Abstract 1715: JS212, a novel bispecific ADC targeting EGFR and HER3, demonstrates superior and broad antitumor activity in preclinical evaluation

Abstract Background: EGFR and HER3 are frequently co-expressed across multiple epithelial tumors. HER3 overexpression is a recognized resistance mechanism to EGFR tyrosine kinase inhibitors (TKIs) in NSCLC. The HER3-targeting antibody-drug conjugates (ADC), such as patritumab deruxtecan, has shown encouraging clinical benefit in NSCLC patients with EGFR mutations. Additionally, an EGFR and HER3 dual targeting ADC, BL-B01D1, demonstrated promising antitumor activities in patients with EGFR-mutated advanced NSCLC, confirming simultaneous targeting of EGFR and HER3 with a bispecific ADC as a promising strategy to achieve good therapeutic efficacy. We have developed JS212, a bispecific ADC targeting EGFR and HER3 with molecular design to enhance antitumor activity while maintaining a favorable safety and pharmacokinetic profile. Methods: JS212 is composed of a Fab arm targeting EGFR, a scFv arm targeting HER3, and DNA topoisomerase I inhibitor, exatecan, linked through a cleavable linker with a homogeneous drug-to-antibody ratio (DAR) of 6. In vitro potencies were measured through cytotoxicity assays. Antitumor activities were evaluated in cell line-derived xenograft (CDX) models. Preclinical safety pharmacokinetics were assessed in cynomolgus monkeys. Results: JS212 exhibited high-affinity binding to tumor cells expressing either or both of EGFR and HER3, resulting in efficient killing of tumor cells with a broad spectrum of EGFR and HER3 expression levels. It also demonstrated superior antitumor activities to BL-B01D1 in CDX models. In the EGFR-dominant NCI-H1975 model, JS212 demonstrated a significant tumor growth inhibition, with a TGI of 113% after the administration of a single dose of 1.9 mg/kg. In comparison, BL-B01D1 at the same molar dose, could only achieve a 75% TGI. In the HER3-dominant SW620 model, JS212 at a single dose of 1.3 mg/kg resulted in complete tumor regression in all 5 mice, whereas BL-B01D1 only suppressed tumor growth at 2.5 mg/kg, D1D8 Q3W. JS212 also had better antitumor activity than BL-B01D1 in an osimertinib-resistant HCC827 model. Additionally, JS212 induced near complete regression in either BL-B01D1 or patritumab-deruxtecan resistant SW620 model. In cynomolgus monkeys, JS212 was well tolerated with repeated doses at 30 mg/kg. It also showed favorable pharmacokinetics profiles with half-life > 3 Days. Conclusion: JS212 is a promising EGFR and HER3 dual targeting ADC that shows superior and broad-spectrum antitumor activities and a favorable safety and pharmacokinetic profiles in preclinical evaluation, supporting its first-in-human studies. Its phase I clinical trial is ongoing, and results will be reported elsewhere. Citation Format: Wenli Shi, Ning Song, Qiang Fu, Li Ye, Aikun Xia, Mingxing Yang, Jiaming Wang, Xuan Wu, Yue Deng, Yanghua Xu, Xin Wang, Honglin He, Yuyuan Yan, Ziyang Zhong. JS212, a novel bispecific ADC targeting EGFR and HER3, demonstrates superior and broad antitumor activity in preclinical evaluation [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 1715.