Abstract 5400: QLS2313, a CD79b/CD20 tri-specific T cell engager with dual-targeting strategy developed as a new therapeutics for the treatment of DLBCL.

Abstract Diffuse large B-cell lymphoma (DLBCL) is the most prevalent subtype of non-Hodgkin lymphoma (NHL), with approximately 40% of patients developing refractory disease or relapsing after initial therapy response. While CD20-targeted T cell engagers (TCEs) have demonstrated clinical efficacy and gained FDA approval for DLBCL, studies indicate that CD20 expression loss occurs in 8-64% of patients following CD20-directed therapies. This loss is often associated with transformation to high-grade lymphoma and poor overall survival. To address this challenge, Dual targeting another DLBCL surface antigen as well as CD20 may enhance therapeutic effects. CD79b is a well-validated therapeutic target expressed in 90% of DLBCL cases anditis critical for the viability of DLBCL cells. Unlike CD20, CD79b-targeted agents are less prone to resistance caused by antigen loss, making it an attractive TCE target. Therefore, a TCE dual targeting of CD79b and CD20 may overcome resistance and improve efficacy compared to a single-antigen targeting TCE. QLS2313 is a human IgG1 tri-specific antibody featuring an anti-CD3 single-chain variable fragment (scFv), an anti-CD20 Fab, an anti-CD79b Fab, and an effector-silent Fc region. In vitro, QLS2313 exhibited higher affinity for DLBCL cell lines than JNJ-80948543 (a clinical-stage CD79b/CD20 TCE from Janssen) while demonstrating significantly lower affinity for primary human T cells and Jurkat cells compared to JNJ-80948543 and FDA-approved CD20/CD3 bi-specifics (mosunetuzumab and glofitamab). QLS2313 effectively depleted both dual- and single-target-expressing cells, showing superior cytotoxicity to JNJ-80948543 and lower IL-6 release than glofitamab. In vivo, QLS2313 demonstrated linear pharmacokinetics in triple transgenic (human CD3/CD20/CD79b) mice, with a half-life of ∼5 days. It inhibited tumor growth in a dose-dependent manner and exhibited greater antitumor efficacy than JNJ-80948543, particularly in CD20-low expression models. QLS2313 was well tolerated in a transgenic mice (QW × 4) GLP toxicity study, with the highest non-severely toxic dose (HNSTD) at 30 mg/kg for both intravenous and subcutaneous administration. In conclusion, QLS2313 show superior efficacy, favorable pharmacokinetics and safety profile, which support the clinical development of this novel therapy for DLBCL treatment. Citation Format: Ting Lu, Liuqing Yang, Fujia Yao, Dongdong Wu, Shuyong Zhao, Hua Ying, Weikang Tao. QLS2313, a CD79b/CD20 tri-specific T cell engager with dual-targeting strategy developed as a new therapeutics for the treatment of DLBCL 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 5400.