Abstract Background: Trophoblast glycoprotein (5T4), an oncofetal protein, is a member of the leucine-rich repeat family of proteins that is associated with intercellular connectivity, cell morphology and movement, and altering cell adhesion in embryonic development and cell differentiation. 5T4 is upregulated in several cancers, including esophageal, head-and-neck, and lung cancers, especially the squamous subtype, with low or absent expression in adult normal tissues. The high expression of 5T4 was notably correlated with poor survival in different cancer types, which makes it an attractive ADC target. The therapeutic potential of 5T4 as ADC modality was recently unraveled by several ADCs with preliminary clinical efficacy reported. In this study, we present the development of a novel 5T4-targeting ADC with Qilu’s proprietary microtubule inhibitor as payload, LUA004, which exhibited excellent efficacy and expanded therapeutic window than vedotin ADC. Method: LUA004 utilizes a novel microtubule inhibitor payload QLS8152 with a proprietary cleavable linker to achieve a homogeneous product with a drug-to-antibody ratio (DAR) of 8 through site-specific conjugation. The payload QLS8152 showed sub-nanomolar activity across a wide range of cancer cell lines in vitro and rapid systematic clearance in rodent models. Our next generation microtubule inhibitor platform QLS8153 demonstrated significantly improved therapeutic window than vedotin technology. Result: LUA004 showed sub-nanomolar binding affinity and dose-dependent internalization in multiple tumor cell lines with different 5T4 expression levels. LUA004 showed strong (nM range IC50) and comparable in vitro cytotoxicity to vedotin-ADC against a variety of 5T4-positive cancer cell lines. Meanwhile, LUA004 showed robust and dose-dependent tumor inhibition in different cell-derived xenograft (CDX) as well as patient-derived xenograft (PDX) models with various 5T4 expression, with comparable tumor inhibition as vedotin-ADC. Moreover, compared to vedotin-ADC, LUA004 exhibits more favorable plasma stability, preclinical pharmacokinetic, and toxicity profiles. LUA004 was well tolerated in cyno monkeys, with HNSTD up to 20 mpk Q3W x 4 in non-GLP toxicity study, indicating a tremendous increase in the therapeutic index compared to vedotin-ADC. Conclusion: LUA004 represents a novel 5T4-targeting ADC with favorable anti-tumor activity and superior tolerability, which can address the high unmet needs in patients with cancers expressing variable levels of 5T4. The promising preclinical profiles of LUA004 warrant its further development into clinical trials. Citation Format: Jinpeng Pei, Shaojuan Zhao, Ying Huang, Junfei Wang, Wei Zheng, Hai Wu, Jie Chen, Ke Li, Xinmei Wang, Shuyong Zhao, Ling Zhang, Yang Yang, Daqing Sun, Hua Ying, Weikang Tao. Preclinical characterization of LUA004, a novel 5T4-targeting ADC with improved therapeutic window 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 5653.
Pei et al. (Fri,) studied this question.