JS212, a novel bispecific ADC targeting EGFR and HER3, demonstrates superior and broad antitumor activity in preclinical evaluation
Presenter: Ziyang Zhong, PhD Session: Antibody-Drug Conjugates and Linker Engineering 2 Time: 4/20/2026 9:00:00 AM → 4/20/2026 12:00:00 PM
Authors
Wenli Shi 1 , Ning Song 1 , Qiang Fu 1 , Li Ye 1 , Aikun Xia 1 , Mingxing Yang 1 , Jiaming Wang 1 , Xuan Wu 1 , Yue Deng 1 , Yanghua Xu 1 , Xin Wang 1 , Honglin He 1 , Yuyuan Yan 1 , Ziyang Zhong 2 1 Shanghai Ruotuo Biosciences Co., Ltd., Shanghai, China, 2 Anwita Bioscience, Inc., San Carlos, CA
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.
Disclosure
W. Shi, None.. N. Song, None.. Q. Fu, None.. L. Ye, None.. A. Xia, None.. M. Yang, None.. J. Wang, None.. X. Wu, None.. Y. Deng, None.. Y. Xu, None.. X. Wang, None.. H. He, None.. Y. Yan, None.. Z. Zhong, None.
Cited in
Control: 3469 · Presentation Id: 5386 · Meeting 21436