DS-2243a, an HLA-A*02/NY-ESO-directed bispecific T‑cell engager, shows potent anti-tumor activity in preclinical models of solid tumors
Presenter: Junya Ichikawa, PhD Session: T Cell Engagers 1 Time: 4/20/2026 9:00:00 AM → 4/20/2026 12:00:00 PM
Authors
Junya Ichikawa , Ayaka Yatsu , Ryuichi Nakamura , Akemi Kita , Shingo Noguchi , Yoko Ishimoto , Chikako Maru , Kento Tanaka , Kensuke Nakamura , Shinji Furuzono , Makiko Nakayama , Toshiaki Ohtsuka , Reimi Kawaida Daiichi Sankyo Co., Ltd., Tokyo, Japan
Abstract
Background : NY-ESO-1 and LAGE-1 are homologous proteins commonly expressed in various tumor tissues but not in normal tissues other than the testis and placenta, making them potential tumor-specific therapeutic targets. Tumor types with prevalent NY-ESO-1 and/or LAGE-1 expression include SS, MRCLS, NSCLC, and UC. Following the intracellular processing of NY-ESO-1 and LAGE-1 proteins (hereafter referred to as NY-ESO) by the proteasome, the same highly immunogenic NY-ESO peptides are presented extracellularly by HLA-A02. DS-2243a is a first-in-class bispecific T-cell engager (BiTCE) with an effectorless Fc region. It is designed with a novel TCR-like antibody that engages both HLA-A02/NY-ESO-expressing tumor cells and T-cells, redirecting T-cell-mediated cytotoxicity toward the tumor. Methods : The binding affinity of DS-2243a to HLA-A02/NY-ESO peptide complex was evaluated by surface plasmon resonance (SPR) analysis, and specificity of DS-2243a for the human HLA-A02/NY-ESO complex was evaluated by a flow cytometry-based binding assay using T2 cell line supplemented with HLA-A02/NY-ESO peptide and various HLA-A02/NY-ESO homologous peptides. Anti-tumor cytotoxicity, T-cell activation, and cytokine release were evaluated by co-culturing tumor cells with human peripheral blood mononuclear cells (hPBMCs) in the presence of DS-2243a. The anti-tumor efficacy of DS-2243a was evaluated against various HLA-A02 positive tumors with different NY-ESO expression levels in human T-cell-transferred mouse models. Results : DS-2243a specifically bound to human HLA-A02/NY-ESO peptide complex with a high affinity of 1.31×10 −9 mol/L, but not to other HLA-A02/homologous peptide complexes. DS-2243a induced T-cell activation, cytokine release, and target cell cytotoxicity in a dose-dependent manner. It demonstrated robust anti-tumor efficacy across multiple tumor types, including those with low NY-ESO expression, and also demonstrated efficacy in a tumor-mixture model of NY-ESO-positive and NY-ESO-negative tumors, supporting potential effectiveness in tumors with heterogeneous NY-ESO expression. Furthermore, DS-2243a exhibited efficacy in combination with immune checkpoint inhibitors, providing a rationale for combination therapies. Conclusions : Preclinical data indicate that DS-2243a has strong potential to deliver clinically meaningful anti-tumor activity in patients with HLA-A02 and NY-ESO-expressing cancers. The first-in-human study DS2243-054 (NCT06644755) is being conducted to evaluate DS-2243a monotherapy in patients with advanced or metastatic solid tumors.
Disclosure
J. Ichikawa, None.. A. Yatsu, None.. R. Nakamura, None.. A. Kita, None.. S. Noguchi, None.. Y. Ishimoto, None.. C. Maru, None.. K. Tanaka, None.. K. Nakamura, None.. S. Furuzono, None.. M. Nakayama, None.. T. Ohtsuka, None.. R. Kawaida, None.
Cited in
Control: 691 · Presentation Id: 4513 · Meeting 21436