The present inventors produced a variety of bispecific antibodies thatspecifically bindto both F. IX/F. IXa and F. X, and functionally substitute for F. VIIIa, i.e.,have a cofactorfunction to promote F. X activation via F. IXa. Among these antibodies, theantibody A44/B26reduced coagulation time by 50 seconds or more as compared to that observedwhen the antibodywas not added. The present inventors produced a commonly shared L chainantibody from thisantibody using L chains of A44, and showed that A44L can be used as commonlyshared Lchains, although the activity of the resulting antibody is reduced compared tothe originalantibody (A44HL-B26HL). Further, with appropriate CDR shuffling, the presentinventorssuccessfully produced highly active multispecific antibodies that functionallysubstitute forcoagulation factor VIII.
