A bispecific antibody NXT007 exerts a hemostatic activity in hemophilia A monkeys enough to keep a non-hemophiliac state

双特异性抗体 抗体 凝结 免疫球蛋白轻链 体外 化学 医学 药理学 免疫学 内科学 单克隆抗体 生物化学
作者
Yuri Teranishi-Ikawa,Tetsuhiro Soeda,Hikaru Koga,Kazuki Yamaguchi,Kazúo Kato,Keiko Esaki,Kentaro Asanuma,Miho Funaki,Mina Ichiki,Yuri Ikuta,Shunsuke Ito,Eri Joyashiki,Shunichiro Komatsu,Atsushi Muto,K. Nishimura,Momoko Okuda,Hisakazu Sanada,Motohiko Sato,Norihito Shibahara,Tetsuya Wakabayashi,Koji Yamaguchi,Akiko Matsusaki,Zenjiro Sampei,Hirotake Shiraiwa,Hiroko Konishi,Yojiro Kawabe,Kunihiro Hattori,Takio Kitazawa,Tomoyuki Igawa
标识
DOI:10.1101/2022.12.19.520692
摘要

Abstract Emicizumab, a factor (F)VIIIa-function mimetic bispecific antibody (BsAb) to FIXa and FX, has become an indispensable treatment for people with hemophilia A (PwHA). Although emicizumab is very potent, long-term outcomes from the clinical studies suggest that a small proportion of PwHA still experiences bleeds. Additionally, non-clinical studies indicate that the maximum cofactor activity of emicizumab is lower than international standard activity (100 IU/dL of FVIII). An increased cofactor activity BsAb would benefit such patients. Here, we report NXT007, a BsAb binding FIXa and FX developed through further engineering of emicizumab. Emicizumab has a common light chain, but through advances in antibody engineering, we were able to create a more potent BsAb with two new non-common light chains. After extensive optimization of the heavy and light chains, the resulting BsAb, NXT007, exerted in vitro thrombin generation (TG) activity in hemophilia A plasma equivalent to 100 IU/dL of FVIII when triggered by tissue factor. NXT007 demonstrated potent hemostatic activity in an acquired hemophilia A model in non-human primates at a much lower dosage than emicizumab, consistent with an around 30-fold dose shift in the in vitro TG activity between NXT007 and emicizumab. Moreover, together with Fc engineering that enhanced FcRn binding and reduced in vivo clearance, we demonstrate that NXT007 could be effective at a much lower dosage with a longer dosing interval compared to emicizumab. These non-clinical results suggest that NXT007 could maintain a non-hemophilic range of coagulation potential in PwHA and provides a rationale for its clinical testing.
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