Abstract 4046: A novel DLL3 trispecific T cell engager antibody integrating the CD2/CD58 co-stimulatory pathway demonstrates superior antitumor efficacy and balanced safety profile

Abstract As a clinically validated therapeutic modality, T-cell engager (TCE) antibodies showed great success in hematological tumors. However, they still face a number of challenges in effectively treating solid tumors, including a lack of tumor-specific targets, insufficient T cell infiltration of some tumors, and immunosuppressive forces within the tumor microenvironment (TME) leading to T cell anergy and exhaustion. These challenges contribute to the narrow therapeutic window of TCEs in treating solid tumors and partially explain why no solid tumor-targeting TCE received regulatory approval until the DLL3-targeting tarlatamab became the first (and only to date) in 2024. To address the aforementioned challenges, a number of approaches are being explored and tested clinically, including those integrating a co-stimulatory moiety into the TCE to prevent or revert T cell exhaustion and promote sustained proliferation of the infiltrated T cells within the TME. Amongst co-stimulatory pathways, those mediated by CD28 and 4-1BB have been the most extensively explored, even though recent studies have shown that they are often associated with excessive toxicity or paradoxical immunosuppression. In contrast, the CD2-CD58 axis offers a promising alternative based on a few possible modes of actions, including promoting a balanced T cell co-stimulation at both the priming and effector stage, and stabilizing immunological synapse. Therefore, to further enhance the efficacy, persistence, and safety of conventional TCEs targeting DLL3 and other solid tumor targets, we designed a novel class of DLL3xCD3xCD2 trispecific antibodies based on an internally developed CD3 VHH antibody with cyno cross-reactivity. These trispecific TCEs were evaluated in a suite of in vitro functional assays whereby they demonstrated superior potency in tumor cell killing and sustaining T cell proliferation compared to the parental bispecific TCE (DLL3xCD3) and tarlatamab, especially at low E/T ratios, which mimics the scarcity of T cell infiltration into the TME of solid tumors. Additionally, this enhanced tumor cytotoxicity was accompanied by an increased, but balanced, cytokine profile with a reduced release of proinflammatory cytokines (TNFa, etc.), and an insignificant level of tumor antigen-independent T cell activation or cytokine release. For in vivo studies, these trispecific TCEs demonstrated a favorable IgG-like pharmacokinetics profile and greater antitumor activity than clinical benchmarks in two human PBMC-reconstituted CDX models (SHP77 and NCI-H82). In summary, the incorporation of a CD2 co-stimulatory moiety into a DLL3-targeting TCE leads to a novel, next-generation TCE with improved efficacy and safety profiles in preclinical studies. IND-enabling studies are ongoing with the potential to advance it to clinical studies in the near future. Citation Format: Cheng Luo, Devin Liu, Yingyu Li, Na jingjing, Nie Li, Fan Zhou, Xin Wang, Yang Xin, Mingzhu Shao, Tingting Yang, Hai Huang, Cheng Chen, Mingrui Du, Jiashun Cai, Li Chen, Yu Liang. A novel DLL3 trispecific T cell engager antibody integrating the CD2/CD58 co-stimulatory pathway demonstrates superior antitumor efficacy and balanced safety profile 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 4046.