Intrinsic differences between FVIIIa mimetic bispecific antibodies and FVIII prevent assignment of FVIII‐equivalence

摘要: Essentials Non-factor VIII (FVIII) therapies for hemophilia A, such as bispecific antibodies (bsAbs), are in development. Bispecific intrinsically different from FVIII and lack many of the same regulatory mechanisms. These differences complicate assignment interpretation FVIII-equivalent activity. Inability to assign equivalence compromises our capacity assess hemostatic potential bsAb therapies. Background Activated factor (FVIIIa) mimetic bsAbs aim enable prophylactic treatment A patients with without inhibitors. With mechanisms action, benchmarking their activity against determine efficacious yet safe dosage is difficult. Objective To compare activities sequence identical emicizumab (SI-Emi) another bsAb, BS-027125, recombinant (rFVIII) using clinical nonclinical assays evaluate ability a value implications thereof. Methods Activities SI-Emi, rFVIII were measured by one-stage clotting assay, chromogenic Xa generation thrombin assay. We also assessed anti-FIXa anti-FX bivalent homodimers each probed effect reagents assay (TGA). Results The FVIII-like SI-Emi BS-027125 ranged greatly across varying both parameter within an used. Notably, homodimer had meaningful several assays, whereas only Surprisingly, displayed absence phospholipids, while minimal phospholipid-independent Conclusions demonstrate little consistency between tested here owing intrinsic bsAbs. While some trends shared, differ mechanism. inconsistencies values Ultimately, deeper mechanistic understanding well bsAb-tailored needed monitor predict long-term efficacy safety confidently.