Abstract 3495: QL535, A novel CD2-costimulating T cell engager targeting PSMA-positive prostate cancer matching CD28 trispecific antibody in cytotoxicity, minimizing cytokine release and T-cell exhaustion

Prostate cancer is a leading cause of cancer-related mortality in men, highlighting the resistance to current treatments and need for new therapeutic options. PSMA (Prostate-Specific Membrane Antigen) is overexpressed in prostate cancer tissues compared to normal prostatic tissue, rendering it an ideal target for prostate cancer therapies, enabling precise delivery of therapeutic agents to cancer cells. We evaluated PSMA expression in 77 Chinese prostate cancer patients using immunohistochemistry (IHC), confirming its high expression in Chinese malignant prostate tissues. Due to the lack of clinical activity from T cell targeted therapies in solid tumors, recent developments in the field have focused on providing a co-stimulatory signal via CD28 or more recently, CD2. Analysis of single-cell RNA sequencing data from 2,170 cells across 14 mCRPC patients revealed that CD2 expression on tumor-infiltrating lymphocytes (TILs), particularly CD8+ T cells, exceeds that of CD28, underscoring the potential for CD2 targeting in enhancing antitumor immunity. We developed QL535, a novel trispecific antibody in a 2+1+1 format designed to bridge tumor cells via PSMA and activate T cells through CD3 (signal 1) and CD2 (signal 2) via its ligand CD58. This design aims to stabilize the immune synapse and enhance T-cell cytotoxicity. Additionally, this combination overcomes T-cell exhaustion, with fine-tuned CD3 affinity to improve safety and reduce the risk of cytokine release syndrome (CRS). Comparative analysis was conducted with three trispecific antibody formats targeting CD28, and three formats targeting CD2, resulting in a lead CD2 trispecific antibody, QL535, alongside a CD28 trispecific antibody as a control. QL535 demonstrated superior tumor-specific killing both in vitro and in vivo compared to bispecific CD2-deficient antibodies, and exhibited a favorable safety profile, characterized by low IL-6, TNFα, IFN-γ and IL-8 levels compared to the CD28 trispecific control, which achieved comparable cytotoxicity. Further evaluation using repeated stimulation assays of prostate cancer patient-derived PBMCs showed that QL535 outperformed the CD28 trispecific control, an analog of the clinical benchmark PSMA targeted T cell engager, and our bispecific antibody control in overcoming T-cell exhaustion. Whereas other agents showed diminished cytotoxicity, potentially due to T-cell exhaustion, QL535 maintained durable tumor-specific lysis. Favorable manufacturing (CMC) studies further support QL535’s developability for clinical applications. In conclusion, QL535 is a novel trispecific T cell engager with improved anti-tumor efficacy and safety profile. These findings warrant further clinical investigation to evaluate its safety and efficacy in patients. Citation Format: Xiao Liu, Shenda Gu, Ke Liu, Joshua Morrissette, Jiantao Kong, Guangjie Guo, Yuxia Wang, Xin Zhang, Jiaming Cao, Moyan Hu, Min Sun, Ruixue Ma, Jane Chen, Nathan Ngo, Hejie Zhu, Liwei Wang, Yan Fang, Hao Liu, Shuyong Zhao, Shihao Chen. QL535, A novel CD2-costimulating T cell engager targeting PSMA-positive prostate cancer matching CD28 trispecific antibody in cytotoxicity, minimizing cytokine release and T-cell exhaustion [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 3495.