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

作者：Kitazawa Takehisa^*; Igawa Tomoyuki; Sampei Zenjiro; Muto Atsushi; Kojima Tetsuo; Soeda Tetsuhiro; Yoshihashi Kazutaka; Okuyama Nishida Yukiko; Saito Hiroyuki; Tsunoda Hiroyuki; Suzuki Tsukasa; Adachi Hideki; Miyazaki Taro; Ishii Shinya; Kamata Sakurai Mika; Iida Takeo; Harada Aya; Esaki Keiko; Funaki Miho; Moriyama Chifumi; Tanaka Eriko; Kikuchi Yasufumi; Wakabayashi Tetsuya; Wada Manabu; Goto Masaaki; Toyoda Takeshi; Ueyama Atsunori; Suzuki Sachiyo; Haraya Kenta

来源：Nature Medicine, 2012, 18(10): 1570-U177.

DOI：10.1038/nm.2942

Hemophilia 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(1-3). Moreover, the poor pharmacokinetics of FVIII, attributed to low subcutaneous bioavailability and a short half-life of 0.5 d, necessitates frequent intravenous injections(3-5). 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.

• 出版日期2012-10