Oncotarget

Research Papers:

Novel therapeutic bispecific antibodies for B-cell lymphoma targeting IgM and other antigens on the B-cell surface

Takahiro Ohashi, Sayuri Terada, Shinsuke Hiramoto, Yuko Nagata, Hirokazu Suzuki, Hitoshi Miyashita, Tetsuo Sasaki, Yasukatsu Tsukada and Keiko Fukushima _

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Oncotarget. 2024; 15:256-274. https://doi.org/10.18632/oncotarget.28578

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Abstract

Takahiro Ohashi1, Sayuri Terada1, Shinsuke Hiramoto1, Yuko Nagata1, Hirokazu Suzuki1, Hitoshi Miyashita1, Tetsuo Sasaki1, Yasukatsu Tsukada1 and Keiko Fukushima1

1 Department of Drug Discovery, Biosciences, R&D Center, Zenyaku Kogyo Co., Ltd., Tokyo, Japan

Correspondence to:

Keiko Fukushima, email: [email protected]

Keywords: bispecific antibody; Cys1m; IgM; lymphoma; cynomolgus monkey

Received: December 08, 2023     Accepted: March 25, 2024     Published: April 12, 2024

Copyright: © 2024 Ohashi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

ABSTRACT

The B-cell receptor regulates B-cell proliferation and apoptosis. Aberrations in BCR signaling are associated with the development and progression of B-cell malignancies, such as mantle cell lymphoma, diffuse large B-cell lymphoma, and chronic lymphocytic leukemia, many of which express the IgM type of BCR on their cellular surface. Therefore, IgM is an attractive target for therapeutic antibodies against B-cell malignancies. However, soluble IgM competitively binds to anti-IgM antibodies in the serum, and these antibodies show insufficient cytotoxic activity. Thus, antibody therapy targeting IgM is hindered by the presence of soluble IgM in the blood. To address this problem, we used a bispecific antibody. We generated bispecific antibodies bound to IgM and other B-cell antigens such as CD20 and HLA-DR using our bispecific antibody-producing technology, Cys1m. These bispecific antibodies directly inhibited cell proliferation via cell-cycle arrest and apoptosis in vitro, although large amounts of soluble IgM were present. Additionally, a bispecific antibody bound to IgM and HLA-DR (BTA106) depleted B-cells in cynomolgus monkeys. These data suggest that anti-IgM/B-cell surface antigen-binding specific antibodies are promising therapeutic agents for B-cell malignancies. Moreover, the bispecific antibody modality can potentially overcome problems caused by soluble antigens.


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