OC 41.5 - Evaluation of factor VIII inhibitor risk under emicizumab prophylaxis using hemophilia A murine models with long-term expression of human factors IX and X

Monday, June 24, 2024

15:45 – 16:00 ICT

Room: Ballroom B1

Presenting Author(s)

Sheng-Chieh Chou, MD.

Hematologist
Department of Internal Medicine, National Taiwan University Hospital
Taipei, Taipei, Taiwan (Republic of China)

Co-Author(s)

YC

Yen-Ting Chang

Research assistant
Department of Clinical Laboratory Science and Medical Biotechnology, National Taiwan University
Taipei, Taipei, Taiwan (Republic of China)
CL

Chien-Hong Liu

Research assistant
Department of Clinical Laboratory Science and Medical Biotechnology, National Taiwan University
Taipei, Taipei, Taiwan (Republic of China)
Li-Fu Chen

Master student
Department of Clinical Laboratory Science and Medical Biotechnology, National Taiwan University
Taipei, Taipei, Taiwan (Republic of China)
GS

Guey-Yueh Shi

Professor
Department of Biochemistry and Molecular Biology, National Cheng Kung University
Tainan, Tainan, Taiwan (Republic of China)
HW

Hua-Lin Wu

Professor
Department of Biochemistry and Molecular Biology, National Cheng Kung University
Tainan, Tainan, Taiwan (Republic of China)
SL

Shu-Wha Lin

Professor
Department of Clinical Laboratory Science and Medical Biotechnology, National Taiwan University
Taipei, Taipei, Taiwan (Republic of China)

Background: Emicizumab is a factor VIII (FVIII)-mimicking bispecific monoclonal antibody that has achieved excellent efficacy and has been approved worldwide. Clinical issues have evolved concerning emicizumab, e.g., the risk of FVIII inhibitors under emicizumab prophylaxis. A murine model suitable for investigating this burning question will be helpful before clinical trials. Because Emicizumab specifically recognizes primates’ factor X and IX (FIX/X), appropriate murine models are not readily available.

Aims: To establish and use a novel murine model to evaluate FVIII inhibitor risk under emicizumab prophylaxis

Methods: Two recombinant AAV2/8 (rAAV) preparations packed with human F9 and F10 cDNA, separately, were administered simultaneously to hemophilia A mice to generate a hFIX/hFX expression murine model, coined HemoAhFIX/hFX. Human specific factor assays were applied for measuring levels of hFIX/hFX. Emicizumab efficacy were assessed by APTT. FVIII inhibitor risks were investigated with 4 groups of mice; (A): FVIII weekly prophylaxis; (B): FVIII on-demand after joint bleeding; (C): emicizumab prophylaxis with additional FVIII prophylactically; and (D): emicizumab prophylaxis with on-demand FVIII. Knee joint puncture is applied to simulate a joint bleeding.

Results: Sustained hFIX/hFX expressions at therapeutic levels were detected in HemoAhFIX/hFX for >14 weeks. Both HemoAhFIX/hFX plasma spiked with 50 µg/mL emicizumab and the plasma from emicizumab-treated HemoAhFIX/hFX showed significantly shorten aPTT, as compares with controls (Figure 1). Of the 4 experimental mouse groups, groups C and D seems to show less risks for FVIII inhibitory antibodies than groups A or B, although the differences were not statistically significant (Figure 2).

Conclusion(s): By expressing hFIX/hFX through AAV, we have established a novel murine model for evaluating FVIII inhibitor risks under emicizumab prophylaxis. Our current preliminary data indicates a comparable risk for FVIII inhibitor development whether FVIII was used as prophylaxis or on-demand under emicizumab.