Engineering and physicochemical characterization of a novel, stable, symmetric bispecific antibody with dual target-binding using a common light chain.

Autor: Saito S; Molecular Analysis Center, R&D Division, Kyowa Kirin Co., Ltd., Tokyo, Japan., Nakayama M; Research Core Function Laboratories, R&D Division, Kyowa Kirin Co., Ltd., Tokyo, Japan., Yamazaki K; Molecular Analysis Center, R&D Division, Kyowa Kirin Co., Ltd., Tokyo, Japan., Miyamoto Y; Molecular Analysis Center, R&D Division, Kyowa Kirin Co., Ltd., Tokyo, Japan., Hiraishi K; Molecular Analysis Center, R&D Division, Kyowa Kirin Co., Ltd., Tokyo, Japan., Tomioka D; Molecular Analysis Center, R&D Division, Kyowa Kirin Co., Ltd., Tokyo, Japan., Takagi-Maeda S; Modality Research Laboratories, R&D Division, Kyowa Kirin Co., Ltd., Tokyo, Japan., Usami K; Modality Research Laboratories, R&D Division, Kyowa Kirin Co., Ltd., Tokyo, Japan., Takahashi N; R&D Division, Kyowa Kirin Co., Ltd., Tokyo, Japan., Nara S; Molecular Analysis Center, R&D Division, Kyowa Kirin Co., Ltd., Tokyo, Japan., Imai E; Molecular Analysis Center, R&D Division, Kyowa Kirin Co., Ltd., Tokyo, Japan.
Jazyk: angličtina
Zdroj: Protein science : a publication of the Protein Society [Protein Sci] 2024 Oct; Vol. 33 (10), pp. e5121.
DOI: 10.1002/pro.5121
Abstrakt: Bispecific antibodies (BsAbs) have emerged as a major class of antibody therapeutics owing to their substantial potential in disease treatment. While several BsAbs have been successfully approved in recent years, ongoing development efforts continue to focus on optimizing various BsAbs tailored to particular antigens and action mechanisms, aiming to achieve favorable physicochemical properties. BsAbs generally encounter challenges due to their unfavorable physicochemical characteristics and poor manufacturing efficiencies, highlighting the need for optimization to achieve reliable productivity and developability. Herein, we describe the development of a novel symmetric BsAb, REGULGENT™ (N-term/C-term), comprising two Fab domains, using a common light chain. The heavy chain fragment encoded two antigen-binding determinants in one chain. The design and production of REGULGENT™ (N-term/C-term) are simple owing to the use of the same light chain, which does not induce heavy and light chain mispairing, frequently observed with the asymmetric BsAb format. REGULGENT™ (N-term/C-term) exhibited high expression and low aggregation characteristics during cell culture and stress treatment under low pH conditions. Differential scanning calorimetric data indicated that REGULGENT™ molecules had high conformational stability, similar to that of stabilized monoclonal antibodies. Surface plasmon resonance data showed that REGULGENT™ (N-term/C-term) could bind to two antigens simultaneously and exhibited a high affinity for two antigens. In summary, the symmetric BsAb format of REGULGENT™ confers its desirable IgG-like physicochemical properties, thus making it an excellent candidate for commercial development. The findings demonstrate a novel BsAb with substantial development potential for clinical applications.
(© 2024 The Author(s). Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society.)
Databáze: MEDLINE
Externí odkaz: