Abstract 7324: ONO-4685: A novel PD-1/CD3 bispecific T-cell engager (TCE) for the treatment of T-cell malignancies
Authors: Naho Tateshita, Noriki Watanabe, Takuya Shimbo, Akihiro Morimoto, Kazuhiko Takeda, Tatsuya Tanihiro
Journal: Cancer Research (2025)

Abstract Mature T and NK-cell neoplasms are of mature T-cell or NK-cell origin and comprise approximately 10% to 15% of non-Hodgkin’s lymphomas (NHLs) all over the world. While new therapies with novel mechanisms of action have become available, their therapeutic outcomes are limited and most subtypes of the neoplasms have a poor prognosis. Therefore, identification of new therapeutic approaches is still an unmet medical need.Programmed cell death 1 (PD-1) is an inhibitory receptor expressed and increased on normal activated T and B cells that promotes T-cell apoptosis, anergy and functional exhaustion. PD-1 is also expressed on multiple different cancer types including major T-cell lymphomas/leukemias: Angioimmunoblastic T-cell lymphoma (AITL); Nodal T-cell lymphoma with T follicular helper (Tfh) phenotype; Follicular T-cell lymphoma; Peripheral T-cell lymphoma (PTCL) not otherwise specified (PTCL-NOS); Cutaneous T-cell lymphoma (CTCL) mycosis fungoides (CTCL-MF); CTCL Sézary syndrome (CTCL-SS), and; Adult T-cell leukemia/lymphoma (ATLL). Thus, PD-1 is a novel potential therapeutic target for T-cell lymphomas/leukemias.ONO-4685 is a first-in-class bispecific TCE antibody that binds to human PD-1 and CD3 to engage T-cells with PD-1 expressing tumor cells. TCEs have recently shown clinical anticancer success with some hematologic malignancies and solid tumor types.Here we performed preclinical studies to evaluate the therapeutic value of ONO-4685 to treat PD-1 expressing T-cell malignancies.To evaluate the effect of ONO-4685 on the cytolytic activity of T-cells, peripheral blood mononuclear cells (PBMCs) from healthy donors as well as PD-1 expressing T cell lymphoma/leukemia cell lines (ILT-Mat, HPB-ALL, and SUP-T1) were co-cultured in the presence of ONO-4685. ONO-4685 induced potent cytolytic cell killing of the cell lines. To assess the effect of ONO-4685 on T-cells, the intracellular expression of T-cell granzyme B was evaluated in in vitro cytotoxicity assay. ONO-4685 induced granzyme B expression in CD4+ and CD8+ T cells in the presence of PD-1-expressing target cells (ILT-Mat). Moreover, ONO-4685-mediated cytotoxicity on PD-1 expressing target cells was observed in the PBMCs from ATLL patients. In vivo anti-tumor activity of ONO-4685 was evaluated in PBMC-humanized mice xenograft models using PD-1 expressing human T cell lymphoma/leukemia cell lines (SUP-T1 and TL-Mor). ONO-4685 treatment showed suppressive effects on tumor growth in a dose-dependent manner.Taken together, these preclinical data support the clinical development of ONO-4685 as a novel TCE targeting PD-1 expressing hematologic malignancies. A Phase I clinical study in the USA is ongoing to evaluate the safety and tolerability of ONO-4685 in relapsed or refractory patients with PTCL and CTCL (NCT05079282). Citation Format: Naho Tateshita, Noriki Watanabe, Takuya Shimbo, Akihiro Morimoto, Kazuhiko Takeda, Tatsuya Tanihiro. ONO-4685: A novel PD-1/CD3 bispecific T-cell engager (TCE) for the treatment of T-cell malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7324.