A bispecific antibody to factors IXa and X restores factor VIII hemostatic activity in a hemophilia A model
| Autor: | Kunihiro Hattori, Yoshiki Kawabe, Tetsuhiro Soeda, Midori Shima, Atsushi Muto, Shinya Ishii, Keiko Esaki, Manabu Wada, Takehisa Kitazawa, Hideki Adachi, Masaaki Goto, Takeshi Toyoda, Hiroyuki Saito, Yasufumi Kikuchi, Akira Yoshioka, Tomoyuki Igawa, Taro Miyazaki, Tatsuhiko Tachibana, Iida Takeo, Mika Kamata-Sakurai, Atsunori Ueyama, Miho Funaki, Hiroyuki Tsunoda, Tsukasa Suzuki, Sachiyo Suzuki, Chifumi Moriyama, Kazutaka Yoshihashi, Aya Harada, Tetsuya Wakabayashi, Tetsuo Kojima, Eriko Tanaka, Kenta Haraya, Yukiko Okuyama-Nishida, Zenjiro Sampei |
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| Rok vydání: | 2012 |
| Předmět: |
congenital
hereditary and neonatal diseases and abnormalities Antigenicity animal diseases Hemophilia A General Biochemistry Genetics and Molecular Biology Factor IXa chemistry.chemical_compound In vivo hemic and lymphatic diseases Antibodies Bispecific Medicine Animals Emicizumab Hemostasis Factor VIII biology business.industry Factor X General Medicine Macaca fascicularis chemistry Coagulation Immunology biology.protein Antibody business |
| Zdroj: | Nature medicine. 18(10) |
| ISSN: | 1546-170X |
| Popis: | 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. 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. |
| Databáze: | OpenAIRE |
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