VPB0206 - Characterization of Anti-Emicizumab Antibodies Using Repository Samples Obtained in Clinical Studies of Emicizumab Conducted in Japan

Sunday, July 10, 2022

6:30 PM – 7:30 PM

Location: Exhibition

Presentation Format: Virtual

Presenting Author(s)

Naoki Matsumoto, PhD

Researcher
Chugai Pharmaceutical Co., Ltd.
Kamakura, Kanagawa, Japan

Co-Author(s)

HA

Hiroto Abe

Researcher
Chugai Pharmaceutical Co., Ltd.
Kamakura, Kanagawa, Japan
RK

Ryohei Kawasaki

Researcher
Chugai Pharmaceutical Co., Ltd.
Kamakura, Kanagawa, Japan
YT

Yoshihito Tashiro

Researcher
Chugai Pharmaceutical Co., Ltd.
Kamakura, Kanagawa, Japan
MN

Mariko Noguchi

Researcher
Chugai Pharmaceutical Co., Ltd.
Kamakura, Kanagawa, Japan
SH

Suguru Harada

Product Research Dept.
Chugai Pharmaceutical Co., Ltd.
Kamakura, Kanagawa, Japan
Koichiro Yoneyama, MSc

Pharmaceutical Science Dept.
Chugai Pharmaceutical Co., Ltd., Tokyo, Japan
Tokyo, Tokyo, Japan
TN

Tomomi Niino

Primary Clinical Development Dept.
Chugai Pharmaceutical Co., Ltd.
Tokyo, Tokyo, Japan
TS

Tetsuhiro Soeda

Researcher
Chugai Pharmaceutical Co., Ltd.
Kamakura, Kanagawa, Japan
YY

Yasushi Yoshimura

Researcher
Chugai Pharmaceutical Co., Ltd.
Kamakura, Kanagawa, Japan

Background: Emicizumab is a factor (F) VIII function-mimetic anti-FIXa/X humanized bispecific monoclonal antibody for use in hemophilia A patients with or without inhibitors. Although the incidence of anti-drug antibodies (ADAs) to emicizumab is low, caution should be exercised in loss of efficacy due to ADAs. Further characterization of the ADAs (e.g. epitope analysis) would be useful.

Aims: To characterize ADAs using repository samples from ADA-positive subjects/patients in phase I, phase I/II and bioavailability studies conducted in Japan.

Methods: This research was conducted in accordance with relevant ethical standards. Neutralizing activity of ADAs against emicizumab was measured in 10 subjects/patients who tested positive for ADAs in the clinical studies, and epitope analysis was performed in 8 of these subjects/patients. Neutralizing activity was assessed by a modified Bethesda assay using FVIII-deficient plasma spiked with emicizumab, and epitope analysis was assessed by an electrochemiluminescence immunoassay.

Results: Neutralizing activity was observed in 3 subjects of 10 subjects/patients, and all epitopes were on the common light chain of emicizumab. ADAs developed in these 3 subjects were associated with decreased emicizumab exposure. Neutralizing activity could not be measured in 7 subjects/patients, including 1 subject who had decreased exposure, because ADA titers were low or the assay was affected by coexisting emicizumab. In 5 of the 7 subjects/patients for whom epitope analysis could be performed, ADAs recognized the Fab-regions (FIXa/FX-arms or FIXa-arm only) or the common light chain.

Conclusion(s): This research confirmed the neutralizing activity of ADAs in 3 subjects of 10 ADA-positive subjects/patients. The epitopes of ADAs in these 3 subjects included regions of the common light chain of emicizumab that is important to exert the pharmacological activity.