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-A*02. 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-A*02/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-A*02/NY-ESO peptide complex was evaluated by surface plasmon resonance (SPR) analysis, and specificity of DS-2243a for the human HLA-A*02/NY-ESO complex was evaluated by a flow cytometry-based binding assay using T2 cell line supplemented with HLA-A*02/NY-ESO peptide and various HLA-A*02/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-A*02 positive tumors with different NY-ESO expression levels in human T-cell-transferred mouse models. Results: DS-2243a specifically bound to human HLA-A*02/NY-ESO peptide complex with a high affinity of 1.31×10−9 mol/L, but not to other HLA-A*02/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-A*02 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. Citation Format: 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, . DS-2243a, an HLA-A*02/NY-ESO-directed bispecific T-cell engager, shows potent anti-tumor activity in preclinical models of solid tumors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1627.
Ichikawa et al. (Fri,) studied this question.