Abstract 5601: LBL-061: A novel EGFR×PD-L1 targeted drug conjugate for the treatment of multiple solid tumors

Abstract Background: EGFR is overexpressed in multiple solid tumors such as head and neck squamous cell carcinoma (HNSCC), non-small cell lung cancer (NSCLC), and nasopharyngeal carcinoma (NPC). Emerging antibody-drug conjugates (ADCs) targeting EGFR have demonstrated preliminary efficacy and safety in clinical trials. PD-L1, a clinically validated immune checkpoint, is frequently overexpressed in tumors including HNSCC and NSCLC, where it is often co-expressed with EGFR. Clinical evidence supporting the combination of ADCs and immune checkpoint inhibitors (ICIs) provides a rationale for developing an EGFR×PD-L1-targeting ADC. Here, we describe the preclinical development of LBL-061, a novel EGFR×PD-L1-targeting ADC composed of a 2:2 format bispecific antibody conjugated via our proprietary TOPiKinecticsTM linker-payload platform. Methods: Cell binding activity of LBL-061 against tumor cells was assessed by flow cytometry. Cytotoxicity of LBL-061 against tumor cells and normal tissue cells was assessed by Cell Counting-Lite Luminescent Cell Viability Assay kit. PD-L1 blocking activity of LBL-061 was evaluated using a PD-1/PD-L1 reporter gene assay system. Bystander killing of LBL-061 was analyzed by flow cytometry. LBL-061 induced tumor cells immunogenic cell death (ICD) was assessed in PBMC-tumor cells co-culture systems. The anti-tumor activity of LBL-061 was evaluated in mouse syngeneic and cell line-derived xenograft (CDX) models. The safety profile and pharmacokinetics (PK) of LBL-061 were evaluated in a cynomolgus monkey dose-range finding (DRF) study. Results: LBL-061 exhibited potent binding activity and cytotoxicity to different tumor cells. It also demonstrated robust PD-1/PD-L1 blocking activity. In vitro, LBL-061 showed minimal cytotoxicity to PD-L1 expressing dendritic cells (DCs) and macrophages. In PBMC-tumor cells co-culture systems, LBL-061 induced tumor cells immunogenic cell death (ICD). It also mediated potent bystander effect on EGFR negative tumor cells. In vivo, LBL-061 showed superior control of tumors’ growth in syngeneic and xenograft mouse models. In a 6-week cynomolgus DRF study, it was well tolerated with a highest non-severely toxic dose (HNSTD) of 40 mg/kg following repeated intravenous infusion (Q3W dosing). LBL-061 exhibited a linear PK characteristic in cynomolgus monkeys at doses ranging from 10 to 40 mg/kg. Conclusions: Our findings indicate that LBL-061, a novel bispecific EGFR×PD-L1-targeting ADC synergizes antitumor effects by combining direct cytotoxicity and immune activation. It showed a favorable PK profile and a good safety profile in cynomolgus monkeys. Taken together, these preclinical data strongly suggest that LBL-061 is a promising candidate worthy of further clinical investigation. Citation Format: Yurong Qin, Yang Ye, Yujia Dang, Juan Tang, Peng Zhang, Yan Zhu, Shuijun Hu, Mi Ye, Xiaoxiao Liu, Xu Bao, Huan Lin, Wanting Wang, Guojin Wu, Jianming Sun, Hui Yuwen, Yuanzhi Lv, Jing Guan, Min Chen, Yue Zhao, Jordan Zhu, Charles Cai, Xiao Huang, Xiaoqiang Kang, Hong Ling. LBL-061: A novel EGFR×PD-L1 targeted drug conjugate for the treatment of multiple 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 5601.