Abstract Number: PB1145
Meeting: ISTH 2020 Congress
Background: Emicizumab is a factor (F)VIII-function mimetic therapeutic antibody for treating persons with hemophilia A (PwHA). Currently it plays a central role in treating PwHA, although there is some room for improvement in dosing frequency/volume and/or hemostatic activity to achieve a non-hemophilic status.
Aims: To address these points, we have further engineered emicizumab.
Methods: Emicizumab used commonized light chains to enable industrial manufacturing, but this limited further optimization. Therefore, we developed a new antibody engineering technology to enable industrial manufacture of a four-chain asymmetric bispecific antibody. We further engineered emicizumab by incorporating new non-commonized light chains with our newly established manufacturing technology and by replacing amino acids in both the variable and constant regions to enhance hemostatic activity and improve pharmacokinetics. Then, we evaluated hemostatic activity and half-life of the engineered antibodies with in vitro and in vivo studies.
Results: We successfully identified emicizumab-based, four-chain asymmetric bispecific antibodies, termed NXT004 to 007, which increased in vitro FVIII-equivalent activity of plasma thrombin generation to levels similar to those of standard FVIII (100%). The undesirable inhibitory interference of NXT004 to the coagulation cascade was not evident at a targeting therapeutic concentration in vitro. The hemostatic activity was also confirmed in non-human primates with acquired hemophilia A at low dose of the antibody. NXT004 had an approximately three week of half-life in non-human primates. From these results, we simulated that the engineered antibody may have a potency to keep a non-hemophilic range of FVIII-equivalent thrombin generation activity by subcutaneous doses every four weeks clinically.
Conclusions: The limitations for further optimization of emicizumab were overcome by the newly established antibody engineering technologies. The further optimized antibody, administered subcutaneously every four weeks, may have the potency to retain a non-hemophilic range of FVIII-equivalent hemostatic activity. Phase I/II clinical study with healthy volunteers and PwHA are on-going.
To cite this abstract in AMA style:Teranishi Y, Soeda T, Koga H, Yamaguchi K, Kato K, Muto A, Esaki K, Okuda M, Sato M, Shibahara N, Yamaguchi K, Wakabayashi T, Shiraiwa H, Konishi H, Kitamura H, Kitazawa T, Igawa T. New Factor VIII Function-Mimetic Bispecific Antibodies Engineered from Emicizumab for Further Improving the Treatment of Hemophilia A [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/new-factor-viii-function-mimetic-bispecific-antibodies-engineered-from-emicizumab-for-further-improving-the-treatment-of-hemophilia-a/. Accessed January 28, 2022.
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