Abstract 4540: BC602: An IND-enabling stage LGR5x EGFR bispecific antibody with superior anti-tumor efficacy in mouse CDX and PDX models

Abstract Epidermal growth factor receptor (EGFR) is a key driver oncogene in the tumorigenesis of many cancer types. EGFR targeting antibodies are approved mainly in EGFR overexpression cancers including colorectal cancer (CRC), head and neck squamous carcinoma (HNSCC), and squamous non-small cell lung cancer (NSCLC). These antibodies exert their function by binding to the extracellular domain(s) to block ligand binding and to induce receptor internalization and degradation. To further enhance EGFR internalization and degradation, we developed an asymmetric LGR5*EGFR bispecific antibody (BsAb) BC602, with one arm as VHH targeting leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5), and the other arm as Fab targeting EGFR. To further increase the anti-tumor activity, BC602 Fc is engineered for enhanced FcγRIII binding and ADCC activity. In ELISA and BLI assays, BC602 binds to the LGR5 protein and EGFR protein with high affinity, respectively. In LGR5 and EGFR expressing cell lines,BC602 showed high binding affinity to cell surface receptors at single digit nM, while isotype control antibody showed no binding. In the pH-rodo internalization assay, BC602 induced significantly higher internalization magnitude than EGFR antibody or LGR5 antibody alone in both cell lines. In growth inhibition assay using the patient-derived organoids (PDO), BC602 showed potent inhibitory activity, much stronger than EGFR antibody. The antitumor efficacy of BC602 was studied in several mouse CDX and PDX models. BC602 demonstrated dose-dependent anti-tumor efficacy, with the antitumor efficacy stronger than EGFR antibody, superior or comparable to its competitor in clinical development stage. In AGS mouse xenograft tumor model, BC602 at 5 mg/kg showed a TGI of 72% while EGFR antibody had a TGI of 50%. In A431-LGR5 mouse xenograft tumor model, BC602 at 1/3/10 mg/kg showed TGI of 42%, 67%, and 83% respectively. BC602 showed no effect on mouse body weight or showed any other safety concerns in these mouse models. BC602 demonstrated good physicochemical properties for CMC, with a high production yield. Non-clinical GLP PK and toxicity studies of BC602 and 200L scale clinical batch production are ongoing. IND filing is expected in 2026 Q3, and the planned indications include cancer types that overexpress both EGFR and LGR5 including HNSCC and CRC. Citation Format: Zhe Shao, Tao Wang, Wen Chao Jia, Keng Hoe Lok, Zhong Zong Pan. BC602: An IND-enabling stage LGR5x EGFR bispecific antibody with superior anti-tumor efficacy in mouse CDX and PDX models [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 4540.