Mathematical analysis of emicizumab: affinity-driven complex formation and lipid-surface reactions

Area of Science:

• Biochemistry
• Pharmacology
• Mathematical Biology

Background:

• Emicizumab is a bispecific antibody replacing Factor VIII in hemophilia A treatment.
• It bridges activated Factor IX (FIXa) and Factor X (FX), but unlike Factor VIII, it doesn't bind lipid surfaces.

Purpose of the Study:

• Investigate emicizumab's lipid-surface dependent mechanisms.
• Utilize mathematical modeling and biochemical assays to understand these interactions.

Main Methods:

• Expanded a mathematical model of tissue factor (TF):VIIa activation of FX to include emicizumab and FIXa.
• Calibrated the model using experimental data.

Main Results:

• High emicizumab concentrations inhibit FX activation by TF:VIIa.
• Model indicates this inhibition occurs when emicizumab-bound FX has restricted binding to lipid surfaces and TF:VIIa.
• Lipid surfaces enhance FIXa activation of FX in the presence of emicizumab, with increased ternary complex formation on lipid surfaces.

Conclusions:

• Emicizumab's high concentrations reduce TF:VIIa-mediated FX activation by limiting FX binding to lipid and TF:VIIa.
• Emicizumab enhances FIXa-mediated FX activation on lipid surfaces by preferentially binding lipid-bound FX and FIXa, increasing association rates through colocalization.