Details

Autor(en) / Beteiligte

• Teranishi-Ikawa, Yuri
• Soeda, Tetsuhiro
• Koga, Hikaru
• Yamaguchi, Kazuki
• Kato, Kazuki
• Esaki, Keiko
• Asanuma, Kentaro
• Funaki, Miho
• Ichiki, Mina
• Ikuta, Yuri
• Ito, Shunsuke
• Joyashiki, Eri
• Komatsu, Shun-Ichiro
• Muto, Atsushi
• Nishimura, Kei
• Okuda, Momoko
• Sanada, Hisakazu
• Sato, Motohiko
• Shibahara, Norihito
• Wakabayashi, Tetsuya
• Yamaguchi, Koji
• Matsusaki, Akiko
• Sampei, Zenjiro
• Shiraiwa, Hirotake
• Konishi, Hiroko
• Kawabe, Yoshiki
• Hattori, Kunihiro
• Kitazawa, Takehisa
• Igawa, Tomoyuki

Titel

A bispecific antibody NXT007 exerts a hemostatic activity in hemophilia A monkeys enough to keep a nonhemophilic state

Ist Teil von

• Journal of thrombosis and haemostasis, 2024-02, Vol.22 (2), p.430-440

Ort / Verlag

England: Elsevier Inc

Erscheinungsjahr

2024

Quelle

MEDLINE

Beschreibungen/Notizen

• Emicizumab, a factor (F) VIIIa-function mimetic bispecific antibody (BsAb) to FIXa and FX, has become an indispensable treatment option for people with hemophilia A (PwHA). However, a small proportion of PwHA still experience bleeds even under emicizumab prophylaxis, as observed in the long-term outcomes of clinical studies. A more potent BsAb may be desirable for such patients. To identify a potent BsAb to FIXa and FX, NXT007, surpassing emicizumab by in vitro and in vivo evaluation. New pairs of light chains for emicizumab’s heavy chains were screened from phage libraries, and subsequent antibody optimization was performed. For in vitro evaluation, thrombin generation assays were performed with hemophilia A plasma. In vivo hemostatic activity was evaluated in a nonhuman primate model of acquired hemophilia A. NXT007 exhibited an in vitro thrombin generation activity comparable to the international standard activity of FVIII (100 IU/dL), much higher than emicizumab, when triggered by tissue factor. NXT007 also demonstrated a potent in vivo hemostatic activity at approximately 30-fold lower plasma concentrations than emicizumab’s historical data. In terms of dose shift between NXT007 and emicizumab, the in vitro and in vivo results were concordant. Regarding pharmacokinetics, NXT007 showed lower in vivo clearance than those shown by typical monoclonal antibodies, suggesting that the Fc engineering to enhance FcRn binding worked well. NXT007, a potent BsAb, was successfully created. Nonclinical results suggest that NXT007 would have a potential to keep a nonhemophilic range of coagulation potential in PwHA or to realize more convenient dosing regimens than emicizumab.