Scientific Evidence
Mimetic Optimization
Optimizing factor VIIIa mimetics to closely mimic the functions of natural factor VIIIa in hemostasis
What Are Factor VIIIa (FVIIIa) Mimetics?
Bispecific antibodies (BsAbs) have been engineered to mimic natural FVIIIa for patients with hemophilia A.1 These mimetic agents can bind both factor IXa (FIXa) and factor X (FX), activating thrombin generation and enhancing the coagulation cascade2
Optimization of Factor VIIIa Mimetics
Optimization of BsAbs is the process of engineering changes in the structure for the purpose of enhancing their function.3
Optimization results in small structural changes in the therapeutic antibody, which can affect:
Natural FVIIIa simultaneously binds to epitopes (specific sites) on FIXa and FX, which promotes binding to the activated platelet membrane and downstream thrombin generation.4
Current FVIIIa mimetics are BsAbs developed to bind epitopes on both FIXa and FX, promoting their interaction and inducing a therapeutic effect similar to natural FVIIIa.5
Optimized FVIIIa mimetics, through precise engineering, may facilitate a more refined FIXa and FX epitope-binding interaction, resulting in changes to its mechanism, which may further improve its effect on thrombin generation.6
Optimized BsAbs for FVIIIa are precisely engineered to selectively bind the epitopes of FIXa and FX.6
Natural FVIIIa enhances the proteolytic activity of FIXa via allosteric activation, which is crucial for FX activation. This is a critical aspect of FVIIIa's function in the coagulation cascade and makes FVIIIa a powerful cofactor for FIXa.6
Current FVIIIa mimetics may enhance the proteolytic activity of FIXa, yet their cofactor activity between FIXa and FX may not effectively mimic the effects of natural FVIIIa.6
Optimized FVIIIa mimetics may induce conformational changes in the 3D structure of FIXa which leads to enhanced FX activation, more closely aligning with natural function of FVIIIa and resulting in optimization of the coagulation cascade.1
Optimized FVIIIa mimetics more closely mimic the activity of natural FVIIIa to:
- Enhance the coagulation cascade1
- Increase fibrin synthesis1
- Strengthen clot formation1
Natural FVIIIa maintains an optimal balance in binding affinity with FIXa and FX. If the binding affinity is too low, binding is inefficient; and too high binding affinity may increase the risk of self-inhibition, both of which can decrease the overall therapeutic effect.2
Current FVIIIa mimetics have a lower binding affinity than natural FVIIIa, which may result in inefficient binding and potentially affect thrombin generation.5
Optimized FVIIIa mimetics may ensure a favorably balanced binding affinity, enabling effective FXa generation while minimizing the risk of self-inhibition. This ensures effective throughput of FXa and thrombin generation.2
Very low binding affinity diminishes thrombin generation.2
Very high binding affinity increases the risk of self-inhibition.2
3D, 3-dimensional; BsAb, bispecific antibody; FIX, factor IX; FIXa, activated factor IX; FX, Factor X;
FXa, activated factor X, FVIIIa, activated factor VIII
References:
- Østergaard H, et al. Blood. 2021;138(14):1258–1268.
- Sampei Z, et al. PLoS One. 2013;8(2):e57479.
- Wang B, et al. Antib Ther. 2021;4(1):45–54.
- Saenko EL, et al. Br J Haematol. 2002;119(2):323–331.
- Gelbenegger G, et al. Thromb Haemost. 2020;120(10):1357–1370.
- Lenting PJ, et al. Blood. 2017;130(23):2463–2468.
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