Background
Activated factor VIII (FVIIIa) mimetic bsAbs
Conclusions
Bispecific antibodies demonstrate little consistency between assays tested here owing to intrinsic differences between FVIII and bsAbs. While some trends are shared, the bsAbs also differ in mechanism. These inconsistencies complicate assignment of FVIII-equivalent values to bsAbs. Ultimately, a deeper mechanistic understanding of bsAbs as well as bsAb-tailored assays are needed to monitor and predict their hemostatic potential and long-term efficacy and safety confidently.
Methods
Activities of SI-Emi, BS-027125, and rFVIII were measured by one-stage clotting assay, chromogenic factor Xa generation assay, and thrombin generation assay. We also assessed the activity of anti-FIXa and anti-FX bivalent homodimers of each bsAb and probed the effect of different reagents in thrombin generation assay (TGA).
Objective
To compare the activities of sequence identical emicizumab (SI-Emi) and another bsAb, BS-027125, to recombinant FVIII (rFVIII) using clinical and nonclinical assays and to evaluate our ability to assign a FVIII-equivalent value to bsAbs and implications thereof.
Results
The FVIII-like activity of SI-Emi and BS-027125 ranged greatly across each assay, varying both by parameter measured within an assay and by reagents used. Notably, SI-Emi anti-FIXa bivalent homodimer had meaningful activity in several assays, whereas BS-027125 anti-FIXa bivalent homodimer only had activity in the chromogenic assay. Surprisingly, SI-Emi displayed activity in the absence of phospholipids, while BS-027125 had minimal phospholipid-independent activity. Conclusions: Bispecific antibodies demonstrate little consistency between assays tested here owing to intrinsic differences between FVIII and bsAbs. While some trends are shared, the bsAbs also differ in mechanism. These inconsistencies complicate assignment of FVIII-equivalent values to bsAbs. Ultimately, a deeper mechanistic understanding of bsAbs as well as bsAb-tailored assays are needed to monitor and predict their hemostatic potential and long-term efficacy and safety confidently.