Characterization of Anti-Emicizumab Antibodies Using Repository Samples Obtained in Clinical Studies of Emicizumab Conducted in Japan
Hiroto Abe,Ryo Kawasaki,Yoshihito Tashiro,Mariko Noguchi-Sasaki,Suguru Harada,Koichiro Yoneyama,Tomomi Niino,Tetsuhiro Soeda,Yasushi Yoshimura +8 more
TL;DR: In this article, the authors evaluated the characteristics of anti-drug antibodies (ADAs) by using repository samples collected in phase 1, phase 1/2 and bioavailability studies conducted in Japan.
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Abstract: 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.
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References
Emicizumab Prophylaxis in Hemophilia A with Inhibitors
Johannes Oldenburg,Johnny Mahlangu,Benjamin Kim,Christophe Schmitt,Michael U. Callaghan,Guy Young,Elena Santagostino,Rebecca Kruse-Jarres,Claude Negrier,Craig M. Kessler,Nancy Valente,Elina Asikanius,Gallia G. Levy,Jerzy Windyga,Midori Shima +14 more
TL;DR: Empicizumab prophylaxis was associated with a significantly lower rate of bleeding events than no proPHylaxis among participants with hemophilia A with inhibitors and resulted in a bleeding rate that was significantly lower by 79% than the rate with previous bypassing‐agent prophylum.
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Emicizumab Prophylaxis in Patients Who Have Hemophilia A without Inhibitors
Johnny Mahlangu,Johannes Oldenburg,Ido Paz-Priel,Claude Negrier,Markus Niggli,M Elisa Mancuso,M Elisa Mancuso,Christophe Schmitt,Víctor Jiménez-Yuste,Christine L. Kempton,Christophe Dhalluin,Michael U. Callaghan,Willem Bujan,Midori Shima,Joanne I. Adamkewicz,Elina Asikanius,Gallia G. Levy,Rebecca Kruse-Jarres +17 more
TL;DR: Empicizumab prophylaxis administered subcutaneously once weekly or every 2 weeks led to a significantly lower bleeding rate than no proPHylaxis among persons with hemophilia A without inhibitors; more than half of the participants who received prophYLaxis had no treated bleeding events.
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A bispecific antibody to factors IXa and X restores factor VIII hemostatic activity in a hemophilia A model
Takehisa Kitazawa,Tomoyuki Igawa,Zenjiro Sampei,Atsushi Muto,Tetsuo Kojima,Tetsuhiro Soeda,Kazutaka Yoshihashi,Yukiko Okuyama-Nishida,Hiroyuki Saito,Hiroyuki Tsunoda,Tsukasa Suzuki,Hideki Adachi,Taro Miyazaki,Shinya Ishii,Mika Kamata-Sakurai,Iida Takeo,Aya Harada,Keiko Esaki,Miho Funaki,Chifumi Moriyama,Eriko Tanaka,Yasufumi Kikuchi,Tetsuya Wakabayashi,Manabu Wada,Masaaki Goto,Takeshi Toyoda,Atsunori Ueyama,Sachiyo Suzuki,Kenta Haraya,Tatsuhiko Tachibana,Yoshiki Kawabe,Midori Shima,Akira Yoshioka,Kunihiro Hattori +33 more
TL;DR: 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, exerted coagulation activity in FV III-deficient plasma, even in the presence of inhibitors.
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Efficacy, safety, and pharmacokinetics of emicizumab prophylaxis given every 4 weeks in people with haemophilia A (HAVEN 4): a multicentre, open-label, non-randomised phase 3 study
Steven W. Pipe,Midori Shima,Michaela Lehle,Amy D. Shapiro,Sammy Chebon,Katsuyuki Fukutake,Nigel S. Key,Agnès Portron,Christophe Schmitt,Maria Podolak-Dawidziak,Nives Selak Bienz,Cédric Hermans,Avrita Campinha-Bacote,Anna Kiialainen,Kathelijne Peerlinck,Gallia G. Levy,Víctor Jiménez-Yuste +16 more
TL;DR: Emicizumab given once every 4 weeks showed clinically meaningful bleed control while being well tolerated, and could improve patient care by decreasing treatment burden and increasing adherence to effective prophylaxis, potentially decreasing the development of secondary complications for people with haemophilia A.
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A multicenter, open-label phase 3 study of emicizumab prophylaxis in children with hemophilia A with inhibitors.
Guy Young,Ri Liesner,Tiffany Chang,Robert F. Sidonio,Johannes Oldenburg,Víctor Jiménez-Yuste,Johnny Mahlangu,Rebecca Kruse-Jarres,Michael Wang,Marianne Uguen,Michelle Y. Doral,Lilyan Wright,Christophe Schmitt,Gallia G. Levy,Midori Shima,Maria Elisa Mancuso +15 more
TL;DR: Emicizumab prophylaxis has been shown to be a highly effective novel medication for children with hemophilia A and inhibitors and two of 88 participants developed antidrug antibodies (ADAs) with neutralizing potential, ie, associated with decreased emicIZumab plasma concentrations.
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