Abstract 1567: GLR1059, next-generation nectin-4-targeted ADC with a novel mechanism-of-action payload, demonstrated significantly potent anti-tumor efficacy and reduced toxicity in preclinical evaluation

Abstract Background: Nectin-4 is a tumor-associated antigen, which was observed in multiple cancer types, including bladder, breast, lung, pancreatic and ovarian cancer. Enfortumab Vedotin (EV) is the first approved nectin-4 antibody-drug conjugate (ADC) with MMAE as its payload for the treatment of urothelial carcinoma (UC). However, beyond UC, EV hasn’t been approved for other indications. In addition, severe skin adverse reactions were reported in EV-treated patients. There are several new nectin-4 ADCs in development but haven’t entered confirmative clinical studies so far. To overcome the limitations of efficacy and safety, we developed a novel mechanism nectin-4 ADC GLR1059, with a payload that was more effective for potential indications with nectin-4 expression and had lower toxicity, including skin adverse reactions. Methods: For in vitro studies, binding affinity and specificity, internalization, cancer cell killing, bystander effect and serum stability were performed. For in vivo studies, efficacy studies were conducted on cell line-derived xenografts (CDX) of multiple cancer types, e.g. breast cancer (including triple-negative breast cancer), and urothelial carcinoma. Pharmacokinetic (PK) properties were studied in BALB/c mice and tumor-bearing nude mice, and safety studies were conducted in humanized nectin-4 mice. Results: GLR1059 is a nectin-4 ADC composed of a novel humanized IgG1 monoclonal antibody, a cleavable linker and a microtubule targeting agent (not auristatin derivatives). Moreover, to generate DAR4 ADCs with higher homogeneity, the payload was site-specifically conjugated to the antibody via a disulfide bond bridge. In surface plasmon resonance (SPR) assays, GLR1059 had strong and specific binding to human nectin-4, and it did not bind to nectin-1, nectin-2, or nectin-3. Furthermore, GLR1059 exhibited efficient internalization and potent activity in nectin-4 expressing cell lines and effective bystander activity. In a panel of CDX models, GLR1059 demonstrated compelling anti-tumor activity across bladder cancer and breast cancer (including TNBC), with tumor growth inhibition rates (TGI) significantly higher than EV (approximately 2-4 times). In the tumor-bearing mice PK study, the Cmax of free payload in tumor tissue was approximately 100-fold higher than that in the blood (131±14ng/g vs 1.04±0.27ng/mL). GLR1059 demonstrated longer survival and less weight loss in the single- and repeated-dose toxicity studies in humanized nectin-4 mice. Notably, GLR1059 significantly reduced the incidence and severity of skin toxicity compared with EV (1/6 vs 6/6). Conclusion: Preclinical data show that GLR1059 has the potential to achieve better efficacy and safety, and the different drug mechanisms provide new options to overcome drug resistance of current nectin-4 ADCs. Citation Format: Jiao Jiao, Yingjie Sun, Jiaxing Wang, Liming Che, Menghan Cui, Wenjie Shao, Hairui Yuan, Yan Huang, Nannan Zhai, Yuling Tang, Xiaomei Zheng, Siyao Li. GLR1059, next-generation nectin-4-targeted ADC with a novel mechanism-of-action payload, demonstrated significantly potent anti-tumor efficacy and reduced toxicity in preclinical evaluation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1567.