title: A bispecific antibody to factors IXa and X restores factor VIII hemostatic activity in a hemophilia A model.
abstract: 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.
authors.affiliation: Fuji-Gotemba Research Laboratories, Chugai Pharmaceutical, Gotemba, Shizuoka, Japan. kitazawatkh@chugai-pharm.co.jp
authors.forename: Takehisa
authors.initials: T
authors.lastname: Kitazawa
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Igawa
authors.forename: Zenjiro
authors.initials: Z
authors.lastname: Sampei
authors.forename: Atsushi
authors.initials: A
authors.lastname: Muto
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Kojima
authors.forename: Tetsuhiro
authors.initials: T
authors.lastname: Soeda
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Yoshihashi
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Okuyama-Nishida
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Saito
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tsunoda
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Suzuki
authors.forename: Hideki
authors.initials: H
authors.lastname: Adachi
authors.forename: Taro
authors.initials: T
authors.lastname: Miyazaki
authors.forename: Shinya
authors.initials: S
authors.lastname: Ishii
authors.forename: Mika
authors.initials: M
authors.lastname: Kamata-Sakurai
authors.forename: Takeo
authors.initials: T
authors.lastname: Iida
authors.forename: Aya
authors.initials: A
authors.lastname: Harada
authors.forename: Keiko
authors.initials: K
authors.lastname: Esaki
authors.forename: Miho
authors.initials: M
authors.lastname: Funaki
authors.forename: Chifumi
authors.initials: C
authors.lastname: Moriyama
authors.forename: Eriko
authors.initials: E
authors.lastname: Tanaka
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Kikuchi
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Wakabayashi
authors.forename: Manabu
authors.initials: M
authors.lastname: Wada
authors.forename: Masaaki
authors.initials: M
authors.lastname: Goto
authors.forename: Takeshi
authors.initials: T
authors.lastname: Toyoda
authors.forename: Atsunori
authors.initials: A
authors.lastname: Ueyama
authors.forename: Sachiyo
authors.initials: S
authors.lastname: Suzuki
authors.forename: Kenta
authors.initials: K
authors.lastname: Haraya
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Tachibana
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Kawabe
authors.forename: Midori
authors.initials: M
authors.lastname: Shima
authors.forename: Akira
authors.initials: A
authors.lastname: Yoshioka
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Hattori
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use; D015949:Factor IXa / Q000276:immunology*; D005169:Factor VIII / Q000502:physiology*; D005170:Factor X / Q000276:immunology*; D006467:Hemophilia A / Q000276:immunology / Q000628:therapy*; D006487:Hemostasis; D008252:Macaca fascicularis
chemical_list: D018033:Antibodies, Bispecific; D005169:Factor VIII; D005170:Factor X; D015949:Factor IXa