathways of blood coagulation is thought to be effective with low risk of bleeding. Coagulation factor IXa is a key factor in intrinsic pathways, the effectiveness and safety of targeting FⅨa for anti-thrombosis therapy remains further investigation.

Aims: To evaluate the effectiveness and safety of monoclonal antibodies targeting factor Ⅸa for anti-thrombosis therapy.

Methods: Chromogenic substrate method was used to detect the effect of antibody on FIXa enzyme activity. The binding sites between FIX and the antibody was identified by cryo-electron microscopy. The mouse FeCl3-induced carotid artery thrombosis model and canine thread-induced venous thrombosis model were used to detect the antithrombotic effect of the antibody in vivo.

Results: An anti-FIXa antibody with high affinity was developed, and it significantly prolonged APTT in a concentration-dependent manner without affecting PT. Cryo-electron microscopy results showed that the antibody occupied residues 313~314(NH), 388~389(FT), 392~393(NN), 446(K) and 449(R) of FIX, which was reported to be the binding sites or very close to the binding sites of FIXa and FVIIIa, which was a key co-factor of FIXa and enhance its proteolytic activity. The antibody did not directly affect enzyme activity of FIXa, but competed with FVIIIa to bind FIXa. In vivo, the antibody significantly inhibited carotid artery thrombosis and venous thrombosis with low bleeding risk. The PK-PD in dog showed that the antibody remains effective for more than two weeks when administered intravenously and it did not induce the clearance of FIX in vivo.

Conclusion(s): This study revealed that monoclonal antibody targeting FⅨa to block Ⅷa interaction with FIXa is a promising strategy for anti-thrombosis therapy with high effectiveness and low bleeding risk.