Abstract 5650: Preclinical development of LUA006: A bispecific EGFR/B7-H3 ADC with dual payloads to address tumor heterogeneity and resistance.

Abstract Background: While antibody-drug conjugates (ADCs) have emerged as a transformative therapeutic class, their clinical utility is largely limited by either on-target, off-tumor toxicities or acquired drug resistance. EGFR and B7-H3 are clinically validated targets that are frequently co-expressed in a range of solid tumors including non-small cell lung cancer (NSCLC), especially lung squamous cell carcinoma (LUSC), esophageal squamous cell carcinoma (ESCC), and Head and neck squamous cell carcinoma (HNSCC), while exhibit rare co-expression in normal tissues. It has been revealed that both heterogeneous expression of a single target and acquired resistance to a single payload often compromise the efficacy of monospecific ADCs containing a single payload. To address these challenges, we generated LUA006, a bispecific ADC targeting both EGFR and B7-H3 with attenuated EGFR binding to reduce on-target, off-tumor toxicity and enhanced B7-H3 binding and internalization dynamics to improve anti-tumor efficacy, particularly in tumors with heterogeneous expression of a single target. Additionally, LUA006 incorporates two distinct payload classes, to achieve deep response and overcome payload-associated resistance. Methods: A bispecific anti-EGFR/B7-H3 IgG was site-specifically conjugated to two payloads with complimentary mechanism of actions and well optimized DAR values. Meanwhile, the linkers for each payload were screened to enable sequential payload release. LUA006 demonstrated high DAR homogeneity and stability in vitro. Results: LUA006 demonstrated superior internalization efficiency versus parental antibodies, indicating synergistic targeting. It achieved nanomolar-level cytotoxicity against diverse cancer cell lines with variable EGFR/B7-H3 expression, while showing minimal toxicity to normal human epidermal keratinocytes, resulting in a broader therapeutic window than clinical stage EGFR monospecific ADCs in vitro. In vivo, a single dose of LUA006 induced profound, durable tumor regression in cell-derived xenograft (CDX) models, surpassing combinations of mono-payload ADCs and monospecific ADCs. Critically, LUA006 maintained efficacy in CDX models with intrinsic low sensitivity to each payload used by LUA006 and in models overexpressing drug efflux pumps, demonstrating robust activity against diverse resistance mechanisms. Conclusion: LUA006 is a novel bispecific ADC with dual payloads that may enhance efficacy in tumors with heterogeneous expression of a single target or with resistance toward either of dual payloads. Its potent efficacy, reduced toxicity profile and activity in resistant models support further development as a promising therapy for EGFR/B7-H3-expressing solid tumors. Citation Format: Shaojuan Zhao, Ling Zhang, Ying Huang, Qian Dong, Xiaofan Gu, Guoshun Tian, Xiaoman Li, Fanrui Meng, Wei Zheng, Xiaoshuang Yan, Xinmei Wang, Yazhi Yuan, Shuyong Zhao, Ken Qin, Yang Yang, Hua Ying, Weikang Tao. Preclinical development of LUA006: A bispecific EGFR/B7-H3 ADC with dual payloads to address tumor heterogeneity and resistance 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 5650.