LBL-061：一种用于治疗多种实体瘤的新型EGFR×PD-L1靶向药物偶联物

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 TOPiKinectics TM 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.