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ORIGINAL RESEARCH article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1574958
This article is part of the Research TopicGenetically Engineered T cells and Recombinant Antibodies to Target Intracellular Neoantigens: Current Status and Future DirectionsView all articles
Bispecific antibody targeting shared indel-derived neoantigen of APC
Provisionally accepted- 1Project for Immunogenomics, Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, Tokyo, Japan
- 2Laboratory of Immunogenomics, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki-shi, Osaka, Japan
- 3Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, Tokyo, Japan
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T cells play a pivotal role in cancer immunotherapy by recognizing tumor-specific neoantigens presented on HLA molecules, which are specifically expressed on cancer cells. While neoantigens are generally unique to individual cancers, certain neoantigens, known as 'shared neoantigens' that are common in a subset of cancer patients, represent promising immunotherapeutic targets. We previously identified an immunogenic shared frameshift neoantigen, 1472SP2, derived from recurrent frameshift indel mutation cluster (APC-F2-1472*) in the APC gene and presented on HLA-A24:02. In this study, we attempted to identify an antibody targeting a complex formed by the APC 1472SP2 neoantigen and HLA-A24. Using the phage display library screening, we isolated singlechain variable fragments (scFvs) that specifically recognize the 1472SP2/HLA-A24 complex. We then designed a bispecific antibody (BsAb) that would connect T cells via an anti-CD3 scFv to the cancer-specific 1472SP2 presented on the HLA-A24 molecule.ELISA analysis revealed that BsAb specifically recognized both 1472SP2-HLA-A24 monomer and CD3 protein. When T cells were co-cultured with antigen-presenting cells expressing HLA-A24:02, IFN-γ release and cytotoxicity were observed only in the presence of 1472SP2-BsAb, indicating that the 1472SP2-BsAb effectively activated T cells to lyse target cells presenting this neoantigen. This approach implies an off-the-shelf, cancer selective approach to target cancers expressing shared neoantigens for patients who are difficult to treat with conventional therapies.
Keywords: cancer immunotherapy, Frameshift Mutations, neoantigens, phage display library, Single-chain variable fragments, Single-chain diabody, TCR-like antibodies
Received: 11 Feb 2025; Accepted: 16 Apr 2025.
Copyright: © 2025 Effenberger, Wu, Zhao, Matsumoto, Nakamura and Kiyotani. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Kazuma Kiyotani, Laboratory of Immunogenomics, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki-shi, Osaka, Japan
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