title: Anti-factor IXa/X bispecific antibody ACE910 prevents joint bleeds in a long-term primate model of acquired hemophilia A.
abstract: ACE910 is a humanized anti-factor IXa/X bispecific antibody mimicking the function of factor VIII (FVIII). We previously demonstrated in nonhuman primates that a single IV dose of ACE910 exerted hemostatic activity against hemophilic bleeds artificially induced in muscles and subcutis, and that a subcutaneous (SC) dose of ACE910 showed a 3-week half-life and nearly 100% bioavailability, offering support for effective prophylaxis for hemophilia A by user-friendly SC dosing. However, there was no direct evidence that such SC dosing of ACE910 would prevent spontaneous bleeds occurring in daily life. In this study, we newly established a long-term primate model of acquired hemophilia A by multiple IV injections of an anti-primate FVIII neutralizing antibody engineered in mouse-monkey chimeric form to reduce its antigenicity. The monkeys in the control group exhibited various spontaneous bleeding symptoms as well as continuous prolongation of activated partial thromboplastin time; notably, all exhibited joint bleeds, which are a hallmark of hemophilia. Weekly SC doses of ACE910 (initial 3.97 mg/kg followed by 1 mg/kg) significantly prevented these bleeding symptoms; notably, no joint bleeding symptoms were observed. ACE910 is expected to prevent spontaneous bleeds and joint damage in hemophilia A patients even with weekly SC dosing, although appropriate clinical investigation is required.
authors.affiliation: Research Division, Chugai Pharmaceutical Co, Ltd, Gotemba, Shizuoka, Japan; and.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Muto
authors.affiliation: Research Division, Chugai Pharmaceutical Co, Ltd, Gotemba, Shizuoka, Japan; and.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Yoshihashi
authors.affiliation: Research Division, Chugai Pharmaceutical Co, Ltd, Gotemba, Shizuoka, Japan; and.
authors.forename: Minako
authors.initials: M
authors.lastname: Takeda
authors.affiliation: Research Division, Chugai Pharmaceutical Co, Ltd, Gotemba, Shizuoka, Japan; and.
authors.forename: Takehisa
authors.initials: T
authors.lastname: Kitazawa
authors.affiliation: Research Division, Chugai Pharmaceutical Co, Ltd, Gotemba, Shizuoka, Japan; and.
authors.forename: Tetsuhiro
authors.initials: T
authors.lastname: Soeda
authors.affiliation: Research Division, Chugai Pharmaceutical Co, Ltd, Gotemba, Shizuoka, Japan; and.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Igawa
authors.affiliation: Research Division, Chugai Pharmaceutical Co, Ltd, Gotemba, Shizuoka, Japan; and.
authors.forename: Zenjiro
authors.initials: Z
authors.lastname: Sampei
authors.affiliation: Research Division, Chugai Pharmaceutical Co, Ltd, Gotemba, Shizuoka, Japan; and.
authors.forename: Taichi
authors.initials: T
authors.lastname: Kuramochi
authors.affiliation: Research Division, Chugai Pharmaceutical Co, Ltd, Gotemba, Shizuoka, Japan; and.
authors.forename: Akihisa
authors.initials: A
authors.lastname: Sakamoto
authors.affiliation: Research Division, Chugai Pharmaceutical Co, Ltd, Gotemba, Shizuoka, Japan; and.
authors.forename: Kenta
authors.initials: K
authors.lastname: Haraya
authors.affiliation: Research Division, Chugai Pharmaceutical Co, Ltd, Gotemba, Shizuoka, Japan; and.
authors.forename: Kenji
authors.initials: K
authors.lastname: Adachi
authors.affiliation: Research Division, Chugai Pharmaceutical Co, Ltd, Gotemba, Shizuoka, Japan; and.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Kawabe
authors.affiliation: Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Nogami
authors.affiliation: Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan.
authors.forename: Midori
authors.initials: M
authors.lastname: Shima
authors.affiliation: Research Division, Chugai Pharmaceutical Co, Ltd, Gotemba, Shizuoka, Japan; and.
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Hattori
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000276:immunology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology / Q000627:therapeutic use*; D002460:Cell Line; D004195:Disease Models, Animal; D015949:Factor IXa / Q000276:immunology*; D005170:Factor X / Q000276:immunology*; D006467:Hemophilia A / Q000150:complications*; D006470:Hemorrhage / Q000150:complications* / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D007596:Joints / Q000187:drug effects / Q000473:pathology; D008252:Macaca fascicularis; D008297:Male; D051379:Mice
chemical_list: D018033:Antibodies, Bispecific; D061067:Antibodies, Monoclonal, Humanized; D005170:Factor X; D015949:Factor IXa