• Nature medicine · Oct 2012

    A bispecific antibody to factors IXa and X restores factor VIII hemostatic activity in a hemophilia A model.

    • Takehisa Kitazawa, Tomoyuki Igawa, Zenjiro Sampei, Atsushi Muto, Tetsuo Kojima, Tetsuhiro Soeda, Kazutaka Yoshihashi, Yukiko Okuyama-Nishida, Hiroyuki Saito, Hiroyuki Tsunoda, Tsukasa Suzuki, Hideki Adachi, Taro Miyazaki, Shinya Ishii, Mika Kamata-Sakurai, Takeo Iida, Aya Harada, Keiko Esaki, Miho Funaki, Chifumi Moriyama, Eriko Tanaka, Yasufumi Kikuchi, Tetsuya Wakabayashi, Manabu Wada, Masaaki Goto, Takeshi Toyoda, Atsunori Ueyama, Sachiyo Suzuki, Kenta Haraya, Tatsuhiko Tachibana, Yoshiki Kawabe, Midori Shima, Akira Yoshioka, and Kunihiro Hattori.
    • Fuji-Gotemba Research Laboratories, Chugai Pharmaceutical, Gotemba, Shizuoka, Japan. kitazawatkh@chugai-pharm.co.jp
    • Nat. Med. 2012 Oct 1; 18 (10): 1570-4.

    AbstractHemophilia A is a bleeding disorder resulting from coagulation factor VIII (FVIII) deficiency. Exogenously provided FVIII effectively reduces bleeding complications in patients with severe hemophilia A. In approximately 30% of such patients, however, the 'foreignness' of the FVIII molecule causes them to develop inhibitory antibodies against FVIII (inhibitors), precluding FVIII treatment in this set of patients. Moreover, the poor pharmacokinetics of FVIII, attributed to low subcutaneous bioavailability and a short half-life of 0.5 d, necessitates frequent intravenous injections. To overcome these drawbacks, we generated a humanized bispecific antibody to factor IXa (FIXa) and factor X (FX), termed hBS23, that places these two factors into spatially appropriate positions and mimics the cofactor function of FVIII. hBS23 exerted coagulation activity in FVIII-deficient plasma, even in the presence of inhibitors, and showed in vivo hemostatic activity in a nonhuman primate model of acquired hemophilia A. Notably, hBS23 had high subcutaneous bioavailability and a 2-week half-life and would not be expected to elicit the development of FVIII-specific inhibitory antibodies, as its molecular structure, and hence antigenicity, differs from that of FVIII. A long-acting, subcutaneously injectable agent that is unaffected by the presence of inhibitors could markedly reduce the burden of care for the treatment of hemophilia A.

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