FVIIIa-mimetic bispecific antibody (Mim8) ameliorates bleeding upon severe vascular challenge in hemophilia A mice.

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Hemophilia A (HA) is a bleeding disorder resulting from deficient Factor VIII (FVIII), which normally functions as a cofactor to activated Factor IX (FIXa) that facilitates activation of Factor X (FX). To mimic this property in a bispecific antibody (biAb) format, a screening was conducted to identify functional pairs of anti-FIXa and anti-FX antibodies, followed by optimization of functional and biophysical properties. The resulting biAb (Mim8) assembled efficiently with FIXa and FX on membranes, and supported activation with an apparent equilibrium dissociation constant (KD) of 16 nM. Binding affinity with FIXa and FX in solution was much lower, with KD-values for FIXa and FX of 2.3 and 1.5 µM, respectively. In addition, the activity of Mim8 was dependent on stimulatory activity contributed by the anti-FIXa arm, which enhanced the proteolytic activity of FIXa by four orders of magnitude. In hemophilia A plasma and whole blood, Mim8 normalized thrombin generation and clot formation with potencies 13 and 18 times higher than a sequence-identical analog of emicizumab, respectively. A similar potency difference was observed in a tail-vein transection model in hemophilia A mice, while reduction of bleeding in a severe tail-clip model was observed only for Mim8. Furthermore, the pharmacokinetics of Mim8 were investigated and a half-life of 14 days demonstrated in cynomolgus monkey. In conclusion, Mim8 is a FVIIIa-mimetic with a potent and efficacious hemostatic effect based on preclinical data.

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Authors: Henrik Østergaard, Jacob Lund, Per Jr Greisen, Stine Kjellev, Anette Henriksen, Nikolai Lorenzen, Eva Johansson, Gustav Røder, Morten Grønbech Rasch, Laust Bruun Johnsen, Thomas Egebjerg, Søren Lund, Henrik Rahbek-Nielsen, Prafull S Gandhi, Kasper Lamberth, Mette Loftager, Lisbeth M Andersen, Amalie Carnbring Bonde, Fabian Stavenuiter, Daniel Elenius Madsen, Xun Li, Thomas Lindebo Holm, Carsten Dan Ley, Peter Thygesen, Haisun Zhu, Rong Zhou, Karina Thorn, Zhiru Yang, Mette Brunsgaard Hermit, Jais Rose Bjelke, Bjarne Gram Hansen, Ida Hilden


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