Characterization of Anti-Emicizumab Antibodies Using Repository Samples Obtained in Clinical Studies of Emicizumab Conducted in Japan.

Emicizumab, a factor (F) VIII function-mimetic bispecific antibody, is used for the treatment with patients with hemophilia A (PwHA). Although the immunogenicity of emicizumab is low, potential of immunogenicity is still remained. Despite some cases of anti-drug antibodies (ADAs) reported, the characteristics of ADAs have not been fully elucidated. In this research, we evaluated the characteristics of ADAs by using repository samples collected in phase 1, phase 1/2 and bioavailability studies conducted in Japan. Ten plasma/serum samples from 6 healthy volunteers (HVs) and 4 PwHA who tested positive for ADAs in the clinical studies were used for the assessment of neutralizing activity, epitope analysis and pharmacokinetics (PK). Neutralizing activity of ADAs was observed in 3 HVs and 1 PwHA. Among these, 3 HVs developed ADAs which bound to the complement-determining region (CDR)1, 3 of the common light chain (cLC) of emicizumab and associated with shorter half-life. Epitopes of ADAs in 1 PwHA were on the Fab-regions of emicizumab, and the ADAs were not associated with decreased exposure in this PwHA. Neutralizing activity was undetectable in 3 HVs and 3 PwHA. Among these, ADAs in 2 HVs and 2 PwHA recognized the Fab-regions or the CDR 1, 3 of the cLC, and 1 of these 2 HVs showed shorter half-life of emicizumab. In conclusion, our analysis of ADAs demonstrated the various characteristics of ADAs, such as ADAs with either neutralizing activity or affected pharmacokinetics, or both properties.