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 patients1,2,3. Moreover, the poor pharmacokinetics of FVIII, attributed to low subcutaneous bioavailability and a short half-life of 0.5 d, necessitates frequent intravenous injections3,4,5. 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.
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We thank T. Matsuura, T. Houjo, K. Kanisawa, R. Takemoto, T. Koike and M. Hiranuma for carrying out the in vivo experiments and M. Fujii, Y. Nakata, H. Ishida and F. Isomura for antibody generation and preparation. We also thank S. Ohtsu for carrying out in vitro experiments.
Declaration: T. Kitazawa, T. Igawa, Z.S., A.M., T. Kojima., T. Soeda, K.Y., Y.O.-N., H.S., T. Suzuki, T.M., C.M. and K. Hattori are employees of Chugai Pharmaceutical and inventors on the patents, patent applications or both relating to the bispecific antibodies to FIXa and FX, of which all rights have been assigned to the company. H.T., H.A., S.I., M.K.-S., T. Iida, A.H., K.E., M.F., E.T., Y. Kikuchi, T.W., M.W., M.G., T. Toyoda, A.U., S.S., K. Haraya, T. Tachibana and Y. Kawabe are employees of Chugai Pharmaceutical. M.S. receives consulting honoraria and research support from Chugai Pharmaceutical. A.Y. previously received research support from Chugai Pharmaceutical.
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Kitazawa, T., Igawa, T., Sampei, Z. et al. A bispecific antibody to factors IXa and X restores factor VIII hemostatic activity in a hemophilia A model. Nat Med 18, 1570–1574 (2012). https://doi.org/10.1038/nm.2942
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